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: 10490981
• 负责人: Kyung Jae Jeong
• 金额: $ 18.07万
• 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/10490981
• 关键词: Address; Affinity; Amputation; Award; Binding Sites; 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.

项目总结