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

用于综合软骨修复的颗粒状人源生物材料的开发和转化

• 批准号: 10718170
• 负责人: Corey P Neu
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718170
• 关键词: Address; Adhesions; Adoption; Allografting; Animals; Biocompatible Materials; Biological; Biological Assay; Biological Products; Bone Injury; Bromodeoxyuridine; Cartilage; Cartilage injury; Cell Count; Cell Differentiation process; Cell Proliferation; Cells; Chemistry; Clinical Trials; Colorado; Community Medicine; Defect; Degenerative polyarthritis; Development; Devices; Disease Progression; Embryo; Ensure; Equipment; Extracellular Matrix; Family suidae; Formulation; Friction; Future; Gene set enrichment analysis; Genes; Goat; Good Manufacturing Process; Grant; Guidelines; Health; Human; Human Resources; Hyaluronic Acid; Implant; Individual; Lubrication; Marketing; Measures; Mechanics; Medical; Mesenchymal Stem Cells; Muscle; Musculoskeletal; Natural regeneration; Ontology; Operative Surgical Procedures; Particle Size; Pathway interactions; Persons; Phenotype; Positioning Attribute; Process; Production; Property; Quality Control; Records; Regenerative Medicine; Reporting; Reproducibility; Research; Shapes; Signaling Molecule; Skin; Source; Specific qualifier value; Standardization; Structure; Structure-Activity Relationship; Sulfhydryl Compounds; Surface; Technology; Temperature; Testing; Tissue Therapy; Tissues; Toxic effect; Translations; United States; Validation; Work; adult stem cell; arthropathies; articular cartilage; bone; cartilage repair; cell motility; commercialization; crosslink; density; differential expression; fetal; healing; human adult stem cell; human stem cells; human tissue; improved; innovation; interstitial; macromolecule; manufacture; mechanical properties; novel; osteochondral repair; osteochondral tissue; particle; pre-clinical; repair strategy; response; stem cell differentiation; stem cell proliferation; stem cells; technology platform; transcriptome sequencing

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.

项目概要/摘要 该提案的目的是研究一种具有颗粒结构的新型人源生物材料， NatruLage，刺激成体干细胞分化以进行综合软骨修复。 关节软骨和骨损伤的治疗已显示出解决基质退化问题的令人兴奋的潜力 与骨关节炎（OA）有关，骨关节炎是一种困扰美国数百万人的关节疾病。 候选疗法利用动物或人类材料来形成独特的微环境 有利于促进健康骨软骨组织愈合和整合的干细胞反应。 细胞外基质被组织成具有特殊细胞和信号传导的间质和细胞周区域 这些成分共同定义了组织特异性和结构功能关系： 不幸的是，综合软骨修复仍然是一种主要的医疗手段。 需要新产品来增强和改进疗法。 骨软骨组织疗法需要降低技术和制造风险以满足广泛的需求 新的创新必须符合现行的良好生产规范 (cGMP)。 规范并证明积极的细胞和生物反应的临床前证据以及 在提交研究器械豁免 (IDE) 包以及随后执行之前没有毒性 为了改善综合软骨修复，我们开发了一种新型颗粒状细胞外基质。 采用称为 NatruLage 的专有交联技术，将其注入骨缺损处并 我们的设备将软骨层形成与自然带状组织结构非常相似的骨软骨组织。 具有“流动性”，可输送致密的组织颗粒，并在输送后通过 通过硫醇官能化大分子进行独特的交联 我们评估了相同的 NatruLage。 技术，使用猪代替人体组织，并在 12- 月大型动物（山羊）骨软骨修复研究。 NatruLage 使用人源同种异体移植组织来输送不同层的骨软骨组织。 定义适当的化学、制造和质量控制来支持 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 NatruLage。在目标 1 中，我们将调整现有的 cGMP 设施。 人类 NatruLage 的生产 在目标 2 中，我们将定义 NatruLage 重现性和供体的规范。 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。 成功的话，我们将为其他被丢弃或无法生存的骨软骨修复市场创造一个理想的二次骨软骨修复市场 同种异体移植组织，这笔赠款将支持提交 NatruLage 的 IDE 包。