MMP-deactivating injectable hydrogel for chronic wounds

项目摘要 慢性伤口是一种疾病状态的结果，在这种疾病状态下，正常的伤口愈合过程受到损害，原因是 创伤的严重程度或其他健康并发症，如糖尿病。如果治疗不当，感染会持续存在， 这会导致组织坏疽和截肢。常见的治疗选择包括应用 伤口敷料，以吸收渗出物，并保持一个保湿的环境。电纺的使用 由生物可降解聚合物或微孔水凝胶制成的纳米纤维已被测试为加速 伤口愈合。尽管做出了这些努力，但治疗慢性伤口的有效方法仍然难以找到。近期 研究表明，高浓度的基质金属蛋白酶(MMPs)是导致 伤口愈合延迟，以及局部递送基质金属蛋白酶抑制剂(MMPI)和针对MMPs的siRNA 在各种慢性伤口模型中显示了加速伤口愈合的有希望的结果。然而， 已知MMPI和siRNAs的全身循环会引起负面副作用，如肌肉骨骼 很痛苦。使用安全的、生物相容的方法来降低伤口处的基质金属蛋白酶活性是非常可取的。 改善慢性伤口护理。这项拟议的研究旨在开发一种可注射的微孔 水凝胶，可通过使MMPs失活来促进慢性伤口的愈合，副作用最小。 基质金属蛋白酶的失活是通过分散在水凝胶中的黑色素纳米颗粒来实现的。黑色素是一种广泛的 一类生物色素，存在于各种生物体内，并已被证明具有高亲和力 包括锌离子在内的多价阳离子。在这里，我们的方法是通过以下方法来停用依赖锌的MMP 耗尽MMPs附近的锌离子，这将导致锌离子从MMPs的催化区域损失 基质金属蛋白酶及其最终的失活。可注射水凝胶是由明胶微凝胶组装而成 它们被酶固化以产生微孔支架，该微孔支架用作 加速伤口愈合。在这项研究中，我们将优化锌的吸收和基质金属蛋白酶的失活 含黑色素的可注射水凝胶，并通过体外细胞迁移证明其治疗效果 实验和体内小鼠伤口愈合研究。综上所述，拟议的研究确定了一项成本- 有效和生物相容的伤口愈合配方，利用自然产生的材料。此外， 这一战略方法可以为治疗其他与基质金属蛋白酶相关的疾病开辟新的途径，包括眼科 炎症性疾病和转移癌。

Project Summary Chronic wounds are the result of a disease state in which the normal wound healing process is impaired due to the severity of trauma or other health complications such as diabetes. If treated improperly, infections persist, which lead to tissue gangrene and amputation. Among the common treatment options are the application of wound dressing to assimilate the exudates and maintain a hydrated environment. The use of electrospun nanofibers made from biodegradable polymers or microporous hydrogels have been tested to accelerate wound healing. Despite these efforts, an effective treatment for chronic wounds remains elusive. Recent studies showed that high concentrations of matrix metalloproteinases (MMPs) are the principal cause of delayed wound healing, and the local delivery of MMP inhibitors (MMPi’s) and siRNA against MMPs have shown promising outcomes for accelerating wound healing for various chronic wound models. However, systemic circulation of MMPi’s and siRNAs is known to induce negative side effects such as musculoskeletal pains. The use of safe, biocompatible methods to reduce MMP activity at the wound site are highly desirable to improve chronic wound care. The proposed research herein aims to develop an injectable microporous hydrogel that can facilitate the healing of chronic wounds by deactivating MMPs with minimal side effects. MMP-deactivation is achieved by melanin nanoparticles dispersed within the hydrogel. Melanins are a broad class of biopigments that are found in various living organisms and have been shown to have high affinity towards multivalent cations including Zn2+. Here, our approach is to deactivate zinc-dependent MMPs by depleting zinc ions in the vicinity of MMPs, which will induce the loss of zinc ions from the catalytic domain of MMPs and their eventual deactivation. The injectable hydrogel is made by the assembly of gelatin microgels which are enzymatically cured to produce a microporous scaffold which serves as a temporary matrix for accelerated wound healing. In this research, we will optimize the zinc absorption and MMP-deactivation by the melanin-containing injectable hydrogel, and demonstrate its therapeutic efficacy by an in vitro cell migration assay and an in vivo mouse wound healing study. Taken together, the proposed research establishes a cost- effective and biocompatible wound healing formulation by utilizing naturally-occurring materials. Furthermore, this strategic approach can open new avenues to treat other MMP-associated diseases including ocular inflammatory diseases and metastatic cancer.