Tissue Engineering Strategies to Revitalize Allografts

振兴同种异体移植物的组织工程策略

基本信息

批准号：
10830613
负责人：
Danielle S. Benoit
金额：
$ 44.88万
依托单位：
UNIVERSITY OF OREGON
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：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10830613
关键词：
ANGPT1 gene Adenoviruses Adhesions Adhesives Allografting Autologous Transplantation Biochemical Biomechanics Blood Vessels Bone Regeneration Bone Transplantation Cell Transplantation Cells Chemistry Clinical Collagen Crosslinker Cues Data Defect Development Diameter Diffuse Encapsulated Endothelial Cells Engineering Excision Experimental Designs Failure Fibronectins Fibrosis Fracture Funding Gel Histology Hydrogels Immunohistochemistry In Vitro Infection Infiltration Laminin Ligands MMP2 gene Matrix Metalloproteinases Mediating Mesenchymal Stem Cells Migration Assay Morbidity - disease rate Mus Natural regeneration Nerve Organ Transplantation Orthopedics Paracrine Communication Patients Peptides Periosteal Cell Periosteum Procedures Process Property Reconstructive Surgical Procedures Role Site Stromal Cell-Derived Factor 1 Testing Thinness Tissue Engineering Tissues Torque Transplantation Trauma Validation Vascular Endothelial Growth Factors Vascularization Work allogenic bone transplantation bone bone reconstruction cell type clinical translation congenital anomaly contrast imaging controlled release crosslink design ethylene glycol graft healing healing implantation improved in vivo in vivo evaluation innovation knock-down meter mimetics osteoprogenitor cell overexpression paracrine peptidomimetics recruit repaired response single-cell RNA sequencing small hairpin RNA stem cells tyrosyl-isoleucyl-glycyl-seryl-arginine

项目摘要

There are limited options for reconstruction of bone defects resulting from congenital anomalies, trauma, infection, and oncologic resection. Over 2 million bone graft procedures are performed annually worldwide, with the clinical ‘gold standard’ being the use of autografts. Autografts fully heal and integrate, mediated by the periosteum, a thin layer of tissue and periosteal cells (PCs) surrounding bone. However, autografts are limited due to tissue availability and donor site morbidity. Thus, decellularized allografts are commonly employed. However, the limited ability of allografts, which lack periosteum, to remodel and integrate with the host tissue directly contributes to ~35% and 60% failure rates within 2 and 10 years of implantation. Periosteal-mediated healing is coordinated by a variety of contextual cues including matrix remodeling and adhesion and temporally defined release of paracrine factors. Our overarching hypothesis is that allograft healing will be dramatically improved by capturing critical healing cues in a tissue engineered periosteum (TEP). In the first funding cycle, we pioneered development of the TEP, which incorporates mesenchymal stem cells (MSCs) and OPs within hydrolytically degradable poly(ethylene glycol)(PEG)-based hydrogels, which are formed around allografts, similar to native periosteum. TEP shows outstanding promise to enhance murine allograft healing, resulting in a 300% increase in maximum fracture torque versus unmodified allografts at 9 weeks post-implantation. However, healing was plagued by fibrotic tissue, which results in the allograft limited to ~50% of autograft maximum torque. Fibrosis is consistent with poorly supported infiltration of TEP by host vessel/tissue, a limitation resulting from bulk hydrolytic TEP degradation which results in structural insufficiencies to support complete host-tissue infiltration. Thus, the focus of this renewal is a cellularly remodeled TEP, which enables localized, cell-demanded degradation while maintaining bulk hydrogel properties to support host-tissue infiltration. Three specific aims are outlined: Specific Aim 1: Tune TEP matrix cues (adhesive peptides and MMP-degradable crosslinks) to coordinate tissue infiltration and improve allograft healing. Specific Aim 2: Characterize TEP-mediated host-tissue recruitment. Specific Aim 3: Exploit the optimized TEP matrix to deliver peptides emulating periosteal paracrine cues as a translatable, acellular TEP. Successful completion of these Aims will significantly advance our understanding of how the periosteum coordinates allograft healing and the design of engineered periosteum to promote these bone regeneration processes. The developed material platforms and general approach are also readily applicable in other tissue engineering applications.

由于先天异常、创伤、全世界每年进行超过 200 万例骨移植手术，临床“黄金标准”是使用自体移植物，由自体移植物介导完全愈合和整合。骨膜，一层薄薄的组织和骨膜细胞（PC）围绕骨。然而，自体移植物是有限的。由于组织可用性和供体部位发病率，通常采用脱细胞同种异体移植物。然而，缺乏骨膜的同种异体移植物重塑并与宿主组织整合的能力有限直接导致骨膜介导的植入后 2 至 10 年内失败率分别为 35% 和 60%。愈合是通过各种背景线索来协调的，包括基质重塑和粘附以及暂时的我们的总体假设是同种异体移植物的愈合将显着加快。在第一个资助周期中，通过捕获组织工程骨膜（TEP）中的关键愈合线索来改善。我们率先开发了 TEP，其中包含间充质干细胞 (MSC) 和 OP 可水解降解的聚乙二醇（PEG）基水凝胶，在同种异体移植物周围形成，与天然骨膜相似，TEP 在增强小鼠同种异体移植愈合方面表现出出色的前景，从而导致植入后 9 周，与未修饰的同种异体移植物相比，最大断裂扭矩增加了 300%。然而，愈合受到纤维化组织的困扰，这导致同种异体移植仅限于自体移植的约 50% 纤维化与宿主血管/组织对 TEP 的渗透支持不良一致，a 由于 TEP 大量水解降解导致结构不足以支持因此，这种更新的重点是细胞重塑的 TEP，这使得 TEP 成为可能。局部的、细胞需要的降解，同时保持本体水凝胶特性以支持宿主组织概述了三个具体目标：具体目标 1：调整 TEP 矩阵线索（粘附肽和 MMP 可降解交联）协调组织浸润并改善同种异体移植物愈合。表征 TEP 介导的宿主组织募集。具体目标 3：利用优化的 TEP 矩阵来实现。模拟骨膜旁分泌信号的肽作为可翻译的非细胞 TEP 成功完成了这些任务。目标将显着增进我们对骨膜如何协调同种异体移植愈合和骨膜如何协调同种异体移植愈合的理解。设计工程骨膜以促进这些骨再生过程。平台和通用方法也很容易适用于其他组织工程应用。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Micelle Delivery of Parthenolide to Acute Myeloid Leukemia Cells.

小白菊内酯胶束递送至急性髓系白血病细胞。

DOI：
发表时间：
2015-09
期刊：
影响因子：
0
作者：
Baranello, Michael P;Bauer, Louisa;Jordan, Craig T;Benoit, Danielle S W
通讯作者：
Benoit, Danielle S W

Delivery of RNAi-Based Therapeutics for Bone Regeneration.

提供基于 RNAi 的骨再生疗法。

DOI：
发表时间：
2020
期刊：
影响因子：
4.3
作者：
Malcolm, Dominic W;Wang, Yuchen;Overby, Clyde;Newman, Maureen;Benoit, Danielle S W
通讯作者：
Benoit, Danielle S W

3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration.

视网膜色素上皮-脉络膜毛细血管复合体的 3D iPSC 建模确定了黄斑变性病理学中涉及的因素。

DOI：
发表时间：
2021-05-06
期刊：
影响因子：
23.9
作者：
Manian, Kannan V;Galloway, Chad A;Dalvi, Sonal;Emanuel, Anthony A;Mereness, Jared A;Black, Whitney;Winschel, Lauren;Soto, Celia;Li, Yiming;Song, Yuanhui;DeMaria, William;Kumar, Akhilesh;Slukvin, Igor;Schwartz, Michael P;Murphy, William L;An
通讯作者：
An

Development and in vitro assessment of enzymatically-responsive poly(ethylene glycol) hydrogels for the delivery of therapeutic peptides.

用于递送治疗性肽的酶响应聚乙二醇水凝胶的开发和体外评估。