Development and Translation of Granulated Human-Derived Biomaterials for Integrative Cartilage Repair

项目总结/摘要 该提案的目的是研究一种新的具有颗粒状结构的人源生物材料， NatruLage，刺激成体干细胞分化，用于整合软骨修复。的最新进展 关节软骨和骨损伤的治疗显示出解决基质变性的令人兴奋的潜力 骨关节炎（OA）是一种折磨美国数百万人的关节疾病。新 候选疗法利用动物或人类来源的材料来配制独特的微环境 有利于促进愈合和整合的干细胞反应。在健康的骨软骨组织中， 细胞外基质被组织成具有特化细胞和信号传导的间质和细胞周结构域 分子。这些成分共同定义了组织特异性和结构-功能关系， 在疾病进展过程中丢失。不幸的是，综合软骨修复仍然是一个主要的医疗 需要新的产品来增强和改进治疗。成功采用 骨软骨组织治疗需要广泛的技术和制造风险，以满足严格的 监管批准要求。新的创新必须符合当前的良好生产规范（cGMP） 并证明阳性细胞和生物学反应的临床前证据，以及 在提交试验用器械豁免（IDE）包之前以及之后执行之前，无毒性 一个临床试验。为了改善软骨的整体修复，我们开发了一种新的颗粒状细胞外基质， 使用专有的交联技术，称为NatruLage，将其注射到骨缺损中， 软骨层以形成紧密模仿天然带状组织结构的骨软骨组织。我们的设备 可“流动”以输送密集包装的组织颗粒， 通过硫醇官能化的大分子进行独特的交联。我们已经评估了相同的自然 技术，使用猪而不是人类组织，并发现有希望的再生和整合在一个12- 月大动物（山羊）骨软骨修复研究。我们现在专注于发展 NatruLage使用人源性同种异体移植组织输送不同层的骨软骨组织。我们将 定义适当的化学、生产和质量控制，以支持cGMP生产 NatruLage用于未来的临床试验，我们将有助于了解干细胞对 自然疗法我们将追求三个相关的具体目标。在目标1中，我们将调整已建立的cGMP设施， 生产人类天然产物。在目标2中，我们将定义NatruLage再现性和供体的质量标准 可变性在目标3中，我们将量化NatruLage对成体干细胞增殖和分化的刺激。如果 如果成功，我们将为那些被丢弃或无法生存的人创造一个理想的二次骨软骨修复市场。 同种异体移植组织，该基金将支持NatruLage的IDE包的提交。

PROJECT SUMMARY / ABSTRACT The objective of this proposal is to study how a new human-derived biomaterial with granulated structure, NatruLage, stimulates adult stem cell differentiation for integrative cartilage repair. Recent advances in the treatment of articular cartilage and bone injuries have shown exciting potential to address matrix degeneration associated with osteoarthritis (OA), a joint disease afflicting millions of people in the United States. New candidate therapies utilize animal- or human-sourced materials to formulate unique microenvironments favorable to stem cell responses that promote healing and integration. In healthy osteochondral tissue, the extracellular matrix is organized into interstitial and pericellular domains with specialized cells and signaling molecules. Together, these components define tissue-specific and structure-function relationships which are lost during disease progression. Unfortunately, integrative cartilage repair still remains as a major medical need, and new products are required for enhanced and improved therapies. Successful adoption of osteochondral tissue therapies requires extensive technical and manufacturing de-risking to meet stringent regulatory approval requirements. New innovations must meet current good manufacturing practice (cGMP) specifications and demonstrate pre-clinical evidence of positive cellular and biological responses as well as lack of toxicity prior to submission of an investigational device exemption (IDE) package and, later, execution of a clinical trial. To improve integrative cartilage repair, we developed a novel granulated extracellular matrix with a proprietary crosslinking technology, termed NatruLage, that is injected into the defect in bone and cartilage layers to form osteochondral tissue that closely mimics the natural zonal tissue structure. Our device is ‘flowable’ to deliver densely-packed tissue particles, and enable forming and shaping after delivery through unique crosslinking via thiol-functionalized macromolecules. We have evaluated the same NatruLage technology, using porcine instead of human tissue, and found promising regeneration and integration in a 12- month large animal (goat) study of osteochondral repair. We are now focused on the development of NatruLage using human-derived allograft tissue for delivery of distinct layers of osteochondral tissue. We will define the appropriate chemistry, manufacturing, and quality controls to support the cGMP production of NatruLage for future clinical trials, and we will contribute to understanding the stem cell responses to NatruLage. We will pursue three related specific aims. In Aim 1, we will adapt established cGMP facilities for production of human NatruLage. In Aim 2, we will define specifications for NatruLage reproducibility and donor variability. In Aim 3, we will quantify NatruLage stimulation of adult stem cell proliferation and differentiation. If successful, we will create an ideal secondary osteochondral repair market for otherwise discarded or nonviable allograft tissue, and the grant will support the submission of an IDE package for NatruLage.