MMP-deactivating injectable hydrogel for chronic wounds

用于慢性伤口的 MMP 失活注射水凝胶

• 批准号: 10288972
• 负责人: Kyung Jae Jeong
• 金额: $ 17.99万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288972
• 关键词: Address; Affinity; Amputation; Award; Binding Sites; Biological; Biological Assay; Biological Process; Blood Circulation; Catalytic Domain; Cations; Chelating Agents; Chronic Disease; Clinical; Coagulation Process; Complex; Cornea; Development; Diabetes Mellitus; Diabetic mouse; Disease; Disseminated Malignant Neoplasm; Dry Eye Syndromes; Edetic Acid; Environment; Enzymes; Epithelial; Exudate; Formulation; Gangrene; Gelatin; Gelatinase A; Gelatinase B; Goals; Health; Homeostasis; Human; Hydration status; Hydrogels; Impaired wound healing; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Injectable; Injury; Interstitial Collagenase; Ions; Lead; Left; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Medical; Melanins; Methods; Migration Assay; Modeling; Monitor; Mus; Musculoskeletal Pain; National Institute of Biomedical Imaging and Bioengineering; Neoplasm Metastasis; Organism; Outcome; Oxidation-Reduction; Permeability; Process; Reporting; Research; Series; Severities; Site; Skin Substitutes; Small Interfering RNA; Testing; Tissue Engineering; Tissues; Trauma; Treatment Efficacy; Wound models; Zinc; absorption; biodegradable polymer; biomaterial compatibility; cancer therapy; chronic wound; common treatment; cost effective; design; diabetic ulcer; effective therapy; healing; histological studies; improved; in vivo; innovation; keratinocyte; melting; nanofiber; nanoparticle; novel; scaffold; side effect; wound; wound care; wound dressing; wound healing

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.

项目概要 慢性伤口是一种疾病状态的结果，其中正常伤口愈合过程由于以下因素而受到损害： 创伤或其他健康并发症（例如糖尿病）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的常见治疗方案是应用。 伤口敷料吸收渗出物并维持水合环境使用静电纺丝。 由可生物降解聚合物或微孔水凝胶制成的纳米纤维已被测试可以加速 尽管做出了这些努力，但慢性伤口的有效治疗方法仍然难以实现。 研究表明，高浓度的基质金属蛋白酶（MMP）是导致 延迟伤口愈合，局部递送 MMP 抑制剂 (MMPi’s) 和针对 MMP 的 siRNA 然而，对于加速各种慢性伤口模型的伤口愈合，显示出有希望的结果。 已知 MMPi 和 siRNA 的体循环会引起负面副作用，例如肌肉骨骼 非常需要使用安全、生物相容的方法来降低伤口部位的 MMP 活性。 本文提出的研究旨在开发一种可注射的微孔伤口护理。 水凝胶可以通过灭活 MMP 来促进慢性伤口的愈合，且副作用最小。 MMP 失活是通过分散在水凝胶中的黑色素纳米颗粒实现的。黑色素是一种广泛的物质。 在各种生物体中发现的一类生物颜料，已被证明具有高亲和力 包括 Zn2+ 在内的多价阳离子在这里，我们的方法是通过使锌依赖性 MMP 失活。 消耗 MMP 附近的锌离子，这将导致锌离子从 MMP 的催化域中损失 MMP 及其最终失活可注射水凝胶是由明胶微凝胶组装而成。 通过酶固化产生微孔支架，作为临时基质 在这项研究中，我们将通过优化锌的吸收和 MMP 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功效 结合起来，该研究建立了成本- 利用天然材料制成的有效且生物相容的伤口愈合配方。 这一战略方法可以为治疗其他 MMP 相关疾病（包括眼病）开辟新途径 炎症性疾病和转移性癌症。