Barui Ayan Kumar, Nethi Susheel Kumar, Basuthakur Papia, Jhelum Priya, Bollu Vishnu Sravan, Reddy Bommana Raghunath, Chakravarty Sumana, Patra Chitta Ranjan
Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, UP, India.
Biomed Mater. 2021 Mar 26;16(4). doi: 10.1088/1748-605X/abebd1.
Critical limb ischemia (CLI) is a severe type of peripheral artery disease (PAD) which occurs due to an inadequate supply of blood to the limb extremities. Patients with CLI often suffer from extreme cramping pain, impaired wound healing, immobility, cardiovascular complications, amputation of the affected limb and even death. The conventional therapy for treating CLI includes surgical revascularization as well as restoration of angiogenesis using growth factor therapy. However, surgical revascularization is only suitable for a small percentage of CLI patients and is associated with a high perioperative mortality rate. The use of growth factors is also limited in terms of their poor therapeutic angiogenic potential, as observed in earlier clinical studies which could be attributed to their poor bio-availability and non-specificity issues. Therefore, to overcome the aforesaid disadvantages of conventional strategies there is an urgent need for the advancement of new alternative therapeutic biomaterials to treat CLI. In the past few decades, various research groups, including ours, have been involved in developing different pro-angiogenic nanomaterials. Among these, zinc oxide nanoflowers (ZONFs), established in our laboratory, are considered one of the more potent nanoparticles for inducing therapeutic angiogenesis. In our earlier studies we showed that ZONFs promote angiogenesis by inducing the formation of reactive oxygen species and nitric oxide (NO) as well as activating Akt/MAPK/eNOS cell signaling pathways in endothelial cells. Recently, we have also reported the therapeutic potential of ZONFs to treat cerebral ischemia through their neuritogenic and neuroprotective properties, exploiting angio-neural cross-talk. Considering the excellent pro-angiogenic properties of ZONFs and the importance of revascularization for the treatment of CLI, in the present study we comprehensively explore the therapeutic potential of ZONFs in a rat hind limb ischemia model (established by ligating the hind limb femoral artery), an animal model that mimics CLI in humans. The behavioral studies, laser Doppler perfusion imaging, histopathology and immunofluorescence as well as estimation of serum NO level showed that the administration of ZONFs could ameliorate ischemia in rats at a faster rate by promoting therapeutic angiogenesis to the ischemic sites. Altogether, the present study offers an alternative nanomedicine approach employing ZONFs for the treatment of PADs.
严重肢体缺血（CLI）是外周动脉疾病（PAD）的一种严重类型，由于肢体末端血液供应不足而发生。CLI患者常遭受极度痉挛性疼痛、伤口愈合受损、行动不便、心血管并发症、患肢截肢甚至死亡。治疗CLI的传统疗法包括手术血运重建以及使用生长因子疗法恢复血管生成。然而，手术血运重建仅适用于一小部分CLI患者，且围手术期死亡率高。正如早期临床研究中所观察到的，生长因子的使用在其治疗性血管生成潜力方面也受到限制，这可能归因于其生物利用度差和非特异性问题。因此，为了克服传统策略的上述缺点，迫切需要开发新的替代治疗生物材料来治疗CLI。在过去几十年中，包括我们在内的各个研究小组都参与了不同促血管生成纳米材料的开发。其中，我们实验室开发的氧化锌纳米花（ZONFs）被认为是诱导治疗性血管生成的更有效纳米颗粒之一。在我们早期的研究中，我们表明ZONFs通过诱导活性氧和一氧化氮（NO）的形成以及激活内皮细胞中的Akt/MAPK/eNOS细胞信号通路来促进血管生成。最近，我们还报道了ZONFs通过其神经生成和神经保护特性，利用血管 - 神经相互作用来治疗脑缺血的治疗潜力。考虑到ZONFs优异的促血管生成特性以及血运重建对CLI治疗的重要性，在本研究中，我们全面探索了ZONFs在大鼠后肢缺血模型（通过结扎后肢股动脉建立）中的治疗潜力，该动物模型模拟人类CLI。行为学研究、激光多普勒灌注成像、组织病理学和免疫荧光以及血清NO水平的测定表明，给予ZONFs可以通过促进缺血部位的治疗性血管生成更快地改善大鼠的缺血情况。总之，本研究提供了一种使用ZONFs治疗PADs的替代纳米医学方法。
