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

• 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
• 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

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.

抽象的 肩袖撕裂很常见，主要始于分层纤维软骨界面（附着点）连接 肌腱到骨头。肌腱与骨的手术重新附着会形成狭窄的纤维血管疤痕，而不是 再生连续的纤维软骨附着点。由此产生的机械之间的尖锐界限 肌腱和骨骼不匹配会导致张力集中和附着点再次失败率很高。这 该提案的目标是指导结构、组成和功能的再生和修复 使用创新的分层生物材料对受伤的肌腱至骨附着点进行机械性能研究。 在手术修复过程中，术中在损伤部位植入间充质干细胞是加速修复过程的一个有吸引力的选择 附着点再生。然而，开发一种生物材料载体以提高保留率和 跨损伤部位的生物活性 MSC 的再生活性。我们将评估创新的设计 分层生物材料提供机械和营养刺激，促进 MSC 保留和附着 再生。我们已经为含有骨的胶原生物材料生成了严格的原理验证数据 和与连续水凝胶界面连接的模拟肌腱支架隔室。我们将展示 水凝胶界面抑制通常在不匹配的生物材料之间形成的应变浓度 负载下的机械性能。此外，水凝胶界面提供了加速纤维软骨形成的位点 例如响应邻近肌腱和骨中产生的营养因子的分化和重塑 模拟支架隔间。综上所述，我们假设包含连续的水凝胶区域 连接肌腱和骨特异性支架隔室提供了机械和营养优势 与整体和传统分层生物材料相比，加速再生能力。为了解决我们的 假设我们首先确定机械优化的水凝胶插入是否以及如何增加 机械性能并支持体外纤维软骨分化（目标 1）。我们随后将 证明分层生物材料中产生的营养因子可加速附着特异性 MSC 体外分化和基质重塑（目标 2）。我们最终将评估功能修复和 使用体内附着点生物材料-MSC 构建体再生大鼠肩袖附着点（目标 3）。我们 将使用体外循环应变生物反应器研究来优化 MSC-生物材料相互作用，然后进行一系列分层的 体内大鼠肩袖损伤模型，通过细胞对附着点再生的质量和动力学进行基准测试， 组织形态和力学指标。该项目将为帮助临床转化提供重要的见解 改善肌肉骨骼附着点再生的生物材料疗法。