Incorporation of Dexamethasone Delivery within Engineered Cartilage

将地塞米松输送纳入工程软骨中

• 批准号: 9724359
• 负责人: Clark T. Hung
• 金额: $ 55.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9724359
• 关键词: Address; Adipose tissue; Adopted; Allografting; Animal Model; Arthroscopy; Biochemical; Canis familiaris; Cartilage; Cells; Chondrocytes; Clinical; Culture Media; Data; Defect; Degenerative polyarthritis; Development; Dexamethasone; Elements; Engineering; FDA approved; Future; Glucocorticoids; Glycolates; Glycolic-Lactic Acid Polyester; Gold; Grant; Growth; Histology; Histopathologic Grade; Hydrogels; Image; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injections; Interleukin-1 beta; Joint repair; Joints; Knee Injuries; Knee joint; Lesion; Measurement; Measures; Mechanics; Methods; Microspheres; Modeling; Organ Donor; Outcome; Polymers; Procedures; Property; Prosthesis; Public Health; Research; Second Look Surgery; Sepharose; Steroids; Supplementation; Surface; Swelling; Synovial Fluid; System; TNF gene; Testing; Therapeutic immunosuppression; Tissue Engineering; Tissues; Transplantation; Trauma; Traumatic injury; X-Ray Computed Tomography; absorption; animal data; articular cartilage; base; bone; cartilage repair; clinical translation; clinically relevant; cytokine; early phase clinical trial; gait examination; healing; iatrogenic injury; implantation; improved; in vivo; inflammatory milieu; microCT; osteochondral tissue; pain reduction; post-transplant; pre-clinical; repaired; response; side effect; success; tissue culture; tissue repair; translational approach

PROJECT SUMMARY The ability to resurface larger defects (>2cm2 up to a hemicondyle) with mature hyaline articular cartilage and address the underlying bone deficit in a single procedure makes osteochondral allograft transplantation an attractive option. The appropriate size and surface contour can be matched when the graft is obtained from an appropriately selected organ donor. Mature chondrocytes can survive for many years post- transplantation without immunosuppressive therapy. As there is insufficient supply of suitable cartilage grafts to meet the clinical demand, the development of tissue engineered osteochondral grafts and strategies to promote their successful application in the joint would have significant clinical impact for treatment of localized cartilage lesions (of focus in this proposal) and whole joint surfaces (to be addressed in the future). Data from animal studies and early clinical trials suggest that early inhibition of the intra-articular inflammatory response (e.g., 4 weeks) posttraumatic injury of the knee may improve clinical outcomes. Research from our team portrays dexamethasone (dex), a synthetic glucocorticoid that has pro-anabolic and anti-catabolic effects in cartilage tissue engineering systems, as a critical element for cultivating cartilage tissues with native properties, as well as for providing chondroprotection to inflammatory cytokines. As these factors are likely to impact the clinical success of cartilage tissue engineering strategies, and dex is FDA- approved and used clinically to reduce pain and inflammation, we sought to develop a strategy to make these tissue culture findings more clinically relevant. From our perspective, an ideal method would retain the benefits of dex on engineered cartilage without the requirement for its exogenous supplementation, as clinical injections of steroids in the joint have been associated with negative side effects. In this new R01 grant, we propose the incorporation of dex-supplemented, poly(lactide-co-glycolide) (PLGA) microspheres into cell-seeded hydrogel constructs as a means for dex delivery from within engineered cartilage. We present preliminary data demonstrating that dex release internally from PLGA microspheres incorporated in chondrocyte-seeded hydrogel constructs promotes growth of mechanically functional cartilage tissue and confers cytokine protection in a manner akin to that observed with dex externally supplemented in culture media. In vivo efficacy of dex-microspheres has been confirmed by our team for adipose tissue engineering applications. With localized dex delivery, these benefits were achievable using concentrations that are orders of magnitude lower than adopted for clinical administration by injection. To build on this promising finding and to further realize the potential for clinical translation of this strategy for cell-based cartilage repair, we pose the following global hypothesis: Incorporation of polymer microspheres that release dex from within cell-seeded hydrogel constructs will protect constructs from the deleterious effects of cytokine exposure and improve cartilage repair in an inflammatory environment.

项目摘要 能够用成熟的透明关节面置换较大的缺损（> 2cm 2，最多半髁） 软骨和解决潜在的骨缺损在一个单一的程序，使骨软骨同种异体移植 移植是一个有吸引力的选择。当移植物被植入时，可以匹配适当的尺寸和表面轮廓。 从适当选择的器官捐赠者那里获得。成熟的软骨细胞可以存活多年， 移植而不进行免疫抑制治疗。由于缺乏合适的软骨移植物， 组织工程化骨软骨移植物的研究进展及临床应用策略 促进其在关节中的成功应用将对治疗局部性 软骨病变（本建议的重点）和整个关节表面（将在未来解决）。 来自动物研究和早期临床试验的数据表明，早期抑制关节内 炎症反应（例如，4周）膝关节创伤后损伤可能会改善临床结局。 我们团队的研究描绘了地塞米松（dex），一种合成糖皮质激素，具有促合成代谢作用， 软骨组织工程系统中的抗分解代谢作用，作为培养软骨的关键要素 具有天然特性的组织，以及用于提供对炎性细胞因子的软骨保护。因为这些 这些因素可能会影响软骨组织工程策略的临床成功，而dex是FDA- 批准并用于临床减轻疼痛和炎症，我们试图开发一种策略，使这些 组织培养结果更有临床意义。从我们的角度来看，一个理想的方法将保留的好处 的dex的工程软骨，而不需要其外源性补充，作为临床注射 关节中类固醇的含量与副作用有关。 在这项新的R 01资助中，我们建议将右旋糖酐补充的聚（丙交酯-乙交酯） 将PLGA微球植入细胞接种的水凝胶构建体中，作为从工程化细胞内递送地塞米松的手段。 软骨我们目前的初步数据表明，地塞米松释放内部从PLGA微球 掺入软骨细胞接种的水凝胶构建体促进机械功能性软骨的生长 并以类似于用外部补充的DEX观察到的方式赋予细胞因子保护， 培养基。我们的研究小组已经证实了dex-微球对脂肪组织的体内疗效 工程应用通过局部dex递送，这些益处可以使用以下浓度来实现， 比临床注射给药低几个数量级。在这个充满希望的 发现并进一步实现这种基于细胞的软骨修复策略的临床转化潜力， 我们提出了以下总体假设：聚合物微球的掺入， 接种细胞的水凝胶构建体将保护构建体免受细胞因子暴露的有害影响， 改善炎症环境中软骨修复。