Scaffold Microenvironments for Tendon-to-Bone Tissue Engineering

肌腱到骨组织工程的支架微环境

• 批准号: 8842592
• 负责人: Dianne Little
• 金额: $ 7.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842592
• 关键词: Address; Adhesives; Adipose tissue; Affect; Animals; Anisotropy; Architecture; Atomic Force Microscopy; Biocompatible Materials; Bioreactors; Bone Tissue; Calcified; Caliber; Caring; Cartilage; Cell Differentiation process; Cells; Clinical; Complex; Cues; Development; Devices; Economic Burden; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Fiber; Fibrocartilages; Foundations; Gene Expression; Goals; Health; Human; In Vitro; Individual; Joint Capsule; Ligaments; Ligands; Mechanics; Modeling; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Outcome; Pattern; Phenotype; Process; Property; Protein Biosynthesis; Quality of life; Reporting; Rotator Cuff; Shoulder; Stem cells; Stress; Structure; Surgical sutures; System; Techniques; Tendon structure; Testing; Tissue Engineering; Tissue-Specific Gene Expression; Tissues; Work; base; bone; cell behavior; cell motility; design; functional outcomes; improved; in vivo; injury and repair; innovation; interfacial; nanoscale; novel; pre-clinical; repaired; response; scaffold; screening; standard of care; stem cell differentiation; tendon development

DESCRIPTION (provided by applicant): Rotator cuff tears of the shoulder result in annual economic burden of $3-4 billion in surgical expenses alone and have major impact on individual quality of life. Suture repair is the standard of care but high re- tear rates have been reported. Extracellular matrix (ECM) augmentation scaffolds are used to try and improve outcomes for massive tears because they contain bioactive molecules that stimulate cell migration, proliferation and ECM synthesis. However, there are limitations to all the currently available scaffolds and they do not recreate the native tendon-to-bone interface, a graded tendon-fibrocartilage-bone composite tissue which functions to reduce stress concentration at the tendon insertion. Therefore there is a need for a device that more closely recapitulates structure and function of the native tendon-bone interface. Our overall goal is to develop a biomaterial scaffold that promotes integrated tendon-to-bone formation for use in rotator cuff repair. To achieve this goal, we will take an innovative approach to challenge the current paradigm for scaffold development. In addition to ECM cues, other microenvironmental factors such as scaffold microarchitecture can control stem cell differentiation and the formation of complex tissues. For example, electrospinning can be used to form fibers with controllable fiber alignment patterns and diameters, each of which induces specific differentiation responses by stem cells. The current paradigm of scaffold development involves selecting several candidate scaffolds, examining cell behavior in response to culture on these scaffolds, and then modifying scaffold design based on the results obtained before repeating the process. With this approach, there is limited ability to independently manipulate and integrate microenvironmental variables (e.g. scaffold fiber diameter and anisotropy, cell-adhesive ECM ligands) that critically affect cel differentiation and the functional properties of resulting tissue. Therefore, our understanding of how scaffold microenvironments affect functional outcomes remains limited, and identifying scaffold conditions that promote functional composite tissue formation is a highly inefficient process. To overcome these limitations, we intend to use an in vitro micro-photopatterning (microPP) technique to systematically screen scaffold fiber diameter and anisotropy for desired effects on stem cell differentiation towards tendon, cartilage and bone. We will then further functionalize the microPP architectures with tendon-, cartilage- and bone-specific ECM to evaluate additional benefit conferred with the integration of ECM specific ligands. Finally, we wil apply these findings to a multi-layered electrospun scaffold that will be evaluated in vitro for it ability to promote development of a vertically graded tendon- fibrocartilage-bone interface, similar to that seen at the normal tendon-bone interface of the rotator cuff. These findings will improve understanding of microenvironmental cues for tendon-bone tissue engineering and are expected to improve tissue engineered regeneration of the rotator cuff tendon-bone interface.

描述（由申请人提供）：肩部肩袖撕裂每年仅造成手术费用 3-40 亿美元的经济负担，并对个人生活质量产生重大影响。缝线修复是护理标准，但据报道，再撕裂率很高。细胞外基质 (ECM) 增强支架用于尝试改善大量撕裂的结果，因为它们含有刺激细胞迁移、增殖和 ECM 合成的生物活性分子。然而，目前所有可用的支架都存在局限性，它们不能重建天然的肌腱-骨界面，即分级的肌腱-纤维软骨-骨复合组织，其作用是减少肌腱插入处的应力集中。因此，需要一种能够更准确地再现天然腱-骨界面的结构和功能的装置。我们的总体目标是开发一种生物材料支架，促进肌腱与骨骼的整合形成，用于肩袖修复。为了实现这一目标，我们将采取创新方法来挑战当前支架开发的范式。除了 ECM 信号外，支架微结构等其他微环境因素也可以控制干细胞分化和复杂组织的形成。例如，静电纺丝可用于形成具有可控纤维排列模式和直径的纤维，每种纤维都会诱导干细胞的特异性分化反应。目前的支架开发范式包括选择几个候选支架，检查这些支架上培养物的细胞行为，然后根据获得的结果修改支架设计，然后重复该过程。使用这种方法，独立操纵和整合微环境变量（例如支架纤维直径和各向异性、细胞粘附 ECM 配体）的能力有限，这些变量严重影响细胞分化和所得组织的功能特性。因此，我们对支架微环境如何影响功能结果的理解仍然有限，并且识别促进功能性复合组织形成的支架条件是一个非常低效的过程。为了克服这些限制，我们打算使用体外微光图案化（microPP）技术来系统地筛选支架纤维直径和各向异性，以达到对干细胞向肌腱、软骨和骨骼分化的预期效果。然后，我们将利用肌腱、软骨和骨特异性 ECM 进一步功能化 microPP 架构，以评估 ECM 特异性配体整合所带来的额外益处。最后，我们将这些发现应用于多层静电纺丝支架，该支架将在体外评估其促进垂直分级肌腱-纤维软骨-骨界面发育的能力，类似于在正常肌腱-骨界面处看到的情况。肩袖。这些发现将增进对肌腱-骨组织工程微环境线索的理解，并有望改善肩袖肌腱-骨界面的组织工程再生。