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

我的职业抱负是发展一项独立的研究事业，探索创新的植入物和 肌肉骨骼组织修复和再生治疗学。我在罗格斯大学读研究生期间 在大学期间，我设计并制作了一种新型的纤维增强半月板支架，并对其进行了长期的 动物模型，并在人体身体膝关节上测试其植入和承重效果。有了这个 在涉及宏观生物力学和组织工程的毕业生涯中，我有幸加入 CMCVAMC和宾夕法尼亚大学为我提供博士后培训，在Robert博士的指导下 为了获得细胞-生物材料相互作用、机械生物学和组织方面的经验和知识 微观尺度的工程学。此外，经验丰富的共同指导团队将为 涉及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接触到这些概念和方法，这些概念和方法对我的 目前的技能，并使用这些微观规模的方法，以提供宏观规模的软骨缺陷的治疗。 关节软骨是一种非凡的组织，具有致密的细胞外基质，使组织能够吸收液体。 压缩加载过程中的加压。软骨缺陷损害了这一功能，导致游离 导致蛋白多糖和其他基质元素流出组织的边界。减少了 缺陷边界处的基质密度使其容易受到渐进性侵蚀，从而引发恶性循环 逐渐增大缺陷大小，最终导致关节范围的骨关节炎(OA)。开发一种新的 延缓或阻止这一进展的治疗将是软骨临床治疗的开创性进展。 受伤。为了解决软骨缺陷，已经开发了各种修复和再生技术，但 大多数都是前后不一致或无效的。而新的和改良的生物材料可以通过以下方式提高治疗效果 靶向受损软骨以改善支架整合或生物因子输送，使用这种分子 旨在从功能上恢复缺陷边界的力学性能的研究还没有被研究。 我们假设，通过引入一种活的纤维屏障来限制流体通过界面的流动(通过靶向 祖细胞的募集和分化)，可以重建正常的软骨生物力学功能 因此保留了缺损区附近的软骨，阻止了骨性关节炎的进展。 为了验证这一假设，这项提议的目标是用可调节的软骨来定位受损的软骨。 可以招募细胞并引导它们的活动形成屏障的微环境 将恢复和保存天然软骨的机械功能和基质内容。具体来说，我们将 (1)开发一种能够有效地定位于受损软骨的生物材料；(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；以及(3)评估这一能力 生活屏障，恢复体液加压能力，防止蛋白多糖在损伤后丢失。第一 这项工作将通过优化向受损软骨输送改性透明质酸来完成， 同时保持天然细胞的细胞相容性。接下来，交付的生物材料将被修改以最大限度地提高细胞 附着和铺展是纤维组织沉积的两个要求。最后，该方案的功效 延缓来自缺陷边界的渐进性基质损失的微环境将在两个方面确定 体外软骨移植培养模型，并在大动物软骨缺损区模型。一种疗法，能产生一种 活的低渗透组织屏障有可能延缓或阻止局灶性缺陷生长到关节- 广域办公。拟议的研究计划和出色的制度环境将为我提供 成为一名成功的退伍军人事务部独立调查员所需的技能和经验。

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.