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ConProject-001

基本信息

批准号：
10261031
负责人：
Brendan A. Harley
金额：
$ 38.23万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-18 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10261031
关键词：
Address Adopted Affect Autologous Benchmarking Biocompatible Materials Biological Availability Bioreactors Cell Differentiation process Cell Therapy Cells Chemistry Cicatrix Clinical Collagen Data Extracellular Matrix Failure Fibrocartilages Financial Hardship Gelatin Harvest Histologic Hydrogels Immunohistochemistry Implant In Situ Hybridization In Vitro Inferior Injury Kinetics Knowledge Link Measures Mechanics Minerals Modeling Morphology Musculoskeletal Natural regeneration Operative Surgical Procedures Pain Pattern Peptide Signal Sequences Performance Periodicity Phenotype Population Process Property Quality of life Rattus Research Rotator Cuff Shoulder Signal Transduction Site Stress Structure Tendon Injuries Tendon structure Thick Tissues Width base clinical translation demographics density graft failure implantation improved in vivo innovation insight mechanical properties mesenchymal stromal cell morphogens regenerative release factor repaired rotator cuff injury rotator cuff tear scaffold

项目摘要

ABSTRACT Rotator cuff tears are common and occur most commonly as partial-width injuries within the fibrocartilage interface (enthesis) linking tendon to bone. Surgical reattachment of tendon to bone forms a narrow fibrovascular scar rather than regenerates a continuous fibrocartilage enthesis. The resultant sharp boundary between mechanically mismatched tendon and bone leads to strain concentrations and high rates of re-failure at the enthesis. The objective of this proposal is to guide functional regeneration of the structure, composition, and mechanical performance of the injured tendon-to-bone enthesis using an innovative biomaterial therapy. Local implantation of MSCs at the injury site during surgical repair is an attractive option to accelerate enthesis regeneration. However it is essential to develop a biomaterial carrier to improve retention of bioactive MSCs at the injury site and to provide an optimized microenvironment to spatially-regulate MSC differentiation and fibrocartilage remodeling. We have generated rigorous proof-of-principle data for an innovative biomaterial that contains porous mineralized (bone) and anisotropic (tendon) scaffold compartments linked with a continuous gelatin hydrogel interface. This hydrogel interface inhibits formation of strain concentrations that typically form between biomaterials with mismatched mechanical properties under load. The hydrogel interface also provides a depot to locally pattern morphogens to accelerate MSC fibrocartilage differentiation and matrix remodeling. To address our objective we will first demonstrate a mechanically-optimized hydrogel insertion increases biomaterial toughness and locally promotes fibrocartilage differentiation. We will subsequently establish a fibrocartilage-optimized biomolecule patterning strategy to accelerate enthesis-specific MSC differentiation and matrix remodeling. We will ultimately evaluate functional regeneration of the rat rotator cuff enthesis using an optimized biomaterial-MSC construct. We will use in vitro cyclic strain bioreactor studies to optimize MSC- biomaterial interactions as well as a rigorous in vivo rat rotator cuff injury model to benchmark the quality and kinetics of enthesis regeneration via cellular, tissue morphology, and mechanical metrics. This project addresses critical gaps in knowledge and will validate an innovative biomaterial paradigm to accelerate musculoskeletal enthesis regeneration.

摘要