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.

项目概要 能够用成熟的透明关节修复较大的缺损（>2cm2 直至半髁） 软骨并通过一次手术解决潜在的骨缺损，使骨软骨同种异体移植物 移植是一个有吸引力的选择。移植物时可以匹配适当的尺寸和表面轮廓 从适当选择的器官捐献者处获得。成熟的软骨细胞可以在术后存活多年 不进行免疫抑制治疗的移植。由于合适的软骨移植物供应不足 满足临床需求、组织工程骨软骨移植物的开发及策略 推广它们在关节中的成功应用将对治疗局部的临床产生重大影响 软骨病变（本提案的重点）和整个关节表面（将来要解决）。 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 膝关节创伤后炎症反应（例如 4 周）可能会改善临床结果。 我们团队的研究描绘了地塞米松 (dex)，这是一种合成糖皮质激素，具有促合成代谢和 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元素 具有天然特性的组织，以及为炎症细胞因子提供软骨保护。正如这些 因素可能会影响软骨组织工程策略的临床成功，而 dex 是 FDA- 批准并在临床上使用以减轻疼痛和炎症，我们试图制定一种策略来使这些 组织培养结果更具临床相关性。从我们的角度来看，理想的方法会保留优点 dex 在工程软骨上的应用，无需外源补充，如临床注射 关节中的类固醇与负面副作用有关。 在这项新的 R01 资助中，我们建议纳入补充右旋糖的聚（丙交酯-乙交酯） (PLGA) 微球进入细胞接种的水凝胶结构中，作为从工程内部传递 dex 的手段 软骨。我们提供的初步数据表明 dex 从 PLGA 微球内部释放 纳入软骨细胞种子水凝胶结构可促进机械功能软骨的生长 组织并以类似于外部补充 dex 观察到的方式赋予细胞因子保护 文化媒体。我们的团队已证实 dex 微球对脂肪组织的体内功效 工程应用。通过局部右旋糖苷递送，可以使用以下浓度来实现这些益处： 比临床注射给药所采用的数量级低。在此基础上再接再厉 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， 我们提出以下总体假设： 掺入聚合物微球，从内部释放 dex 细胞接种的水凝胶结构将保护结构免受细胞因子暴露的有害影响 改善炎症环境中的软骨修复。