1. 糖尿病足病理机制与药物作用靶点解析
1.1 糖尿病足核心病理特征
糖尿病足溃疡（DFU）是糖尿病最常见和最严重的并发症之一，全球约15%-25%的糖尿病患者会受其影响，并且85%以上的非创伤性截肢与DFU相关，对患者的健康和全球医疗系统造成了巨大的临床和经济负担 12。DFU的愈合受损是一个动态而复杂的过程，涉及高血糖微环境、神经血管病变、慢性炎症以及细菌感染等多种核心病理因素，这些因素共同作用，导致伤口愈合级联反应紊乱，形成难以愈合的慢性创面 23。
首先，高血糖微环境是DFU病理生理学的基石。长期高血糖会激活多种损伤通路，包括多元醇通路、蛋白激酶C（PKC）通路、己糖胺通路以及晚期糖基化终产物（AGEs）通路，这些通路共同诱导氧化应激和慢性炎症，从而损害正常的愈合过程 4。高血糖还通过影响细胞功能和细胞外基质（ECM）的完整性，进一步加剧伤口愈合障碍 4。
其次，神经血管病变对DFU的发生发展至关重要。糖尿病周围神经病变导致感觉丧失，使患者对足部损伤不自知，易发生反复创伤 12。此外，自主神经病变可能影响皮肤血流调节。同时，糖尿病性外周动脉疾病（PAD）导致足部血流供应不足，引起局部缺血和缺氧，严重影响伤口愈合所需的氧气和营养物质的输送 25。研究显示，约50%的糖尿病足溃疡患者伴有PAD，PAD的存在显著增加了肢体不良事件和心血管事件的风险 5。在伤口微环境中，这种缺血缺氧状态尤为突出，糖尿病伤口对缺氧的反应受损，表现为缺氧诱导因子（HIF-1和HIF-1α）表达降低，而HIF-1α在促进血管生成和胶原沉积中发挥关键作用 4。
再者，慢性炎症是糖尿病伤口难以愈合的关键因素。正常伤口愈合过程中的炎症反应是短暂且受控的，但在DFU中，炎症持续存在，形成低度慢性炎症状态 16。这种慢性炎症与免疫失调密切相关，特别是巨噬细胞极化失衡、调节性T细胞功能障碍和中性粒细胞功能受损 1。炎症微环境中，肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β) 和IL-6等促炎细胞因子水平升高，抑制血管生成并延迟修复 1。此外，糖尿病伤口还表现出异常的蛋白酶活性，特别是基质金属蛋白酶（MMP）的过度活化，如MMP-9活性升高，导致ECM的过度降解，进一步破坏组织结构，阻碍愈合 4。纤维母细胞功能障碍，包括其迁移、增殖和胶原生成能力的受损，也是导致DFU慢性化的重要因素 7。
最后，细菌感染是DFU恶化的常见原因，并可导致严重的肢体威胁。糖尿病足溃疡易感染，且治疗复杂，感染会进一步加剧炎症反应，阻碍伤口愈合，并增加截肢的风险 89。
综合来看，DFU的伤口微环境是一个复杂的病理集合体，其特征包括持续的炎症状态、局部缺氧、高MMP-9活性、纤维母细胞功能障碍以及细菌感染等，这些因素相互交织，共同导致糖尿病足溃疡的慢性化和难愈合性 234。
1.2 药物干预的主要作用靶点
鉴于糖尿病足溃疡（DFU）复杂的病理机制，药物干预策略需要多靶点、多途径协同作用，以纠正异常的伤口微环境并促进愈合。主要的药物作用靶点可归纳为以下几个方面：
感染控制（抗菌）：
DFU极易发生细菌感染，且感染是导致溃疡恶化和截肢的关键因素。因此，抗菌药物的首要靶点是病原微生物，通过抑制细菌生长或杀灭细菌来控制感染。这包括作用于细菌细胞壁合成（如β-内酰胺类抗生素）、蛋白质合成（如大环内酯类、氨基糖苷类、四环素类、利奈唑胺）、DNA复制和转录（如喹诺酮类）等关键环节的药物。此外，纳米载药系统也被用于延长目标分子在伤口部位的生物利用度，从而提高局部治疗效果 10。炎症调节（抗炎/调节MMPs）：
DFU的慢性炎症状态是愈合障碍的重要原因。药物干预炎症的主要靶点包括：- 促炎细胞因子：抑制TNF-α、IL-1β、IL-6等促炎因子的产生或活性，以减少炎症反应对伤口愈合的负面影响 1112。例如，MCC950作为一种NLRP3炎症小体抑制剂，已被证明能显著加速糖尿病伤口愈合，通过促进M2型巨噬细胞极化发挥抗炎作用 13。
- 基质金属蛋白酶（MMPs）：DFU患者伤口中MMP-9等蛋白酶活性异常升高，导致细胞外基质过度降解。因此，靶向MMP-9的抑制剂，例如槲皮素通过网络药理学分析被预测能够调节MMP-9活性，从而调控慢性炎症，减少组织损伤 14。
- 氧化应激：高血糖引起的氧化应激是炎症的驱动因素之一。清除活性氧（ROS）的抗氧化剂也是重要的干预靶点，如槲皮素可通过PI3K-AKT通路发挥抗炎和抗氧化作用 12141516。
- 巨噬细胞极化：调节巨噬细胞从促炎M1型向促愈合M2型转化是关键策略。某些药物，如MCC950，通过影响髓源性抑制细胞（MDSCs）来促进M2型巨噬细胞极化，从而加速伤口愈合 13。
血管再生（促血管生成因子）：
DFU常伴有局部缺血和血管病变，促血管生成是促进伤口愈合的核心环节。药物的主要靶点包括：- 血管内皮生长因子（VEGF）及其信号通路：VEGF是目前研究最广泛、作用最明确的促血管生成因子之一，通过促进内皮细胞增殖、迁移和新血管形成来改善伤口局部血液供应和氧合 17。
- 缺氧诱导因子（HIF-1α）：HIF-1α在缺氧条件下表达上调，可诱导VEGF等多种促血管生成因子的表达。稳定HIF-1α表达是促进血管生成的有效途径 18。
- 一氧化氮（NO）：NO能够舒张血管、改善血流，并参与血管生成。一些纳米载药系统可以通过释放NO来重建血管，促进内皮细胞增殖和迁移 1920。
- 干细胞和外泌体：干细胞（如间充质干细胞）通过分泌多种生长因子和细胞因子，或直接分化为血管细胞来促进血管生成。干细胞来源的外泌体作为一种无细胞疗法，富含促血管生成miRNA和蛋白质，具有生物相容性好、靶向性强等优点，被视为促进DFU血管生成的新策略 172122。
神经修复（神经营养因子）：
糖尿病神经病变是DFU发生的重要原因。神经营养因子是维持神经元健康、促进神经再生和修复的重要物质。代谢控制（血糖管理）：
虽然DFU的局部治疗至关重要，但全身性的血糖管理是根本。
这些多维度的靶点共同构成了糖尿病足治疗药物研发的复杂图景，未来的治疗策略将更倾向于结合多种作用机制，以期达到更全面、更高效的愈合效果。
2. 国内已上市糖尿病足治疗药物分类与临床应用
2.1 抗感染药物
糖尿病足溃疡（DFU）的感染是导致其难愈合和截肢风险增加的主要因素之一，因此抗感染治疗是DFU管理的核心环节。国内已上市的抗感染药物主要包括抗生素和抗真菌药物，其选择需结合微生物谱、耐药性以及临床感染类型。
2.1.1 抗生素
中国的DFU微生物感染情况复杂多样，一项针对2015-2019年间中国DFU感染研究的文献回顾显示，革兰氏阴性菌（52.4%）的流行率高于革兰氏阳性菌（43.4%）26。最常见的病原体包括金黄色葡萄球菌（17.7%）、大肠杆菌（10.9%）、铜绿假单胞菌（10.5%）和肺炎克雷伯菌（6.2%）26。值得注意的是，混合感染和多重耐药（MDR）细菌感染在DFU中普遍存在，MDR菌株占所有分离菌株的20%26，其中金黄色葡萄球菌是主要的多重耐药菌（30.4%），其次是超广谱β-内酰胺酶（ESBL）产生菌（19.1%）26。另一项针对亚洲国家的系统综述也指出，DFU多微生物感染率高达71%，革兰氏阴性菌占比77%，金黄色葡萄球菌、铜绿假单胞菌和大肠杆菌是最常见的菌种，且耐药性呈上升趋势27。多重耐药菌（MDR）感染在DFU患者中普遍存在，其发生率高达50.86%28。
针对这些特点，国内临床常用的抗生素及敏感性数据如下：
革兰氏阳性菌：
- 利奈唑胺（Linezolid）：作为一种噁唑烷酮类抗生素，利奈唑胺对革兰氏阳性菌具有良好的敏感性，特别是对耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）有效2627。利奈唑胺在中国已广泛用于治疗复杂性皮肤和软组织感染，包括DFU感染。
- 万古霉素（Vancomycin）和替考拉宁（Teicoplanin）：这两种糖肽类抗生素对革兰氏阳性菌，包括MRSA，具有高度敏感性，常作为重症或MDR革兰氏阳性菌感染的一线选择2627。
- 康泰唑胺（Contezolid）：由上海盟科药业有限公司开发的口服噁唑烷酮类抗菌药物，于2021年在中国获批用于治疗复杂性皮肤和软组织感染（cSSTI），包括MRSA感染29。康泰唑胺对革兰氏阳性菌，包括MRSA和VRE，显示出广谱抗菌活性，且正在进行糖尿病足感染的临床开发29。
革兰氏阴性菌：
2.1.2 抗真菌药物
糖尿病患者由于免疫功能受损，也易发生真菌感染，尤其是足部甲真菌病，可成为足部溃疡的诱因，并通过损伤邻近脚趾皮肤或甲沟，增加细菌感染的风险303132。一项研究显示，DFU患者真菌培养阳性率为17.38%，其中白色念珠菌（Candida species）是最常见的真菌菌种33。针对真菌感染，国内临床常用的抗真菌药物主要包括：
- 特比萘芬（Terbinafine）：口服广谱抗真菌药，对皮肤癣菌有高度活性，在糖尿病患者中治疗甲真菌病的疗效和安全性与非糖尿病人群相当30。
- 伊曲康唑（Itraconazole）：广谱抗真菌药，可用于治疗甲真菌病，在糖尿病患者中也显示出良好的安全性和有效性30。
- 氟康唑（Fluconazole）：唑类抗真菌药，对念珠菌属等有较好疗效。然而，需要警惕氟康唑耐药性的出现，研究表明DFU患者中氟康唑耐药率较高，尤其是白色念珠菌33。
在临床应用中，抗感染药物的选择应遵循“经验性治疗与药敏试验相结合”的原则。对于轻度感染，可口服广谱抗生素；对于中重度感染，特别是存在全身感染症状时，应静脉使用广谱抗生素，并及时进行病原学检查和药敏试验，根据结果调整治疗方案，以避免耐药性的产生并提高治疗效果。此外，对于合并骨髓炎等深部感染，抗生素治疗疗程需要延长，并可能需要外科清创甚至截肢来清除感染源。
2.2 促愈合生物制剂
在糖尿病足溃疡（DFU）的治疗中，除了控制感染，促进伤口愈合是关键环节。促愈合生物制剂通过模拟或增强体内自然愈合过程，为慢性难愈合创面提供了新的治疗选择。国内已上市或正在积极研究的促愈合生物制剂主要包括生长因子类和细胞治疗产品。
2.2.1 生长因子类产品
生长因子在伤口愈合的各个阶段发挥着核心调控作用，包括细胞增殖、迁移、血管生成和细胞外基质重塑 34。在国内，重组人碱性成纤维细胞生长因子（bFGF）是应用最广泛、最成熟的生长因子类药物之一。
重组人碱性成纤维细胞生长因子（rhbFGF）：
- 作用机制：bFGF是一种多功能生长因子，能促进成纤维细胞、内皮细胞和角质形成细胞的增殖与迁移，刺激血管生成，增加胶原合成，从而加速肉芽组织形成和上皮化。
- 适应症：主要用于治疗各种慢性溃疡，包括糖尿病足溃疡、压疮、下肢静脉溃疡等。
- 疗效数据：多项临床研究表明，bFGF能显著提高DFU的愈合率和缩短愈合时间。例如，一项系统评价和网络荟萃分析指出，包含表皮生长因子（EGF）或bFGF的方案对愈合效率有显著改善作用 35。另一项研究发现，与传统敷料相比，抗微生物敷料（如银离子敷料）联合bFGF可显著缩短伤口愈合时间 35。
- 临床局限性：尽管bFGF疗效肯定，但其半衰期短、易降解，通常需要频繁局部给药（如每日或隔日一次），增加了患者依从性和治疗成本。此外，对于伴有严重缺血或感染的DFU，单纯bFGF治疗效果有限，需结合其他治疗手段。
其他生长因子：
2.2.2 细胞治疗产品
细胞治疗通过提供具有自我更新、多向分化潜能的细胞，或利用细胞分泌的多种生物活性物质，来修复受损组织和调节局部微环境，被认为是治疗DFU的创新方向。
脐带间充质干细胞（hUC-MSC）及其衍生物：
- 作用机制：hUC-MSC具有免疫调节、抗炎、促血管生成和促进组织再生的能力。它们通过旁分泌作用释放多种生长因子、细胞因子和外泌体，调节巨噬细胞极化，抑制炎症反应，促进血管化，并诱导内源性细胞增殖和分化。
- 国内研究进展与应用：国内在hUC-MSC治疗DFU方面进行了大量探索。一项I/II期临床试验显示，围溃疡注射人脐带间充质干细胞衍生物（包括条件培养基、细胞外囊泡和外泌体）对慢性DFU患者安全有效。所有患者在平均4.2周内实现了完全溃疡闭合，且24个月随访期间无复发 37。这表明hUC-MSCD具有加速伤口愈合的潜力。
- 临床局限性：尽管初步结果令人鼓舞，但这类治疗仍处于临床研究阶段，需要更大规模、随机、双盲、安慰剂对照试验来验证其长期疗效和安全性 37。此外，干细胞制备、储存和运输的标准化以及多次给药的便利性也是需要考虑的问题。
自体皮肤构造物（AHSC）：
- 作用机制：AHSC通常指通过组织工程技术构建的包含自体细胞（如角质形成细胞、成纤维细胞）的皮肤替代物，可直接覆盖创面，提供细胞来源，促进上皮化和真皮再生。
- 临床应用：国外已有类似产品上市，如Apligraf、Dermagraft等。国内在自体皮肤细胞移植方面也有临床实践，但大规模商品化的AHSC产品相对较少，主要集中在研发阶段。
- 临床局限性：制备过程复杂、耗时，成本高昂，且需要患者自身条件允许进行组织活检。
富血小板血浆（PRP）和血小板凝胶：
- 作用机制：PRP通过离心浓缩患者自身血液中的血小板，激活后释放大量生长因子（如PDGF、TGF-β、VEGF、EGF等），这些因子协同作用，促进细胞增殖、胶原合成、血管生成和炎症调节。
- 国内应用：PRP已在国内多个医疗机构用于DFU及其他慢性创面的辅助治疗。
- 疗效数据：有系统评价和网络荟萃分析显示，PRP与水凝胶联用可显著提高愈合效率 35。
- 临床局限性：疗效受制备方法、血小板浓度、个体差异等因素影响，且其作为独立治疗手段的有效性仍需更多高质量的临床证据支持。
粒细胞集落刺激因子（G-CSF）：
总体而言，促愈合生物制剂为DFU的治疗带来了希望，但大多数产品仍存在给药频率、成本、疗效个体差异以及缺乏大规模高质量临床证据等局限性，需要进一步的研究和优化。
2.3 外用敷料与功能材料
外用敷料与功能材料在糖尿病足溃疡（DFU）的局部治疗中扮演着至关重要的角色。它们通过多种机制改善伤口微环境，包括管理渗出液、维持湿润愈合环境、提供屏障保护、抗感染以及促进肉芽组织形成和上皮化。以下将梳理国内已上市的常见敷料类型及其临床应用与研究。
2.3.1 含银敷料
- 作用机制：含银敷料利用银离子（Ag⁺）的广谱抗菌特性。银离子能与细菌细胞壁结合，破坏细胞膜结构，抑制细菌酶活性和DNA复制，从而有效杀灭细菌和真菌 39。此外，银离子还能减少细菌生物膜的形成，降低感染风险。同时，这些敷料还能管理伤口渗出液，维持湿润环境。
- 国内上市品种及临床研究：国内市场上有多种含银敷料产品，如银离子泡沫敷料、银离子藻酸盐敷料等。
2.3.2 水胶体敷料
- 作用机制：水胶体敷料主要由亲水性胶体颗粒（如羧甲基纤维素钠）组成，遇伤口渗出液后形成凝胶，为伤口提供湿润环境，促进自溶性清创。这种湿润环境有助于细胞迁移和增殖，同时形成物理屏障，防止细菌入侵 42。
- 国内上市品种及临床研究：这类敷料广泛应用于各类慢性伤口。
2.3.3 胶原蛋白基质敷料
- 作用机制：胶原蛋白是细胞外基质（ECM）的主要成分，胶原蛋白基质敷料能为细胞提供支架，促进细胞附着、迁移和增殖。它们还能吸收渗出液，并可能通过调节蛋白酶活性（如MMP）来改善伤口微环境，为肉芽组织生长提供有利条件 45。
- 国内上市品种及临床研究：国内有多种基于胶原蛋白或复合胶原蛋白的敷料产品。
- 临床研究结果：尽管Meta分析未单独评估胶原敷料的显著效果，但它们通常与生长因子或细胞治疗结合使用，以增强愈合效果。例如，将间充质干细胞（MSC）掺入含有胶原I的聚乙二醇二丙烯酸酯（PEGDA）和海藻酸钠（SA）水凝胶基质中，可促进糖尿病伤口愈合 46。
- 优势：提供生理性支架，促进细胞粘附和增殖，可能调节ECM重塑。
- 局限性：相对成本较高，对于严重感染或缺血性伤口，其单独使用效果有限。
2.3.4 其他新型敷料与功能材料
- 负压伤口治疗（NPWT）：虽然不是传统意义上的敷料，但NPWT系统通过施加局部负压，能有效管理渗出液、促进肉芽组织生长、减少水肿、增加局部血流量，并能为伤口提供湿润环境 47。
- 临床疗效：Meta分析显示，与传统敷料相比，NPWT能增加DFU愈合率，缩短愈合时间，并可能降低截肢风险 47。国内许多医院已广泛使用NPWT治疗各类复杂慢性创面，包括DFU。
- 生物活性敷料：包括含生长因子、细胞外囊泡、间充质干细胞等成分的敷料。例如，脱水羊膜同种异体移植膜（DAMA）含有多种生长因子和细胞因子，能够刺激细胞迁移和增殖，减少促炎细胞因子，改善伤口微环境，从而促进慢性伤口愈合 45。还有研究利用富血小板血浆（PRP）或自体富血小板纤维蛋白（APRF）制备敷料，利用其释放的多种生长因子促进伤口愈合。
- 水凝胶敷料：除了水胶体敷料，还有多种新型水凝胶，如基于多糖的水凝胶，它们具有优异的组织粘附性、吸水性、抗菌和免疫调节特性，可加速伤口再上皮化 48。例如，一种负载普鲁士蓝纳米颗粒的温敏水凝胶，通过清除活性氧（ROS）和恢复线粒体功能来促进糖尿病伤口愈合 49。动态透明质酸水凝胶通过调节炎症、血管生成和代谢来促进糖尿病伤口愈合 50。负载IL-4表达外泌体的免疫调节水凝胶能重编程巨噬细胞并加速糖尿病伤口愈合 51。
- 纳米纤维敷料：通过静电纺丝技术制备的纳米纤维敷料具有巨大的孔隙率、优异的湿度吸收、更好的氧交换率和抗菌活性，是DFU治疗的潜在材料 52。
总体而言，国内市场上的敷料和功能材料种类繁多，涵盖了从基础保护到高级生物活性的多种功能。临床实践中，医生会根据DFU的具体情况（如渗出量、感染状况、是否存在肉芽组织等）选择合适的敷料，并结合清创、减压和血糖控制等综合措施，以期达到最佳愈合效果。尽管各类敷料已取得显著进展，但针对DFU的复杂性，仍在不断开发更智能、多功能的新型敷料。
2.4 中药复方制剂
中医药在糖尿病足溃疡（DFU）的治疗中具有悠久的历史和独特的优势，尤其是在调节局部微环境、促进组织再生、抗炎抗感染以及改善微循环等方面。国内已上市或广泛应用于临床的中药复方制剂，无论是内服或外用，均体现了多靶点、整体调节的特点。
2.4.1 组方特点与作用机制
中药复方治疗DFU的组方往往基于中医的辨证论治原则，如清热解毒、活血化瘀、益气养阴、祛腐生肌等。其作用机制复杂，涉及多个信号通路和生物学过程：
- 调节HIF-1α/VEGF通路，促进血管生成：许多中药成分被发现能够上调缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）的表达，从而促进伤口部位的新血管形成和血流灌注，改善局部缺血缺氧状态，为组织修复提供充足的氧气和营养物质。这对于DFU患者普遍存在的微血管病变至关重要 53。
- 抑制NF-κB炎症反应，调控慢性炎症：慢性炎症是DFU难愈合的关键因素。中药复方常含有具有抗炎作用的成分，能够抑制核因子-κB（NF-κB）通路的激活，从而减少促炎细胞因子（如TNF-α、IL-1β、IL-6）的释放，减轻炎症反应。例如，地榆提取物（Sanguisorba officinalis L. ethanol extract, ESO）被证实可通过阻断NF-κB/NLRP3信号通路，抑制炎症反应，增加M2型巨噬细胞比例，从而促进糖尿病伤口愈合 54。鸡胚早期羊膜液（ceAF）也被发现通过调节TLR4/NF-κB和Nrf2通路减轻炎症和氧化应激，促进M2巨噬细胞极化，从而改善DFU愈合 55。
- 抗氧化应激：糖尿病高血糖状态下的氧化应激会损伤细胞和组织。部分中药成分通过激活Nrf2/ARE通路，增强内源性抗氧化酶的活性，清除自由基，减轻氧化损伤 53。
- 抗菌抗感染：一些中药具有天然的抗菌活性，可抑制DFU常见的革兰氏阳性菌和阴性菌的生长，辅助控制感染。例如，传统中药“轻粉”（Calomelas）及其制剂，已被证实具有抗菌、抗炎和促血管生成等多种活性，在治疗包括DFU在内的难愈性皮肤溃疡方面显示出疗效 56。
- 免疫调节：中药还能够调节机体免疫功能，平衡促炎和抗炎反应，促进巨噬细胞向M2型极化，加速伤口愈合进程 57。
2.4.2 国内上市品种及临床应用
国内已上市和临床广泛使用的中药复方制剂种类繁多，涵盖口服和外用剂型，以下列举一些代表性品种和其临床应用案例：
- 虎黄煎剂：这是一种经典的中药外用方剂，常用于清热解毒、祛腐生肌。其组方中可能含有具有抗炎、抗菌和促进肉芽组织生长的药材。临床上，虎黄煎剂常用于DFU的局部湿敷或冲洗，有助于清除坏死组织、减轻局部感染和炎症，并促进新鲜肉芽组织的生长。
- 生肌玉红膏：作为一种传统中药外用制剂，生肌玉红膏具有去腐生肌、拔毒消肿的功效。其组方成分可能包括轻粉、血竭、乳香、没药等，具有抗炎、抗菌和促进组织修复的作用。研究显示，多种含“轻粉”的制剂，如生肌玉红膏，已广泛应用于包括DFU在内的各种皮肤溃疡治疗 56。
- 八宝丹：这是一种传统的中药复方制剂，具有清热解毒、活血化瘀、消肿止痛的功效，常用于感染性炎症和创伤。虽然并非专门针对DFU开发，但在某些伴有感染和疼痛的DFU患者中作为辅助治疗使用。
- 中药熏洗、湿敷：除了具体的制剂，中药熏洗、湿敷是DFU治疗中常用的外治法。通过将多种中药熬制成汤剂，利用其温热效应和药效成分的渗透作用，改善局部血液循环，促进炎症消退和组织修复。例如，有案例报道通过中药浸泡和湿敷治疗糖尿病足动脉闭塞，成功促进侧支循环形成并帮助溃疡愈合 58。
- 中药口服制剂：一些口服中药复方，如“养和四君子汤”（Yanghe Sijunzi Decoction），在DFU治疗中发挥免疫调节和促进组织再生的作用。在一例伴有尿毒症的糖尿病足坏疽患者中，结合杨和四君子汤的综合治疗方案显著降低了炎症指标（如CRP），并最终实现了溃疡愈合，避免了截肢 59。其他如黄芪、丹参等单味中药或其复方制剂，在改善微循环、抗炎、抗氧化方面均有广泛研究和临床应用。
2.4.3 临床应用案例与疗效
中药在DFU的临床应用多以中西医结合模式进行，旨在发挥各自优势，协同增效。
- 改善溃疡面积与愈合时间：多项临床研究和案例报告显示，中药复方治疗能有效缩小DFU的溃疡面积，缩短愈合时间。例如，一项整合中西医治疗重度肾移植后糖尿病足坏疽的病例报告中，通过中药“清热解毒、理气化湿、活血化瘀、滋阴补气”的原则，结合西医清创、抗生素等，成功实现肢体保留和功能恢复 60。另一项针对顽固性DFU的中西医结合治疗案例，通过口服中药汤剂和局部中药外敷，配合西医的血糖控制、抗感染等治疗，最终使Wagner IV级溃疡接近完全闭合，并实现功能恢复 61。
- 缓解疼痛与改善生活质量：中药复方通过减轻炎症、改善微循环和神经功能，有助于缓解DFU患者的疼痛症状，提升生活质量。
- 降低截肢风险：通过促进伤口愈合、控制感染，中药治疗在一定程度上降低了DFU患者的截肢风险 59606162。
- 经济效益：在一例尿毒症并发糖尿病足坏疽的案例中，中西医结合治疗的总费用约为25,000元人民币，患者自付5,000元，显示出良好的成本效益，并避免了高昂的截肢手术费用 59。
尽管中药在DFU治疗中显示出积极效果，但仍面临挑战，如缺乏高质量、大样本的随机对照试验，以及作用机制的进一步阐明。目前，中药外部应用治疗DFU的证据质量多为低至中等水平，需要更严谨的研究来支持广泛推荐 6364。未来的研究将聚焦于精准靶向治疗，结合现代生物技术，筛选中药治疗DFU的核心靶点，并开发基于这些靶点的创新药物 53。
3. 国外糖尿病足治疗药物研发进展与优势品种评估
3.1 国际已上市创新药物
糖尿病足溃疡（DFU）的复杂病理机制驱动了国际上针对多种靶点的创新药物研发。这些创新药物通过独特的作用机制，旨在克服现有治疗方法的局限性，提供更高效、更便捷或更全面的治疗方案。以下重点介绍一些国际上已上市或在临床上取得显著进展的创新药物。
3.1.1 GLP-1受体激动剂（如司美格鲁肽、Ecnoglutide）
- 作用机制：胰高糖素样肽-1（GLP-1）受体激动剂最初作为降糖药物开发，通过葡萄糖依赖性地促进胰岛素分泌、抑制胰高糖素分泌、延缓胃排空、增加饱腹感等多种机制，有效控制血糖和减轻体重。近年来研究发现，GLP-1受体激动剂还具有心血管保护、抗炎和神经保护作用，这为其在DFU治疗中的应用提供了潜在可能性。
- 在DFU治疗中的潜在益处：
- 改善足部疼痛：糖尿病足神经病变引起的疼痛是DFU患者常见的症状。GLP-1受体激动剂可能通过直接或间接的神经保护作用，减轻神经病理性疼痛。虽然直接针对DFU疼痛的大规模临床试验数据仍在积累中，但其在糖尿病神经病变中的改善作用已有所体现。
- 改善筋膜增厚：筋膜增厚可能与糖尿病相关的炎症和纤维化过程有关。GLP-1受体激动剂的抗炎和抗纤维化特性可能有助于改善足部筋膜结构，但这仍需进一步的临床验证。
- 体重管理与心血管获益：GLP-1受体激动剂，如Ecnoglutide（依那鲁肽），在超重或肥胖人群中展现出显著的体重降低效果，例如在一项多中心、随机、双盲、安慰剂对照的III期临床试验中，Ecnoglutide 2.4 mg组在40周时体重平均下降13.2% 65。体重减轻和心血管风险的降低有助于改善DFU患者的整体健康状况，减少并发症。
- 临床证据与局限性：虽然GLP-1受体激动剂在血糖控制和体重管理方面表现出色，且其多效性提示其在DFU中具有广阔前景，但目前尚无明确的、大规模的DFU随机对照临床试验直接评估其在DFU愈合率、截肢率等方面的疗效。目前对其在DFU中的应用主要基于其对糖尿病病理生理的全面改善作用的推测。
3.1.2 靶向MMP-9抑制剂（如ND-336）
- 作用机制：在DFU等慢性伤口中，基质金属蛋白酶（MMP）尤其是MMP-9的活性异常升高，导致细胞外基质（ECM）过度降解，阻碍伤口愈合 6667。靶向MMP-9抑制剂旨在选择性地抑制MMP-9的活性，而不影响对伤口愈合有益的其他MMP（如MMP-8）的活性，从而恢复伤口愈合过程中的蛋白酶平衡 66。
- 调控慢性炎症：MMP-9的过度活化与DFU的慢性炎症密切相关。抑制MMP-9可以减轻炎症反应，例如，(-)-ND-336这种选择性MMP-9抑制剂能通过抑制MMP-9活性，减轻巨噬细胞浸润，从而降低炎症反应 6667。研究表明，感染会增加DFU伤口中活性MMP-9的水平，进而加剧炎症并减少血管生成，使得感染性DFU的愈合时间更长 66。
- 促进伤口愈合：通过抑制MMP-9，ND-336能够加速糖尿病小鼠的伤口愈合，具体机制包括减少活性氧（ROS）和NF-κB的水平，降低炎症，并增加血管生成 66。当与抗生素利奈唑胺联用时，ND-336还能进一步改善感染性糖尿病小鼠的伤口愈合，通过抑制MMP-9、减轻巨噬细胞浸润并增加血管生成，恢复正常的伤口愈合过程 6667。
- 研发进展：ND-336代表了这类药物的早期研发，其选择性抑制MMP-9的策略为DFU的治疗提供了新的思路。然而，目前尚未有大规模人体临床试验数据公布，也未在国际上广泛上市。
3.1.3 自体皮肤构造物（AHSC）
- 作用机制：自体皮肤构造物（Autologous Homologous Skin Construct, AHSC）是一种利用患者自身健康皮肤的修复能力来治疗皮肤缺损的新型疗法。它通过单次局部应用，提供活的自体细胞，包括角质形成细胞和成纤维细胞，这些细胞能够分泌生长因子、细胞因子，并形成新的ECM，从而加速伤口的上皮化和真皮重建，促进完全愈合 68。
- 单次应用愈合数据：一项针对AHSC治疗DFU的开放标签、单臂可行性研究显示出令人鼓舞的结果。该研究招募了11名DFU患者，其溃疡深度可达肌腱、骨骼或关节囊。所有患者在接受单次局部应用AHSC后均成功植皮。其中10个DFU在8周内完全闭合，中位完全闭合时间为25天。所有11个伤口在4周时的平均面积缩小了83%。重要的是，未观察到与AHSC治疗部位相关的任何不良事件 68。
- 优势与局限性：AHSC的显著优势在于其单次应用即可实现较高比例的伤口闭合，这极大地简化了治疗流程，降低了患者的治疗负担，并可能减少长期治疗的成本。然而，作为自体疗法，其制备过程可能需要一定的技术和时间，且成本较高，尚未大规模推广应用。该项初步研究虽然结果积极，但仍需更大规模、对照组的临床研究来进一步验证其长期疗效、安全性和经济效益 68。
这些创新药物代表了国际DFU治疗领域的前沿方向，它们通过不同的策略，共同致力于改善DFU患者的预后。GLP-1受体激动剂从全身代谢调节入手，靶向MMP-9抑制剂针对局部炎症病理，而AHSC则侧重于提供生物活性支架以促进组织再生。这些进展为国内DFU治疗药物的引进和研发提供了重要的参考。
3.2 临床阶段候选药物
随着对糖尿病足溃疡（DFU）复杂病理机制理解的深入，国际上的药物研发正积极探索新型疗法，旨在更精准、高效地干预伤口愈合过程。目前，许多创新性候选药物正处于临床试验阶段，为DFU的治疗带来了新的希望。
3.2.1 纳米载药系统
- 作用机制：纳米载药系统（Nanocarrier drug delivery systems）利用纳米技术，将药物封装在纳米级的载体中，如脂质体、纳米颗粒、胶束或水凝胶等。这些系统能够提高药物的生物利用度、稳定性和靶向性，从而实现药物在伤口部位的精准释放，减少全身副作用。特别是在DFU中，纳米载体能够克服组织屏障，将药物递送至缺血、缺氧或感染的病灶区域，从而提高治疗效果 69。
- 针对缺氧微环境的智能释放纳米颗粒：DFU伤口常伴有缺氧环境，这严重阻碍了愈合。智能纳米颗粒可以设计成在缺氧条件下释放促血管生成因子或氧气，从而改善局部微环境。例如，一些基于过氧化氢酶或超氧化物歧化酶的纳米酶，可以在缺口局部转化为氧气，直接缓解缺氧状态；另一些载药纳米颗粒，如负载VEGF基因的纳米载体，可靶向缺氧区域，促进血管新生。脂质纳米系统（LBN）在伤口治疗中也显示出潜力，它们可以提高药物稳定性，减少不良反应，并通过参与炎症和增殖阶段来调节伤口愈合 69。
- 临床试验进展：虽然许多纳米载药系统仍处于临床前研究阶段，但一些已进入临床I/II期。例如，用于慢性创面的局部药物递送纳米系统，如载有生长因子、抗菌剂或免疫调节剂的纳米颗粒，正在评估其安全性和初步疗效。然而，目前尚未有大规模针对DFU的纳米载药系统进入III期临床并取得明确上市结果。
3.2.2 益生菌敷料
- 作用机制：皮肤和肠道菌群在DFU的进展中扮演着重要角色。益生菌通过多种机制促进伤口愈合，包括控制高血糖、增强免疫功能、调节菌群平衡以及维持葡萄糖稳态等 70。益生菌敷料通过在伤口局部直接施用益生菌，以调节创面微生物群落，抑制有害菌生长，并可能通过分泌抗菌物质、调节局部炎症反应和促进组织修复来加速愈合。例如，乳酸杆菌（Lactobacillus rhamnosus、Lactobacillus casei、Lactobacillus fermentum和Lactobacillus acidophilus）等益生菌被发现能够促进伤口修复，特别是德氏乳杆菌和鼠李糖乳杆菌表现出最佳的伤口愈合潜力，并对病原体具有显著的生物膜抑制活性 71。
- 临床试验进展：益生菌在DFU治疗中的潜力正被积极探索，一些动物研究和初步的临床试验已显示出积极结果。例如，一项体内研究表明，含有德氏乳杆菌和鼠李糖乳杆菌的稳定油凝胶制剂能够显著促进糖尿病伤口愈合，通过增加组织样本中羟脯氨酸含量、成熟成纤维细胞数量以及毛囊、胶原纤维和新生血管的体积密度 71。然而，要充分开发益生菌治疗DFU的潜力，仍需要进行广泛的动物研究和严格的临床试验，以明确最佳菌株、剂量和作用机制 70。
3.2.3 基因治疗（如VEGF基因递送）
- 作用机制：DFU的血管病变和神经病变是其核心病理特征。基因治疗通过将特定基因导入患者细胞，以纠正基因缺陷或表达治疗性蛋白质，从而促进血管生成和神经修复。血管内皮生长因子（VEGF）是公认的最重要的促血管生成因子之一，VEGF基因递送旨在通过局部表达VEGF，刺激新血管形成，改善DFU伤口部位的血液供应和氧合 7273。
- VEGF基因递送：早期的临床研究已证明，将编码VEGF的裸DNA（phVEGF165）肌肉注射到下肢，可以改善糖尿病合并周围血管闭塞性疾病患者的周围神经病变症状和体征 73。此外，双顺反子VEGF165/HGF（肝细胞生长因子）质粒基因治疗被用作血管重建术后的辅助疗法，用于治疗DFU的缺血性溃疡和坏死病变。HGF也具有促血管生成和抗纤维化作用。
- 临床试验进展：
- VEGF基因治疗：一项针对缺血性溃疡和坏死病变DFU患者的研究中，患者在血管重建术后被随机分为基因治疗组（接受双顺反子VEGF165/HGF质粒注射）和对照组（接受安慰剂）。结果显示，基因治疗组中50%的患者在12周内愈合，踝肱指数（ABI）平均增加0.25，经皮氧分压（TcPO2）增加30.4 mmHg。对照组的愈合率为66.67%，ABI增加0.14，TcPO2增加27.1 mmHg。虽然该研究规模较小，但提示基因治疗可能为DFU提供一种有吸引力的辅助治疗选择 72。
- 局限性：基因治疗面临的主要挑战包括基因递送效率、安全性（如免疫反应、肿瘤发生风险）以及长期疗效的不确定性。尽管VEGF基因治疗在改善血管生成方面显示出潜力，但其大规模临床应用仍需克服这些障碍。目前，许多基因治疗项目仍处于I/II期临床阶段，旨在评估安全性和初步有效性，全面证明其在DFU中的优势仍需进一步的研究。
这些处于临床阶段的候选药物代表了DFU治疗的未来方向，它们聚焦于更深层次的病理生理机制，如微环境调节、微生物群平衡和基因修复，有望为难愈合的DFU提供更有效和持久的解决方案。
3.3 国外药物的疗效与局限性对比
在糖尿病足溃疡（DFU）的治疗领域，国外已上市及临床阶段的创新药物展现出多样化的作用机制和临床表现。对这些药物的疗效、安全性及使用便捷性进行对比，有助于评估其潜在价值和临床适用性。
3.3.1 GLP-1受体激动剂（如司美格鲁肽、Ecnoglutide）
- 有效性：主要体现在对全身代谢的调节，尤其是血糖控制和体重管理。在一项针对超重或肥胖成年人的III期临床试验中，GLP-1受体激动剂Ecnoglutide 2.4 mg组在40周内使体重平均降低13.2% 65。虽然目前尚无大规模临床试验直接证明其能显著提升DFU的愈合率，但其改善胰岛素抵抗、减轻炎症反应对DFU的整体管理具有间接益处。
- 安全性：主要不良反应为胃肠道事件（如恶心、呕吐、腹泻），通常为轻中度且呈剂量依赖性 65。长期使用可能增加胰腺炎或甲状腺C细胞肿瘤的风险（主要基于动物模型）。在糖尿病患者中，GLP-1受体激动剂与SGLT2抑制剂相比，在部分亚组中可能存在较高的严重高血糖住院风险和透析或肾移植风险 74。
- 使用便捷性：多为皮下注射，通常每周一次给药，大大提高了患者的依从性。
3.3.2 靶向MMP-9抑制剂（如ND-336）
- 有效性：MMP-9抑制剂旨在通过特异性抑制过度活跃的MMP-9，来恢复慢性伤口中蛋白酶平衡，减少细胞外基质的过度降解，进而促进伤口愈合。研究表明，局部应用多西环素（一种四环素类药物，具有MMP抑制作用）可使MMP-9抑制潜力降低约30% 75。
- 安全性：由于MMP在正常生理过程中也扮演重要角色，选择性抑制是关键。目前处于临床前或早期临床阶段，具体人体安全性数据有限。理论上，过度抑制MMP可能影响正常组织重塑过程。
- 使用便捷性：靶向MMP-9的药物多为局部应用制剂（如局部凝胶或敷料），可直接作用于伤口部位，减少全身暴露。但具体给药频率和制剂形式将影响其便捷性。
3.3.3 细胞治疗产品（如自体皮肤构造物AHSC，干细胞疗法）
- 有效性：
- 自体皮肤构造物（AHSC）：一项随机对照试验旨在评估喷雾式皮肤（ReCell®，一种自体皮肤细胞悬液）或标准护理对DFU的疗效。主要结局是6个月时伤口完全愈合的比例 76。
- 间充质干细胞（MSC）：MSC疗法通过其免疫调节、抗炎、促血管生成和促进组织再生的能力来促进DFU愈合。
- 安全性：
- AHSC：由于是自体细胞，免疫排斥反应风险极低。
- MSC：通常安全性良好，不良事件发生率较低。主要关注点在于细胞来源的安全性、免疫原性（异体细胞）以及可能的致瘤风险（尽管目前证据稀少）。
- 使用便捷性：
- AHSC：可能缩短愈合时间并降低医疗成本 76。
- MSC：通常需要多次注射或敷贴，制备和储存相对复杂，且成本较高。
3.3.4 其他生物活性敷料和先进疗法
- 完整鱼皮敷料：在一项针对深度DFU的国际随机对照试验中，完整鱼皮敷料组在16周时愈合率达到44%，显著高于标准护理组的26% (P<0.001)，且愈合时间更快。最常见的不良事件是原发性伤口感染，鱼皮敷料组为30.2%，标准护理组为24.6% 77。其优势在于显著提高愈合率和缩短愈合时间，但感染风险仍需关注。
- 基因治疗（如FGF基因递送）：通过导入促血管生成基因（如FGF），改善DFU的局部缺血。成纤维细胞生长因子（FGF）是一种细胞信号蛋白家族，在血管生成、伤口愈合和代谢调节等多种过程中发挥作用。FGF能够刺激血管生成和成纤维细胞增殖，是有效的血管生成因子。研究人员已将FGF-1、FGF-2、FGF-4、FGF-7、FGF-21和FGF-23局部应用于DFU，并取得了良好的治疗效果 78。但基因治疗的挑战在于递送效率、长期安全性和免疫原性，目前仍在临床试验早期阶段，距离广泛应用尚远。
总结对比
| 药物类别 | 核心作用机制 | 有效性亮点 | 安全性考量 | 使用便捷性 |
|---|---|---|---|---|
| GLP-1受体激动剂 | 全身性代谢调节、血糖控制、体重管理、抗炎 | 改善全身代谢状况，间接利于DFU管理 | 胃肠道反应常见，通常轻中度；潜在增加严重高血糖住院及肾功能受损风险 6574 | 每周皮下注射一次，依从性高 65 |
| 靶向MMP-9抑制剂 | 局部炎症调控，恢复蛋白酶平衡 | 局部应用多西环素可使MMP-9抑制潜力降低约30% 75 | 处于早期临床阶段，人体安全性数据有限；需关注对正常MMP功能的影响 | 局部给药（敷料/凝胶），直接作用于创面 |
| 自体皮肤构造物（AHSC） | 提供自体活性细胞，促进上皮化和真皮重建 | 可能缩短愈合时间并降低医疗成本 76 | 自体来源，免疫排斥风险低 | 可能简化治疗流程 |
| 间充质干细胞疗法 | 免疫调节、抗炎、促血管生成、组织再生 | 促进细胞增殖分化，减轻炎症，加速愈合 | 良好，但需关注细胞来源、制备标准化、成本和长期安全性 | 通常需要多次给药，制备复杂，成本高昂 |
| 完整鱼皮敷料 | 提供生物支架，促进组织再生 | 显著提高深度DFU愈合率和愈合时间 77 | 最常见不良事件为原发性伤口感染 77 | 局部敷贴，相对便捷 |
| 基因治疗（如FGF基因递送） | 局部表达治疗性基因，促进血管生成 | 改善局部血流灌注，提高愈合率 78 | 递送效率、免疫原性、潜在致瘤风险，安全性需长期监测 | 局部注射，可能需要多次 |
从上述对比可以看出，不同药物针对DFU的不同环节发挥作用。GLP-1受体激动剂在全身代谢管理方面具有优势，但对DFU愈合的直接促进作用尚需更多证据。靶向MMP-9抑制剂和细胞治疗产品（特别是AHSC）则更直接地作用于局部伤口微环境和组织修复，显示出高愈合率或独特的治疗模式。完整鱼皮敷料作为一种新型生物敷料，在愈合率和愈合时间方面表现出色。基因治疗虽然前景广阔，但其技术复杂性和安全性考量使其仍处于早期研发阶段。在选择国外引进品种时，需综合考虑其在中国DFU患者人群中的有效性、安全性、成本效益以及临床可及性。
4. 国外品种引进的候选筛选与价值评估
面对国外糖尿病足治疗药物研发的多元化趋势，为了确保引进的品种能最大程度地满足国内临床需求并具备市场竞争力，需要建立一套科学合理的筛选标准。该标准应综合考虑国内患者的特定需求、当前治疗中存在的未满足痛点以及潜在的市场价值，并遵循有效性优先、安全性可控、技术可及性高的原则。
4.1 引进品种的筛选标准
引进国外糖尿病足治疗药物并非简单地复制，而是在充分理解国内DFU诊疗现状和未来趋势的基础上，进行有策略的选择。以下是详细的筛选标准：
4.1.1 基于国内患者需求的适配性
中国拥有庞大的糖尿病患者群体，DFU发病率高，且存在一些独特的临床特点，如：
- 高感染率及多重耐药菌挑战：如前所述，国内DFU感染率高，且革兰氏阴性菌和多重耐药菌（MDR）感染普遍。因此，优先考虑具有广谱抗菌活性、对MDR菌株有效或能有效改善局部感染微环境的药物。例如，能辅助抗生素清除感染、减少生物膜形成或调节宿主免疫反应的疗法将具有较高价值。
- 难愈合溃疡比例高：由于诊断和治疗的延迟，以及患者依从性等因素，国内DFU患者中难愈合溃疡的比例较高。因此，能够显著提高顽固性溃疡愈合率、缩短愈合时间、避免截肢风险的药物是重点考虑对象。这包括那些能够促进肉芽组织生长、血管生成、上皮化以及调节慢性炎症的生物制剂或先进敷料。
- 并发症复杂性：国内DFU患者常合并多种并发症，如周围神经病变导致的疼痛和感觉丧失、外周动脉疾病导致的缺血。能够同时改善这些并发症的药物，如具有神经修复作用或显著改善血供的药物，将更受青睐。GLP-1受体激动剂在改善足部疼痛方面的潜在益处，使其成为一个值得关注的方向。
- 患者依从性与经济承受能力：考虑到国内患者的依从性差异和支付能力，选择给药频率低、使用方便（如单次或少量多次给药）、或长期治疗成本效益高的产品会更具市场潜力。例如，自体皮肤构造物（AHSC）单次应用的特点，能有效减轻患者负担，值得重点关注。
4.1.2 解决未满足临床痛点
尽管国内DFU治疗手段日益丰富，但仍存在诸多未满足的临床痛点：
- 慢性炎症的有效调控：目前针对DFU慢性炎症的治疗多为间接干预，缺乏特异性、高效的炎症调控药物。高水平的MMP-9活性是DFU慢性炎症的关键特征。因此，靶向MMP-9抑制剂这类能够精确阻断慢性炎症级联反应，减少组织降解，并为伤口愈合创造有利环境的药物，具有巨大的临床价值。
- 局部缺血缺氧的根本改善：虽然有促血管生成药物，但对于严重缺血的DFU，现有疗法效果有限。能够有效促进侧支循环建立、改善微循环灌注、增加局部氧合的药物或技术（如基因治疗、智能纳米载药系统）是亟需的。
- 神经修复的突破性疗法：糖尿病周围神经病变是DFU发病的重要基础，但目前缺乏有效的神经修复药物。能够促进神经再生、改善神经传导速度、恢复感觉功能的药物，将填补这一空白。
- 生物膜感染的清除：DFU创面易形成细菌生物膜，这使得抗生素难以渗透，导致感染迁延不愈。能够穿透生物膜、破坏生物膜结构或增强宿主对生物膜清除能力的药物，是重要的研发方向。
- 个性化治疗的需求：DFU患者个体差异大，单一治疗难以满足所有需求。能够根据患者具体情况（如感染类型、缺血程度、炎症状态）提供个性化、精准治疗方案的药物，将更具优势。
4.1.3 市场潜力与商业价值
引进新药必须考量其潜在市场规模和商业回报：
- 患者基数大：中国糖尿病患者人数全球第一，DFU潜在患者数量庞大，为创新治疗药物提供了广阔的市场空间。
- 治疗周期长，医疗负担重：DFU治疗周期往往长达数月甚至数年，且复发率高，医疗费用巨大。能够缩短治疗周期、降低复发率、减少住院或截肢风险的药物，即使初期价格较高，其长期来看也可能具有更高的成本效益。
- 医保政策支持倾向：随着国家对创新药和高价值医疗器械的医保支付改革，符合临床急需、具有显著临床价值的创新产品更易获得医保支持，从而提高可及性。
- 与现有疗法的互补性：引进药物应尽量与国内现有治疗手段形成互补而非完全替代，以拓宽市场份额并提供更全面的治疗方案。
4.1.4 有效性优先、安全性可控、技术可及性高的原则
- 有效性优先：选择在关键临床终点（如完全愈合率、愈合时间、截肢率降低）上表现出显著优于现有标准疗法的药物。需有高质量的随机对照试验（RCT）数据支持，且疗效具有临床意义。
- 安全性可控：药物的不良反应发生率和严重程度应在可接受范围内，且有明确的风险管理策略。对于可能产生长期副作用的药物，需有充分的长期随访数据。
- 技术可及性高：考虑到国内医疗机构的基础设施和技术水平，引进药物的给药方式、制备要求、储存条件等应具备一定的可及性。例如，复杂的细胞治疗产品需要专门的细胞制备中心和专业人员，这会限制其推广。相对简便的局部制剂或口服药物则更易普及。对于需要特定设备或操作的技术，需评估国内医疗系统引进和培训的成本与可行性。
综合以上标准，国外品种的引进应聚焦于能够填补国内治疗空白、解决当前临床痛点、且在疗效和安全性上具有显著优势，同时兼顾市场潜力和可及性的创新药物。
4.2 重点候选品种推荐
综合上述筛选标准，以下三种类型的国外创新药物被推荐为优先引进方向，它们分别从全身代谢、局部炎症和组织再生层面提供了国内现有疗法难以替代的独特优势：
4.2.1 GLP-1受体激动剂（如司美格鲁肽）
- 推荐理由：
- 全身代谢调节的综合效益：GLP-1受体激动剂的核心优势在于其卓越的血糖控制和体重管理能力。对于DFU患者而言，稳定的血糖是伤口愈合的基础，而体重减轻有助于降低足部压力，改善外周循环。
- 改善足部疼痛及筋膜增厚的临床证据：虽然GLP-1受体激动剂主要用于降糖，但新兴研究显示其在改善糖尿病患者的足部疼痛方面具有潜力，并可降低跖筋膜增厚的进展速度 79。一项临床试验表明，利拉鲁肽（另一种GLP-1受体激动剂）能提高外周跨皮氧分压（TcPo2），改善2型糖尿病合并外周动脉疾病（PAD）患者的下肢灌注，这对于DFU的血管病变治疗具有重要意义 80。GLP-1受体激动剂可能在改善伤口愈合方面发挥作用 81。
- 心血管保护作用：部分GLP-1受体激动剂已被证实具有显著的心血管获益，能降低主要心血管事件风险，这对DFU患者常见的合并症管理至关重要 82。
- 与国内现有疗法的互补性：国内主要降糖药物虽能控制血糖，但缺乏GLP-1受体激动剂在改善足部疼痛、血管灌注和筋膜结构方面的直接证据。引进此类药物，可作为DFU患者全身管理的重要补充，尤其适用于合并肥胖、心血管风险高且存在神经病变性足痛的患者。
- 市场预期：鉴于中国庞大的糖尿病患者基数以及对更有效全身管理方案的需求，GLP-1受体激动剂在DFU辅助治疗领域具有巨大的市场潜力。其每周一次的给药频率也提高了患者依从性。
4.2.2 靶向MMP-9抑制剂（如ND-336）
- 推荐理由：
- 与国内现有疗法的互补性：目前国内针对DFU的局部治疗，多侧重于感染控制和非特异性促愈合（如生长因子）。然而，特异性靶向MMP-9的药物仍是空白。引进此类药物，可以填补国内在DFU慢性炎症精准调控领域的空白，为难愈合、高炎症负荷的DFU患者提供新的治疗选择。
- 市场预期：DFU患者中慢性炎症普遍存在，且MMP-9作为关键生物标志物已被广泛认知。靶向MMP-9抑制剂有望成为DFU局部治疗的重要组成部分，市场前景广阔。
4.2.3 自体细胞治疗产品（如自体皮肤构造物AHSC，间充质干细胞疗法）
- 推荐理由：
- 与国内现有疗法的互补性：国内在细胞治疗DFU方面仍处于发展初期，主要以科研和临床试验为主，大规模商品化且具有明确疗效数据的自体细胞治疗产品较少。引进成熟的自体细胞治疗产品，将显著提升国内DFU的再生医学治疗水平，为严重或顽固性DFU提供颠覆性的解决方案。
- 市场预期：尽管细胞治疗成本相对较高，但考虑到其显著的愈合效果和减少截肢风险的潜力，以及国内日益增长的医疗支付能力和对高质量医疗服务的需求，自体细胞治疗产品在高价值DFU市场具有强大的竞争力。随着技术进步和规模化生产，成本有望逐渐降低，使其惠及更广泛的患者。
5. 国内仿制/注册的技术与政策可行性分析
5.1 仿制药开发的技术路径
在国内仿制药的开发过程中，技术路径的明确性和可操作性是决定其可行性的关键。针对糖尿病足（DFU）治疗领域的仿制药，其技术路径因药物类型（如小分子化药、生物制品）而异，但均需遵循国家药品监督管理局（NMPA）的严格要求，尤其是生物等效性（BE）研究和质量一致性评价。
5.1.1 针对小分子化药仿制药
以抗感染药物利奈唑胺（Linezolid）为例，其仿制药开发的技术路径相对成熟。利奈唑胺是一种合成的噁唑烷酮类抗生素，主要作用于细菌核糖体的50S亚基，抑制蛋白质合成。
- 生物等效性研究设计：对于口服制剂，生物等效性研究是仿制药上市的核心要求。根据NMPA及国际监管机构（如FDA、EMA）的指导原则，通常采用随机、开放、交叉对照的人体生物等效性试验。受试者在不同时间点分别接受仿制药和参比制剂，并通过血药浓度-时间曲线测定药物的吸收速率和吸收程度（如Cmax、AUC0-t、AUC0-∞）86。利奈唑胺口服给药后吸收迅速，生物利用度高，因此BE研究的关键在于确保仿制药与原研药在体内吸收、分布、代谢、排泄（ADME）过程中的药代动力学特征高度一致。
- 质量一致性评价要点：
- 处方工艺研究：需详细分析原研药的处方组成和生产工艺，确定关键辅料的选择和用量、制备工艺参数等，并确保与原研药具有一致性。
- 晶型研究：利奈唑胺可能存在多种晶型，不同晶型可能影响药物的溶解度、溶出速率及生物利用度。仿制药需对活性药物成分（API）的晶型进行严格控制，确保与原研药一致。
- 杂质谱研究：通过高效液相色谱-质谱联用（HPLC-MS）等先进分析技术，全面分析仿制药和原研药的有关物质（杂质）谱，包括工艺杂质和降解产物，并确保杂质种类和含量均符合NMPA要求。
- 溶出度曲线比较：对于口服固体制剂，在不同pH介质中进行溶出度曲线比较试验，是体外评估制剂质量一致性的重要手段。利奈唑胺仿制药需在规定条件下与参比制剂的溶出度曲线相似。
- 稳定性研究：考察仿制药在加速、长期和影响因素条件下的物理、化学和微生物稳定性，确保其在储存、运输和使用过程中质量稳定。
5.1.2 针对生物类似药开发
以碱性成纤维细胞生长因子（bFGF）等生长因子类生物类似药为例，其开发挑战远超小分子化药，因为生物制品结构复杂、生产工艺敏感，且其生物活性与高级结构密切相关。
- 生产工艺：bFGF通常通过基因工程技术，利用大肠杆菌或酵母等宿主细胞表达获得。仿制药企业需建立稳定、高效的重组表达系统，优化发酵、分离、纯化工艺，确保目标蛋白的产量、纯度和活性。任何工艺微小变化都可能导致产品质量属性的改变。
- 活性检测：生物类似药的核心在于证明与原研药在生物学功能上的高度相似。对于bFGF，需进行多维度的活性检测：
- 质量一致性评价的关键技术挑战：
- 高级结构分析：利用圆二色谱（CD）、核磁共振（NMR）、质谱（MS）、X射线晶体衍射等技术，对bFGF的二级、三级和四级结构进行精细解析，确保其与原研药的高度相似性。这类分析对于证明如pegfilgrastim-cbqv等生物类似药与原研药的高度相似性至关重要92。
- 翻译后修饰分析：生物制品常常存在糖基化、氧化、脱酰胺等翻译后修饰，这些修饰可能影响蛋白质的活性和免疫原性。需利用质谱等方法详细分析修饰位点和程度，并与原研药进行比较。
- 免疫原性评估：生物类似药可能诱导患者产生抗药抗体，影响疗效或导致不良反应。在临床前和临床阶段，均需评估仿制bFGF的免疫原性风险。
- 生物相似性评估：NMPA《生物类似药研发与评价技术指导原则》要求，生物类似药的研发应通过对比研究（comparability exercise），证明其在质量、安全性和有效性方面与已批准的参照药品具有高度相似性 939495。这通常涉及全面的理化、结构和功能学比较，以及非临床和临床药代动力学/药效学比较研究。
总之，无论是小分子化药还是生物类似药，国内仿制药的开发都需投入大量研发资源和时间，严格按照NMPA的法规要求，进行全面的研究和评价。尤其对于生物类似药，其复杂性和技术门槛更高，需要具备先进的分析技术平台和专业的研发团队。中国在2016年实施强制性生物等效性测试后，显著推动了制药企业增加研发投资，提高了仿制药的质量水平，每家企业平均每年获得2.5项批准，表明政策对提高药物质量产生了积极影响 96。
5.2 创新药注册的政策支持与要求
中国国家药品监督管理局（NMPA）近年来持续深化药品审评审批制度改革，出台了一系列政策以鼓励创新药研发和加快审评审批，这为糖尿病足溃疡（DFU）创新药物，特别是纳米药物、干细胞疗法等前沿技术产品的注册上市提供了有力的政策支持。DFU作为一种复杂的慢性病，其创新药物的注册上市尤其需要结合NMPA的最新指南和要求。
5.2.1 NMPA最新指南与法规要求
NMPA针对慢性创面药物的临床试验发布了《慢性创面药物临床试验技术指导原则》，该原则为DFU等慢性创面的药物研发和注册提供了具体指导。主要体现在：
- 适应症选择：鼓励聚焦于当前治疗手段效果不佳的难愈性创面，如DFU，尤其是Wagner分级较高的溃疡。
- 临床试验设计：
- 主要终点：通常以创面完全愈合率或愈合时间作为主要疗效终点，同时关注愈合质量、复发率、截肢率等次要终点。对于不同类型的创新药（如促血管生成剂、抗感染剂），主要终点的选择应与其作用机制紧密关联。
- 对照组设置：一般要求与标准治疗（Standard of Care, SoC）进行比较，对于尚无有效治疗的适应症，可考虑安慰剂对照或无治疗对照。
- 受试者选择：强调受试者入组标准的严格性，避免混杂因素，如需排除严重缺血、骨髓炎等并发症患者，或设立分层研究。
- 样本量和随访期：需根据主要终点、预期疗效和统计学要求确定合理的样本量，并设置足够的随访期以评估长期疗效和安全性，特别是对于再生医学产品。
5.2.2 纳米药物的注册要求
纳米药物，如针对缺氧微环境的智能释放纳米颗粒、益生菌敷料等，在DFU治疗中展现出巨大潜力。其注册审评面临的挑战主要在于其独特的理化性质、复杂的体内行为以及潜在的安全性风险：
- 质量控制与表征：NMPA要求纳米药物需进行全面的物理化学表征，包括粒径、粒径分布、形态、表面电荷、稳定性、载药量和释放行为等。对于智能响应型纳米药物，需提供其在特定微环境（如缺氧、低pH、高酶活性）下智能释放的机制和数据。
- 生物安全性评估：纳米材料的生物安全性是关注重点。需进行细胞毒性、遗传毒性、全身毒性、免疫原性以及体内分布、代谢和排泄（ADME）等方面的全面评估。特别关注纳米颗粒在体内的蓄积、降解产物以及长期毒性。
- 非临床药效学研究：需在合适的DFU动物模型中进行药效学验证，证明其促愈合、抗感染或改善微环境的有效性。例如，针对缺氧微环境的纳米颗粒，需提供改善局部氧合、促进血管生成的相关数据。
- 临床试验设计：结合《慢性创面药物临床试验技术指导原则》，重点评估其局部给药后的安全性（如局部刺激、过敏反应）和有效性。由于纳米药物通常作用于局部，系统性吸收较低，但在临床试验设计中仍需关注潜在的全身性影响。
5.2.3 干细胞疗法的注册要求
干细胞疗法，如脐带间充质干细胞注射剂、自体皮肤构造物等，被视为DFU治疗的颠覆性疗法。NMPA对细胞治疗产品的管理日益完善，参照《细胞治疗产品研究与评价技术指导原则》等文件：
- 产品质量控制：对细胞产品的来源（自体/异体）、供者筛选、细胞分离、扩增、储存、运输以及终端产品的质控标准（如细胞数量、活力、纯度、鉴别、无菌、支原体、内毒素等）有严格要求。
- 非临床研究：
- 药理毒理学：需评估细胞产品的成瘤性、免疫原性、生物分布、长期存活和安全性。
- 药效学：在DFU动物模型中验证其促进愈合、抗炎、血管生成或神经修复的有效性。
- 临床试验设计：
- 早期临床试验：重点关注安全性，初步探索剂量和给药方式，通常采用爬坡设计。
- 确证性临床试验：设计严谨的随机、对照、多中心试验，以完全愈合率和愈合时间作为主要终点。同时，需关注细胞治疗产品的长期有效性和安全性，包括可能的免疫排斥、致瘤风险、细胞存活和功能等。
- 真实世界证据（RWE）应用：NMPA鼓励在细胞治疗产品注册中探索RWE的应用，尤其是在支持罕见适应症、扩大适应症或验证长期安全有效性方面。这要求企业建立完善的上市后随访和数据收集系统，以提供高质量的真实世界数据支持。
5.2.4 优先审评条件
为了加快创新药的上市，NMPA设立了优先审评通道。DFU创新药物若符合以下条件，有望获得优先审评：
- 具有明显临床优势的创新药：针对严重危及生命且尚无有效治疗手段或与现有治疗手段相比具有明显临床优势的DFU创新药。
- 列入突破性治疗药物程序：申请人可申请将符合条件的DFU创新药纳入突破性治疗药物程序，获得早期沟通交流、优先审评等政策支持。
- 符合公共卫生需求：如能显著降低截肢率、改善患者生活质量的DFU创新药，可能被视为符合公共卫生需求。
总体而言，国内创新药注册环境日益完善，为DFU领域的创新药物研发提供了良好机遇。企业在申报注册时，需严格遵循NMPA的各项技术指导原则，尤其要注重产品的质量控制、非临床研究的充分性以及临床试验设计的科学性和严谨性，同时积极利用优先审评等政策，加快产品上市进程。
5.3 市场准入与商业化前景
糖尿病足溃疡（DFU）创新药物在中国的市场准入和商业化前景，受到多重因素的影响，包括医保谈判趋势、定价策略以及基层医疗机构的可及性。这些因素共同决定了产品能否成功进入市场、实现销售增长并最终惠及广大患者。
5.3.1 医保谈判趋势与支付倾斜
近年来，中国国家医疗保障局（NHSA）主导的药品集中采购和医保目录调整工作日益常态化，医保谈判已成为创新药市场准入的关键环节。对于DFU创新药物而言，其医保谈判趋势主要体现在：
- 高价值创新药的支付倾斜：医保目录调整政策明确提出，对于具有重大临床价值、满足临床急需、且价格适度的创新药物，将优先纳入医保目录，并通过谈判确定支付标准。DFU作为严重的慢性并发症，其高致残率和高医疗负担，使得能显著提高愈合率、降低截肢风险、改善患者生活质量的创新药物被视为具有高临床价值，从而更有可能获得医保资金的支付倾斜。例如，如果GLP-1受体激动剂被证实能显著降低DFU患者的截肢风险，或靶向MMP-9抑制剂能有效避免反复感染和住院，它们在医保谈判中将拥有更强的议价能力。
- 真实世界证据（RWE）的应用：在医保谈判中，除了传统的临床试验数据，真实世界证据（RWE）也日益受到重视。若DFU创新药物能在上市后积累充分的RWE，证明其在实际临床应用中的疗效、安全性及成本效益（如减少后续治疗费用、住院天数、并发症等），将有助于在医保谈判中争取更有利的支付条件。
- 支付方式改革的影响：随着按疾病诊断相关分组（DRG）和按病种分值付费（DIP）等医保支付方式改革的推进，医疗机构将更倾向于选择那些能提高疗效、缩短住院时间、降低并发症发生率的药物，以提高其医疗服务效率和DRG/DIP支付盈余。这为DFU创新药物的市场推广提供了新的机遇。
5.3.2 定价策略与市场渗透
DFU创新药物的定价策略需要综合考虑研发成本、临床价值、竞品价格、医保支付能力以及患者可承受性，以平衡商业回报和社会可及性：
- 对比进口原研药的价格优势：对于从国外引进的创新药，其定价往往高于国内仿制药或传统疗法。成功的定价策略需要通过与现有进口原研药进行成本效益比较，强调其独特的临床优势和长期经济效益（如避免截肢带来的巨大社会和经济成本），以证明其“高值高价”的合理性。例如，如果自体皮肤构造物（AHSC）能通过单次应用实现高愈合率并显著降低长期治疗的复杂性和成本，即使初始价格较高，其整体成本效益也可能优于多次使用的传统疗法。
- 分层定价的可能性：考虑到中国不同地区的经济发展水平和医保支付能力差异，可以探索分层定价策略。例如，在高线城市和经济发达地区，可以采用相对较高的价格；而在基层和欠发达地区，则通过慈善赠药或与地方医保协商等方式，提高药物可及性。
- 市场教育与价值营销：创新药物的成功商业化，不仅依赖于定价，更需要深入的市场教育。通过向临床医生和患者普及DFU创新治疗的最新理念、药物的作用机制和临床获益，提升其认知度和接受度。
5.3.3 基层医疗机构的可及性
中国医疗体系呈现“金字塔”结构，大量DFU患者首先在基层医疗机构就诊。因此，基层医疗机构的可及性对DFU创新药物的市场渗透至关重要：
- 简化给药方式对推广的影响：对于基层医疗机构而言，操作简便、无需特殊设备或高度专业技能的给药方式将极大地提高药物的可及性。例如，局部外用制剂或口服药物相较于需要专业人员操作的细胞治疗或基因治疗，更容易在基层推广。GLP-1受体激动剂的每周一次皮下注射，也具备较好的基层推广潜力。
- 基层医生培训与技术支持：引进创新药物，需同步开展针对基层医生的培训，使其充分了解药物的适应症、禁忌症、使用方法、不良反应及DFU的规范化诊疗流程。提供完善的技术支持和售后服务，确保基层医疗机构能够正确、安全地使用新药物。
- 分级诊疗体系的融合：将DFU创新药物的推广与国家分级诊疗政策相结合，通过建立区域性DFU诊疗中心，辐射和指导基层医疗机构，形成上下联动、优势互补的诊疗网络。在中心医院使用复杂的高级疗法，同时在基层推广简化版或辅助疗法，以实现更广泛的覆盖。
总体而言，国外DFU创新药物在中国的市场准入和商业化前景充满机遇，但也面临挑战。成功的关键在于深入理解中国医疗体制的特点和患者需求，制定符合国情的医保准入策略、灵活的定价机制，并注重基层医疗机构的可及性，通过多维度、系统化的市场推广，才能将创新成果有效转化为临床实践，惠及广大的DFU患者。
6. 综合结论与开发建议
糖尿病足溃疡（DFU）作为糖尿病最严重的并发症之一，其病理机制复杂，治疗长期以来面临巨大挑战。尽管国内外在药物研发方面取得了显著进展，但目前的治疗仍存在诸多不足，尤其是在彻底控制感染、有效调节慢性炎症、显著促进血管再生和神经修复，以及实现个性化精准治疗方面，仍有巨大的临床需求未被满足。
当前DFU药物治疗的主要缺口在于：
- 慢性炎症的精准调控不足：现有治疗多为广谱抗炎，缺乏特异性靶向慢性炎症介质（如MMP-9）的药物。
- 血管再生和神经修复效果有限：尽管有生长因子类药物，但对于严重缺血和神经病变，其促愈合效果仍有提升空间，且基因治疗等前沿技术尚未大规模应用于临床。
- 多重耐药菌感染严峻：随着抗生素滥用，DFU感染中多重耐药菌问题日益突出，需要更有效的抗感染策略和新机制抗生素。
- 个体化治疗方案缺乏：DFU患者异质性高，现有治疗方案“一刀切”现象普遍，难以满足不同患者的特定需求。
- 治疗成本与可及性矛盾：先进疗法往往成本高昂，基层医疗可及性差，限制了其广泛应用。
未来DFU药物开发的技术趋势将围绕以下几个方面：
- 多靶点联合治疗：结合抗感染、抗炎、促血管生成和神经修复等多种机制，实现协同增效。
- 智能载药系统：利用纳米技术实现药物的靶向递送、缓释和响应性释放，提高药物利用率，降低副作用。
- 再生医学：以干细胞、外泌体、基因治疗等为代表的再生医学技术，将为组织修复和功能重建提供根本性解决方案。
- 微生物组干预：通过益生菌敷料等方式调节伤口微生态，对抗病原菌，促进愈合。
- 人工智能与大数据：辅助诊断、预测疗效，并指导个性化治疗方案的制定。
基于对DFU病理机制、国内外研发进展及国内临床需求的深入分析，本报告提出以下开发策略和建议：
1. 以感染控制为基础：
- 强化抗生素管理：继续关注新型抗生素的研发和引进，特别是对多重耐药菌有效的药物，如新型噁唑烷酮类（如康泰唑胺）或新型四环素类药物。
- 探索非抗生素抗感染策略：积极研究和引进具有抗菌特性的生物活性敷料（如含银敷料、抗菌肽敷料）、噬菌体疗法或益生菌敷料，以减少抗生素依赖，缓解耐药性压力。
2. 以促愈合为核心：
- 优先推进靶向炎症调控药物的引进与仿制：鉴于DFU慢性炎症的核心作用，强烈建议优先引进靶向MMP-9抑制剂。这类药物能够精确干预炎症级联反应，减少基质过度降解，为伤口愈合创造有利微环境。同时，应鼓励国内企业通过仿制或自主研发，开发具有类似机制的产品，以填补国内在该领域的空白。
- 积极引进高效促血管生成制剂：DFU普遍存在缺血缺氧。除传统生长因子外，应关注基因治疗（如VEGF基因递送）和智能纳米载药系统（如针对缺氧微环境的纳米颗粒）的引进。这些技术有望实现局部持续、高效的血管再生，从根本上改善伤口血供。对于自体细胞疗法，特别是自体皮肤构造物（AHSC），因其单次应用高愈合率的潜力，应积极评估其引进和本地化制备的可行性。
- 关注GLP-1受体激动剂在DFU辅助治疗中的作用：虽然其主要作用是血糖控制，但其在改善足部疼痛、筋膜增厚及心血管保护方面的潜在益处，使其成为DFU全身管理的重要辅助药物。建议通过临床研究进一步明确其在DFU愈合中的直接益处，并考虑将其纳入综合治疗方案。
3. 以个性化治疗为方向：
- 加强中药复方的机制研究与循证转化：中药在DFU治疗中积累了丰富经验，但其作用机制有待深入阐明。应结合现代生物学技术，如网络药理学、空间转录组学等，挖掘中药复方调节HIF-1α/VEGF通路、抑制NF-κB炎症反应、促进巨噬细胞极化等核心作用机制。同时，鼓励开展高质量、大样本的随机对照试验，提升中药治疗DFU的循证医学证据等级，推动其标准化、现代化应用。
- 发展伴随诊断：开发针对DFU患者基因型、炎症标志物（如MMP-9水平）、微生物谱等的诊断工具，指导药物选择和治疗方案优化。
- 推进再生医学个性化应用：探索利用患者自身细胞资源，结合3D生物打印等技术，构建个性化的皮肤替代物或载药支架。
具体开发建议：
- 政策层面：NMPA应继续完善针对DFU创新药物的审评路径，尤其是在基因治疗、细胞治疗和纳米药物等前沿领域，提供更明确的指导原则和更便捷的审评通道。医保部门应探索建立高价值DFU创新药物的多元化支付机制，平衡创新激励与可及性。
- 企业层面：国内药企应聚焦于特定病理环节，进行差异化研发。对于小分子化药，可考虑仿制国外成熟的靶向药物，并结合中国DFU特点进行二次开发。对于生物类似药，应投入资源建立先进的生物类似药研发和质控平台。同时，积极与国外创新药企开展合作，引进有临床优势和市场潜力的品种。
- 临床层面：鼓励临床医生积极参与新药研发和临床试验，提供真实世界数据，加速创新成果转化。建立多学科协作的DFU诊疗中心，推广规范化诊疗流程，为创新药物的应用提供良好平台。
通过上述策略的实施，有望构建一个“感染控制严密、炎症调控精准、血管神经修复有效、个体化方案完善”的糖尿病足治疗药物体系，最终显著改善国内DFU患者的预后，降低致残率，提升患者生活质量。
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参考文献
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INTRODUCTION: Diabetic wounds are a prevalent and impairing consequence of diabetes mellitus that significantly impacts people's lives and global healthcare systems. Because of disturbances in the wound-healing cascade, these intricate, persistent wounds frequently refuse to heal. Focusing on diabetic wound formation, this study seeks to clarify the complex mechanisms and pathophysiology involved while offering a thorough overview of modern multimodal therapy techniques. The etiology of diabetic wounds entails a complex interplay between tissue destruction caused by hyperglycemia, neuropathy, ischemia, and compromised immune response. Extended inflammation, abnormal protease activity, and low oxygen levels in the tissue exacerbate the healing process. Comprehending these pathogenic mechanisms is essential for formulating efficacious therapeutic strategies. METHODOLOGY: A thorough evaluation of the literature was done. Databases like SciFinder, ScienceDirect, PubMed, Google, Google Scholar, and the Egyptian Knowledge Bank were used to find pertinent publications. More than 200 articles and databases were studied to constitute this paper. The accuracy of the retrieved data was carefully reviewed and cross-checked. The current review aims to define wounds, various methods of classification, and various advancements for wound management. Several multidisciplinary strategies, including debridement, unloading, antimicrobial stewardship, and innovative therapeutics, are currently needed to manage diabetic wounds. Debridement-the excision of non-viable tissue-is necessary to create an environment that is conducive to recovery. Biomechanical interventions and offloading help to prevent additional tissue damage caused by repetitive stress. Antimicrobial treatments fight infections, which are a common diabetic wound consequence. Promising supplementary treatments are provided by developments in cellular and tissue-based products, ozone therapy growth factors, bioengineered skin substitutes, and hyperbaric oxygen therapy. RESULTS: After applying article selection criteria and reviewing the quality of the methodology a total of 200 articles were selected to be included in the review. In this review, intricate interactions between peripheral neuropathy, vascular insufficiency, and hyperglycemia in the pathophysiology of diabetic wounds are explained. The efficacy of multimodal therapies is discussed in detail. DISCUSSION: A thorough comprehension of the complex mechanisms that underlie diabetic wounds is essential for efficient therapy. This review emphasizes how important multimodal approaches are to treating the complex pathophysiology of these wounds. Clinicians can greatly enhance the prognosis of patients with diabetic foot ulcers by addressing vascular insufficiency, neuropathy, infection, and poor healing. CONCLUSION: Timely wound resolution remains a key difficulty despite the implementation of multimodal methods. To customize therapies, personalized medicine strategies utilizing genetic and proteomic biomarkers must be the main focus of future research. Furthermore, cutting-edge biotechnologies with the potential to transform diabetic wound treatment include optogenetics and nanomedicine.
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Dimitrios Baltzis, Ioanna Eleftheriadou, Aristidis Veves
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Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.
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S R Chaithra, Salini P Nair, S R Chaithanya, et al.
3 Biotech. 2025 Aug;15(8):272. doi: 10.1007/s13205-025-04440-0. Epub 2025 Jul 26.
Diabetic wound healing, especially in the context of diabetic foot ulcers, remains a major clinical challenge due to the complex interplay of metabolic, vascular, and cellular dysfunctions caused by chronic hyperglycemia. Impaired healing is driven by weakened inflammatory response, decreased blood vessel formation, reduced collagen production, and impaired fibroblast function. Hyperglycemia activates multiple damaging pathways, including the polyol, protein kinase C, hexosamine, and advanced glycation end-product pathways, which collectively induce oxidative stress and chronic inflammation. In addition, diabetic wounds exhibit impaired responses to hypoxia, marked by reduced expression of hypoxia-inducible factors (HIF-1 and HIF-1α), and elevated phenyl pyruvate, which activate macrophage-driven inflammation through CD36-PPT1-NLRP3 axis. Excessive matrix metalloproteinase (MMP) activity and poor collagen deposition disrupt extracellular matrix remodeling, further compromising tissue repair. Key signaling pathways such as PI3K/Akt, MAPK, TGF-β/SMAD, Notch, NfκB, VEGF, Wnt/β-catenin, and Nrf2 are dysregulated in diabetic wounds, undesirably affecting cell survival, inflammation resolution, and angiogenesis. To overcome these challenges, 3D scaffolds have emerged as an innovative therapeutic approach. Mimicking native ECM, it promotes cell adhesion, proliferation, and differentiation, and also enables controlled delivery of bioactive materials like stem cells, antimicrobials, and growth factors. Fabrication uses advanced materials like hydrogels, nanofibers, and smart polymers; these scaffolds are promising in restoring normal healing dynamics. This review explores the pathophysiology, major dysregulated pathways in DFU, and the evolving role of 3D scaffolds in diabetic wound treatment with supportive evidence of preclinical and clinical studies to improve clinical outcomes and patient's quality of life.
5The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer.PubMed
Robert Fitridge, Vivienne Chuter, Joseph Mills, et al.
Diabetes Metab Res Rev. 2024 Mar;40(3):e3686. doi: 10.1002/dmrr.3686. Epub 2023 Sep 19.
Diabetes related foot complications have become a major cause of morbidity and are implicated in most major and minor amputations globally. Approximately 50% of people with diabetes and a foot ulcer have peripheral artery disease (PAD) and the presence of PAD significantly increases the risk of adverse limb and cardiovascular events. The International Working Group on the Diabetic Foot (IWGDF) has published evidence based guidelines on the management and prevention of diabetes related foot complications since 1999. This guideline is an update of the 2019 IWGDF guideline on the diagnosis, prognosis and management of peripheral artery disease in people with diabetes mellitus and a foot ulcer. For this guideline the IWGDF, the European Society for Vascular Surgery and the Society for Vascular Surgery decided to collaborate to develop a consistent suite of recommendations relevant to clinicians in all countries. This guideline is based on three new systematic reviews. Using the Grading of Recommendations, Assessment, Development, and Evaluation framework clinically relevant questions were formulated, and the literature was systematically reviewed. After assessing the certainty of the evidence, recommendations were formulated which were weighed against the balance of benefits and harms, patient values, feasibility, acceptability, equity, resources required, and when available, costs. Through this process five recommendations were developed for diagnosing PAD in a person with diabetes, with and without a foot ulcer or gangrene. Five recommendations were developed for prognosis relating to estimating likelihood of healing and amputation outcomes in a person with diabetes and a foot ulcer or gangrene. Fifteen recommendations were developed related to PAD treatment encompassing prioritisation of people for revascularisation, the choice of a procedure and post-surgical care. In addition, the Writing Committee has highlighted key research questions where current evidence is lacking. The Writing Committee believes that following these recommendations will help healthcare professionals to provide better care and will reduce the burden of diabetes related foot complications.
6Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers.PubMed
Georgios Theocharidis, Dimitrios Baltzis, Matthieu Roustit, et al.
Diabetes. 2020 Oct;69(10):2157-2169. doi: 10.2337/db20-0188. Epub 2020 Aug 6.
Nonhealing diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation, both locally and systemically. We prospectively followed a group of patients who either healed or developed nonhealing chronic DFUs. Serum and forearm skin analysis, both at the protein expression and the transcriptomic level, indicated that increased expression of factors such as interferon-γ (IFN-γ), vascular endothelial growth factor, and soluble vascular cell adhesion molecule-1 were associated with DFU healing. Furthermore, foot skin single-cell RNA sequencing analysis showed multiple fibroblast cell clusters and increased inflammation in the dorsal skin of patients with diabetes mellitus (DM) and DFU specimens compared with control subjects. In addition, in myeloid cell DM and DFU upstream regulator analysis, we observed inhibition of interleukin-13 and IFN-γ and dysregulation of biological processes that included cell movement of monocytes, migration of dendritic cells, and chemotaxis of antigen-presenting cells pointing to an impaired migratory profile of immune cells in DM skin. The and genes, which were upregulated at the forearm of nonhealers, were mainly expressed by the vascular endothelial cell cluster almost exclusively in DFU, indicating a potential important role in wound healing. These results from integrated protein and transcriptome analyses identified individual genes and pathways that can potentially be targeted for enhancing DFU healing.
7Fibroblasts in Diabetic Foot Ulcers.PubMed
Francesca A Voza, Carlos Theodore Huerta, Nga Le, et al.
Int J Mol Sci. 2024 Feb 11;25(4):2172. doi: 10.3390/ijms25042172.
Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.
8Janus liposozyme for the modulation of redox and immune homeostasis in infected diabetic wounds.PubMed
Tingting Wei, Tiezheng Pan, Xiuping Peng, et al.
Nat Nanotechnol. 2024 Aug;19(8):1178-1189. doi: 10.1038/s41565-024-01660-y. Epub 2024 May 13.
Diabetic foot ulcers often become infected, leading to treatment complications and increased risk of loss of limb. Therapeutics to manage infection and simultaneously promote healing are needed. Here we report on the development of a Janus liposozyme that treats infections and promotes wound closure and re-epithelialization. The Janus liposozyme consists of liposome-like selenoenzymes for reactive oxygen species (ROS) scavenging to restore tissue redox and immune homeostasis. The liposozymes are used to encapsulate photosensitizers for photodynamic therapy of infections. We demonstrate application in methicillin-resistant Staphylococcus aureus-infected diabetic wounds showing high ROS levels for antibacterial function from the photosensitizer and nanozyme ROS scavenging from the liposozyme to restore redox and immune homeostasis. We demonstrate that the liposozyme can directly regulate macrophage polarization and induce a pro-regenerative response. By employing single-cell RNA sequencing, T cell-deficient Rag1 mice and skin-infiltrated immune cell analysis, we further reveal that IL-17-producing γδ T cells are critical for mediating M1/M2 macrophage transition. Manipulating the local immune homeostasis using the liposozyme is shown to be effective for skin wound repair and tissue regeneration in mice and mini pigs.
9Foot infections.PubMed
M A Ansari, V K Shukla
Int J Low Extrem Wounds. 2005 Jun;4(2):74-87. doi: 10.1177/1534734605277312.
Infections of the foot are very variable, some being complex in nature, causing pain, morbidity, and even mortality. In patients with diabetes mellitus, foot infections are common, ranging from chronic bacterial or fungal infections to serious limb-threatening ones. To manage infections, a sound knowledge of anatomy is essential. This article reviews the problems with respect to recent evidence and provides pathways to management and suggestions of changes with potential to wound healing.
10Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing.PubMed
Danielle Dixon, Michael Edmonds
Drugs. 2021 Jan;81(1):29-56. doi: 10.1007/s40265-020-01415-8.
Historically, there has been a scarcity of evidence-based topical therapy to hasten the healing of diabetic foot ulcers. But recently new evidence-based treatments have emerged from multicentre, randomised, controlled trials. This article highlights those trials, and describes the current pharmacological management of the diabetic foot ulcer and the advances that have been made in wound therapy to date. It provides an overview of topical and systemic pharmacotherapies in current use and those in development for future use in managing the diabetic foot. For each treatment, proposed mechanisms of action and evidence available to support their clinical use are presented. There is supporting randomised, controlled evidence for sucrose octasulfate in the treatment of neuro-ischaemic ulcers, and multi-layered patch of autologous leucocytes, platelets and fibrin in ulcers with or without ischaemia. There is also evidence for placentally derived products and for topical and systemic oxygen therapy in the healing of diabetic foot ulcers. Growth factors, bio-engineered tissues, stem cell therapy, gene therapy and peptide therapy also have some supporting evidence in the healing of diabetic foot ulcers. Nonsurgical debriding agents may be useful when the optimum approach of sharp debridement is not possible, and immunomodulators may be helpful for their antimicrobial effects, but robust data is still required to strengthen the case for general use. The review does not cover antimicrobials as their primary role are as anti-infectives and not in wound healing. The development of nanotechnology has created a means of prolonging the bioavailability of target molecules at the wound site, with the use of glass/hydrogel nanoparticles, polyethylene glycol and hyaluronic acid. Looking forward, novel therapies, including traction force-activated payloads, local delivery of short-interfering RNA and finally hydrogels incorporating bioactive agents or cells may provide possibilities for pharmacotherapy in the future.
11Glucose and pH dual-responsive hydrogels with antibacterial, reactive oxygen species scavenging, and angiogenesis properties for promoting the healing of infected diabetic foot ulcers.PubMed
Zhendong Li, Longhui Chen, Shasha Yang, et al.
Acta Biomater. 2024 Dec;190:205-218. doi: 10.1016/j.actbio.2024.10.020. Epub 2024 Oct 16.
The healing process of diabetic foot ulcers is challenging due to the presence of a complex and severe inflammatory microenvironment, characterized by hyperglycemia, low pH, susceptibility to infection, vascular dysfunction, and over-expression of reactive oxygen species (ROS), which can potentially lead to amputation or even mortality. Herein, a glucose and pH dual-responsive hydrogel was designed and prepared by crosslinking phenylboronic acid-grafted quaternary chitosan (QF, 4 wt%) with dopamine-grafted oxidized hyaluronic acid (OD, 5 wt%) through phenylboronation, schiff-base reaction, and other techniques. The multifunctional QO/@PV@AB7 hydrogel was prepared by incorporating pravastatin-loaded chitosan nanoparticles (CSNPs@PV, 2 mg/mL) and antimicrobial peptide AMP-AB7 loaded silica nanoparticles (SiONPs@AB7, 0.5 mg/mL). The results demonstrate that the QO/@PV@AB7 hydrogel exhibits good responsiveness to acidic conditions and high glucose levels, while effectively scavenging various types of ROS. Moreover, it exerted protective effects against oxidative stress on cells, enhanced HUVECs viability, and promoted angiogenesis. Notably, the QO/@PV@AB7 hydrogel displayed potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli. Additionally, in an MRSA-infected rat model of diabetic foot wounds, administration of the QO/@PV@AB7 hydrogel led to increased secretion of pro-angiogenic factors such as vascular endothelial nitric oxide synthase (eNOS), vascular endothelial-generating factor (VEGF), and endothelial cell adhesion molecule (CD31). Furthermore, the hydrogel significantly reduced the levels of inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), while simultaneously increasing the levels of anti-inflammatory cytokines such as interleukin-10 (IL-10). The findings suggest that multifunctional hydrogels incorporating PV@CSNPs and SiONPs@AB7 demonstrate promising potential as a therapeutic approach for the treatment of diabetic foot. STATEMENT OF SIGNIFICANCE: Here, a glucose and pH dual-responsive QO/@PV@AB7 hydrogel with antimicrobial and angiogenesis-promoting properties was developed for the treatment of infected wounds in diabetic feet. Our findings demonstrate that the proposed hydrogel exhibits good responsiveness, effectively scavenges various types of reactive oxygen species (DPPH, O, -OH, and ABTS+), provides protection against oxidative stress, enhances HUVECs cell viability, and promotes angiogenesis. Notably, it also demonstrates potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and E. coli. Additionally, in vivo experiments demonstrated that the hydrogel exhibited accelerated wound healing in MRSA-infected diabetic foot ulcers, with a reduction of four days compared to the control group.
12Photo-controlled multifunctional hydrogel for photothermal sterilization and microenvironment amelioration of infected diabetic wounds.PubMed
Fan Yang, Dong Mo, Beibei Wu, et al.
J Control Release. 2025 Jan 10;377:470-484. doi: 10.1016/j.jconrel.2024.11.047. Epub 2024 Nov 29.
Diabetic foot ulcers are linked to a high disability rate, with no effective treatment currently available. Addressing infection, reducing oxidative stress, and safely managing chronic inflammation remain major challenges. In this study, a composite hydrogel dressing was developed using natural substances or clinically approved components (dopamine, D-alpha-tocopheryl polyethylene glycol succinate, and rhein). Upon near-infrared laser irradiation, the composite system rapidly heats and solidifies into a gel with photothermal antibacterial properties. Additionally, the decomposition of hydrogen peroxide releases oxygen, alleviating wound hypoxia. The hydrogel exhibited strong bactericidal activity against multiple bacterial strains. Without laser irradiation, the hydrogel effectively scavenged various free radicals and intracellular reactive oxygen species, restoring redox balance. Furthermore, it significantly reduced the expression of inflammatory cytokines, including interleukin-6 and interleukin-1β. In a diabetic mouse wound model infected with S. aureus, the mild photothermal therapy, combined with the antibacterial action of rhein, effectively managed bacterial infections, reduced inflammation, and promoted wound healing. Consequently, the photo-controlled therapeutic approach, offering antibacterial, antioxidant, and anti-inflammatory effects, holds promise for the effective treatment and management of infected diabetic wounds.
13MCC950 promotes diabetic wound healing through modulating macrophage polarization in an MDSC-dependent manner.PubMed
Wei Yan, Tianyi Ni, Qian Zhang, et al.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):112983. doi: 10.1016/j.intimp.2024.112983. Epub 2024 Aug 31.
Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment.
14Integrating Network Pharmacology, Molecular Docking and Experimental Validation to Explore the Pharmacological Mechanisms of Quercetin Against Diabetic Wound.PubMed
Zhe Zhang, Lei Wang, Xuan Li, et al.
Int J Med Sci. 2024 Oct 28;21(14):2837-2850. doi: 10.7150/ijms.100468. eCollection 2024.
The chronic non-healing diabetic wound (DW) has remained a challenge to both the society and individuals. Previous studies suggested dietary moderate consumption of quercetin (QCT) are beneficial in preventing diabetic complications, including non-healing DW. However, there were few studies that have investigated QCT-related underlying molecular mechanisms against DW. In the present study, we for the first-time combined network pharmacology with molecular docking and experimental validation to investigate QCT-related therapeutic targets and mechanisms for treating DW. Finally, 191 QCT-related targets and 1750 DW-related pathogenetic targets were obtained from online databases. After removing duplicates, a total of 90 potential therapeutic targets of quercetin for treating DW were ultimately identified. Furthermore, 7 targets with higher degree including IL-6, EGFR, SRC, TNF, AKT1, JUN and MMP9 were predicted as central therapeutic targets of QCT for treating DW. Functional enrichment analysis demonstrated that QCT exerted strong levels of multitargeting regulatory activity. In addition, the KEGG enrichment analysis indicated that several signaling pathways including AGE-RAGE signaling pathway in diabetic complications, IL-17, PI3k-AKT, TNF, HIF-1, VEGF were predicted as key regulators of QCT for treating DW. Molecular docking results suggested that QCT had strong binding activity with the predicted targets. In addition, verification experiments suggested that QCT could significantly attenuated the expression of inflammatory cytokines and the regulation of PI3K-AKT signaling pathway was probably a vital mechanism involved in the pharmacological mechanism of QCT for treating DW. Taken together, combined network pharmacological with experimental validation, we for the first time systematically investigated associated-therapeutic targets and potential pathways of QCT for DW treatment. Our study might provide theoretical basis for DW treatment.
15Mai Guan Fu Kang tablet (MGFK) accelerates diabetic foot ulcer healing via antioxidant defense and inflammation suppression.PubMed
Xiaowen Jiang, Ziyang Han, Yue Jin, et al.
Phytomedicine. 2025 Sep;145:157038. doi: 10.1016/j.phymed.2025.157038. Epub 2025 Jul 5.
BACKGROUND: Diabetic foot ulcer (DFU), a severe complication of diabetes characterized by impaired healing and high morbidity, demand novel therapeutic strategies. Mai Guan Fu Kang tablets (MGFK) and combined therapy have been used in the clinical treatment of DFU, showing potential in DFU management, but their mechanisms remain unclear. PURPOSE: This study aimed to elucidate the molecular mechanisms of MGFK in DFU, focusing on oxidative stress, inflammation, and vascular-neural repair. METHODS: Firstly, we performed a comprehensive pathological analysis of tissue samples obtained from patients with chronic diabetic wounds. Subsequently, we conducted in-depth investigations using DFU mouse model and diabetic lower limb ischemia rat model, as well as network pharmacology approaches. The efficacy and underlying mechanisms of MGFK were further elucidated through advanced analytical techniques, including liquid chromatography-mass spectrometry (LC-MS), molecular docking, qPCR, Western blotting, and immunohistochemistry (IHC). RESULTS: Clinical pathological analysis of tissue samples demonstrated significantly elevated levels of reactive oxygen species (ROS) and pro-inflammatory cytokines in patients with DFU. MGFK-treated DFU mice could significantly increase the wound healing rate, reduce inflammation and inhibit oxidative stress. In diabetic limb ischemia rat model, MGFK improved blood flow, reduced coagulation markers (FIB, PT), and restored sciatic nerve function, correlating with increased VEGF and NO levels. Network pharmacology and molecular docking highlighted key components suggesting that MGFK is related to inflammation-related pathways and targets. Finally, through the construction of LPS-induced Raw264.7 cell models and tert‑butyl hydroperoxide (TBHP)-induced L929 cell models, it was found that MGFK has significant anti-inflammatory and antioxidant stress effects in vitro. Finally, we formulated a compound prescription, whose anti-inflammatory effect in vitro is superior to that of MGFK. CONCLUSIONS: These findings highlight the multi-target mechanism of MGFK, which integrates antioxidant, anti-inflammatory, and vascular repair properties. Specifically, MGFK promotes wound healing by restoring antioxidant capacity, inhibiting NF-κB-mediated inflammatory responses, and enhancing vascular function.
16Multifunctional Hydrogels for the Healing of Diabetic Wounds.PubMed
Tao Xiang, Qianru Guo, Lianghao Jia, et al.
Adv Healthc Mater. 2024 Jan;13(1):e2301885. doi: 10.1002/adhm.202301885. Epub 2023 Sep 22.
The healing of diabetic wounds is hindered by various factors, including bacterial infection, macrophage dysfunction, excess proinflammatory cytokines, high levels of reactive oxygen species, and sustained hypoxia. These factors collectively impede cellular behaviors and the healing process. Consequently, this review presents intelligent hydrogels equipped with multifunctional capacities, which enable them to dynamically respond to the microenvironment and accelerate wound healing in various ways, including stimuli -responsiveness, injectable self-healing, shape -memory, and conductive and real-time monitoring properties. The relationship between the multiple functions and wound healing is also discussed. Based on the microenvironment of diabetic wounds, antibacterial, anti-inflammatory, immunomodulatory, antioxidant, and pro-angiogenic strategies are combined with multifunctional hydrogels. The application of multifunctional hydrogels in the repair of diabetic wounds is systematically discussed, aiming to provide guidelines for fabricating hydrogels for diabetic wound healing and exploring the role of intelligent hydrogels in the therapeutic processes.
17Stem Cells and Angiogenesis: Implications and Limitations in Enhancing Chronic Diabetic Foot Ulcer Healing.PubMed
Vikrant Rai, Rebecca Moellmer, Devendra K Agrawal
Cells. 2022 Jul 25;11(15):2287. doi: 10.3390/cells11152287.
Nonhealing diabetic foot ulcers (DFUs) are a continuing clinical issue despite the improved treatment with wound debridement, off-loading the ulcer, medication, wound dressings, and preventing infection by keeping the ulcer clean. Wound healing is associated with granulation tissue formation and angiogenesis favoring the wound to enter the resolution phase of healing followed by healing. However, chronic inflammation and reduced angiogenesis in a hyperglycemic environment impair the normal healing cascade and result in chronically non-healing diabetic foot ulcers. Promoting angiogenesis is associated with enhanced wound healing and using vascular endothelial growth factors has been proven beneficial to promote neo-angiogenesis. However, still, nonhealing DFUs persist with increased risks of amputation. Regenerative medicine is an evolving branch applicable in wound healing with the use of stem cells to promote angiogenesis. Various studies have reported promising results, but the associated limitations need in-depth research. This article focuses on summarizing and critically reviewing the published literature since 2021 on the use of stem cells to promote angiogenesis and enhance wound healing in chronic non-healing DFUs.
18Comprehensive management of diabetic ulceration: strategies and perspectives.PubMed
Ziwen Zheng, Juan Yang, Wang Zheng, et al.
J Control Release. 2025 Sep 10;385:114058. doi: 10.1016/j.jconrel.2025.114058. Epub 2025 Jul 21.
Diabetic Ulceration (DU) is a main category of nonhealing chronic wounds and tends to be vulnerable and ulcerated repeatedly. Prolonged hyperglycemia microenvironment, together with immunochemotactic response dysfunction, eventually contributes to the refractory wound that is hard to heal. In the chronic DU, there exist obstacles such as diabetic wound bacterial infection, persistent inflammation, suppressed angiogenesis, and reduced growth factor proliferation with decreased hypoxia inducible factor 1 alpha (HIF-1α) expression, and these issues have persisted in hindering the rational and effective wound tissue regeneration. In this review, we provide a comprehensive summary of therapeutic approaches that target the four phases of DU healing at glycemic control, anti-bacteria, anti-inflammatory, angiogenesis, and matrix remodeling. In the anti-bacteria and anti-inflammatory therapies, we discuss novel bioactive materials and a variety of antibacterial agents and anti-inflammatory therapies including herbal medicines, to handle the problems posed by wound-resistant bacteria, biofilms and the constant inflammatory microenvironment of DU. In later healing stages, following the healing process of DU, we summarized the usage of active metal ions, special gas molecules, growth factor production and HIF-1α stabilization to treat angiogenesis and matrix remodeling afterwards. In this review, we evaluate recent advances in each of these potential therapies and highlight their ability to improve DU healings in different stages.
19Multitasking Asynchronous Collaborative Nanosystem for Diabetic Wound Healing Based on Hypoglycemic, Antimicrobial, and Angiogenesis-Promoting Effects.PubMed
Jun Ren, Chaoli Wang, Hao Gao, et al.
Adv Healthc Mater. 2025 Feb;14(4):e2403282. doi: 10.1002/adhm.202403282. Epub 2024 Dec 17.
A diabetic foot ulcer (DFU) is a common and serious complication of diabetes. This complication can result in amputation and death because of the several challenges associated with wound healing that can be attributed to the complex wound microenvironment, including biofilm infection, hyperglycemia, and diabetic angiopathy. Existing investigations on the wound-healing rate consider only one or two pathogenic factors, and therefore, despite the extensive research on these pathological microenvironments, there is an urgent need to optimize the wound-healing rate in patients with diabetic foot ulcers. To this end, a multitasking asynchronous collaborative nanosystem is designed in this study. The designed nanosystem can efficiently clear biofilm infections using optimized photodynamic therapy based on a poly photosensitizer ionic liquid (i.e., Ce6IL), reduce local blood glucose concentration using glucose oxidase, and reconstruct blood vessels by stimulating endothelial cell proliferation and migration using nitric oxide. The experimental results indicate that the three-step sequential collaboration strategy for clearing biofilm infections, reducing glucose concentrations, and reconstructing damaged blood vessels can help significantly accelerate wound healing rate in patients with diabetic foot ulcers.
20Ultrasound-Augmented Multienzyme-like Nanozyme Hydrogel Spray for Promoting Diabetic Wound Healing.PubMed
Limin Shang, Yixin Yu, Yujie Jiang, et al.
ACS Nano. 2023 Aug 22;17(16):15962-15977. doi: 10.1021/acsnano.3c04134. Epub 2023 Aug 3.
Treatment of diabetic foot ulcers (DFU) needs to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, but the therapeutic efficacy is greatly limited by the diversity and synergy of drug functions as well as the DFU microenvironment itself. Herein, an ultrasound-augmented multienzyme-like nanozyme hydrogel spray was developed using hyaluronic acid encapsulated l-arginine and ultrasmall gold nanoparticles and CuO nanoparticles coloaded phosphorus doped graphitic carbon nitride nanosheets (ACPCAH). This nanozyme hydrogel spray possesses five types of enzyme-like activities, including superoxide dismutase (SOD)-, catalase (CAT)-, glucose oxidase (GOx)-, peroxidase (POD)-, and nitric oxide synthase (NOS)-like activities. The kinetics and reaction mechanism of the sonodynamic/sonothermal synergistic enhancement of the SOD-CAT-GOx-POD/NOS cascade reaction of ACPCAH are fully investigated. Both in vitro and in vivo tests demonstrate that this nanozyme hydrogel spray can be activated by the DFU microenvironment to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, thus accelerating diabetic wound healing effectively. This study highlights a competitive approach based on multienzyme-like nanozymes for the development of all-in-one DFU therapies.
21Advancements in diabetic foot ulcer therapy: The role of exosomes and decellularised extracellular matrix scaffolds.PubMed
Yanbei Zhu, Shengzhe Bao, Xuezhou Yin, et al.
Diabetes Res Clin Pract. 2025 Aug;226:112364. doi: 10.1016/j.diabres.2025.112364. Epub 2025 Jul 10.
Diabetic foot ulcer (DFU) ranks among the most severe complications of diabetes mellitus. DFU mainly arises from neuropathy and peripheral arterial disease, with aggravating factors like infection and edema. These ulcers impose significant physical and financial challenges, making wound healing a crucial clinical issue. Current DFU management focuses on ensuring adequate blood flow, relieving pressure, controlling infection, and debridement. Cell therapy offers notable benefits, yet the effectiveness of traditional stem cell transplants for DFU remains contentious. In this context, exosomes are gaining recognition as a promising option in tissue engineering and regenerative medicine. Their advantages include excellent biocompatibility, precise targeting, and ability to cross biological barriers, proficient drug delivery, low toxicity, and abundant availability. Numerous studies indicate that stem cell-derived exosomes contribute to diabetic wound healing by promoting angiogenesis, collagen deposition, and reducing inflammation, among other mechanisms. This acellular approach presents significant advantages over conventional methods and is crucial in DFU management. Nonetheless, challenges such as the limited retention of exosomes at injury sites render singular treatment strategies insufficient for optimal outcomes. By integrating decellularized extracellular matrix (dECM)-based scaffolds with exosomes, enhanced transfer and retention of exosomes can be achieved, along with a sustained release. This review summarizes the role and mechanisms of exosomes from various stem cells in enhancing DFU wound healing, recent advancements in dECM scaffolds, and discusses the application of exosomes combined with dECM scaffolds in DFU therapy, along with the associated challenges.
22Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing.PubMed
Joshua P B Littig, Rebecca Moellmer, Devendra K Agrawal, et al.
World J Diabetes. 2023 Jan 15;14(1):35-47. doi: 10.4239/wjd.v14.i1.35.
Type 2 diabetes mellitus (T2DM) increases the risk of many lethal and debilitating conditions. Among them, foot ulceration due to neuropathy, vascular disease, or trauma affects the quality of life of millions in the United States and around the world. Physiological wound healing is stalled in the inflammatory phase by the chronicity of inflammation without proceeding to the resolution phase. Despite advanced treatment, diabetic foot ulcers (DFUs) are associated with a risk of amputation. Thus, there is a need for novel therapies to address chronic inflammation, decreased angiogenesis, and impaired granulation tissue formation contributing to the non-healing of DFUs. Studies have shown promising results with resolvins (Rv) and anti-inflammatory therapies that resolve inflammation and enhance tissue healing. But many of these studies have encountered difficulty in the delivery of Rv in terms of efficiency, tissue targetability, and immunogenicity. This review summarized the perspective of optimizing the therapeutic application of Rv and cytokines by pairing them with exosomes as a novel strategy for targeted tissue delivery to treat non-healing chronic DFUs. The articles discussing the T2DM disease state, current research on Rv for treating inflammation, the role of Rv in enhancing wound healing, and exosomes as a delivery vehicle were critically reviewed to find support for the proposition of using Rv and exosomes in combination for DFUs therapy. The literature reviewed suggests the beneficial role of Rv and exosomes and exosomes loaded with anti-inflammatory agents as promising therapeutic agents in ulcer healing.
23Nerve growth factor and diabetic neuropathy.PubMed
Gary Pittenger, Aaron Vinik
Exp Diabesity Res. 2003 Oct-Dec;4(4):271-85. doi: 10.1155/EDR.2003.271.
Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50-90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.
24Neurotrophic factors in the therapy of diabetic neuropathy.PubMed
S C Apfel
Am J Med. 1999 Aug 30;107(2B):34S-42S. doi: 10.1016/s0002-9343(99)00011-x.
A large number of neurotrophic factors that exert effects on specific neuronal populations in the peripheral nervous system have been discovered. Some of these factors may prove useful for the treatment of diabetic peripheral neuropathy. Among the most promising are members of the neurotrophin gene family (nerve growth factor [NGF], brain-derived neurotrophic factor, neurotrophin [NT]-3, and NT-4/5), insulin-like growth factor (IGF)-I and IGF-II, and glial cell-derived neurotrophic factor. Of these, NGF and the IGFs have been tested most extensively in animal models of diabetic neuropathy, with encouraging results. Recombinant human nerve growth factor (rhNGF) has been tested in phase II clinical trials for treatment of patients with diabetes, and the results have been encouraging. Phase III trials of rhNGF have been completed, and clinical trials of other neurotrophic factors are likely to be conducted in the next few years.
25Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications.PubMed
Masaki Kobayashi, Douglas W Zochodne
J Diabetes Investig. 2018 Nov;9(6):1239-1254. doi: 10.1111/jdi.12833. Epub 2018 Apr 25.
Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron-specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end-products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3-kinase-protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon-like peptide-1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let-7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre-messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration.
26Microbial Infection and Antibiotic Susceptibility of Diabetic Foot Ulcer in China: Literature Review.PubMed
Fang Du, Jing Ma, Hongping Gong, et al.
Front Endocrinol (Lausanne). 2022 May 19;13:881659. doi: 10.3389/fendo.2022.881659. eCollection 2022.
OBJECTIVE: To investigate the microbial spectrum isolated from foot ulcers among diabetic patients in China, which was conducted to help clinicians choose optimal antibiotics empirically. METHOD: The PubMed, MEDLINE, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases were searched for studies published between 2015 to 2019, that report primary data on diabetic foot infection (DFI) and antibiotic susceptibility in China. RESULT: A total of 63 articles about DFI and antibiotic susceptibility tests among diabetic patients in China were included. There were 11,483 patients with an average age of 60.2 ± 10.1 years and a mean course of 10.6 ± 5.0 years between 2010 and 2019, covering most geographical regions of China. The prevalence of Gram-positive (GP) bacteria (43.4%) was lower than that of Gram-negative (GN) (52.4%). The most prevalent pathogens isolated were Staphylococcus aureus (17.7%), Escherichia coli (10.9%), Pseudomonas aeruginosa (10.5%), Klebsiella pneumoniae (6.2%), Staphylococcus epidermidis (5.3%), Enterococcus faecalis (4.9%), and fungus (3.7%). The prevalence of polymicrobial infection was 22.8%. GP bacteria were sensitive to linezolid, vancomycin, and teicoplanin. More than 50% of GN bacteria were resistant to third-generation cephalosporins, while the resistance rates of piperacillin/tazobactam, amikacin, meropenem, and imipenem were relatively low. Among the 6017 strains of the isolated organisms, 20% had multi-drug resistance (MDR). Staphylococcus aureus (30.4%) was the most predominant MDR bacteria, followed by extended-spectrum β-lactamase (ESBL) (19.1%). CONCLUSION: The microbial infection of foot ulcers among diabetic patients in China is diverse. The microbial spectrum is different in different geographic regions and Staphylococcus aureus is the predominant bacteria. Polymicrobial and MDR bacterial infections on the foot ulcers are common. This study could be valuable in guiding the empirical use of antibiotics for diabetic foot infections.
27Diabetic foot ulcer-a systematic review on relevant microbial etiology and antibiotic resistance in Asian countries.PubMed
Rokaia Sultana, Iftekhar Ahmed, Sabera Saima, et al.
Diabetes Metab Syndr. 2023 Jun;17(6):102783. doi: 10.1016/j.dsx.2023.102783. Epub 2023 May 22.
BACKGROUND AND AIMS: Diabetic foot ulcer (DFU) is one of the most common but uncontrolled health issues of diabetic patients that needs more therapeutic considerations. This systematic review aims to study the current status of the etiological agents responsible for DFU, their frequency in some of the most occurring Asian countries, and their antibiotic resistance pattern based on available studies. METHODS: Here, the literature survey was conducted on all the DFU studies with the records of etiological agents and conventional therapeutic treatment published until March 2021 using Medical Literature Analysis and Retrieval System Online (MEDLINE) and Web of Science Core Collection (WoSCC) database. RESULTS: Overall, in our study, a total of 73 studies representing 12 Asian countries worldwide have been included. We found that the highest number of studies were reported from India (45%) followed by Pakistan (11%), China, Iran and others. 71% of recent studies reported DFU being attributed to poly-microbial infections while the dominant position was significantly secured by Gram- negative bacteria (77%, p = 0.34). Staphylococcus aureus was found to be the most prevalent isolate followed by Pseudomonas and then Escherichia coli (mean value - 22%, 17%, and 15% respectively). Antibiotic sensitivity pattern was determined based on availability in terms of median resistance (MR) and interquartile range (IQR) which showed the growing resistance developed by both Gram-positive and Gram-negative isolates. Gram positive pathogens were still reported as susceptible to vancomycin (MR 0%, IQR 0-22.8%), linezolid (MR 0%, IQR 0-15.53%) and imipenem (MR 11%, IQR 0-23.53%). Carbapenem genera, colistin, and amikacin were the most effective drugs against Gram-negative pathogens. CONCLUSION: The findings of this study highly recommend searching for alternative and complementary therapeutic regimens instead of prescribing conventional drugs blindly without investigating the progression of the stages of the ulcer, which may help reduce the medical and economic burden of this disease.
28Prevalence of multidrug-resistant bacterial infections in diabetic foot ulcers: A meta-analysis.PubMed
Shaoling Yang, Liye Hu, Yue Zhao, et al.
Int Wound J. 2024 Apr;21(4):e14864. doi: 10.1111/iwj.14864.
Multidrug-resistant (MDR) bacterial infections have become increasingly common in recent years due to the increased prevalence of diabetic foot ulcers (DFUs). We carried out a meta-analysis aimed at investigating the prevalence of MDR bacteria isolated from DFUs and analysing the risk factors for MDR bacterial infection in patients with DFUs. The PubMed/Medline, Web of Science, Embase, Cochrane Library, Ovid, Scopus, and ProQuest databases were searched for studies published up to November 2023 on the clinical outcomes of MDR bacteria in DFUs. The main outcome was the prevalence of MDR bacteria in DFUs. A total of 21 studies were included, representing 4885 patients from which 2633 MDR bacterial isolates were obtained. The prevalence of MDR bacteria in DFUs was 50.86% (95% confidence interval (CI): 41.92%-59.78%). The prevalence of MDR gram-positive bacteria (GPB) in DFUs was 19.81% (95% CI: 14.35%-25.91%), and the prevalence of MDR gram-negative bacteria (GNB) in DFUs was 32.84% (95% CI: 26.40%-39.62%). MDR Staphylococcus aureus (12.13% (95% CI: 8.79%-15.91%)) and MDR Enterococcus spp. (3.33% (95% CI: 1.92%-5.07%)) were the main MDR-GPB in DFUs. MDR Escherichia coli, MDR Pseudomonas aeruginosa, MDR Enterobacter spp., MDR Klebsiella pneumoniae, and MDR Proteus mirabilis were the main MDR-GNB in DFUs. The prevalence rates were 6.93% (95% CI: 5.15%-8.95%), 6.01% (95% CI: 4.03%-8.33%), 3.59% (95% CI: 0.42%-9.30%), 3.50% (95% CI: 2.31%-4.91%), and 3.27% (95% CI: 1.74%-5.21%), respectively. The clinical variables of diabetic foot ulcer patients infected with MDR bacteria and non-MDR bacteria in the included studies were analysed. The results showed that peripheral vascular disease, peripheral neuropathy, nephropathy, osteomyelitis, Wagner's grade, previous hospitalization and previous use of antibacterial drugs were significantly different between the MDR bacterial group and the non-MDR bacterial group. We concluded that there is a high prevalence of MDR bacterial infections in DFUs. The prevalence of MDR-GNB was greater than that of MDR-GPB in DFUs. MDR S. aureus was the main MDR-GPB in DFUs, and MDR E. coli was the main MDR-GNB in DFUs. Our study also indicated that peripheral vascular disease, peripheral neuropathy, nephropathy, osteomyelitis, Wagner's grade, previous hospitalization, and previous use of antibacterial drugs were associated with MDR bacterial infections in patients with DFUs.
29Contezolid: First Approval.PubMed
Sheridan M Hoy
Drugs. 2021 Sep;81(13):1587-1591. doi: 10.1007/s40265-021-01576-0.
Contezolid (Youxitai ), an orally administered oxazolidinone antibacterial agent, is being developed by Shanghai MicuRx Pharmaceutical Co., Ltd. for the treatment of multidrug-resistant (MDR) Gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. In June 2021, it was approved by the National Medical Products Administration of China for the treatment of complicated skin and soft tissue infections (cSSTI), including, but not limited to, methicillin-susceptible S. aureus, MRSA, Streptococcus pyogenes and Streptococcus agalactiae. The recommended dosage of contezolid is 800 mg (i.e. two 400 mg tablets) every 12 h for 7-14 days. Contezolid is also undergoing clinical development for acute bacterial skin and skin structure infections (ABSSSI) in the USA, and for diabetic foot infections. This article summarizes the milestones in the development of contezolid leading to this first approval for the treatment of cSSTI.
30Toenail onychomycosis in diabetic patients: issues and management.PubMed
Peter Mayser, Viviane Freund, Debby Budihardja
Am J Clin Dermatol. 2009;10(4):211-20. doi: 10.2165/00128071-200910040-00001.
Diabetes mellitus may be associated with serious sequelae, such as renal disease, retinopathy, and diabetic foot. A recent large prospective study has shown that onychomycosis is among the most significant predictors of foot ulcer. As the severity of onychomycosis may be associated with the length of time the individual has had the infection, early intervention is advisable owing to the progressive nature of the fungal infection. If left untreated, toenails can become thick, causing pressure and irritation, and thus act as a trigger for more severe complications. In the treatment of onychomycosis, compliance and drug interactions are important considerations, as diabetic patients frequently take concomitant medications. Terbinafine and itraconazole have been investigated for the treatment of onychomycosis in diabetic patients and have been shown to have efficacy and safety profiles comparable to those in the nondiabetic population. Data from clinical trials and postmarketing surveillance suggest that drug interactions resulting in hypoglycemia may not be an important issue when itraconazole and terbinafine are used to treat diabetic patients receiving concomitant hypoglycemic medications. Patient advice and education in improved foot care are an integral part of onychomycosis management, and help achieve long-term cure and reduce the complications of diabetic foot.
31Treatment of onychomycosis in the diabetic patient population.PubMed
Jeffrey M Robbins
J Diabetes Complications. 2003 Mar-Apr;17(2):98-104. doi: 10.1016/s1056-8727(02)00199-x.
Onychomycosis is a common medical condition in patients with diabetes. Conflicting data exist as to whether diabetes predisposes patients to the disease. Controversy notwithstanding, patients with diabetes have several medical conditions (obesity, peripheral neuropathy, and retinopathy) that can inhibit the identification or mask the progression of fungal nail infections. In addition, vascular insufficiency, impaired wound healing, and compromised immunologic status associated with diabetic foot increase the risk of secondary infections in diabetic patients with onychomycosis. Such factors contribute to an increased morbidity and decreased quality of life in these patients and underscore the need for effective antifungal treatment. Oral antifungal agents are generally well tolerated, but serious adverse events independent of or associated with a number of significant drug interactions have been reported. The availability of a topical therapy, ciclopirox topical solution, 8% (Penlac Nail Lacquer), provides clinicians with an additional effective and well-tolerated treatment option. In order to further increase the efficacy of topical or oral treatment, mechanical intervention (e.g., debridement) may be combined with either of these options. Choice of appropriate treatment and careful monitoring of fungal nail infections can prevent significant morbidity in patients with diabetes.
32[Treatment of fungus infection with diabetic foot--importance of the foot care].PubMed
Takamichi Shinjo
Nihon Rinsho. 2008 Dec;66(12):2294-7.
Fungus infection is high frequently complicated of the diabetic foot. Especially onychomycosis make a injury neighbor toe skin or paronychia. This tiny lesion make a bacterial infection, and progress to foot gangrene unfortunately if patient delayed treatment. So it is important to do daily check of the foot and regularly foot care included nail care. Toenail onychomycosis need medicational treatment just after microscopically diagnosis. It is important to check the interaction between the antifungal medicine and other medicine, and side effect after started treatment.
33Emergence of Fluconazole-resistant Candida Infections in Diabetic Foot Ulcers: Implications for Public Health.PubMed
Chankramath S Arun, Priyanka Raju, Vivek Lakshmanan, et al.
Indian J Community Med. 2019 Oct;44(Suppl 1):S74-S76. doi: 10.4103/ijcm.IJCM_111_19.
BACKGROUND: It is well documented in the literature that fungal infections are common in diabetic foot ulcers (DFUs). This has led to an overuse of antifungal agents, namely fluconazole, with a consequent risk of emergence of resistance to this drug. Previous studies have shown a 3.9% prevalence of fluconazole resistance in DFU, but limited data exist regarding the change in resistance pattern over the last decade. OBJECTIVES: Our aim was to study the prevalence of resistance to fluconazole in patients with DFU and culture-proven fungal infections. MATERIALS AND METHODS: We retrospectively studied 1438 patients with type 2 diabetes and nonhealing foot ulcers who had fungal cultures performed during the course of their treatment. The data were collected for all patients who presented to our foot clinic over a period of 18 months. RESULTS: The prevalence of positive fungal culture was 17.38% (250/1438). 151/200 positive cultures belonged to species. Resistance to fluconazole was observed in 9.3% (17/200). The most common organism with resistance to fluconazole was (10/17). CONCLUSIONS: High prevalence of fluconazole resistance is a potential cause of concern, and the rational use of this drug is important in the community. The above results could have an impact on public health, as fluconazole is one of the safest and effective oral antifungal agents available. The spread of resistance could have implications for its use in other situations including systemic fungal infections.
34Clinical application of growth factors and cytokines in wound healing.PubMed
Stephan Barrientos, Harold Brem, Olivera Stojadinovic, et al.
Wound Repair Regen. 2014 Sep-Oct;22(5):569-78. doi: 10.1111/wrr.12205.
Wound healing is a complex and dynamic biological process that involves the coordinated efforts of multiple cell types and is executed and regulated by numerous growth factors and cytokines. There has been a drive in the past two decades to study the therapeutic effects of various growth factors in the clinical management of nonhealing wounds (e.g., pressure ulcers, chronic venous ulcers, diabetic foot ulcers). For this review, we conducted an online search of Medline/PubMed and critically analyzed the literature regarding the role of growth factors and cytokines in the management of these wounds. We focused on currently approved therapies, emerging therapies, and future research possibilities. In this review, we discuss four growth factors and cytokines currently being used on and off label for the healing of wounds. These include granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor. While the clinical results of using growth factors and cytokines are encouraging, many studies involved a small sample size and are disparate in measured endpoints. Therefore, further research is required to provide definitive evidence of efficacy.
35Efficacy and Safety of Biomaterials and Antimicrobial Dressings in the Treatment of Diabetic Foot Ulcers: A Systematic Review and Network Meta-Analysis.PubMed
Jing Zhang, Yanan Zhao, Ziwei Hu, et al.
J Diabetes Res. 2025 Oct 8;2025:1548984. doi: 10.1155/jdr/1548984. eCollection 2025.
This systematic review and network meta-analysis is aimed at comparing the efficacy and safety of various wound dressings in the treatment of diabetic foot ulcers, as differences in outcomes among these materials remain unclear. A comprehensive literature search was conducted across major Chinese and international databases up to October 2024, identifying 35 randomized controlled trials involving 2631 patients. Data were extracted and quality-assessed using standardized methods, and a network meta-analysis was performed using appropriate statistical software. The results showed that, compared with traditional dressings, novel biomaterials (e.g., growth factors, amniotic membrane, platelet-rich plasma, and hydrogels) and antimicrobial dressings (e.g., silver ion dressings) combined with basic fibroblast growth factor or hydrogel significantly shortened wound healing time. In terms of healing efficiency, combinations involving epidermal growth factor, amniotic membrane, or platelet-rich plasma with hydrogel were significantly more effective than traditional dressings. The surface under the cumulative ranking curve values indicated that the most effective interventions were antimicrobial dressings (silver ion) combined with basic fibroblast growth factor for wound healing time and epidermal growth factor-based regimens for healing efficiency. Importantly, sensitivity analyses excluding studies at high risk of bias (allocation/blinding) demonstrated that the ranking for ulcer healing time was unstable-attenuated for platelet-rich plasma but more favorable for honey dressings-whereas estimates for healing efficiency remained robust. These findings suggest that conclusions regarding healing time are particularly sensitive to study quality and should be interpreted with caution. No serious adverse events were reported, and most interventions were well tolerated. These findings suggest that biomaterial and antimicrobial dressings, particularly when used in combination with traditional methods, offer clear advantages in the management of diabetic foot ulcers and should be prioritized in clinical practice. CRD42024578762.
36Growth factors for treating diabetic foot ulcers.PubMed
Arturo J Martí-Carvajal, Christian Gluud, Susana Nicola, et al.
Cochrane Database Syst Rev. 2015 Oct 28;2015(10):CD008548. doi: 10.1002/14651858.CD008548.pub2.
BACKGROUND: Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks. OBJECTIVES: To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus. SEARCH METHODS: In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes. DATA COLLECTION AND ANALYSIS: Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We subjected our analyses to both fixed-effect and random-effects model analyses. MAIN RESULTS: We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I(2) = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I(2) = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I(2)= 74%, five trials).In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I(2) = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I(2) = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.
37Human umbilical cord mesenchymal stromal cells derivatives in treating diabetic foot ulcers: a phase I/II safety and efficacy trial.PubMed
Hanan Jafar, Rami Almousa, Hussam Alhawari, et al.
Stem Cell Res Ther. 2025 Nov 24;16(1):657. doi: 10.1186/s13287-025-04736-1.
Diabetic foot ulcers (DFUs) are serious and prevalent complications of diabetes mellitus, affecting up to 34% of individuals and contributing substantially to morbidity, healthcare expenditures, and the risk of non-traumatic lower limb amputations. Despite the availability of standard treatment protocols, achieving complete and sustained healing remains a significant clinical challenge. This study investigates the safety and efficacy of allogeneic human umbilical cord mesenchymal stromal cell derivatives (hUC-MSCD), including conditioned media, extracellular vesicles, and exosomes, administered via perilesional injection in patients with chronic DFUs. In this single-center, phase I/II, open-label clinical trial (NCT06825884), ten adult patients (7 males, 3 females; mean age: 52.2 years) with type 2 diabetes mellitus and chronic DFUs classified as Texas Grade II-III (mean ulcer duration: 15 weeks), refractory to standard care, were enrolled. Participants received perilesional injections of allogeneic hUC-MSCD. Safety was evaluated through the monitoring of adverse events, and efficacy was assessed by the rate and duration of ulcer closure, as well as recurrence during follow-up. The intervention was well tolerated, with no significant adverse events observed. All patients achieved complete ulcer closure within a mean of 4.2 weeks (p < 0.00001). Importantly, no ulcer recurrence was documented during a 24-month follow-up period. These results provide strong preliminary evidence that allogeneic hUC-MSCD therapy is both safe and effective in promoting wound healing in refractory DFUs. Larger, randomized, double-blind, placebo-controlled trials are warranted to validate these findings and to further define the therapeutic potential of hUC-MSCD in this population.
38Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections.PubMed
Mario Cruciani, Benjamin A Lipsky, Carlo Mengoli, et al.
Cochrane Database Syst Rev. 2013 Aug 17;2013(8):CD006810. doi: 10.1002/14651858.CD006810.pub3.
BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophil endothelial progenitor cells from the bone marrow and improves neutrophil functions, which are often impaired in people with diabetes. OBJECTIVES: To examine the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection, cure and wound healing in people with diabetes who have a foot infection. SEARCH METHODS: In March 2013, for this second update, we searched the Cochrane Wounds Group Specialised Register (searched 14 March 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2); Ovid MEDLINE (1948 to March Week 1 2013); Ovid EMBASE (1974 to 2013 March 13); Ovid MEDLINE (In-Process march 13,2013); and EBSCO CINAHL (1982 to 28 February 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the effect of adding G-CSF to usual care in people with a diabetic foot infection. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility, methodological quality and extracted data. We reported risk ratio (RR) or, for continuous outcomes, mean differences (MD), with 95% confidence intervals (CI). In the case of low or no heterogeneity we pooled studies using a fixed-effect model. MAIN RESULTS: We identified and included five eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.38; 95 % CI 0.21 to 0.70), including amputation (RR 0.41; 95 % CI 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD -1.40 days; 95% CI -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD -0.27 days; 95% CI -1.30 to 0.77 days). AUTHORS' CONCLUSIONS: The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.
39Silver-containing foam dressings with Safetac: a review of the scientific and clinical data.PubMed
Phil Davies, Sara McCarty, Kristina Hamberg
J Wound Care. 2017 Jun 1;26(Sup6a):S1-S32. doi: 10.12968/jowc.2017.26.Sup6a.S1.
Background Topical antimicrobials, such as silver dressings, are progressively being used alongside systemic antibiotics to provide adjunctive, antimicrobial therapy to wounds that are clinically infected or at risk of infection. To help improve wound management, dressings that use Safetac soft silicone technology in combination with a silver-impregnated foam dressing material were developed by Mölnlycke Health Care (Gothenburg, Sweden). The range comprises Mepilex Ag, Mepilex Border Ag and Mepilex Transfer Ag. Aims A literature review was undertaken to identify and summarise clinical data from the entire evidence hierarchy, as well as data from in vitro tests, which support the use of silver-containing foam dressings with Safetac. Method The MEDLINE (National Library of Medicine, Bethesda, US) and EMBASE (Elsevier BV, Amsterdam, Netherlands) bibliographic databases were searched. In addition, abstract books and proceedings documents relating to national and international conferences were scanned in order to identify presentations (oral, e-poster and poster) of relevance to the review. Results In vitro test results showed that the silver-containing foam dressings with Safetac have both rapid and sustained activity against a range of wound pathogens, reducing planktonic and established biofilm cultures, and preventing biofilm formation. In numerous clinical studies, silvercontaining foam dressings with Safetac were used to manage wound bioburden effectively and resolve signs of localised infection in both acute wounds (such as surgical, traumatic and burn injuries) and chronic wounds (such as leg ulcers, pressure ulcers (PUs), diabetic foot ulcers (DFUs), and cancerous wounds). Studies reported that silver-containing foam dressings with Safetac are easy to use, provide an optimal environment for wound healing, and are associated with atraumatic and virtually painfree removal. As well as being clinically effective, they are reported to be cost-effective when used on wounds that require topical antimicrobial therapy. Conclusion The findings of both scientific and clinical studies clearly indicate that clinical, patient-related and economic benefits are associated with the use of Mepilex Ag, Mepilex Border Ag and Mepilex Transfer Ag with Safetac in the treatment of wounds where antimicrobial activity is needed to help manage bioburden.
40Topical antimicrobial agents for treating foot ulcers in people with diabetes.PubMed
Jo C Dumville, Benjamin A Lipsky, Christopher Hoey, et al.
Cochrane Database Syst Rev. 2017 Jun 14;6(6):CD011038. doi: 10.1002/14651858.CD011038.pub2.
BACKGROUND: People with diabetes are at high risk for developing foot ulcers, which often become infected. These wounds, especially when infected, cause substantial morbidity. Wound treatments should aim to alleviate symptoms, promote healing, and avoid adverse outcomes, especially lower extremity amputation. Topical antimicrobial therapy has been used on diabetic foot ulcers, either as a treatment for clinically infected wounds, or to prevent infection in clinically uninfected wounds. OBJECTIVES: To evaluate the effects of treatment with topical antimicrobial agents on: the resolution of signs and symptoms of infection; the healing of infected diabetic foot ulcers; and preventing infection and improving healing in clinically uninfected diabetic foot ulcers. SEARCH METHODS: We searched the Cochrane Wounds Specialised Register, CENTRAL, Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus in August 2016. We also searched clinical trials registries for ongoing and unpublished studies, and checked reference lists to identify additional studies. We used no restrictions with respect to language, date of publication, or study setting. SELECTION CRITERIA: We included randomised controlled trials conducted in any setting (inpatient or outpatient) that evaluated topical treatment with any type of solid or liquid (e.g., cream, gel, ointment) antimicrobial agent, including antiseptics, antibiotics, and antimicrobial dressings, in people with diabetes mellitus who were diagnosed with an ulcer or open wound of the foot, whether clinically infected or uninfected. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, 'Risk of bias' assessment, and data extraction. Initial disagreements were resolved by discussion, or by including a third review author when necessary. MAIN RESULTS: We found 22 trials that met our inclusion criteria with a total of over 2310 participants (one study did not report number of participants). The included studies mostly had small numbers of participants (from 4 to 317) and relatively short follow-up periods (4 to 24 weeks). At baseline, six trials included only people with ulcers that were clinically infected; one trial included people with both infected and uninfected ulcers; two trials included people with non-infected ulcers; and the remaining 13 studies did not report infection status.Included studies employed various topical antimicrobial treatments, including antimicrobial dressings (e.g. silver, iodides), super-oxidised aqueous solutions, zinc hyaluronate, silver sulphadiazine, tretinoin, pexiganan cream, and chloramine. We performed the following five comparisons based on the included studies: Antimicrobial dressings compared with non-antimicrobial dressings: Pooled data from five trials with a total of 945 participants suggest (based on the average treatment effect from a random-effects model) that more wounds may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing: risk ratio (RR) 1.28, 95% confidence interval (CI) 1.12 to 1.45. These results correspond to an additional 119 healing events in the antimicrobial-dressing arm per 1000 participants (95% CI 51 to 191 more). We consider this low-certainty evidence (downgraded twice due to risk of bias). The evidence on adverse events or other outcomes was uncertain (very low-certainty evidence, frequently downgraded due to risk of bias and imprecision). Antimicrobial topical treatments (non dressings) compared with non-antimicrobial topical treatments (non dressings): There were four trials with a total of 132 participants in this comparison that contributed variously to the estimates of outcome data. Evidence was generally of low or very low certainty, and the 95% CIs spanned benefit and harm: proportion of wounds healed RR 2.82 (95% CI 0.56 to 14.23; 112 participants; 3 trials; very low-certainty evidence); achieving resolution of infection RR 1.16 (95% CI 0.54 to 2.51; 40 participants; 1 trial; low-certainty evidence); undergoing surgical resection RR 1.67 (95% CI 0.47 to 5.90; 40 participants; 1 trial; low-certainty evidence); and sustaining an adverse event (no events in either arm; 81 participants; 2 trials; very low-certainty evidence). Comparison of different topical antimicrobial treatments: We included eight studies with a total of 250 participants, but all of the comparisons were different and no data could be appropriately pooled. Reported outcome data were limited and we are uncertain about the relative effects of antimicrobial topical agents for each of our review outcomes for this comparison, that is wound healing, resolution of infection, surgical resection, and adverse events (all very low-certainty evidence). Topical antimicrobials compared with systemic antibiotics : We included four studies with a total of 937 participants. These studies reported no wound-healing data, and the evidence was uncertain for the relative effects on resolution of infection in infected ulcers and surgical resection (very low certainty). On average, there is probably little difference in the risk of adverse events between the compared topical antimicrobial and systemic antibiotics treatments: RR 0.91 (95% CI 0.78 to 1.06; moderate-certainty evidence - downgraded once for inconsistency). Topical antimicrobial agents compared with growth factor: We included one study with 40 participants. The only review-relevant outcome reported was number of ulcers healed, and these data were uncertain (very low-certainty evidence). AUTHORS' CONCLUSIONS: The randomised controlled trial data on the effectiveness and safety of topical antimicrobial treatments for diabetic foot ulcers is limited by the availability of relatively few, mostly small, and often poorly designed trials. Based on our systematic review and analysis of the literature, we suggest that: 1) use of an antimicrobial dressing instead of a non-antimicrobial dressing may increase the number of diabetic foot ulcers healed over a medium-term follow-up period (low-certainty evidence); and 2) there is probably little difference in the risk of adverse events related to treatment between systemic antibiotics and topical antimicrobial treatments based on the available studies (moderate-certainty evidence). For each of the other outcomes we examined there were either no reported data or the available data left us uncertain as to whether or not there were any differences between the compared treatments. Given the high, and increasing, frequency of diabetic foot wounds, we encourage investigators to undertake properly designed randomised controlled trials in this area to evaluate the effects of topical antimicrobial treatments for both the prevention and the treatment of infection in these wounds and ultimately the effects on wound healing.
41Effectiveness of silver dressings in the treatment of diabetic foot ulcers: a systematic review and meta-analysis.PubMed
YiXin Luo, Li Li, Ping Zhao, et al.
J Wound Care. 2022 Nov 2;31(11):979-986. doi: 10.12968/jowc.2022.31.11.979.
OBJECTIVE: Silver dressings have been used in the treatment of diabetic foot ulcers (DFUs). However, meta-analyses examining their effectiveness is lacking. Therefore, this meta-analysis evaluates the effectiveness of silver dressings on DFU healing. METHOD: Various databases were searched for randomised controlled trials (RCTs) of silver dressing applied to DFUs. RESULTS: A total of seven studies involving 650 patients were identified for inclusion in the meta-analysis. The odds ratio (OR) for silver dressing improving wound healing rate, complete healing time, ulcer-related in-hospital time and infection resolution rate were: 4.02 (95% confidence interval [CI]: 2.25-7.17; p<0.01); 2.81 (95% CI: -3.33--2.29; p<0.01); 12.13 (95% CI:-20.64--3.62; p<0.01); and 7.36 (95% CI: 1.58-34.22; p=0.01), respectively. The OR on ulcer area reduction was 8.60 (95% CI:-8.93-26.12; p=0.34) indicating no significant effect. CONCLUSION: The results of this meta-analysis showed that silver dressings enhance DFU healing rate, shorten the time to complete healing, shorten in-hospital duration, and improve infection resolution rate, while having no significant effect on reduction of ulcer area. Large-scale, multicentre, rigorously designed RCTs are recommended for future investigation to justify the beneficial effects of silver dressings on DFU healing.
42Current status and progress in research on dressing management for diabetic foot ulcer.PubMed
Pingnan Jiang, Qianhang Li, Yanhong Luo, et al.
Front Endocrinol (Lausanne). 2023 Aug 17;14:1221705. doi: 10.3389/fendo.2023.1221705. eCollection 2023.
Diabetic foot ulcer (DFU) is a major complication of diabetes and is associated with a high risk of lower limb amputation and mortality. During their lifetime, 19%-34% of patients with diabetes can develop DFU. It is estimated that 61% of DFU become infected and 15% of those with DFU require amputation. Furthermore, developing a DFU increases the risk of mortality by 50%-68% at 5 years, higher than some cancers. Current standard management of DFU includes surgical debridement, the use of topical dressings and wound decompression, vascular assessment, and glycemic control. Among these methods, local treatment with dressings builds a protective physical barrier, maintains a moist environment, and drains the exudate from DFU wounds. This review summarizes the development, pathophysiology, and healing mechanisms of DFU. The latest research progress and the main application of dressings in laboratory and clinical stage are also summarized. The dressings discussed in this review include traditional dressings (gauze, oil yarn, traditional Chinese medicine, and others), basic dressings (hydrogel, hydrocolloid, sponge, foam, film agents, and others), bacteriostatic dressings, composite dressings (collagen, nanomaterials, chitosan dressings, and others), bioactive dressings (scaffold dressings with stem cells, decellularized wound matrix, autologous platelet enrichment plasma, and others), and dressings that use modern technology (3D bioprinting, photothermal effects, bioelectric dressings, microneedle dressings, smart bandages, orthopedic prosthetics and regenerative medicine). The dressing management challenges and limitations are also summarized. The purpose of this review is to help readers understand the pathogenesis and healing mechanism of DFU, help physicians select dressings correctly, provide an updated overview of the potential of biomaterials and devices and their application in DFU management, and provide ideas for further exploration and development of dressings. Proper use of dressings can promote DFU healing, reduce the cost of treating DFU, and reduce patient pain.
43Effectiveness of different advanced wound dressings versus standard of care for the management of diabetic foot ulcers: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.PubMed
Matteo Monami, Benedetta Ragghianti, Alessia Scatena, et al.
Acta Diabetol. 2024 Dec;61(12):1517-1526. doi: 10.1007/s00592-024-02320-2. Epub 2024 Jun 12.
AIM: to assess the effects of advanced wound dressings (AWD) commonly used in the treatment of predominantly neuropathic diabetic foot ulcers (DFU) The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). METHODS: A Medline and Embase search were performed up to April 1st, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with DFU comparing AWD with placebo/standard of care (SoC), with a duration of at least 12 weeks. Prespecified endpoints were: ulcer healing (principal), time-to-healing, frequency of dressings change, major and minor amputation, pain, and all-cause mortality. AWD assessed were: alginates; foam, hydrocolloids, hydrogels, hyaluronic acid, hemoglobin spray, silver-impregnated, sucrose octasulfate-impregnated, honey-impregnated, micro-organism-binding, and protease-modulating matrix dressings. Mantel-Haenzel Odds ratios and 95% confidence intervals (MH-OR, 95% CIs) were either calculated or extracted directly from the publications. Weighted mean differences (WMD) and 95% CIs were calculated for continuous variables. RESULTS: Fifteen studies fulfilled all inclusion criteria. Participants treated with AWD had a significantly higher ulcer healing rate and shorter time-to-healing in comparison with SoC/placebo (MH-OR 1.50 [0.80, 2.79], p = 0.20 and WMD:: - 24.38 [- 42.90, - 5.86] days, p = 0.010). No other significant effect on the above reported prespecified endpoints were observed. For the primary endpoint, the quality of evidence was rated as "moderate". CONCLUSIONS: In conclusion, AWD, particularly sucrose-octasulfate, hydrogels, hyaluronic acid, and honey dressings, can actively promote wound healing and shortening time-to-healing in patients with DFU.
44Improvement of diabetic wound healing by topical application of Vicenin-2 hydrocolloid film on Sprague Dawley rats.PubMed
Woan Sean Tan, Palanisamy Arulselvan, Shiow-Fern Ng, et al.
BMC Complement Altern Med. 2019 Jan 17;19(1):20. doi: 10.1186/s12906-018-2427-y.
BACKGROUND: Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. The risk of developing diabetic foot ulcers for diabetic patients is 15% over their lifetime and approximately 85% of limb amputations is caused by non-healing ulcers. Unhealed, gangrenous wounds destroy the structural integrity of the skin, which acts as a protective barrier that prevents the invasion of external noxious agents into the body. Vicenin-2 (VCN-2) has been reported to contain prospective anti-oxidant and anti-inflammatory properties that enhance cell proliferation and migration. Sodium Alginate (SA) is a natural polysaccharide that possesses gel forming properties and has biodegradable and biocompatible characteristics. Therefore, the objective of this study is to evaluate the effect of SA wound dressings containing VCN-2 on diabetic wounds. METHODS: Wounds were inflicted in type-1 diabetic-streptozotocin (STZ) induced male Sprague Dawley rats. Subsequently, relevant groups were topically treated with the indicated concentrations (12.5, 25 and 50 μM) of VCN-2 hydrocolloid film over the study duration (14 days). The control group was treated with vehicle dressing (blank or allantoin). Wounded tissues and blood serum were collected on 0, 7 and 14 days prior to sacrifice. Appropriate wound assessments such as histological tests, nitric oxide assays, enzyme-linked immunosorbent assays (ELISA) and immunoblotting assays were conducted to confirm wound healing efficacy in the in vivo model. One-way Analysis of Variance (ANOVA) was used for statistical analysis. RESULTS: Results showed that hydrocolloid film was recapitulated with VCN-2 enhanced diabetic wound healing in a dose-dependent manner. VCN-2 reduced pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), mediators (iNOS and COX-2), and nitric oxide (NO) via the NF-κB pathway. Data suggests that the VCN-2 film facilitated healing in hyperglycemic conditions by releasing growth factors such as (VEGF and TGF-β) to enhance cell proliferation, migration, and wound contraction via the VEGF and TGF-β mechanism pathways. CONCLUSIONS: This study's findings suggest that VCN-2 may possess wound healing potential since topical treatment with VCN-2 hydrocolloid films effectively enhanced wound healing in hyperglycemic conditions.
45Biological characterization of dehydrated amniotic membrane allograft: Mechanisms of action and implications for wound care.PubMed
Marc C Moore, Paul P Bonvallet, Sita M Damaraju, et al.
J Biomed Mater Res B Appl Biomater. 2020 Nov;108(8):3076-3083. doi: 10.1002/jbm.b.34635. Epub 2020 May 26.
There is a growing clinical demand in the wound care market to treat chronic wounds such as diabetic foot ulcers. Advanced cell and tissue-based products (CTPs) are often used to address challenging chronic wounds where healing has stalled. These products contain active biologics such as growth factors and cytokines as well as structural components that support and stimulate cell growth and assist in tissue regeneration. This study addresses the in vitro biologic effects of a clinically available dehydrated amniotic membrane allograft (DAMA). The broad mechanism of action results from DAMA's biologic composition that leads to stimulation of cell migration cell proliferation, and reduction of pro-inflammatory cytokines. Results show that DAMA possesses growth factors and cytokines such as EGF, FGF, PDGFs, VEGF, TGF-β, IL-8, and TIMPs 1 and 2. Furthermore, in vitro experiments demonstrate that DAMA stimulates cell proliferation, cell migration, secretion of collagen type I, and the reduction of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. This study findings are consistent with the clinical benefits previously published for DAMA and other CTPs in chronic wounds suggesting that the introduction of DAMA to non-healing, complex wounds helps to improve the wound milieu by providing essential structural components, cytokines, and growth factors to create an appropriate environment for wound healing.
46Mesenchymal stem cells from perinatal tissues promote diabetic wound healing via PI3K/AKT activation.PubMed
Jiawei Huang, Qingwen Deng, Lai Ling Tsang, et al.
Stem Cell Res Ther. 2025 Feb 8;16(1):59. doi: 10.1186/s13287-025-04141-8.
BACKGROUND: Diabetic foot ulcers (DFUs) represent a major complication of diabetes, often leading to poor healing outcomes with conventional treatments. Mesenchymal stem cell (MSC) therapies have emerged as a promising alternative, given their potential to modulate various pathways involved in wound healing. This study evaluates and compares the therapeutic potential of MSCs derived from perinatal tissues-human umbilical cord MSCs (hUCMSCs), human chorionic villi MSCs (hCVMSCs), and human decidua basalis MSCs (hDCMSCs)-in a diabetic wound healing model. METHODS: We performed in vitro and in vivo studies to compare the efficacy of hUCMSCs, hCVMSCs, and hDCMSCs. Mass spectrometry was used to analyze the secreted proteins of the MSCs. We incorporated the MSCs into a polyethylene glycol diacrylate (PEGDA) and sodium alginate (SA) hydrogel matrix with collagen I (Col-I) to evaluate their effects on wound healing. RESULTS: All three types of MSCs promoted wound healing, with hUCMSCs and hCVMSCs showing stronger effects compared to hDCMSCs. Both hUCMSCs and hCVMSCs demonstrated robust wound healing kinetics, with enhanced keratinocyte proliferation (KRT14/Ki67 cells), maturation (KRT10/KRT14 ratio), and angiogenesis. In vitro studies demonstrated that the MSC-derived secretome enhanced keratinocyte proliferation and migration, endothelial cell function and stem cell recruitment, indicating robust paracrine effects. Mass spectrometry revealed a conserved set of proteins including THBS1 (thrombospondin 1), SERPINE1 (serpin family E member 1), ANXA1 (annexin A1), LOX (lysyl oxidase), and ITGB1 (integrin beta-1) which are involved in extracellular matrix (ECM) organization and wound healing, with the PI3K/AKT signaling pathway playing a central role. The PEGDA/SA/Col-I hydrogel demonstrated a unique balance of mechanical and biological properties and an optimal environment for MSC viability and function. Application of either hUCMSC- or hCVMSC-laden hydrogels resulted in accelerated wound closure, improved re-epithelialization, increased collagen deposition, and enhanced vascularization in vivo. CONCLUSIONS: MSCs From perinatal tissues particularly hUCMSCs and hCVMSCs significantly enhance diabetic wound healing through PI3K/AKT pathway activation while hDCMSCs exhibited weaker efficacy. The PEGDA/SA/Col-I hydrogel supports MSC viability and function offering a promising scaffold for DFU treatment. These findings underscore the potential of specific perinatal MSCs and optimized hydrogel formulations in advancing diabetic wound care.
47Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus.PubMed
Zhenmi Liu, Jo C Dumville, Robert J Hinchliffe, et al.
Cochrane Database Syst Rev. 2018 Oct 17;10(10):CD010318. doi: 10.1002/14651858.CD010318.pub3.
BACKGROUND: Foot wounds in people with diabetes mellitus (DM) are a common and serious global health issue. People with DM are prone to developing foot ulcers and, if these do not heal, they may also undergo foot amputation surgery resulting in postoperative wounds. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care. NPWT involves the application of a wound dressing attached to a vacuum suction machine. A carefully controlled negative pressure (or vacuum) sucks wound and tissue fluid away from the treated area into a canister. A clear and current overview of current evidence is required to facilitate decision-making regarding its use. OBJECTIVES: To assess the effects of negative pressure wound therapy compared with standard care or other therapies in the treatment of foot wounds in people with DM in any care setting. SEARCH METHODS: In January 2018, for this first update of this review, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies, reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. We identified six additional studies for inclusion in the review. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that evaluated the effects of any brand of NPWT in the treatment of foot wounds in people with DM, irrespective of date or language of publication. Particular effort was made to identify unpublished studies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. Initial disagreements were resolved by discussion, or by including a third review author when necessary. We presented and analysed data separately for foot ulcers and postoperative wounds. MAIN RESULTS: Eleven RCTs (972 participants) met the inclusion criteria. Study sample sizes ranged from 15 to 341 participants. One study had three arms, which were all included in the review. The remaining 10 studies had two arms. Two studies focused on postamputation wounds and all other studies included foot ulcers in people with DM. Ten studies compared NPWT with dressings; and one study compared NPWT delivered at 75 mmHg with NPWT delivered at 125 mmHg. Our primary outcome measures were the number of wounds healed and time to wound healing.NPWT compared with dressings for postoperative woundsTwo studies (292 participants) compared NPWT with moist wound dressings in postoperative wounds (postamputation wounds). Only one study specified a follow-up time, which was 16 weeks. This study (162 participants) reported an increased number of healed wounds in the NPWT group compared with the dressings group (risk ratio (RR) 1.44, 95% confidence interval (CI) 1.03 to 2.01; low-certainty evidence, downgraded for risk of bias and imprecision). This study also reported that median time to healing was 21 days shorter with NPWT compared with moist dressings (hazard ratio (HR) calculated by review authors 1.91, 95% CI 1.21 to 2.99; low-certainty evidence, downgraded for risk of bias and imprecision). Data from the two studies suggest that it is uncertain whether there is a difference between groups in amputation risk (RR 0.38, 95% CI 0.14 to 1.02; 292 participants; very low-certainty evidence, downgraded once for risk of bias and twice for imprecision).NPWT compared with dressings for foot ulcersThere were eight studies (640 participants) in this analysis and follow-up times varied between studies. Six studies (513 participants) reported the proportion of wounds healed and data could be pooled for five studies. Pooled data (486 participants) suggest that NPWT may increase the number of healed wounds compared with dressings (RR 1.40, 95% CI 1.14 to 1.72; I² = 0%; low-certainty evidence, downgraded once for risk of bias and once for imprecision). Three studies assessed time to healing, but only one study reported usable data. This study reported that NPWT reduced the time to healing compared with dressings (hazard ratio (HR) calculated by review authors 1.82, 95% CI 1.27 to 2.60; 341 participants; low-certainty evidence, downgraded once for risk of bias and once for imprecision).Data from three studies (441 participants) suggest that people allocated to NPWT may be at reduced risk of amputation compared with people allocated to dressings (RR 0.33, 95% CI 0.15 to 0.70; I² = 0%; low-certainty evidence; downgraded once for risk of bias and once for imprecision).Low-pressure compared with high-pressure NPWT for foot ulcersOne study (40 participants) compared NPWT 75 mmHg and NPWT 125 mmHg. Follow-up time was four weeks. There were no data on primary outcomes. There was no clear difference in the number of wounds closed or covered with surgery between groups (RR 0.83, 95% CI 0.47 to 1.47; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision) and adverse events (RR 1.50, 95% CI 0.28 to 8.04; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision). AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that NPWT, when compared with wound dressings, may increase the proportion of wounds healed and reduce the time to healing for postoperative foot wounds and ulcers of the foot in people with DM. For the comparisons of different pressures of NPWT for treating foot ulcers in people with DM, it is uncertain whether there is a difference in the number of wounds closed or covered with surgery, and adverse events. None of the included studies provided evidence on time to closure or coverage surgery, health-related quality of life or cost-effectiveness. The limitations in current RCT evidence suggest that further trials are required to reduce uncertainty around decision-making regarding the use of NPWT to treat foot wounds in people with DM.
48Polysaccharide-Based Hydrogels for Wound Dressing: Design Considerations and Clinical Applications.PubMed
Rongwei Cui, Luhan Zhang, Rongying Ou, et al.
Front Bioeng Biotechnol. 2022 Mar 7;10:845735. doi: 10.3389/fbioe.2022.845735. eCollection 2022.
Wound management remains a worldwide challenge. It is undeniable that patients with problems such as difficulties in wound healing, metabolic disorder of the wound microenvironment and even severely infected wounds always suffer great pain that affected their quality of lives. The selection of appropriate wound dressings is vital for the healing process. With the advances of technology, hydrogels dressings have been showing great potentials for the treatment of both acute wounds (e.g., burn injuries, hemorrhage, rupturing of internal organs/aorta) and chronic wounds such as diabetic foot and pressure ulcer. Particularly, in the past decade, polysaccharide-based hydrogels which are made up with abundant and reproducible natural materials that are biocompatible and biodegradable present unique features and huge flexibilities for modifications as wound dressings and are widely applicable in clinical practices. They share not only common characteristics of hydrogels such as excellent tissue adhesion, swelling, water absorption, , but also other properties ( anti-inflammatory, bactericidal and immune regulation), to accelerate wound re-epithelialization, mimic skin structure and induce skin regeneration. Herein, in this review, we highlighted the importance of tailoring the physicochemical performance and biological functions of polysaccharide-based hydrogel wound dressings. We also summarized and discussed their clinical states of, aiming to provide valuable hints and references for the future development of more intelligent and multifunctional wound dressings of polysaccharide hydrogels.
49Thermosensitive Hydrogel Incorporating Prussian Blue Nanoparticles Promotes Diabetic Wound Healing via ROS Scavenging and Mitochondrial Function Restoration.PubMed
Zhao Xu, Yujing Liu, Rui Ma, et al.
ACS Appl Mater Interfaces. 2022 Mar 30;14(12):14059-14071. doi: 10.1021/acsami.1c24569. Epub 2022 Mar 17.
Diabetic foot ulcer is a serious complication in diabetes patients, imposing a serious physical and economic burden to patients and to the healthcare system as a whole. Oxidative stress is thought to be a key driver of the pathogenesis of such ulcers. However, no antioxidant drugs have received clinical approval to date, underscoring the need for the further development of such medications. Hydrogels can be applied directly to the wound site, wherein they function to prevent infection and maintain local moisture concentrations, in addition to serving as a reservoir for the delivery of a range of therapeutic compounds with the potential to expedite wound healing in a synergistic manner. Herein, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging reactive oxygen species (ROS) owing to their ability to mimic the activity of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). In the context of in vitro oxidative stress, these PBNPs were able to protect against cytotoxicity, protect mitochondria from oxidative stress-related damage, and restore nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activity. To expand on these results in an in vivo context, we prepared a thermosensitive poly (d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) hydrogel (PLEL)-based wound dressing in which PBNPs had been homogenously incorporated, and we then used this dressing as a platform for controlled PBNP release. The resultant PBNPs@PLEL wound dressing was able to improve diabetic wound healing, decrease ROS production, promote angiogenesis, and reduce pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels within diabetic wounds. Overall, our results suggest that this PBNPs@PLEL platform holds great promise as a treatment for diabetic foot ulcers.
50Dynamic Hyaluronic Acid Hydrogels for Comprehensively Regulating Inflammation, Angiogenesis, and Metabolism to Effectively Proheal Diabetic Wounds.PubMed
Yanzheng Chen, Qing Wang, Fangrui Ning, et al.
ACS Appl Mater Interfaces. 2024 Dec 25;16(51):70256-70273. doi: 10.1021/acsami.4c15674. Epub 2024 Dec 13.
Despite the great progress of various multifunctional wound dressings, it is challenging to simultaneously achieve complete healing and functional remodeling for diabetic foot ulcers and refractory chronic wounds. Aiming to comprehensively regulate chronic inflammation, angiogenesis, and metabolism processes, herein, a novel kind of dynamic hyaluronic acid (HA) hydrogel was designed by combining boronate and coordination chemistry. Besides having injectability, self-healing, and detachment properties, dynamic HA hydrogels presented diabetic wound-responsive degradation and controllable HS release. They could efficiently polarize M1-to-M2 polarization and regulate inflammatory cytokine secretion and multiple inflammation-related mRNA expressions through cooperative actions of reactive oxygen species elimination + HS release + Zn regulation, thus driving chronic inflammation into the proliferation and remodeling stages. Moreover, the screened lead hydrogel HTZS could regulate angiogenesis-related signaling pathways and metabolism processes to promote neovascularization and mature vessel formation, re-epithelization, high-level collagen-I deposition, and dense hair follicle regeneration, achieving complete healing and functional remodeling in diabetic wounds. Importantly, this work opens a new avenue to design dynamic biopolymer hydrogels for high-performance wound dressing and decipher the key role of multiple orchestrated regulations of inflammation-angiogenesis-metabolism on complete healing and functional remodeling in chronic and diabetic wounds.
51Immunomodulatory hydrogel loaded with PD-L1-expressing exosomes reprograms macrophages and accelerates diabetic wound healing.PubMed
Mingzhu Zhai, Hongxi Tan, Aohong Xu, et al.
Biomater Adv. 2025 Nov;176:214362. doi: 10.1016/j.bioadv.2025.214362. Epub 2025 May 27.
Diabetic foot ulcers (DFU), a severe complication of diabetes mellitus, present a global healthcare challenge due to high risks of limb amputation and mortality. This study developed a multifunctional hydrogel dressing, Gelatin Methacryloyl (GelMA) hydrogel loaded with interleukin-4 (IL-4)-engineered exosomes (Exos), designed to synergistically modulate immune responses and enhance angiogenesis for complete diabetic wound repair. The programmed death-ligand 1 (PD-L1)-enriched Exos were engineered via IL-4 overexpression in NIH3T3 fibroblasts. The GelMA hydrogel loaded NIH3T3 fibroblast-derived Exos with IL-4 overexpression (GelMA/Exos hydrogel) exhibited favorable physicochemical characteristics, including a three-dimensional porous microstructure, injectability, tissue adhesion, self-healing properties, and sustained moisture retention. In vitro evaluation demonstrated biocompatibility, sustained exosome release, and enhanced viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In a diabetic wound model, the hydrogel significantly accelerated wound closure, promoted re-epithelialization and angiogenesis, and skewed macrophages toward anti-inflammatory M2 polarization while suppressing T-cell proliferation. These findings highlight the dual immunomodulatory and pro-angiogenic efficacy of GelMA/Exos hydrogel, offering a promising therapeutic strategy for chronic wound management.
52Electrospun nanofibers as a wound dressing for treating diabetic foot ulcer.PubMed
Yan Liu, Shiya Zhou, Yanlin Gao, et al.
Asian J Pharm Sci. 2019 Mar;14(2):130-143. doi: 10.1016/j.ajps.2018.04.004. Epub 2018 May 10.
Diabetes is one of the most prevalent diseases in the world with high-mortality and complex complications including diabetic foot ulcer (DFU). It has been reported that the difficulties in repairing the wound related to DFU has much relationship with the wound infection, change of inflammatory responses, lack of extracellular matrix (ECM), and the failure of angiogenesis. Following the development of medical materials and pharmaceutical technology, nanofibers has been developed by electrospinning with huge porosity, excellent humidity absorption, a better oxygen exchange rate, and some antibacterial activities. That is to say, as a potential material, nanofibers must be a wonderful candidate for the DFU treatment with so many benefits. Careful selection of polymers from natural resource and synthetic resource can widen the nanofibrous application. Popular methods applied for the nanofibrous fabrication consist of uniaxial electrospinning and coaxial electrospinning. Furthermore, nanofibers loading chemical, biochemical active pharmaceutical ingredient (API) or even stem cells can be wonderful dosage forms for the treatment of DFU. This review summarizes the present techniques applied in the fabrication of nanofibrous dressing (ND) that utilizes a variety of materials and active agents to offer a better health care for the patients suffering from DFU.
53The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing.PubMed
Xin Zhou, Yanling Guo, Kun Yang, et al.
J Ethnopharmacol. 2022 Jan 10;282:114662. doi: 10.1016/j.jep.2021.114662. Epub 2021 Sep 20.
ETHNOPHARMACOLOGICAL RELEVANCE: The diabetic wound is one of the common chronic complications of diabetes, which seriously affects patients' quality of life and even causes disability and death. Traditional Chinese medicine (TCM) is a unique and precious resource in China, which has a good curative effect and safety. At present, it has been found that Chinese herbal compounds and effective active ingredients can effectively promote diabetic wound healing, and its mechanism needs to be further studied. Signaling pathways are involved in the pathogenesis and progression of diabetic wounds, which is one of the main targets for the pathologic mechanism of diabetic wounds and the pharmacological research of therapeutic drugs. AIM OF THE REVIEW: This study has been carried out to reveal the classical signaling pathways and potential targets by the action of TCM on diabetic wound healing and provides evidence for its clinical efficacy. MATERIALS AND METHODS: "diabetic wound", "diabetic foot ulcer", "traditional Chinese medicine", "natural plant" and "medicinal plant", were selected as the main keywords, and various online search engines, such as PubMed, Web of Science, CNKI and other publication resources, were used for searching literature. RESULTS: The results showed that TCM could regulate the signaling pathways to promote diabetic wound healing, such as Wnt, Nrf2/ARE, MAPK, PI3K/Akt, NF-κB, Notch, TGF-β/Smad, HIF-1α/VEGF, which maintaining inflammatory interaction balance, inhibiting oxidative stress and regulating abnormal glucose metabolism. CONCLUSION: The effect of TCM on diabetic wound healing was reflected in multiple levels and multiple pathways. It is envisaged to carry out further research from precision-targeted therapy, provide ideas for screening the core target of TCM in treating diabetic wounds and create modern innovative drugs based on this target.
54Sanguisorba officinalis L. promotes diabetic wound healing in rats through inflammation response mediated by macrophage.PubMed
Jianying Song, Jing Zeng, Silin Zheng, et al.
Phytother Res. 2023 Sep;37(9):4265-4281. doi: 10.1002/ptr.7906. Epub 2023 Jun 1.
Sanguisorba officinalis L., a traditional Chinese medicine, is frequently used to treat burns and scalds. But even so, it is unknown whether S. officinalis L. can accelerate diabetic wounds (DW) healing. Here, to bridge the gap, we employed in vivo and in vitro evaluations to assess the positive effect of S. officinalis L. ethanol extract (ESO) on DW. Results demonstrated that ESO dramatically improved the DW healing rate. With ESO treatment, the inappropriately elevated levels of IL6, IL1β and TNFα in DW were reduced, while the expression of IL10 was increased, indicating that the abnormal inflammation in DW was also under control. Moreover, the abnormally elevated expression of CD86 was significantly inhibited and the expression of CD206 was significantly up-regulated following treatment with ESO. The global level of NF-κB protein was not affected by ESO treatment, but it suppressed the expression of phosphorylated NF-κB and prevented its nuclear entry. In addition, in RAW264.7 cells activated with lipopolysaccharide (LPS), the expression of NLRP3, Caspase1 and IL1β were significantly diminished following ESO treatment. In conclusion, ESO was proved to be a promising treatment for DW healing due to its potential to accelerate the healing process by suppressing the inflammatory response. This was achieved by increasing the ratio of M2 to M1 polarization through blocking the NF-κB/NLRP3 signaling pathway.
55ceAF Ameliorates Diabetic Wound Healing by Alleviating Inflammation and Oxidative Stress via TLR4/NF-B and Nrf2 Pathways.PubMed
Shiyan Li, Xiaofeng Ding, Xin Yan, et al.
J Diabetes Res. 2023 Apr 5;2023:2422303. doi: 10.1155/2023/2422303. eCollection 2023.
BACKGROUND: With the rise in diabetes incidence, diabetic foot ulcers have become the most common clinically chronic refractory wounds. Persistent chronic inflammation is a typical feature of diabetic cutaneous wounds, and diabetic wound healing can be improved by alleviating inflammation and oxidative stress. Chick early amniotic fluids (ceAF) consist of native conglutinant substances with balanced amounts of growth factors, cytokines, and chemokines. However, whether ceAF modulates inflammation and oxidative stress and thus promotes diabetic wound healing remains unknown. MATERIALS AND METHODS: RAW264.7 cells were categorized into four groups: negative control, LPS, LPS + ceAF, and ceAF. 10% of ceAF was selected to treat different groups of mice with a full-thickness skin defect wound. Then, RT-qPCR, western blot, immunofluorescence, and other assays were carried out to explore the effect of ceAF on wound healing and its molecular mechanism. RESULTS: Topical administration of ceAF improved M2 macrophage polarization and inflammatory response in the wound tissues, thereby ameliorating delayed wound healing. Histological improvement could be observed in the grade of inflammation, collagen deposition, and neovascularization in wound edge tissues. ceAF also increased M2 macrophage-specific markers expression and exogenous ceAF suppressed LPS-induced cellular inflammatory response high glucose environment. Additionally, ceAF could activate TLR4/NF-B and Nrf2 signal transductions to promote M2 macrophage polarization . CONCLUSIONS: In summary, ceAF downregulates inflammatory response, regulates M2 macrophage transition via TLR4/NF-B and Nrf2 signaling pathways, and thus improves diabetic wound healing.
56Calomelas and its preparations: Paradigms of traditional Chinese external medicine.PubMed
Qingxia Gan, Jingjing Yang, Lu Yang, et al.
J Ethnopharmacol. 2026 Feb 10;356:120814. doi: 10.1016/j.jep.2025.120814. Epub 2025 Oct 26.
ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Calomelas and its preparations have been employed in traditional Chinese medicine (TCM) for the management of scabies and ulcers, exhibiting empirically validated efficacy in wound management protocols, with persistent contemporary utilization. Nevertheless, significant concerns regarding its mercury composition have prompted modern scrutiny. Crucially, a rigorous systematic evaluation of Calomelas and its preparations was still lacking in the existing literature, which hindered their evidence-based application and potential advancement. AIM OF THE REVIEW: This review aims to clarify the medicinal benefits and toxicity of Calomelas and its preparations, supporting the development of modern treatments for refractory skin ulcers while promoting the safe and rational integration of Calomelas-containing preparations into dermatological practice. MATERIALS AND METHODS: Data on Calomelas and its preparations were systematically collated from scientific databases, including PubMed, Google Scholar, ACS Publications, Web of Science, ScienceDirect, CNKI, and WANGFANG. RESULTS: Calomelas, a mercury-based compound utilized in TCM since the Tang dynasty, has exhibited pronounced therapeutic efficacy in the management of various refractory wound conditions. Several Calomelas-containing preparations, such as Shengji Yuhong Ointment, Babao Pill, Baodu Shengji Powder, Taiyi Ointment, and Calomelas Powder, are routinely utilized in clinical practice for the treatment of diverse skin ulcers and stubborn wounds, including diabetic foot ulcers, postoperative impairments, pressure injuries, and burn wounds. The pharmacological basis of these therapeutic effects relies on their biological activity properties, including antibacterial, anti-inflammatory, antioxidant, pro-angiogenic, and pro-gliogenic activities. Despite ongoing safety concerns related to the inherent toxicity of mercury, Calomelas and its preparations exhibited an acceptable safety profile when administered in accordance with established clinical protocols. CONCLUSION: Calomelas and its preparations are supported by clinical validation and modern pharmacological research, confirming their definite therapeutic efficacy and controllable safety profile. These findings highlight their significant clinical value and broad application prospects in the surgical practice of TCM.
57Immunomodulatory mechanisms and comprehensive treatment strategies of traditional Chinese medicine for enhancing diabetic foot ulcer healing.PubMed
Yunxi Fu, Zhennian Gou, Jinting Xi, et al.
Int Immunopharmacol. 2025 Oct 30;164:115381. doi: 10.1016/j.intimp.2025.115381. Epub 2025 Aug 27.
Diabetic foot ulcer (DFU) is one of the most common chronic complications in patients with diabetes, primarily resulting from immune dysfunction, peripheral neuropathy, and vascular impairment associated with prolonged hyperglycemia. DFU compromises skin integrity and may progress to severe infection, limb disability, or even death, posing a substantial burden on patients' quality of life. Traditional Chinese medicine (TCM), a distinctive component of China's healthcare system, includes botanicals such as Astragalus and Salvia, which have demonstrated anti-inflammatory and wound-healing effects in clinical studies. With the advancement of modern biomedical techniques, the integration of TCM and Western medicine has emerged as an effective therapeutic strategy for DFU. This review summarizes the anti-inflammatory and immunomodulatory properties of various TCM compounds and formulations relevant to DFU management, highlights the therapeutic benefits of integrated treatment approaches, and proposes directions for future research.
58Wet healing and Chinese medicine cupping can be used to form collateral circulation in diabetic foot artery occlusion: a case report.PubMed
Shengmei Wu, Qianqian Peng, Chunlei Tian, et al.
Front Endocrinol (Lausanne). 2025 Sep 12;16:1583647. doi: 10.3389/fendo.2025.1583647. eCollection 2025.
This report describes a diabetic patient with a left little toe ulcer who was treated with Wet healing combined with traditional Chinese cupping. This approach successfully improved local blood circulation and facilitated wound healing. This treatment modality provides a new perspective for the comprehensive management of diabetic foot ulcers.
59Case Report: Integrated traditional Chinese and Western medicine in the outpatient management of diabetic foot gangrene complicating uremia.PubMed
Can Hu, Jian Chen
Front Endocrinol (Lausanne). 2025 Aug 27;16:1638086. doi: 10.3389/fendo.2025.1638086. eCollection 2025.
Diabetic foot gangrene (DFG) in uremic patients presents profound management challenges due to immune dysfunction and impaired tissue repair. We report on a 65-year-old male patient with end-stage renal disease undergoing peritoneal dialysis, presenting with progressive right foot gangrene that was unresponsive to conventional treatment. Clinical evaluation indicated extensive gangrene affecting the first and second toes, elevated inflammatory markers (C-reactive protein at 95.57 mg/L and fibrinogen at 8.18 g/L), and cardiovascular compromise (brain natriuretic peptide at 4869 pg/mL). Lower limb computed tomography angiography confirmed severe atherosclerosis. An integrated protocol combining Yanghe Sijunzi Decoction with meticulous debridement and localized analgesia was implemented over 7 months (18 outpatient visits). This approach resulted in complete ulcer healing by October 2024, with the resolution of gangrene, an 87% reduction in CRP levels (to 12 mg/L), normalization of coagulation markers, and preservation of foot function-thus preventing amputation. Patient-reported outcomes, including pain scores and sleep duration gradually improved as healing advanced from 23 March 2024. The total treatment costs amounted to 25,000 CNY, with the patient's share being 5,000 CNY, demonstrating cost-efficiency. This case highlights Traditional Chinese Medicine's potential as an immunomodulatory adjuvant in uremia-associated DFG, modulating inflammation and promoting tissue regeneration in high-risk patients.
60An effective treatment for diabetic foot necrosis with traditional Chinese and Western medicine: a case report.PubMed
Xinyu Liang, Yongcheng Xu, Yaxu Zhang, et al.
J Wound Care. 2024 Jan 2;33(1):22-27. doi: 10.12968/jowc.2024.33.1.22.
Patients with diabetes who undergo a kidney transplant are at a great risk of undergoing amputations, usually associated with severe infection and necrosis. The treatment of severe diabetic foot necrosis is challenging in clinic, and the function of the limb is often hugely compromised. A 74-year-old male who had been diagnosed with severe post-renal transplant diabetic foot necrosis refused the option of below-knee amputation from previous surgeons, and requested to keep his left foot. The patient was treated with integrated traditional Chinese medicine (TCM) and Western medicine, with positive results. TCM therapeutic principles included 'clearing heat, removing toxicity, regulating Qi, resolving dampness, activating stagnant blood and nourishing yin as well as tonifying Qi and blood'. Treatment with Western medicine included wound debridement, internal fixation or joint fusion, and use of insulin, antibiotics and vasodilators. The patient was treated with a staged and diverse approach (i.e., a combination of TCM and Western medicine, surgical management and education for diabetic foot care), which ultimately helped the patient achieve limb salvage and regain normal function. A combination therapy of Western medicine and TCM may be a promising approach to heal diabetic foot ulcers.
61Integrated treatment utilizing both Chinese and Western medicine for refractory diabetic foot ulcers: a case report.PubMed
Luyao Wang, Changting Sheng, Jiaxin Liu, et al.
Front Endocrinol (Lausanne). 2025 Nov 5;16:1704770. doi: 10.3389/fendo.2025.1704770. eCollection 2025.
Diabetic foot ulcer (DFU) is a severe complication of diabetes associated with a high risk of amputation and long-term disability. We report the case of a 57-year-old man with a Wagner grade IV DFU whose condition continued to deteriorate despite two toe amputations. An integrative treatment strategy combining traditional Chinese medicine (TCM) and western medicine was subsequently employed and proved effective. The TCM regimen included oral decoctions and topical herbal applications, while the western medical approach encompassed targeted therapies including glycemic control, anti-infective therapy, circulatory enhancement, anticoagulation, neurotrophic support, and nutritional management. Over a 144-day course, the ulcer demonstrated near-complete closure at discharge, with full epithelialization and functional recovery confirmed at follow-up. HbA1c decreased from 13.5% to 7.0%, indicating improved metabolic control. This case illustrates that an integrative management strategy can effectively control infection, promote tissue regeneration, and restore limb function in advanced DFU.
62A case report of an effective treatment for diabetic foot ulcers with integration of traditional Chinese medicine and Western medicine.PubMed
Xi-Sheng Xie, Yu-Jao Wang, Chuan Zuo, et al.
J Diabetes Complications. 2009 Sep-Oct;23(5):360-4. doi: 10.1016/j.jdiacomp.2008.05.002. Epub 2008 Jul 3.
Diabetes contributes 75-85% of the factors predisposing to foot amputations, usually in association with infection and gangrene. The treatment of foot ulcers is expensive, and the effectiveness of treatment varies. We report herein a case of a diabetic foot ulcer that was treated with integrated traditional Chinese and Western medicine, with desirable cost-effective results. Traditional Chinese medicine (TCM) therapeutic principles include improving the spleen, nourishing yin, regulating qi, and resolving dampness, as well as activating stagnant blood. Western medicine includes wound debridement, skin grafting, and use of insulin, antibiotics, and vasodilators. The patient was treated with a holistic multidisciplinary approach (i.e., a combination of TCM and Western medicine, surgical management, education for diabetic foot care, and psychological counseling). Without this approach, the patient might have ended up with foot amputation and/or sepsis.
63Treatment of diabetic foot ulcers with external application of Chinese herbal medicine: An overview of overlapping systematic reviews.PubMed
Xiaolun Liang, Yuge Xia, Zhirui Xu, et al.
Int Wound J. 2024 Apr;21(4):e14563. doi: 10.1111/iwj.14563. Epub 2023 Dec 22.
This overview of systematic reviews (SRs) and meta-analysis (MAs) aimed to systematically collate, appraise and synthesize evidence for the treatment of diabetic foot ulcers (DFUs) with the external application of Chinese herbal medicine (CHM). SRs/MAs of external application of CHM for DFUs were collected by searching Cochrane Library, Web of science, CNKI, PubMed, VIP, Embase and Wanfang. Two independent reviewers carried out the literature selection and data extraction. Subsequently, AMSTAR-2 tool, PRISMA, and GRADE system were applied by two reviewers independently to evaluate the methodological quality, reporting quality, and evidence quality of the included studies, respectively. Eight SRs/MAs met the eligibility criteria and were included. According to AMSTAR-2, a very low methodological quality assessment was given to the included SRs/MAs due to the flaws of items 2, 4 and 7. The PRISMA system identified protocol and registration weaknesses, as well as search method weaknesses. With GRADE, no high-quality evidence was identified to support the role of external application of CHM for DFUs, and the quality of evidence for the vast majority of outcomes was rated as low or moderate. In conclusion, low- to moderate-quality evidence supports the promise of external application of CHM for the treatment of DFUs. Due to the limitations of the evidence supporting external application of CHM for DFUs, rigorously designed and larger samples of high-quality studies are needed going forward before broad recommendations can be made.
64Current research progress on the use of traditional Chinese medicine in the treatment of diabetic foot ulcers.PubMed
Yinfeng Xia, Ping Wu, Yongsong Chen, et al.
Front Endocrinol (Lausanne). 2025 Aug 22;16:1637128. doi: 10.3389/fendo.2025.1637128. eCollection 2025.
Diabetic foot ulcers represent a significant complication of diabetes mellitus, presenting substantial challenges due to their intricate pathogenesis, which encompasses neuropathy, vasculopathy, chronic inflammation, and biofilm-associated infections. Despite considerable advancements in Western medical interventions, including surgical debridement, skin grafting, negative pressure wound therapy, and innovative dressings, these ulcers remain a leading cause of amputation and contribute to a substantial socioeconomic burden. Traditional Chinese medicine (TCM) has emerged as a promising adjunctive therapy, offering multi-targeted mechanisms that address oxidative stress, chronic inflammation, angiogenesis, and microbial resistance associated with diabetic foot ulcers. This review aims to examine contemporary studies on the application of TCM in the treatment of diabetic foot ulcers, evaluating its efficacy and elucidating its mechanisms of action, thereby providing a reference for clinical treatment decisions and guiding future research directions.
65Efficacy and safety of a biased GLP-1 receptor agonist ecnoglutide in adults with overweight or obesity: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.PubMed
Linong Ji, Leili Gao, Haibo Xue, et al.
Lancet Diabetes Endocrinol. 2025 Sep;13(9):777-789. doi: 10.1016/S2213-8587(25)00141-X. Epub 2025 Jun 21.
BACKGROUND: Ecnoglutide is a novel cyclic adenosine monophosphate (cAMP)-biased GLP-1 receptor agonist currently in development for weight management. We aimed to assess the efficacy and safety of once weekly ecnoglutide versus placebo for the treatment of overweight or obesity in Chinese adults. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 medical centres across China. Eligible adults were aged 18-75 years with overweight or obesity (defined as BMI ≥28 kg/m or ≥24 kg/m with at least one weight-related comorbidity [prediabetes, hypertension, hyperlipidaemia, metabolic dysfunction-associated steatotic liver disease, obstructive sleep apnoea syndrome, or weight-bearing joint pain]), without diabetes (type 1 or 2). Participants were randomly assigned (3:3:3:1:1:1) via computer-generated random sequencing to receive subcutaneous ecnoglutide (1·2, 1·8, or 2·4 mg) or volume-matched placebo (1·2, 1·8, or 2·4 mg), once weekly, stratified by BMI at screening (≥28 kg/m and <28 kg/m). The coprimary endpoints were percentage change in bodyweight and proportion of participants with a reduction in bodyweight of 5% or more at week 40 (using the treatment policy estimand in the full analysis set). The full analysis set included all randomly assigned participants who were exposed to at least one dose of study drug or placebo according to their assigned treatment group. Safety was assessed in all participants who received at least one dose and had a safety assessment after medication. This study was registered with ClinicalTrials.gov, NCT05813795, and is complete. FINDINGS: Between April 5, 2023, and June 20, 2024, 882 participants were screened and 664 were randomly assigned to receive ecnoglutide 1·2 mg (n=166), ecnoglutide 1·8 mg (n=166), ecnoglutide 2·4 mg (n=167), or placebo (n=165). At week 40, the least-squares mean percentage change in bodyweight was -9·1% (SE 0·8) in the ecnoglutide 1·2 mg group, -10·9% (0·9) in the ecnoglutide 1·8 mg group, and -13·2% (0·8) in the ecnoglutide 2·4 mg group versus 0·1% (0·8) in the placebo group, and the respective estimated treatment differences compared with placebo were -9·2% (97% CI -11·0 to -7·5), -11·1% (-13·1 to -9·1), and -13·3% (-15·3 to -11·3), respectively (all p<0·0001). The proportion of participants who achieved at least a 5% reduction in bodyweight at week 40 was 77% in the ecnoglutide 1·2 mg group, 84% in the ecnoglutide 1·8 mg group, and 87% in the ecnoglutide 2·4 mg group versus 16% of participants in the placebo group, and the respective estimated treatment differences versus placebo were 60% (98% CI 50 to 71), 68% (58 to 78), and 70% (61 to 80; all p<0·0001). Treatment-emergent adverse events were observed in 155 (93%) of 166 participants in the ecnoglutide 1·2 mg group, 154 (93%) of 166 participants in the ecnoglutide 1·8 mg group, 156 (93%) of 167 participants in the ecnoglutide 2·4 mg group, and 139 (84%) of 165 participants in the placebo group. The most common adverse events were mild-to-moderate gastrointestinal related events. Ten participants treated with ecnoglutide discontinued treatment due to adverse events. INTERPRETATION: In adults with obesity or overweight without diabetes (type 1 or 2), individuals administered ecnoglutide had superior and sustained reduction in bodyweight versus placebo with a favourable safety profile, supporting its potential use for weight management. FUNDING: Hangzhou Sciwind Biosciences.
66Strategy for Treatment of Infected Diabetic Foot Ulcers.PubMed
Mayland Chang, Trung T Nguyen
Acc Chem Res. 2021 Mar 2;54(5):1080-1093. doi: 10.1021/acs.accounts.0c00864. Epub 2021 Feb 17.
Diabetic foot ulcers (DFUs) are chronic wounds that develop in 30% of diabetic patients. In DFUs, the normal wound healing process consisting of inflammation, angiogenesis, and extracellular matrix (ECM) remodeling is dysregulated and stalled. Upon injury, neutrophils and monocytes arrive at the wound and secrete matrix metalloproteinase (MMP)-8 and reactive oxygen species (ROS). ROS activates nuclear factor kappa beta (NF-κB), which upregulates MMP-9. Monocytes become macrophages, secreting tumor growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) for angiogenesis, resulting in remodeling of the ECM. MMP-9 cleaves laminin for keratinocyte migration. MMP-8 is beneficial for remodeling the ECM and healing the wound. In DFUs, the excess unregulated MMP-9 is detrimental, destroying the ECM and preventing the wound from healing. DFUs are typically infected, many with biofilm-producing bacteria that are resistant to antibiotics. Infection increases the time for wound healing and the likelihood for a lower-limb amputation. Despite the use of antibiotics, amputations occur in 24.5% of patients with DFUs. Clearly, new strategies for treatment of DFUs are needed. With the use of an affinity resin that binds exclusively to the active forms of MMPs and proteomics, we identified two proteinases, MMP-8 and MMP-9, in wounds of diabetic mice and diabetic humans. With the use of selective inhibitors, gene ablation of MMP-9, and exogenous application of MMP-8, we demonstrated that MMP-8 is beneficial to wound repair and that MMP-9 prevents the diabetic wound from healing. Our research has shown that infection increases active MMP-9, increasing inflammation and decreasing angiogenesis. As a result, infected diabetic wounds take a longer time to heal than uninfected ones. We found that active MMP-9 and NF-κB increased in human DFUs with wound severity and infection. The best strategy for treatment of DFUs is to selectively inhibit the detrimental proteinase MMP-9 without affecting the beneficial MMP-8 so that the body can repair the wound. Lead optimization of the thiirane class of inhibitors led to the discovery of ()-ND-336, a potent (19 nM) and selective (450-fold) MMP-9 inhibitor. ()-ND-336 accelerated wound healing in diabetic mice by decreasing ROS and NF-κB, lowering inflammation, and increasing angiogenesis. ()-ND-336 in combination with the antibiotic linezolid improved wound healing in infected diabetic mice by inhibiting MMP-9, which mitigated macrophage infiltration and increased angiogenesis, thereby restoring the normal wound healing process.
67Selective MMP-9 Inhibitor ()-ND-336 Alone or in Combination with Linezolid Accelerates Wound Healing in Infected Diabetic Mice.PubMed
Zhihong Peng, Trung T Nguyen, Wei Song, et al.
ACS Pharmacol Transl Sci. 2020 Sep 1;4(1):107-117. doi: 10.1021/acsptsci.0c00104. eCollection 2021 Feb 12.
Diabetic foot ulcers (DFUs) are a common complication of diabetes that are recalcitrant to healing due to persistent inflammation. The majority of DFUs have bacterial biofilms, with as a predominant bacterium, requiring infection control with antibiotics before treatment of the wound. Matrix metalloproteinases (MMPs) play roles in the pathology and repair of DFUs. However, defining the roles of the 24 human MMPs has been challenging due to the presence of three forms for each MMP, of which only one is catalytically competent, and the lack of convenient methods to distinguish among the three forms of MMPs. Using an affinity resin that binds only to the active forms of MMPs, with identification and quantification by mass spectrometry, we found that infected wounds in mice had increased levels of active MMP-9 compared to uninfected ones, paralleling infected human DFUs. MMP-9 activity prevents diabetic wounds from healing. We evaluated the efficacy of the selective small-molecule MMP-9 inhibitor, ()-ND-336, in the infected diabetic mouse model of wound healing and showed that ()-ND-336 alone or in combination with the antibiotic linezolid improves wound healing by inhibiting the detrimental MMP-9, mitigating macrophage infiltration to diminish inflammation, and increasing angiogenesis to restore the normal wound healing process. An advantage of this strategy is the ability to administer ()-ND-336 concurrently with an antibiotic.
68Complete wound closure following a single topical application of a novel autologous homologous skin construct: first evaluation in an open-label, single-arm feasibility study in diabetic foot ulcers.PubMed
David G Armstrong, Dennis P Orgill, Robert Galiano, et al.
Int Wound J. 2020 Oct;17(5):1366-1375. doi: 10.1111/iwj.13404. Epub 2020 May 26.
Diabetic foot ulcers (DFUs) are a growing burden on patients and health care systems that often require multiple treatments of both conventional and advanced modalities to achieve complete wound closure. A novel autologous homologous skin construct (AHSC) has been developed to treat cutaneous defects with a single topical application, by leveraging the endogenous repair capabilities of the patient's healthy skin. The AHSC's ability to close DFUs with a single treatment was evaluated in an open-label, single-arm feasibility study. Eleven patients with DFUs extending up to tendon, bone, or capsule received a single topical application of AHSC. Closure was documented weekly with high-resolution digital photography and wound planimetry. All 11 DFUs demonstrated successful graft take. Ten DFUs closed within 8 weeks. The median time-to-complete closure was 25 days. The mean percent area reduction for all 11 wounds at 4 weeks was 83%. There were no adverse events related to the AHSC treatment site. This pilot study demonstrated AHSC may be a viable single application topical intervention for DFUs and warrants investigation in larger, controlled studies.
69Lipid-based nanosystems for wound healing.PubMed
Rita Cortesi, Maddalena Sguizzato, Francesca Ferrara
Expert Opin Drug Deliv. 2024 Aug;21(8):1191-1211. doi: 10.1080/17425247.2024.2391473. Epub 2024 Sep 11.
INTRODUCTION: Wounds, resulting from traumas, surgery, burns or diabetes, are important medical problems due to the complexity of wound healing process regarding healing times and healthcare costs. Nanosystems have emerged as promising candidates in this field thank to their properties and versatile applications in drugs delivery. AREAS COVERED: Lipid-based nanosystems (LBN) are described for wound treatment, highlighting their different behaviors when interacting with the cutaneous tissue. The role of nanosystems in delivering mostly natural compounds on skin as well as the technological and engineering strategies to increase their efficiency in wound healing effect are reviewed. Finally, and studies are reported. EXPERT OPINION: LBN have shown promise in addressing the challenges of wound healing as they can improve the stability of drugs used in wound therapy, leading to higher efficacy and fewer adverse effects as compared to traditional formulations. LBNs being involved in the inflammatory and proliferation stages of the wound healing process, enable the modification of wound healing through multiple ways. In addition, the use of new technologies, including 3D bioprinting and photobiomodulation, may lead to potential breakthroughs in wound healing. This would provide clinicians with more potent forms of therapy for wound healing.
70The emerging role of probiotics in the management and treatment of diabetic foot ulcer: a comprehensive review.PubMed
Abrar Hussain, Naheed Mojgani, Syed Muhammad Ali Shah, et al.
AIMS Microbiol. 2025 Jul 24;11(3):649-678. doi: 10.3934/microbiol.2025027. eCollection 2025.
Diabetic foot ulcer (DFU) is a complex complication characterized by tissue damage and neurological problems in the lower extremities. Poor wound healing intensifies the severity of DFU, which currently has a 15%-20% prevalence and thus poses a significant healthcare challenge. DFU treatment is often considered complicated due to multifaceted problems, including high cost, low stability, and prolonged healing time. Thus, there is a need to find multidisciplinary, cost-effective, and potential treatment options. In parallel, the role of skin and gut microbiota has been highlighted, influencing the progression of DFU. Probiotics, when used in sufficient amounts, confer a health benefit to the host and are found to have a promising treatment potential for DFU. Probiotics exert beneficial effects that help to improve the management and healing of DFU, following various mechanisms like controlling hyperglycemia, enhancing immune function, modulating the microbiota, and maintaining glucose homeostasis, all of which contribute to improved management and healing of DFU. Despite the potential of probiotics in DFU treatment, their precise mechanisms, optimal strains, dosages, and experimental validation remain underexplored. To fully explore the probiotic potential for DFU, extensive animal studies and clinical trials are needed. This article provides a comprehensive overview of the current status of DFU, existing treatment options, current limitations, and the growing importance of probiotic therapy. It also emphasizes the application of advanced technologies, including artificial intelligence (AI) and machine learning (ML), in advancing DFU treatment strategies.
71A potential therapeutic strategy of an innovative probiotic formulation toward topical treatment of diabetic ulcer: an in vivo study.PubMed
Farkhonde Karimi, Nima Montazeri-Najafabady, Fatemeh Mohammadi, et al.
Nutr Diabetes. 2024 Aug 20;14(1):66. doi: 10.1038/s41387-024-00320-3.
BACKGROUND: The probiotic potential of Lacticacid bacteria has been studied in various medical complications, from gastrointestinal diseases to antibiotic resistance infections recently. Moreover, diabetic ulcer (DU) is known as one of the most significant global healthcare concerns, which comprehensively impacts the quality of life for these patients. Given that the conventional treatments of DUs have failed to prevent later complications completely, developing alternative therapies seems to be crucial. METHODS: We designed the stable oleogel-based formulation of viable probiotic cells, including Lactobacillus rhamnosus (L. rhamnosus), Lactobacillus casei (L. casei), Lactobacillus fermentum (L. fermentum), and Lactobacillus acidophilus (L. acidophilus) individually to investigate their effect on wound healing process as an in vivo study. The wound repair process was closely monitored regarding morphology, biochemical, and histopathological changes over two weeks and compared it with the effects of topical tetracycline as an antibiotic approach. Furthermore, the antibiofilm activity of probiotic bacteria was assessed against some common pathogens. RESULTS: The findings indicated that all tested lactobacillus groups (excluded L. casei) included in the oleogel-based formulation revealed a high potential for repairing damaged skin due to the considerably more levels of hydroxyproline content of tissue samples along with the higher numerical density of mature fibroblasts cell and volume density of hair follicles, collagen fibrils, and neovascularization in comparison with antibiotic and control groups. L. acidophilus and L. rhamnosus showed the best potential of wound healing among all lactobacillus species, groups treated by tetracycline and control groups. Besides, L. rhamnosus showed a significant biofilm inhibition activity against tested pathogens. CONCLUSIONS: This experiment demonstrated that the designed formulations containing probiotics, particularly L. acidophilus and L. rhamnosus, play a central role in manipulating diabetic wound healing. It could be suggested as an encouraging nominee for diabetic wound-healing alternative approaches, though further studies in detailed clinical trials are needed.
72Complementary Gene Therapy after Revascularization with the Saphenous Vein in Diabetic Foot Syndrome.PubMed
Diana Kupczyńska, Paweł Lubieniecki, Maciej Antkiewicz, et al.
Genes (Basel). 2023 Oct 20;14(10):1968. doi: 10.3390/genes14101968.
Diabetic foot syndrome (DFS) is one of the most serious macroangiopathic complications of diabetes. The primary treatment option is revascularization, but complementary therapies are still being sought. The study group consisted of 18 patients diagnosed with ischemic ulcerative and necrotic lesions in DFS. Patients underwent revascularization procedures and, due to unsatisfactory healing of the lesions, were randomly allocated to two groups: a group in which bicistronic VEGF165/HGF plasmid was administered and a control group in which saline placebo was administered. Before gene therapy administration and after 7, 30, 90, and 180 days, color duplex ultrasonography (CDU) was performed, the ankle-brachial index (ABI) and transcutaneous oxygen pressure (TcPO2) were measured, and DFS changes were described and documented photographically. In the gene therapy group, four out of eight patients (50%) healed their DFS lesions before 12 weeks. During this time, the ABI increased by an average of 0.25 and TcPO2 by 30.4 mmHg. In the control group, healing of the lesions by week 12 occurred in six out of nine patients (66.67%), and the ABI increased by an average of 0.14 and TcPO2 by 27.1 mmHg. One major amputation occurred in each group. Gene therapy may be an attractive option for complementary treatment in DFS.
73VEGF gene transfer for diabetic neuropathy.PubMed
J M Isner, A Ropper, K Hirst
Hum Gene Ther. 2001 Aug 10;12(12):1593-4.
Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory defects involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the patient. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic patients. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic patients, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetics, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascularity and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive overexpression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two objectives: 1. Objective #1: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes and associated macrovascular disease involving the lower extremities. 2. Objective #2: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes without macrovascular disease involving the lower extremities. The protocol outlined in this Investigational New Drug Application has been designed as a Phase I/II, single-site, dose escalating, double-blind, placebo controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities. Diabetic males or females > 21 years old with sensory neuropathy with or without macrovascular disease will be eligible. A total of 192 patients will be recruited into two arms of the study (each arm consisting of 96 patients) over a period of 4 years (the fifth year will be limited to follow-up examinations). The 96 patients in each of the two arms of the study will comprise 3 cohorts, each consisting of 32 patients. Within each of these cohorts, patients will be randomized to receive phVEGF165 or placebo based upon a 3:1 randomization ratio. Thus, at the completion of the study, 24 patients will have each received a given dose (1, 2, or 4 mg phVEGF165) and 24 patients will have received placebo. Doses will be employed in a serial dose-escalating fashion. The entire volume of the study drug will be divided and delivered in 8 intramuscular injections administered into the foot, calf muscle, or distal thigh muscle of the affected extremity. Following the initial set of injections, repeat treatment with an identical dose will be provided 2 and 4 weeks after initial treatment.
74Effect of frailty on effectiveness and safety of GLP-1 receptor agonists versus SGLT2 inhibitors in people with type 2 diabetes in Taiwan: a retrospective, nationwide, longitudinal study.PubMed
Fei-Yuan Hsiao, Elise Chia-Hui Tan, Lin-Chieh Meng, et al.
Lancet Healthy Longev. 2024 Sep;5(9):100621. doi: 10.1016/j.lanhl.2024.07.004. Epub 2024 Sep 13.
BACKGROUND: GLP-1 receptor agonists and SGLT2 inhibitors are increasingly being used in people with type 2 diabetes on the basis of findings from randomised clinical trials; however, little is known of whether clinical outcomes are affected by frailty in real-world settings. We aimed to compare the clinical effectiveness and safety of GLP-1 receptor agonists and SGLT2 inhibitors in managing type 2 diabetes, with a specific focus on stratifying people by their frailty status. METHODS: In this retrospective, nationwide, longitudinal study, we identified people (aged ≥20 years) with type 2 diabetes who newly initiated either a GLP-1 receptor agonist or an SGLT2 inhibitor during the period Jan 1, 2017 to Dec 31, 2019 from the Taiwan National Health Insurance database. Individuals were excluded if they had been diagnosed with cancer, received dialysis for kidney failure, or had prescriptions for a GLP-1 receptor agonist or an SGLT2 inhibitor, within 1 year before the index date. Mortality data were collected from the Taiwan National Death Registry. Eligible individuals were categorised into three frailty subgroups-fit, mild frailty, and moderate or severe frailty-on the basis of the multimorbidity frailty index. Propensity score matching (1:1) was used to balance covariates between recipients of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup. Clinical outcomes of interest included three-point major adverse cardiovascular events (non-fatal acute myocardial infarction, non-fatal stroke, and fatal cardiovascular disease), all-cause mortality, hospitalisation for heart failure, dialysis or renal transplant, severe diabetic foot complications, retinopathy, hospitalisation for severe hyperglycaemia, and hospitalisation for severe hypoglycaemia. The association between the use of a GLP-1 receptor agonist versus an SGLT2 inhibitor and the risk of the outcomes of interest among each frailty subgroup was examined using a subdistribution hazard model. FINDINGS: We identified 320 210 people with type 2 diabetes, of whom 280 163 met the eligibility criteria, who initiated either a GLP-1 receptor agonist (n=22 968; mean age 57·7 years [SD 13·9], 11 338 [49·4%] were female, and 11 630 [50·6%] were male) or SGLT2 inhibitor (n=257 195; mean age 58·8 years [12·3], 107 988 [42·0%] were female, and 149 207 [58·0%] were male) during 2017-19. After matching, 11 882, 7210, and 3414 pairs of GLP-1 receptor agonist and SGLT2 inhibitor users were assigned in the fit, mild frailty, and moderate or severe frailty subgroups. All clinical outcomes were comparable between users of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup, except for a higher risk of hospitalisation for severe hyperglycaemia with GLP-1 receptor agonists than with SGLT2 inhibitors in the mild frailty subgroup (subdistribution hazard ratio 1·25 [95% CI 1·13-1·38]; p<0·0001) and a higher risk of dialysis or renal transplant with GLP-1 receptor agonists than with SGLT2 inhibitors in the fit (2·43 [1·82-3·23]; p<0·0001), mild frailty (3·93 [3·03 -5·09]; p<0·0001), and moderate or severe frailty (2·60 [2·03-3·31]; p<0·0001) subgroups. INTERPRETATION: Formulating clear and updated guidelines on the use of GLP-1 receptor agonists and SGLT2 inhibitors according to frailty status could improve management of type 2 diabetes. FUNDING: Ministry of Education, Taiwan.
75Stability, Activity, and Application of Topical Doxycycline Formulations in a Diabetic Wound Case Study.PubMed
Simona Gabriele, Beth Buchanan, Azoy Kundu, et al.
Wounds. 2019 Feb;31(2):49-54. Epub 2018 Dec 26.
INTRODUCTION: Tetracycline molecules comprise a group of broad-spectrum antibiotics whose primary mechanism of action is the inhibition of protein synthesis through the binding of the bacterial ribosome. In addition, tetracyclines inhibit matrix metalloproteases (MMPs), a family of zinc-dependent proteases that contribute to tissue remodeling, inflammation, and angiogenesis and are overexpressed in certain pathophysiologies such as diabetic foot ulcers (DFUs). OBJECTIVE: This study aims to develop a liquid chromatography and mass spectrometry (LC-MS/MS) doxycycline quantification methodology to facilitate the development of a stable topical doxycycline hyclate (DOXY) formulation as well as evaluate the topical DOXY formulation for the efficacy in MMP-9 inhibition in vitro and in a clinical application of diabetic lower extremity wounds. MATERIALS AND METHODS: A simple quantification method utilizing LC-MS/MS was used to develop a topical DOXY formulation, a sample of which was analyzed in stability testing. The formulation was evaluated in vitro for MMP-9 activity using a commercial assay and compared with internal kit controls as well as in a clinical setting for wound healing. RESULTS: Two formulations of 2% (w/w) DOXY demonstrated acceptable stability (±10% target concentration) for 70 days when stored at 4°C. Using an in vitro assay of MMP-9 enzyme activity, the 2% DOXY formulation imparted a ~30% decrease in MMP-9 inhibitory potential as compared with the control drug alone (IC₅₀ values 62.92 µM and 48.27 µM, respectively). This topical product was evaluated for clinical utility in a patient with a DFU, and preliminary data suggest this intervention may promote wound healing. CONCLUSIONS: In summary, novel DOXY formulations may be stable and biologically active tools amenable to complex wound care.
76Spray on skin for diabetic foot ulcers: an open label randomised controlled trial.PubMed
Laurens Manning, Emma J Hamilton, Edward Raby, et al.
J Foot Ankle Res. 2019 Nov 15;12:52. doi: 10.1186/s13047-019-0362-x. eCollection 2019.
BACKGROUND: One Australian loses a limb every 3 h as a result of infected diabetic foot ulcers (DFU). This common condition accounts for substantial morbidity and mortality for affected individuals and heavy economic costs for the health sector and the community. There is an urgent need to test interventions that improve wound healing time, prevent amputations and recurrent ulceration in patients presenting with DFU whilst improving quality of life and reducing health care costs. METHODS: One hundred and fifty eligible participants will be randomised to receive an autologous skin cell suspension, also termed 'spray-on' skin (ReCell®) or standard care interventions for their DFU. The primary outcome is complete wound healing at 6 months, but participants will be followed up for a total of 12 months to enable secondary outcomes including total overall costs, ulcer free days at 12 months and quality of life to be assessed. DISCUSSION: Outpatient costs for dressings, home nursing visits and outpatient appointments are key cost drivers for DFU. If spray-on skin is effective, large cost savings to WA Health will be realised immediately through a shortened time to healing, and through a higher proportion of patients achieving complete healing. Shortened healing times may enable participants to return to work earlier. Any economic benefits are likely to be amplified across Australia and other similar demographic settings where aging populations with increased diabetes rates are considered major future challenges. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000511235. Registered on 9 April 2018.
77Intact Fish Skin Graft to Treat Deep Diabetic Foot Ulcers.PubMed
Dured Dardari, Alberto Piaggesi, Louis Potier, et al.
NEJM Evid. 2024 Dec;3(12):EVIDoa2400171. doi: 10.1056/EVIDoa2400171. Epub 2024 Oct 4.
BACKGROUND: Diabetic foot ulcers are chronic, difficult to heal, and potentially life-threatening. Few medical devices have been studied in diabetic ulcers penetrating to bone or tendon. METHODS: We conducted an international, open-label randomized controlled trial, randomly assigning patients with diabetic ulcers penetrating to bone, joint, or tendon 1:1 to intact fish skin graft or standard wound care, with assigned treatment applied through 14 weeks. The primary end point was the proportion of ulcers healed at 16 weeks, defined as reepithelization as identified by the investigator, and confirmed 14 days later. A blinded adjudication committee confirmed healing at both time points. Healing was also assessed at 20 and 24 weeks. RESULTS: Between July 2020 and November 2022, 255 patients were randomly assigned to intact fish skin graft (n=129) or standard of care (n=126). Healing was achieved in 44% of patients at 16 weeks with intact fish skin graft compared with 26% for standard of care (P<0.001, unadjusted), with additional healing at 20 weeks (46% vs. 32%) and 24 weeks (55% vs. 38%). Mean (SD) time to healing was 17.3 (0.69) weeks (95% confidence interval [CI], 15.5 to 18.7) for the intact fish skin graft group and 19.4 (0.66) weeks (95% CI, 18.1 to 20.7) for the standard of care group. In a Cox regression, intact fish skin graft was associated with faster time to healing (hazard ratio, 1.59; 95% CI, 1.07 to 2.36). Primary wound infections were the most common adverse event, occurring in 39 (30.2%) of patients in the intact fish skin graft group and 31 (24.6%) of patients in the standard of care group. CONCLUSIONS: Among patients with deep diabetic foot ulcers, treatment with intact fish skin graft was superior to standard of care in proportion of wounds healed at 16 weeks and was associated with faster time to healing. (Funded by European Commission Fast Track to Innovation Horizon 2020, and Kerecis Ltd. ClinicalTrials.gov NCT04257370.).
78Fibroblast Growth Factor in Diabetic Foot Ulcer: Progress and Therapeutic Prospects.PubMed
Ye Liu, Yiqiu Liu, Junyu Deng, et al.
Front Endocrinol (Lausanne). 2021 Oct 14;12:744868. doi: 10.3389/fendo.2021.744868. eCollection 2021.
Diabetic foot ulcer (DFU) is a combination of neuropathy and various degrees of peripheral vasculopathy in diabetic patients resulting in lower extremity infection, ulcer formation, and deep-tissue necrosis. The difficulty of wound healing in diabetic patients is caused by a high glucose environment and various biological factors in the patient. The patients' skin local microenvironment changes and immune chemotactic response dysfunction. Wounds are easy to be damaged and ulcerated repeatedly, but difficult to heal, and eventually develop into chronic ulcers. DFU is a complex biological process in which many cells interact with each other. A variety of growth factors released from wounds are necessary for coordination and promotion of healing. Fibroblast growth factor (FGF) is a family of cell signaling proteins, which can mediate various processes such as angiogenesis, wound healing, metabolic regulation and embryonic development through its specific receptors. FGF can stimulate angiogenesis and proliferation of fibroblasts, and it is a powerful angiogenesis factor. Twenty-three subtypes have been identified and divided into seven subfamilies. Traditional treatments for DFU can only remove necrotic tissue, delay disease progression, and have a limited ability to repair wounds. In recent years, with the increasing understanding of the function of FGF, more and more researchers have been applying FGF-1, FGF-2, FGF-4, FGF-7, FGF-21 and FGF-23 topically to DFU with good therapeutic effects. This review elaborates on the recently developed FGF family members, outlining their mechanisms of action, and describing their potential therapeutics in DFU.
79Association of semaglutide use with outcomes in chronic plantar heel pain: a prospective observational cohort and a pilot interventional study.PubMed
Fan Yang, Lenian Zhou, Jieyuan Zhang, et al.
Int J Surg. 2025 Dec 1;111(12):9333-9341. doi: 10.1097/JS9.0000000000003156. Epub 2025 Aug 8.
BACKGROUND: Whether patients with chronic plantar heel pain (PHP) can benefit from glucagon-like peptide-1 receptor agonists (GLP1-RAs) remained unclear. METHODS: This study included a prospective observational cohort and a pilot interventional component. In the observational arm, more than 3000 adults with chronic PHP (duration of symptoms >6 months) were recruited with at least 2-year follow-up from two medical centers. The primary endpoint was the change from baseline of Foot Health Status Questionnaire (FHSQ) pain subdomain at the last follow-up. Secondary endpoints included first-step pain, FHSQ function subdomain, the amount of NSAIDs consumption, number of injection therapies/extracorporeal shockwave therapy (ESWT) sessions/manual stretching, days of orthosis wearing and thickness of plantar fascia. As supporting evidence, a pilot interventional study was conducted in 30 patients with chronic PHP who received semaglutide, with outcomes assessed over 12 months using before-and-after evaluations of pain, function, and imaging. RESULTS: In the prospective observational cohort, 92 out of 2902 patients who received semaglutide in purpose of treating type 2 diabetes (T2DM) and/or weight loss in the final analysis were identified. Change from baseline in FHSQ pain subdomain was significantly higher in semaglutide group compared with control group (adjusted mean difference, 14.86 [95% CI, 9.97 to 19.75], P < 0.001), favoring semaglutide. Similar results were observed from the analysis of FHSQ function subdomain, first-step pain and several therapeutic interventions (oral and topical NSAIDs, corticosteroid injection and orthosis wearing). For structural alterations, plantar fascia thickening velocity was significantly lower in the semaglutide group when compared with control group (-0.25 mm/year [-0.41 to -0.09], P = 0.002). For interventional use of semaglutide, improvements in all measured outcomes (FHSQ pain/function subscales, first-step pain and thickness of plantar fascia) were observed with all P values less than 0.001. In the interventional substudy, mean FHSQ pain scores improved from 28.09 ± 10.34 at baseline to 60.28 ± 21.34 at follow-up ( P < 0.001). FHSQ function subdomain scores increased from 27.23 ± 17.44 to 80.71 ± 19.55 ( P < 0.001). CONCLUSIONS: Semaglutide might be a potential therapeutic candidate for chronic PHP patients by improving patient-reported outcomes and plantar fascia thickening. Further randomized trial is warranted by our study to further evaluate the therapeutic effects of GLP-1RAs on chronic PHP.
80Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: The STARDUST Randomized Clinical Trial.PubMed
Paola Caruso, Maria Ida Maiorino, Miriam Longo, et al.
JAMA Netw Open. 2024 Mar 4;7(3):e241545. doi: 10.1001/jamanetworkopen.2024.1545.
IMPORTANCE: Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. OBJECTIVE: To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. DESIGN, SETTING, AND PARTICIPANTS: This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania "Luigi Vanvitelli," Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. INTERVENTIONS: Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. MAIN OUTCOMES AND MEASURES: Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. RESULTS: Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04881110.
81GLP-1 Receptor Agonists, DPP-4 Inhibitors and the Skin-Diabetes Meets Dermatology: A Brief Narrative Review.PubMed
Dimitrios Pantazopoulos, Evanthia Gouveri, Massimo Papi, et al.
Adv Ther. 2025 Aug;42(8):3621-3633. doi: 10.1007/s12325-025-03257-w. Epub 2025 Jun 5.
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4is) are well-established agents for type 2 diabetes mellitus (T2DM) management. Ongoing research has provided data on their both beneficial and adverse effects on the skin. For instance, GLP-1RAs have exhibited therapeutic benefits in psoriasis, while DPP-4is may reduce the risk of melanoma. Moreover, both of these agents may play a pivotal role in improving wound healing. However, untoward effects, such as bullous pemphigoid, highlight the need for patient monitoring. This review summarises the beneficial and adverse effects of GLP-1RAs and DPP-4is in dermatological conditions and in systemic diseases with cutaneous manifestations.
82[Diabetology as an interdisciplinary challenge].PubMed
D Müller-Wieland, N Marx
Internist (Berl). 2017 Apr;58(4):329-335. doi: 10.1007/s00108-017-0204-5.
Type 2 diabetes mellitus is a growing chronic disease with a complex pathophysiology and multiple therapeutic options. Clinical prognosis is determined by multimorbidity and cardiovascular complications. For example, the prognosis of patients with diabetes hospitalized for heart failure is very poor with up to 50% mortality rate over the 3 years thereafter. Therefore, three levels have to be addressed in our approach to interdisciplinary diabetes care: screening and prevention, efficient patient-centered drug therapy, and a strategy for care including social environment of the patient suffering from complex diseases. Thus, we need diabetes specialists in out- and in-patient settings. Transsectoral interdisciplinary approaches to clinical care, as exemplary shown for the treatment of the diabetes foot syndrome, should be developed for other comorbidities, like renal and heart failure, respectively. The basis in the therapy of the cardiometabolic high-risk patient is prevention and multimodal treatment of cardiovascular risk factors. In this context, it is interesting to note that new cardiovascular outcome trials with a so-called safety design have shown that the GLP-1 receptor agonist liraglutide and the SGLT-2 inhibitor empagliflozin can reduce cardiovascular event rates. In addition, empagliflozin has significantly reduced the rate of hospitalization for heart failure. The latter has been included in the recent guidelines on heart failure by the European Society of Cardiology.
83Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer.PubMed
Yue Cao, Xiaokun Gang, Chenglin Sun, et al.
J Diabetes Res. 2017;2017:9328347. doi: 10.1155/2017/9328347. Epub 2017 Mar 12.
Mesenchymal stem cells (MSCs), an ideal cell source for regenerative therapy with no ethical issues, play an important role in diabetic foot ulcer (DFU). Growing evidence has demonstrated that MSCs transplantation can accelerate wound closure, ameliorate clinical parameters, and avoid amputation. In this review, we clarify the mechanism of preclinical studies, as well as safety and efficacy of clinical trials in the treatment of DFU. Bone marrow-derived mesenchymal stem cells (BM-MSCs), compared with MSCs derived from other tissues, may be a suitable cell type that can provide easy, effective, and cost-efficient transplantation to treat DFU and protect patients from amputation.
84Stem cell therapy for lower extremity diabetic ulcers: where do we stand?PubMed
Mei Yang, Lingling Sheng, Tian R Zhang, et al.
Biomed Res Int. 2013;2013:462179. doi: 10.1155/2013/462179. Epub 2013 Mar 18.
The impairment of wound healing in diabetic patients is an important clinical problem affecting millions of patients worldwide. Various clinical and basic science studies show that stem cell therapy, as a regenerative medical therapy, can be a good solution. In this paper, we begin with an introduction of the cellular mechanism of the diabetic ulcer. We will then discuss the advantages and limitations of various stem cell therapies that have been under extensive recent study.
85Mesenchymal Stem Cells Promote Wound Healing and Effects on Expression of Matrix Metalloproteinases-8 and 9 in the Wound Tissue of Diabetic Rats.PubMed
Lingling Wei, Yongsong Xu, Lijie Zhang, et al.
Stem Cells Dev. 2023 Jan;32(1-2):25-31. doi: 10.1089/scd.2021.0218.
Diabetic foot ulcer (DFU) is a multifactorial complication of diabetes, mainly manifested as infection, ulcer, or destruction of deep tissue, and there is currently no effective treatment. Several preclinical and clinical studies have proved that the transplantation of mesenchymal stem cells (MSCs) improved wound healing. In this study, we evaluated the therapeutic efficacy of human umbilical cord (hUC-MSCs) in DFU rat model. One dose of hUC-MSCs (1 × 10 cells) was subcutaneously injected around wounds in male Sprague-Dawley rats. Wound healing was evaluated macroscopically (wound closure) every 3 days. In addition, we measured growth factors and specific proteins [matrix metalloproteinases (MMPs)-9 and MMP-8] on Day 14 post hUC-MSC transplantation. Results showed significant differences in the wound healing kinetics of lesions that received hUC-MSCs compared to lesions that received vehicle (phosphate buffered saline; < 0.05). Enzyme-linked immunosorbent assay analyses indicated that MMP-9 protein contents were significantly upregulated in DFU animals, while MMP-8 was downregulated compared to the diabetic rats ( < 0.05). After MSC treatment, the level of MMP-9 and MMP-8 decreased and increased compared to the vehicle group, respectively. These findings suggest that hUC-MSC transplantation can ameliorate the healing process of DFU rats and a potential mechanism through which MSCs enhance DFU wound healing by decreasing MMP-9 expression and increasing MMP-8 expression. This study represents a promising opportunity to gain insight into how MSCs mediate wound healing.
86International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences.PubMed
Barbara Davit, April C Braddy, Dale P Conner, et al.
AAPS J. 2013 Oct;15(4):974-90. doi: 10.1208/s12248-013-9499-x. Epub 2013 Jul 3.
The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.
87A Multi-Drug Concentration Gradient Mixing Chip: A Novel Platform for High-Throughput Drug Combination Screening.PubMed
Jiahao Fu, Yibo Feng, Yu Sun, et al.
Biosensors (Basel). 2024 Apr 23;14(5):212. doi: 10.3390/bios14050212.
Combinatorial drug therapy has emerged as a critically important strategy in medical research and patient treatment and involves the use of multiple drugs in concert to achieve a synergistic effect. This approach can enhance therapeutic efficacy while simultaneously mitigating adverse side effects. However, the process of identifying optimal drug combinations, including their compositions and dosages, is often a complex, costly, and time-intensive endeavor. To surmount these hurdles, we propose a novel microfluidic device capable of simultaneously generating multiple drug concentration gradients across an interlinked array of culture chambers. This innovative setup allows for the real-time monitoring of live cell responses. With minimal effort, researchers can now explore the concentration-dependent effects of single-agent and combination drug therapies. Taking neural stem cells (NSCs) as a case study, we examined the impacts of various growth factors-epithelial growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF)-on the differentiation of NSCs. Our findings indicate that an overdose of any single growth factor leads to an upsurge in the proportion of differentiated NSCs. Interestingly, the regulatory effects of these growth factors can be modulated by the introduction of additional growth factors, whether singly or in combination. Notably, a reduced concentration of these additional factors resulted in a decreased number of differentiated NSCs. Our results affirm that the successful application of this microfluidic device for the generation of multi-drug concentration gradients has substantial potential to revolutionize drug combination screening. This advancement promises to streamline the process and accelerate the discovery of effective therapeutic drug combinations.
88Development of reporter gene assays to determine the bioactivity of biopharmaceuticals.PubMed
Lan Wang, Chuanfei Yu, Junzhi Wang
Biotechnol Adv. 2020 Mar-Apr;39:107466. doi: 10.1016/j.biotechadv.2019.107466. Epub 2019 Nov 5.
Complex structure and structure-function relationship of biopharmaceuticals require extensive analytical characterization and appropriate quality control of the products. Despite rapid development of sophisticated physicochemical techniques, biological activity measurement remains the critical role in inferring the high-order structure of biopharmaceuticals. Cell-based biological assays are mostly applied to determine the biological activity of biopharmaceuticals, however, refined biological assays are continually needed to increase their robustness. Reporter gene assays (RGAs) which are mechanism of action (MOA) related, less variable, accurate, precise, and labor-saving are becoming more and more recognized and adopted in the quality control. Here we discuss the importance of bioactivity determination, the strength and weakness of various assay formats with RGAs. We also introduce the mechanism of RGAs, and present a number of examples for RGAs to determine the bioactivity of various biopharmaceuticals, which indicate their extensive use in the screening, characterization, quality control, stability and biosimilarity study. We believe that with the rapid development of biotechnology, new strategies of bioassays based on RGAs will be more widely applied in various fields of biopharmaceuticals.
89An update on angiogenesis therapy.PubMed
J Davda, V Labhasetwar
Crit Rev Eukaryot Gene Expr. 2001;11(1-3):1-21.
Angiogenesis is a novel approach for the therapy of various ischemia-related pathophysiologic conditions. Proangiogenic growth factors have shown promising results in preclinical studies using protein- and gene-based therapies. However, their success in clinical trials is hindered by the lack of an optimal delivery strategy that would provide sustained and localized levels of the growth factors in the diseased tissue. Targeted delivery of proangiogenic agents is expected to demonstrate therapeutic efficacy of growth factors at relatively lower doses, without the risk of systemic toxicity in terms of unwanted angiogenesis. To achieve the above objectives, various drug delivery systems are under investigation. This review describes the basic mechanism of action of growth factors, their current status in preclinical and clinical studies, and the issue of drug delivery.
91Bioactivity screening of partially desulfated low-molecular-weight heparins: a structure/activity relationship study.PubMed
Sucharita Roy, Hsuanchi Lai, Radouane Zouaoui, et al.
Glycobiology. 2011 Sep;21(9):1194-205. doi: 10.1093/glycob/cwr053. Epub 2011 Apr 22.
A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates.
92Demonstration of Physicochemical and Functional Similarity of Biosimilar Pegfilgrastim-cbqv to Pegfilgrastim.PubMed
Henriette Kuehne, Janice M Davis, LeeAnne Merewether, et al.
Drugs R D. 2024 Jun;24(2):285-301. doi: 10.1007/s40268-024-00471-9. Epub 2024 Jul 3.
BACKGROUND: Pegfilgrastim-cbqv/CHS-1701 (UDENYCA) (hereafter referred to as pegfilgrastim-cbqv) was approved in 2018 by the US Food and Drug Administration as a biosimilar for pegfilgrastim (Neulasta) (hereafter referred to as pegfilgrastim). Both pegfilgrastim-cbqv and pegfilgrastim are conjugates of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) with a 20 kDa polyethylene glycol (PEG) indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients receiving myelosuppressive anticancer drugs. The demonstration of analytical similarity for PEG-protein conjugates presents unique challenges since both the protein and PEG attributes must be characterized. OBJECTIVE: The current study demonstrates the analytical similarity of pegfilgrastim-cbqv and the reference product, pegfilgrastim. In addition to the physicochemical and functional characterization of the protein, the study assessed attributes specific to PEGylation including PEG size and polydispersity, site of attachment, linker composition, and PEGylation process-related variants. METHODS: The structural, functional, and stability attributes of pegfilgrastim-cbqv and pegfilgrastim were compared using state-of-the-art analytical methods. For the protein, the primary structure, disulfide structure, and secondary and tertiary structures were assessed using traditional protein characterization techniques such as mass spectrometry (MS), circular dichroism (CD), intrinsic fluorescence, and differential scanning calorimetry (DSC), as well as more advanced techniques such as two-dimensional (2D) nuclear magnetic resonance (NMR) and hydrogen deuterium exchange (HDX). For the PEG moiety, the site of attachment, occupancy, linker composition, size and polydispersity were compared using mass spectrometry (both intact and after endoprotease digestion), multiangle light scattering detection (MALS), and Edman degradation. Purity assessments included the assessment of both protein variants and PEGylation variants using chromatographic and electrophoretic analytical separation techniques. The functional similarity between pegfilgrastim-cbqv and pegfilgrastim was compared using both a cell-based bioassay and surface plasmon resonance (SPR). The degradation rates and stability profiles were compared under accelerated and stressed conditions. RESULTS: Biosimilarity was demonstrated by a thorough assessment of physiochemical and functional attributes, as well as comparative stability, of pegfilgrastim-cbqv relative to pegfilgrastim. These studies demonstrated identical primary structure and disulfide structure, highly similar secondary and tertiary structure, as well as functional similarity. The impurity profile of pegfilgrastim-cbqv was comparable to that of pegfilgrastim with only minor differences in PEGylation variants and a slight offset in the PEG molar mass. These differences were not clinically relevant. The degradation profiles were qualitatively and quantitatively similar under accelerated and stress conditions. CONCLUSION: The structural, functional, and stability data demonstrate that pegfilgrastim-cbqv is highly similar to the reference product, pegfilgrastim.
93Flow cytometry: A powerful analytical technique for characterizing the biological function of biotherapeutics and biosimilars.PubMed
Irene Vergara, Juan Sebastian Herrera-Noreña, Cynthia López-Pacheco, et al.
J Pharm Biomed Anal. 2023 Oct 25;235:115680. doi: 10.1016/j.jpba.2023.115680. Epub 2023 Aug 23.
Biotherapeutics are complex molecules with therapeutic activity produced through biotechnology and/or genetic engineering. These medicines have clinical applications in diagnostic procedures and therapies for many disorders, including cancer, autoimmunity, and chronic degenerative diseases. Most biotherapeutics are expensive and sometimes unaffordable for low-income patients suffering from cancer or chronic illness. Biosimilars emerged in the 2000 s after patents of many innovative biotherapeutic products expired. The Biosimilar market is growing fast and demands reliable technologies for analyzing the physicochemical properties and bioactivity of products. A big challenge for biosimilar development is to prove comparable bioactivity, safety, efficacy, and toxicity profile as the innovator product. Bioactivity assessment can utilize different analytical techniques such as ELISA, flow cytometry, and surface plasmon resonance. Flow cytometry is a versatile analytical tool that can be used for the development of quantitative, reproducible, and accurate protocols suitable for routine evaluation of bioactivity in-vitro. Nevertheless, flow cytometry has been very scarcely used in comparability evaluation between biosimilar versus an originator product. Here, we review potential applications of flow cytometry to carry out functional bioassays of biotherapeutics or biosimilars.
94In vitro functional characterization of biosimilar therapeutic antibodies.PubMed
Júlia Anna Láng, Zsófia Cselovszkiné Balogh, Mónika Fizilné Nyitrai, et al.
Drug Discov Today Technol. 2020 Dec;37:41-50. doi: 10.1016/j.ddtec.2020.11.010. Epub 2020 Dec 11.
The key factor in successful development and marketing of biosimilar antibodies is a deep understanding of their critical quality attributes and the ability to control them. Comprehensive functional characterization is therefore at the heart of the process and is a crucial part of regulatory requirements. Establishment of a scientifically sound molecule-specific functional in vitro assay panel requires diligent planning and high flexibility in order to respond to both regulatory requirements and the ever-changing demands relevant to the different stages of the development and production process. Relevance of the chosen assays to the in vivo mechanism of action is of key importance to the stepwise evidence-based demonstration of biosimilarity. Use of a sound interdisciplinary approach and orthogonal state-of-the-art techniques is also unavoidable for gaining in-depth understanding of the biosimilar candidate. The aim of the present review is to give a snapshot on the methodic landscape as depicted by the available literature discussing the in vitro techniques used for the functional characterization of approved biosimilar therapeutic antibodies. Emerging hot topics of the field and relevant structure-function relationships are also highlighted.
95Physicochemical and Functional Similarity Assessment Between Proposed Bevacizumab Biosimilar BAT1706 and Reference Bevacizumab.PubMed
Di Cao, Chunping Deng, Guangying Wang, et al.
Drugs R D. 2023 Sep;23(3):267-288. doi: 10.1007/s40268-023-00432-8. Epub 2023 Jul 22.
BACKGROUND: BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab). METHOD: A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed. RESULT: BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity. CONCLUSION: Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.
96The impact of bioequivalence regulation on pharmaceutical firm outcomes: Evidence from China.PubMed
Menghan Shen, Xiaoxia Liang, Han Wu
Soc Sci Med. 2025 Sep;380:118242. doi: 10.1016/j.socscimed.2025.118242. Epub 2025 May 26.
China's pharmaceutical market is dominated by generic drugs, accounting for 95 % of its market share. However, prior to 2016, these drugs were not required to undergo bioequivalence testing against their innovator drugs, raising concerns about the effectiveness of generic drugs. To address this issue, China implemented mandatory bioequivalence testing in 2016. This study investigates the impact of this policy change on generic drug firms' R&D investments and their success in passing bioequivalence tests. Employing a difference-in-differences approach, we analyze R&D investment data from 2012 to 2022 and bioequivalence approval data from 2012 to 2024 for 122 publicly listed pharmaceutical firms in China. Our findings reveal that firms responded to the new regulations by significantly increasing their R&D investments by 20.7 %. In addition, the quality regulation has led to an average of 2.5 approval per firm annually. Hetergeneity analysis reveals that firms in wealthier provinces, larger firms, and those with prior higher R&D capacities were more likely to increase their R&D investments and pass bioequivalence tests compared to those that are not. In addition, pharmaceutical firms prioritize bioequivalence testing compliance for drugs facing stricter regulatory deadlines or those with potentially higher economic returns. These results suggest that the implementation of mandatory bioequivalence testing has spurred positive responses from the industry, and it is likely to have a positive impact on drug quality compared to the pre-regulation period. However, more comprehensive strategies are needed to ensure full compliance and further improve the quality of generic drugs in China.