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.

项目摘要 慢性伤口是疾病状态的结果，在这种状态下，正常伤口愈合过程受到了损害 创伤或其他健康并发症（例如糖尿病）的严重程度。如果受到不当治疗，感染持续存在， 导致组织坏疽和截肢。在常见的治疗选择中，应用 伤口敷料吸收成年人并保持水合环境。电纺的使用 已经测试了由可生物降解聚合物或微孔水凝胶制成的纳米纤维，以加速 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。最近的 研究表明，高浓度的基质金属蛋白酶（MMP）是 延迟伤口愈合，MMP抑制剂（MMPI）和针对MMP的siRNA的局部递送具有 显示了各种慢性伤口模型加速伤口愈合的有希望的结果。然而， 已知MMPI和siRNA的全身循环会引起负面副作用，例如肌肉骨骼 痛苦。使用安全，生物相容性的方法来减少伤口部位的MMP活性非常需要 改善慢性伤口护理。本文提出的研究旨在开发可注射的微孔 可以通过极少副作用停用MMP来促进慢性伤口的愈合的水凝胶。 MMP偏活活化是通过分散在水凝胶内的黑色素纳米颗粒来实现的。黑色素是广阔的 在各种生物体中发现的一类生物形象，已被证明具有高亲和力 朝着包括Zn2+在内的多价阳离子。在这里，我们的方法是通过 在MMP附近耗尽锌离子，这将诱导从催化结构域的锌离子损失 MMP及其最终停用。可注射水凝胶是通过明胶微凝胶组装而成的 用酶固化的，产生微孔支架，该支架用作临时基质的 加速伤口愈合。在这项研究中，我们将优化通过 含黑色素的注射水凝胶，并通过体外细胞迁移证明其治疗效率 测定和一项体内小鼠伤口愈合研究。综上所述，拟议的研究确立了成本 - 通过利用自然疾病的材料，有效且具有生物相容性的伤口愈合配方。此外， 这种战略方法可以打开新的途径，以治疗其他MMP相关疾病，包括眼 炎症性疾病和转移性癌症。