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: 10442216
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442216
• 关键词: Tuning; Delivery; Response; Injectable; Stem

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.

我的职业抱负是发展一个独立的研究事业，探索创新的植入物， 用于肌肉骨骼组织修复和再生的治疗剂。我在罗格斯大学读研究生期间 大学，我设计并制造了一种新型的纤维增强半月板支架，在一个长期的大规模评估， 动物模型，并测试其在人尸体膝关节中的植入和承载功效。与此 我的研究生生涯涉及宏观生物力学和组织工程，我很幸运地加入了 CMCVAMC和宾夕法尼亚大学为我的博士后培训，在导师罗伯特博士 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， 微观尺度的工程学。此外，经验丰富的共同指导团队将提供重要的支持， 生物材料合成和改性、手术模型和方法以及临床翻译。 拟议的研究计划将使我接触到这些概念和方法，这些概念和方法与我的工作相辅相成。 目前的技能，并使用这些微观尺度的方法，通知软骨缺损的宏观尺度的治疗。 关节软骨是一个显着的组织，具有致密的细胞外基质，使组织经历流体 在压缩载荷期间加压。Carbohydrate缺陷损害了这一功能，引入了免费的 导致蛋白聚糖和其他基质成分流出组织的边界。减少 缺陷边界处的基质密度使它们容易受到渐进侵蚀，从而引发恶性循环， 逐渐增加缺损尺寸，并以关节广泛性骨关节炎（OA）结束。的发展 治疗延迟或防止这种进展将是开创性的临床管理软骨 受伤为了解决软骨缺损，已经开发了各种修复和再生技术，然而， 大多数是不一致或无效的。虽然新的和改性的生物材料可以通过以下方式提高治疗效果： 靶向受损的软骨以改善支架整合或生物因子递送， 还没有研究功能性地恢复缺陷边界的机械性能的目标。 我们假设，通过引入活纤维屏障，限制流体流过界面（通过靶向 祖细胞募集和分化），可能会重建正常的软骨生物力学功能 从而保留缺损附近的软骨，阻止OA进展。 为了验证这一假设，本提案的目的是用可调的 微环境可以招募细胞并将其活动导向形成屏障， 将恢复和保存天然软骨的机械功能和基质含量。具体来说，我们将 (1)开发可以有效定位于缺损软骨的生物材料;（2）调整生物分子， 生物力学线索，以吸引细胞和促进纤维屏障的形成;和（3）评估这种能力， 活屏障，以恢复液体加压能力，并防止损伤后蛋白聚糖丢失。第一 将通过优化修饰的透明质酸向受损软骨的递送来完成任务， 同时保持天然细胞的细胞相容性。接下来，将对递送的生物材料进行修改，以最大化细胞 附着和铺展，纤维组织沉积的两个要求。最后， 微环境在延迟渐进基质损失从缺陷边界将确定在这两个 体外软骨外植体培养模型和大动物软骨缺损模型。一种治疗剂， 活的低渗透性组织屏障有可能延迟或防止局部缺损生长到关节内， 宽OA拟议的研究计划和出色的机构环境将为我提供 必要的技能和经验，成为一个成功的VA为基础的独立调查员。