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: 10250667
• 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
• 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/10250667
• 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

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 肩袖撕裂是常见的，最常见的是纤维软骨内的部分宽度损伤 连接肌腱和骨的界面（附着点）。通过手术将肌腱重新连接到骨头上，形成一个狭窄的 纤维血管瘢痕而不是再生连续的纤维软骨附着点。由此产生的尖锐边界 机械不匹配的肌腱和骨之间的不匹配导致应变集中和高再失效率 在终点。该建议的目的是指导结构、组成、 和机械性能的损伤肌腱-骨附着点使用创新的生物材料疗法。 在手术修复过程中，在损伤部位局部植入MSC是加速肌腱附着的一个有吸引力的选择 再生然而，开发生物材料载体以改善生物活性MSC的保留是至关重要的。 损伤位点，并提供优化的微环境以空间调节MSC分化， 纤维软骨重塑我们已经为一种创新生物材料生成了严格的原理验证数据， 包含多孔矿化（骨）和各向异性（肌腱）支架隔室， 明胶水凝胶界面。这种水凝胶界面抑制了通常形成的应变浓度的形成， 在负载下具有不匹配的机械性能的生物材料之间。水凝胶界面还提供 局部形成形态发生素的贮库，以加速MSC纤维软骨分化和基质重塑。 为了解决我们的目标，我们将首先证明机械优化的水凝胶插入增加了 生物材料的韧性和局部促进纤维软骨分化。随后，我们将建立一个 纤维软骨优化的生物分子图案化策略，以加速附着点特异性MSC分化， 基质重塑我们将最终评估大鼠肩袖附着点的功能再生， 优化的生物材料-MSC构建体。我们将使用体外循环菌株生物反应器研究来优化MSC- 生物材料相互作用以及严格的体内大鼠肩袖损伤模型，以基准的质量和 通过细胞、组织形态学和机械度量的附着点再生动力学。这个项目 解决知识的关键差距，并将验证创新的生物材料范例，以加速 肌肉骨骼附着点再生