Engineering the open porous nanofibrous microsphere integrated fibrillar hydrogel for the co-delivery of antibacterial and angiogenic agents aimed at the rapid diabetic wound repair

设计开放多孔纳米纤维微球集成纤维水凝胶，用于共同递送抗菌剂和血管生成剂，旨在快速修复糖尿病伤口

• 批准号: 10737115
• 负责人: Johnson Vitharikunnil John
• 金额: $ 25.62万
• 依托单位: TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737115
• 关键词: Acceleration; Affect; Amputation; Angiogenic Peptides; Anti-Bacterial Agents; Anti-Inflammatory Agents; Architecture; Bacterial Infections; Biocompatible Materials; Cell Migration Induction; Cells; Cessation of life; Chemistry; Cicatrix; Complication; Diabetic Foot Ulcer; Diabetic mouse; Disulfides; Engineering; Extracellular Matrix; Family suidae; Flow Cytometry; Gel; Gelatin; Glucose; Glycolates; Goals; Granulation Tissue; Growth Factor; Histology; Human; Hybrids; Hydrogels; Immune response; In Vitro; Individual; Infection Control; Infection prevention; Injectable; Matrix Metalloproteinases; Methacrylates; Microbial Biofilms; Microspheres; Modality; Modeling; Monitor; Mus; Nanofiber Scaffold; Natural regeneration; Nutrient; Oxidation-Reduction; Oxygen; Patients; Peptides; Photochemistry; Play; Porosity; Process; Production; Proliferating; Property; Protease Inhibitor; Quality of life; Role; Site; Skin; Splint Device; Sterile coverings; Sterility; Stimulus; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Type 2 diabetic; Vascular Endothelial Growth Factors; Vascularization; Wound Infection; Wound models; angiogenesis; antimicrobial; cathelicidin; cathelicidin antimicrobial peptide; cell motility; combinatorial; controlled release; cytotoxicity; design; diabetic patient; diabetic ulcer; diabetic wound healing; effective therapy; efficacy evaluation; healing; improved; in vivo; infection rate; innovation; invention; methicillin resistant Staphylococcus aureus; migration; mimetics; minimally invasive; nanofiber; neovascularization; novel; prevent; response; treatment strategy; wound; wound closure; wound dressing; wound environment; wound healing

PROJECT SUMMARY This proposal aims to engineer a multifactorial wound dressing composed of open porous nanofibrous microspheres (NMs) integrated with a stimuli-responsive fibrillar hydrogel (FHG) to release therapeutics to accelerate diabetic wound healing. The open porous structure in the proposed wound dressing can enhance cell migration and granulation tissue formation for rapid wound closure. Initially, the porous NMs will be fabricated from electrospun short nanofiber segments using our newly invented core-shell electrospray technique with bubble technology. Afterward, the peptide-tethered matrix metalloproteinases (MMP) responsive FHG will be integrated with porous NMs to develop an injectable hybrid gel followed by photocrosslinking. Previously, we demonstrated that porous nanofiber scaffolds show tremendous improvements in cell migration and cell/tissue integration. Inspired by the results, we will develop a new wound dressing platform that improves the wound healing process in several aspects; (i) The extracellular matrix (ECM) mimetic porous structure of the NMs can accelerate the cell migration during the healing. (ii) Engineering an ECM mimetic FHG with methacrylate gelatin (GelMA) and MMP responsive peptide linker can offer to maintain the moist conditions and sustained delivery of therapeutic agents locally. (iii) The engineered peptide conjugated NMs integrated FHG can prevent diabetic wound infection and tune the angiogenesis by sustained release of antibacterial and angiogenic peptides. To achieve these goals, we will incorporate antibacterial LL-37 mimic W379 peptide, and vascular endothelial growth factor (VEGF) mimetic QK peptide to the NMs integrated FHG. Specifically, we have identified that porous NMs properties can modulate cell migration through the porous microarchitecture and improve wound healing compared with nonporous NMs composed gel. The fibrillar hydrogel network will provide moist conditions in the wound similar to ECM and the controlled release of peptides in the wound milieu. We will evaluate and optimize material properties using the following characterization workflow: the porosity of NMs, the injectability of hybrid gel, in vitro cytotoxicity quantification, in vitro gel degradation with different MMP cell responses (survival, proliferation, and migration), in vitro antibacterial efficacy of W379 peptide, in vitro angiogenic properties of QK peptide, in vivo immune response (analysis by Flow cytometry), in vivo material degradation (analysis by histology), and in vivo tissue healing/regeneration (analysis by immunohistology). Afterward, we will focus on an infected diabetic mouse (db/db) splinted wound healing model to evaluate the efficacy of the dressing with and without peptides . We expect to see accelerated wound healing through the open porous NMs composed of the injectable hydrogel compared with commercially available Geistlich Derma gideTM composed of the injectable hydrogel. This project has the potential to develop a new class of biomaterial and create an inexpensive and effective treatment for diabetic wounds by increasing our understanding of how to inhibit biofilm formation and porosity-induced cell migration in diabetic wound closure.

项目摘要 该建议旨在设计由开放多孔纳米纤维组成的多因素伤口敷料 与刺激响应原纤维水凝胶（FHG）集成的微球（NMS），以将治疗剂释放到 加速糖尿病伤口愈合。拟议的伤口敷料中的开放多孔结构可以增强细胞 迁移和肉芽组织形成，以快速伤口闭合。最初，多孔NMS将被制造 使用我们的新发明的核心壳电喷雾技术，从电纺短纳米纤维段与 气泡技术。之后，肽螺旋的基质金属蛋白酶（MMP）反应性FHG将是 与多孔NMS集成以开发可注射的杂种凝胶，然后进行光叠链接。以前，我们 证明多孔纳米纤维支架显示出细胞迁移和细胞/组织的巨大改善 一体化。受结果的启发，我们将开发一个新的伤口敷料平台，以改善伤口 几个方面的康复过程； （i）NMS的细胞外基质（ECM）模拟多孔结构 在愈合过程中加速细胞迁移。 （ii）用甲基丙烯酸酯明胶工程ECM模拟FHG （Gelma）和MMP响应性肽接头可以提供以维持潮湿条件并持续交付 本地治疗剂。 （iii）工程肽共轭的NMS集成FHG可以预防糖尿病 伤口感染并通过持续释放抗菌和血管生成肽来调节血管生成。到 实现这些目标，我们将结合抗菌LL-37模拟W379肽和血管内皮 生长因子（VEGF）模拟QK肽与NMS综合FHG。具体来说，我们已经确定了多孔 NMS性质可以通过多孔微体系结构调节细胞迁移并改善伤口愈合 与非孔NMS组成的凝胶相比。纤维水凝胶网络将在 与ECM相似的伤口以及伤口环境中肽的受控释放。我们将评估和优化 使用以下表征工作流的材料特性：NMS的孔隙率，杂种的注射性 凝胶，体外细胞毒性定量，体外凝胶降解，具有不同的MMP细胞反应（生存， QK的体外血管生成特性，增殖和迁移），体外抗菌疗效 肽，体内免疫反应（通过流式细胞仪分析），体内材料降解（通过 组织学）和体内组织愈合/再生（通过免疫组织学分析）。之后， 我们将专注于 感染的糖尿病小鼠（DB/DB）夹住伤口愈合模型，以评估与和 没有肽 。我们希望看到通过由敞开的多孔NMS加速伤口愈合 与可注射的可注射的Geistlich Derma Gidetm相比，可注射的水凝胶相比 水凝胶。该项目有可能开发新的生物材料，并创建一个便宜的和 通过增加我们对如何抑制生物膜形成和 孔隙率引起的糖尿病伤口闭合中的细胞迁移。