A nanofiber-hydrogel composite plug for perianal fistula repair

用于肛周瘘修复的纳米纤维-水凝胶复合塞

基本信息

批准号：
10607324
负责人：
Hai-Quan Mao
金额：
$ 65.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607324
关键词：
Age American Anal Fistula Animal Model Anus Biocompatible Materials Biological Response Modifier Therapy Biology Biomimetics Caring Cell Adhesion Cells Characteristics Clinical Collagen Communication Complication Crohn&apos s disease Deposition Development Devices Diagnosis Drainage procedure Elasticity Engineering Extracellular Matrix Family suidae Fecal Incontinence Fistula Foundations Fright Funding Future Generations Goals Hyaluronic Acid Hydrogels Impairment In Vitro Incidence Infection Infiltration Inflammatory Bowel Diseases Inflammatory Response Injectable Injections Kinetics Lead Mechanics Modeling Operative Surgical Procedures Outcome Pain Patients Polyesters Porosity Process Property Protocols documentation Quality of life Rattus Rectum Reproducibility Rodent Model Series Site Skin Structure Structure-Activity Relationship Surgical sutures Testing Tissues Vascularization Work adipose derived stem cell angiogenesis caprolactone cell motility clinical translation clinically relevant conditioning covalent bond effective therapy efficacy evaluation exosome fabrication healing high risk immunoregulation implantation improved in vivo mechanical properties migration nanofiber novel porcine model rectal regenerative repaired research clinical testing response restoration soft tissue stem cell exosomes stem cell therapy success synergism translational potential

项目摘要

SUMMARY Perianal fistulas (PAF) occur in 30-40% of Crohn’s disease patients and their complications lead to a significant impairment in quality of life. Current treatments are effective in less than 50% of cases. The overall objective of this proposed study is to develop a biostimulatory nanofiber-hydrogel composite (NHC) plug to promote tissue healing and to test its efficacy to repair PAF in clinically relevant animal models. Previous work from the Mao and Selaru labs laid the foundation for this study. Specifically, we have established novel rodent and swine models of PAF that faithfully recapitulate the biology of PAF in patients. In parallel, we have developed a first-generation injectable biodegradable nanofiber-hydrogel composite (NHC) from poly(e-caprolactone) (PCL) nanofibers covalently bonded to hyaluronic acid (HA) hydrogel; and demonstrated its ability to deliver adipose stem cells (ADSCs) and repair PAF by conditioning inflammatory responses, permitting host cell infiltration, and facilitating angiogenesis and progressive remodeling. Building on these preliminary results, we plan to engineer a second generation NHC plug with enhanced mechanical strength and integrity as an off-the-shelf device and optimize its biostimulatory activities to induce more favorable cellular responses governing fistula healing. We hypothesize that this NHC plug with structurally, mechanically, and biofunctionally optimized features will effectively promote angiogenesis and soft tissue restoration; and serve as a carrier for ADSCs and ADSC- derived exosomes to further improve the PAF tissue healing. To test this hypothesis and demonstrate its translational potential, we will pursue three specific aims (1) develop a collagen nanofiber-based NHC plug with optimal mechanical properties and porous structure for ease of implantation to support perianal fistula healing, (2) utilize a rat model to evaluate the efficacy for PAF healing when used alone or in conjunction with ADSCs or ADSC-derived exosomes, and elucidate the pro-regenerative mechanism by assessing cell infiltration, angiogenesis, extracellular matrix deposition, and tissue remodeling, and (3) utilize a swine model to demonstrate the synergistic effect in tissue remodeling by combining the optimized NHC plug with ADSC-derived exosomes. This study will deliver a translatable off-the-shelf biomimetic NHC microporous plugs for the delivery of ADSC-derived exosomes capable of promoting soft tissue remodeling and healing for PAF repair.

概括特内利亚瘘（PAF）发生在30-40％的克罗恩病患者中，其并发症导致生活质量的重大损害。目前的治疗在不到50％的病例中有效。总体这项拟议的研究的目的是开发生物刺激性纳米纤维 - 凝胶复合材料（NHC）插头促进组织愈合并测试其在临床相关动物模型中修复PAF的有效性。以前的工作来自毛和塞拉鲁实验室为这项研究奠定了基础。具体来说，我们已经建立了新颖的啮齿动物 PAF的猪模型忠实地概括了患者PAF的生物学。同时，我们已经开发了来自聚（E-Caprolactone）（PCL）的第一代可生物降解的可生物降解纳米纤维 - 凝胶复合材料（NHC）纳米纤维共价键与加氢酸（HA）水凝胶；并证明了其提供脂肪的能力干细胞（ADSC）和通过调节炎症反应，允许宿主细胞浸润和修复PAF 促进血管生成和进行性重塑。在这些初步结果的基础上，我们计划设计第二代NHC插头具有增强的机械强度和完整性，作为现成的设备，优化其生物刺激活性，以引起更有利的细胞反应，控制瘘管愈合。我们假设这种NHC插头在结构，机械和生物功能优化的功能上将有效促进血管生成和软组织恢复；并充当ADSC和ADSC-的载体衍生的外泌体以进一步改善PAF组织愈合。检验这一假设并证明其转化潜力，我们将追求三个具体目标（1）开发基于胶原蛋白的NHC插头最佳的机械性能和多孔结构，以方便植入以支持植物瘘愈合，（2）使用大鼠模型在单独使用或与ADSC结合时评估PAF愈合的效率 ADSC衍生的外泌体，并通过评估细胞浸润，阐明促增再生产机制血管生成，细胞外基质沉积和组织重塑，（3）利用猪模型通过将优化的NHC插头与ADSC衍生的衍生外泌体。这项研究将提供可翻译的现成的仿生NHC微孔插头，用于交付 ADSC来源的外泌体能够促进软组织重塑和愈合以进行PAF修复。