Biomimetic approaches for enthesis tissue engineering

附着点组织工程的仿生方法

• 批准号: 10586825
• 负责人: Stavros Thomopoulos
• 金额: $ 47.97万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-21 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586825
• 关键词: Address; Adult; Agonist; Animal Model; Architecture; Biomedical Engineering; Biomimetics; Bone Development; Cells; Chondrocytes; Clinical; Connective Tissue; Control Groups; Cues; Deposition; Development; Elderly; Equilibrium; Erinaceidae; Extracellular Matrix; Failure; Geometry; Goals; Human; In Vitro; Injury; Interdisciplinary Study; Lasers; Ligaments; Location; Mechanics; Meniscus structure of joint; Mesenchymal Stem Cells; Methods; Minerals; Modeling; Modulus; Muscle; Nanotechnology; Natural regeneration; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Oryctolagus cuniculus; Osteoblasts; Outcome; Pathology; Phenotype; Physiological; Population; Postoperative Period; Recreation; Research Project Grants; Rotator Cuff; Shapes; Shoulder; Site; Stress; Structure; Study models; Tendon structure; Testing; Tissue Engineering; Tissues; Translating; Translations; United States; Universities; anterior cruciate ligament reconstruction; bone; bone healing; bone repair; cell motility; clinically relevant; comparison control; cost; design; efficacy testing; fabrication; healing; improved; improved outcome; injured; injury and repair; materials science; mineralization; musculoskeletal injury; neonatal mice; neonatal period; novel; patient population; prevent; repaired; response; rotator cuff injury; rotator cuff tear; scaffold; stem cells; translational study

ABSTRACT Rotator cuff tears are prevalent, particularly in the elderly population, and typically require surgical repair to regain shoulder function. Unfortunately, successful repair remains a major clinical challenge, with high post- operative failure rates. At the root of these failures is poor healing at the repaired tendon-to-bone interface, which does not regenerate the native tendon enthesis attachment structures. Specifically, the healthy tendon enthesis consists of a transitional tissue with spatial gradations in composition (e.g., mineral content) and cell phenotype (e.g., tenocytes, chondrocytes, and osteoblasts), which provides a strong and tough attachment to transfer muscle load from tendon to bone. To address the critical clinical need to improve outcomes after tendon-to-bone repair, this project brings together a multidisciplinary research team to develop, validate, and translate a novel class of biomimetic scaffolds for enhancing healing. The team is led by Dr. Thomopoulos (MPI, an expert in tendon-to-bone development, pathology, and repair) from Orthopedics and Biomedical Engineering at Columbia University and Dr. Xia (MPI, an expert in materials science and nanotechnology) from Biomedical Engineering at Georgia Tech. Key compositional and structural features of the natural tendon-to-bone attachment will be directly fabricated in Aim 1 or generated by stem cells provided with the appropriate cues in Aim 2. The first (acellular) approach has the benefit of high throughput and off-the-shelf availability whereas the second (cellular) approach has the advantage of a responsive extracellular matrix generating component. Funnel-shaped microchannels will be laser drilled through the depth of the scaffolds to encourage cell migration and extracellular matrix deposition, and thus alleviate the concern that the interposed scaffold will be a barrier to healing between the tendon and bone. These two designs will be independently fabricated and evaluated in vitro and then tested in a clinically relevant animal model of rotator cuff injury and repair in Aim 3. Reducing the failure rates of rotator cuff surgical repairs will have a major impact on a large population of patients. The proposed clinically relevant translational studies have the potential to directly impact the treatment of rotator cuff injuries. Furthermore, the results will be broadly applicable to connective tissue-to-bone repair in other locations (e.g., ACL reconstruction, meniscal repair).

摘要 肩袖撕裂很普遍，特别是在老年人群中，通常需要手术修复， 恢复肩部功能。不幸的是，成功的修复仍然是一个主要的临床挑战，高术后并发症， 手术失败率。这些失败的根源是修复的肌腱-骨界面愈合不良， 不会再生天然肌腱附着点附着结构。具体来说，健康肌腱附着点 由在组成上具有空间梯度的过渡组织组成（例如，矿物质含量）和细胞表型 (e.g.,腱细胞、软骨细胞和成骨细胞），其提供了牢固和坚韧的附着以转移 从肌腱到骨骼的肌肉负荷。为了满足改善肌腱-骨移植术后结局的关键临床需求， 修复，这个项目汇集了一个多学科的研究团队，开发，验证和翻译一本小说 一类用于促进愈合的仿生支架。该团队由Mesopoulos博士领导（MPI， 腱-骨发育、病理学和修复），来自哥伦比亚大学骨科和生物医学工程系 大学和夏博士（MPI，材料科学和纳米技术专家）从生物医学工程 在格鲁吉亚理工大学天然肌腱-骨连接的关键组成和结构特征将是 在目标1中直接制造或由在目标2中提供适当线索的干细胞产生。第一 （无细胞）方法具有高通量和现成可用性的益处，而第二种（细胞）方法具有高通量和现成可用性的益处， 该方法具有产生响应性细胞外基质组分的优点。漏斗形 微通道将被激光钻穿支架的深度，以促进细胞迁移和细胞外 基质沉积，并因此减轻了插入支架将成为之间愈合的障碍的担忧。 肌腱和骨头这两种设计将在体外独立制造和评估，然后进行测试 在目标3中的肩袖损伤和修复的临床相关动物模型中。降低旋转器的故障率 袖带外科修复将对大量患者产生重大影响。拟定的临床相关 转化研究有可能直接影响肩袖损伤的治疗。而且 结果将广泛适用于其它位置的结缔组织-骨修复（例如，前交叉韧带重建， 神经修复）。