Tuning the Delivery and Response of Injectable Stem Cells for Cartilage Repair

调整可注射干细胞的输送和反应以进行软骨修复

• 批准号: 10025605
• 负责人: Jay M Patel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025605
• 关键词: Address; Adhesives; Aldehydes; Animal Model; Animals; Biocompatible Materials; Biological; Biology; Biomechanics; Biopolymers; Cadaver; Cartilage; Cartilage Matrix; Cartilage injury; Cell Adhesion; Cell physiology; Cell-Matrix Junction; Cells; Cicatrix; Clinical Management; Clinical Treatment; Coupled; Cues; Defect; Degenerative polyarthritis; Deposition; Development; Elements; Environment; Extracellular Matrix; Fiber; Goals; Growth; Human; Hyaline Cartilage; Hyaluronic Acid; Implant; In Vitro; Injectable; Injections; Injury; Interruption; Joints; Knee; Knowledge; Liquid substance; Mechanics; Meniscus structure of joint; Mentors; Mentorship; Methacrylates; Methods; Miniature Swine; Modeling; Modification; Molecular; Molecular Target; Molecular Weight; Musculoskeletal; Natural regeneration; Patients; Pennsylvania; Peptides; Permeability; Phenotype; Physical environment; Physiological; Property; Proteoglycan; Research; Research Personnel; Seasons; Site; Structure; Surface; Surgical Models; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Thick; Tissue Engineering; Tissues; Translational Research; Treatment Efficacy; Universities; Veterans; Weight-Bearing state; Work; articular cartilage; base; biomechanical engineering; career; cartilage repair; clinical translation; density; design; experience; fluid flow; implantation; improved; improved outcome; in vivo; innovation; insight; mechanical properties; novel; novel therapeutics; osteogenic; post-doctoral training; preservation; pressure; prevent; progenitor; recruit; repaired; response; scaffold; skills; stem; stem cells; tissue regeneration; tissue repair

My professional aspiration is to develop an independent research career exploring innovative implants and therapeutics for musculoskeletal tissue repair and regeneration. During my graduate studies at Rutgers University, I designed and fabricated a novel fiber-reinforced meniscus scaffold, evaluated it in a long-term large animal model, and tested its implantation and load-bearing efficacy in human cadaveric knees. With this productive graduate career involving macro-scale biomechanics and tissue engineering, I was fortunate to join the CMCVAMC and the University of Pennsylvania for my postdoctoral training, under the mentorship Dr. Robert Mauck, in order to gain experience and knowledge in cell-biomaterial interactions, mechano-biology, and tissue engineering at the micro-scale. Furthermore, a seasoned co-mentoring team will provide significant support with regards to biomaterials synthesis and modification, surgical models and approaches, and clinical translation. The proposed research plan will expose me to these concepts and methods that work complimentarily to my current skillset, and uses these micro-scale approaches to inform a macro-scale therapy for cartilage defects. Articular cartilage is a remarkable tissue, with a dense extracellular matrix that allows the tissue to undergo fluid pressurization during compressive loading. Cartilage defects compromise this function, introducing free boundaries that result in the flow of proteoglycans and other matrix elements out of the tissue. Decreases in matrix density at defect boundaries make them vulnerable to progressive erosion, instigating a vicious cycle that gradually increases defect size and concludes with joint-wide osteoarthritis (OA). The development of a therapeutic to delay or prevent this progression would be groundbreaking in the clinical management of cartilage injuries. To address cartilage defects, various repair and regeneration techniques have been developed, yet most are inconsistent or ineffective. While new and modified biomaterials can improve treatment efficacy by targeting damaged cartilage to improve scaffold integration or biofactor delivery, the use of such molecular targeting to functionally restore the mechanical properties of the defect boundary has not yet been investigated. We hypothesize that, by introducing a living fibrous barrier that limits fluid flow through the interface (via targeted progenitor cell recruitment and differentiation), one might reestablish normal cartilage biomechanical function and therefore preserve cartilage in the vicinity of a defect, stemming OA progression. To test this hypothesis, the objective of this proposal is to target damaged cartilage with a tunable microenvironment that can recruit cells and direct their activities towards the formation of a barrier that will restore and preserve the native cartilage mechanical function and matrix content. Specifically, we will (1) develop a biomaterial that can effectively localize to defected cartilage; (2) tune the biomolecular and biomechanical cues to attract cells and promote formation of a fibrous barrier; and (3) evaluate the ability of this living barrier to restore fluid pressurization capacity and prevent proteoglycan loss after injury. The first undertaking will be accomplished by optimizing the delivery of modified hyaluronic acid to damaged cartilage, while maintaining native cell cytocompatibility. Next, the delivered biomaterial will be modified to maximize cell attachment and spreading, two requirements for fibrous tissue deposition. Lastly, the efficacy of the microenvironment in delaying progressive matrix loss from defect boundaries will be determined in both an in vitro cartilage explant culture model, and in a large-animal cartilage defect model. A therapeutic that produces a living low-permeability tissue barrier has the potential to delay or prevent the growth of focal defects into joint- wide OA. The proposed research plan and outstanding institutional environment will provide me with the necessary skills and experiences to become a successful VA-based independent investigator.

我的专业愿望是开发独立的研究职业，探索创新植入物和 用于肌肉骨骼组织修复和再生的治疗剂。在我在罗格斯的研究生学习期间 大学，我设计并制造了一种新颖的纤维增强弯板脚手架，并长期对其进行了评估 动物模型，并在人尸体膝盖中测试了其植入和承重功效。与此 涉及宏观生物力学和组织工程的生产研究生职业，我很幸运能加入 CMCVAMC和宾夕法尼亚大学接受我的博士后培训的指导，由Robert博士 Mauck，为了获得细胞生物材料相互作用，机械生物学和组织的经验和知识 微型尺度工程。此外，经验丰富的联盟团队将为 关于生物材料的合成和修饰，手术模型和方法以及临床翻译。 拟议的研究计划将使我了解这些概念和方法，这些概念和方法是对我的 当前的技能，并使用这些微尺度方法为软骨缺陷提供了宏观尺度疗法。 关节软骨是一种显着的组织，具有密集的细胞外基质，使组织能够进行液体 压缩加载期间的加压。软骨缺陷妥协此功能，引入免费 导致蛋白聚糖和其他基质元件流出组织的边界。减少 缺陷边界处的矩阵密度使它们容易受到渐进性侵蚀的影响，煽动了一个恶性循环 逐渐增加了缺陷的大小，并结合联合骨关节炎（OA）结论。一个发展 在软骨的临床管理中，延迟或防止这种进展的治疗方法将是开创性的 受伤。为了解决软骨缺陷，已经开发了各种维修和再生技术 大多数是不一致或无效的。尽管新的和改良的生物材料可以通过 靶向损坏的软骨以改善脚手架整合或生物活性剂的递送，使用这种分子 尚未研究靶向功能恢复缺陷边界的机械性能。 我们假设这是通过引入活纤维屏障来限制流体流过界面的（通过目标） 祖细胞募集和分化），可能会重新建立正常软骨生物力学功能 因此，在缺陷的附近保留软骨，促成OA的进展。 为了检验这一假设，该提案的目的是针对可调的软骨靶向损坏的软骨 可以招募细胞并将其活动引导到形成屏障的微环境 将恢复并保留天然软骨机械功能和基质含量。具体来说，我们会的 （1）开发一种可以有效定位到软骨的生物材料； （2）调整生物分子和 生物力学提示吸引细胞并促进纤维屏障的形成； （3）评估这一点的能力 恢复液体加压能力并防止受伤后蛋白聚糖损失的生命障碍。第一个 通过优化修饰的透明质酸到软骨损坏的递送来实现承诺， 同时维持天然细胞的细胞相容性。接下来，将修改递送的生物材料以最大化细胞 附着和扩散，纤维组织沉积的两个要求。最后， 在延迟缺陷边界延迟渐进式矩阵损失方面的微环境将在两者中确定 体外软骨外植体培养模型，以及大动物软骨缺陷模型。产生一个的治疗性 生活低渗透性组织屏障有可能延迟或防止局灶性缺陷的生长到关节 宽OA。拟议的研究计划和杰出的机构环境将为我提供 成为成功的基于VA的独立调查员的必要技能和经验。