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Stratified and mechanically-tough biomaterial implant to improve tendon-to-bone enthesis regeneration

分层且机械坚固的生物材料植入物可改善肌腱到骨附着点的再生

基本信息

批准号：
10495364
负责人：
Brendan A. Harley
金额：
$ 32.08万
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：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10495364
关键词：
Address Adopted Affect Allogenic Autologous Benchmarking Biocompatible Materials Bioreactors Cell Differentiation process Cells Cicatrix Clinical Collagen Data Extracellular Matrix Failure Fibrocartilages Financial Hardship Functional Regeneration Gelatin Harvest Histology Hydrogels Immunohistochemistry Implant In Situ Hybridization In Vitro Injury Kinetics Link Measures Mechanical Stimulation Mechanics Modeling Morphology Musculoskeletal Natural regeneration Nature Operative Surgical Procedures Pain Pattern Peptide Signal Sequences Performance Periodicity Phenotype Population Process Quality of life Rattus Rotator Cuff Shoulder Site Source Stimulus Stress Structure Tendon Injuries Tendon structure Tissues biomaterial interface bone clinical translation demographics density design implantation improved in vivo in vivo Model innovation insight mechanical properties mesenchymal stromal cell mimetics regeneration potential regenerative repaired response rotator cuff injury rotator cuff tear scaffold standard of care

项目摘要

ABSTRACT Rotator cuff tears are common and primarily initiate at the stratified 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 and repair of the structure, composition, and mechanical performance of the injured tendon-to-bone enthesis using an innovative stratified biomaterial. Intraoperative 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 and regenerative activity of bioactive MSCs across the injury site. We will evaluate the design of an innovative stratified biomaterial to provide mechanical and trophic stimuli to promote MSC retention and enthesis regeneration. We have generated rigorous proof-of-principle data for a collagen biomaterial that contains bone- and tendon-mimetic scaffold compartments linked with a continuous hydrogel interface. We will show the hydrogel interface inhibits strain concentrations that typically form between biomaterials with mismatched mechanical properties under load. Further, the hydrogel interface provides a site to accelerate fibrocartilage- like differentiation and remodeling in response to trophic factors produced in adjacent tendon- and bone- mimetic scaffold compartments. Taken together, we hypothesize inclusion of a continuous hydrogel zone linking tendon- and bone-specific scaffold compartments provides mechanical and trophic advantages to accelerate regenerative potency versus monolithic and conventional stratified biomaterials. To address our hypothesis we will first determine if and how a mechanically-optimized hydrogel insertion both increases mechanical performance and supports fibrocartilage differentiation in vitro (Aim 1). We will subsequently demonstrate trophic factors produced across the stratified biomaterial accelerate enthesis-specific MSC differentiation and matrix remodeling in vitro (Aim 2). We will ultimately evaluate functional repair and regeneration of the rat rotator cuff enthesis using an enthesis biomaterial-MSC construct in vivo (Aim 3). We will use in vitro cyclic strain bioreactor studies to optimize MSC-biomaterial interactions, then a tiered set of in vivo rat rotator cuff injury models to benchmark the quality and kinetics of enthesis regeneration via cellular, tissue morphology, and mechanical metrics. This project will provide essential insight to aid clinical translation of a biomaterial therapy to improve musculoskeletal enthesis regeneration.

摘要