MMP-deactivating injectable hydrogel for chronic wounds

项目摘要 慢性伤口是疾病状态的结果，其中正常的伤口愈合过程由于以下原因而受损： 创伤或其他健康并发症（如糖尿病）的严重程度。如果治疗不当，感染会持续存在， 导致组织坏疽和截肢在常见的治疗方案中， 伤口敷料以吸收渗出物并维持水合环境。静电纺丝的应用 由可生物降解的聚合物或微孔水凝胶制成的纳米纤维已经被测试用于加速 伤口愈合尽管做出了这些努力，但对慢性伤口的有效治疗仍然难以捉摸。最近 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，MMP抑制剂（MMPi）和针对MMP的siRNA的局部递送具有 显示出加速各种慢性伤口模型的伤口愈合的有希望的结果。然而，在这方面， 已知MMPi和siRNA的体循环诱导负面副作用， 痛苦使用安全的、生物相容的方法来降低伤口部位的MMP活性是高度期望的， 改善慢性伤口护理。本文提出的研究旨在开发一种可注射的微孔 这种水凝胶可以通过使MMP失活而促进慢性伤口的愈合，副作用最小。 MMP失活通过分散在水凝胶内的黑色素纳米颗粒实现。黑色素是一种 在各种生物体中发现的一类生物色素，已被证明具有高亲和力 朝向包括Zn 2+的多价阳离子。在这里，我们的方法是通过以下方式使锌依赖性MMP失活： 耗尽MMP附近的锌离子，这将诱导锌离子从MMP的催化结构域损失。 MMP及其最终失活。可注射水凝胶是由明胶微凝胶组装而成的 其被酶促固化以产生微孔支架，所述微孔支架用作临时基质， 加速伤口愈合在这项研究中，我们将优化锌的吸收和MMP-失活， 含有黑色素的可注射水凝胶，并通过体外细胞迁移证明其治疗功效 测定和体内小鼠伤口愈合研究。总的来说，拟议的研究确定了一个成本- 有效和生物相容的伤口愈合制剂。此外，委员会认为， 这一战略方法可以开辟新的途径来治疗其他MMP相关疾病， 炎性疾病和转移性癌症。

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.