Lou Dong, Luo Yu, Pang Qian, Tan Wei-Qiang, Ma Lie
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, PR China.
Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, PR China.
Bioact Mater. 2020 May 8;5(3):667-679. doi: 10.1016/j.bioactmat.2020.04.018. eCollection 2020 Sep.
Diabetic chronic wound, characterized by prolonged inflammation and impaired angiogenesis, has become one of the most serious challenges in clinic and pose a significant healthcare burden worldwide. Although a great variety of wound dressings have been developed, few of encouraged achievements were obtained so far. In this study, the gene-activated strategy was applied to enhance sustained expression of vascular endothelial growth factor (VEGF) and achieve better healing outcomes by regulating inflammation and promoting angiogenesis. The gene-activated bilayer dermal equivalents (Ga-BDEs), which has good biocompatibility, were fabricated by loading the nano-sized complexes of Lipofectamine 2000/plasmid DNA-encoding VEGF into a collagen-chitosan scaffold/silicone membrane bilayer dermal equivalent. The DNA complexes were released in a sustained manner and showed the effective transfection capacities to up-regulate the expression of VEGF in vitro. To overcome cutaneous contraction of rodents and mimic the wound healing mechanisms of the human, a reformative rat model of full-thickness diabetic chronic wound was adopted. Under the treatment of Ga-BDEs, speeding wound healing was observed, which is accompanied by the accelerated infiltration and phenotype shift of macrophages and enhanced angiogenesis in early and late healing phases, respectively. These proved that Ga-BDEs possess the functions of immunomodulation and pro-angiogenesis simultaneously. Subsequently, the better regeneration outcomes, including deposition of oriented collagen and fast reepithelialization, were achieved. All these results indicated that, being different from traditional pro-angiogenic concept, the up-regulated expression of VEGF by Ga-BDEs in a sustained manner shows versatile potentials for promoting the healing of diabetic chronic wounds.
糖尿病慢性伤口以炎症持续时间长和血管生成受损为特征，已成为临床上最严峻的挑战之一，并在全球范围内造成了巨大的医疗负担。尽管已经研发出了各种各样的伤口敷料，但迄今为止取得的鼓舞人心的成果却很少。在本研究中，采用基因激活策略来增强血管内皮生长因子（VEGF）的持续表达，并通过调节炎症和促进血管生成来实现更好的愈合效果。通过将Lipofectamine 2000/编码VEGF的质粒DNA的纳米复合物负载到胶原-壳聚糖支架/硅酮膜双层真皮替代物中，制备了具有良好生物相容性的基因激活双层真皮替代物（Ga-BDEs）。DNA复合物以持续的方式释放，并在体外显示出上调VEGF表达的有效转染能力。为了克服啮齿动物的皮肤收缩并模拟人类的伤口愈合机制，采用了改良的大鼠全层糖尿病慢性伤口模型。在Ga-BDEs的治疗下，观察到伤口愈合加快，分别伴随着巨噬细胞在愈合早期的加速浸润和表型转变以及在愈合后期的血管生成增强。这些证明Ga-BDEs同时具有免疫调节和促血管生成的功能。随后，实现了更好的再生效果，包括定向胶原的沉积和快速再上皮化。所有这些结果表明，与传统的促血管生成概念不同，Ga-BDEs持续上调VEGF的表达在促进糖尿病慢性伤口愈合方面具有多种潜力。
