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 具有成熟的透明关节 软骨并解决单个过程中潜在的骨不足，使骨软骨同种异体移植 移植是一个有吸引力的选择。当移植物为时，可以匹配适当的尺寸和表面轮廓 从适当选择的器官供体获得。成熟的软骨细胞可以在多年内生存 - 没有免疫抑制治疗的移植。由于不足以供应合适的软骨移植物 满足临床需求，组织设计的骨软骨移植物的发展以及策略 促进他们在关节中的成功应用将对局部治疗产生重大临床影响 软骨病变（该提案中的重点）和整个联合表面（将来将在未来解决）。 来自动物研究和早期临床试验的数据表明，关节内的早期抑制 膝盖创伤后炎症反应（例如4周）可能会改善临床结局。 我们团队的研究描绘了地塞米松（DEX），这是一种合成的糖皮质激素，具有亲甲米代谢和 软骨组织工程系统中的抗代谢作用，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。这样 因素可能会影响软骨组织工程策略的临床成功，而DEX是FDA- 我们在临床上批准并使用以减轻疼痛和炎症，我们试图制定一种制造这些策略 组织培养发现在临床上更相关。从我们的角度来看，理想的方法将保留好处 在工程软骨上的DEX无需外源性注射而不需要外源性 关节中的类固醇与负副作用有关。 在这项新的R01赠款中，我们提出了掺杂dex的聚（乳酸 - 糖糖苷）的掺入 （PLGA）微球进入细胞种子水凝胶构建体，以作为从工程中递送DEX的一种手段 软骨。我们提供了初步数据，表明DEX从PLGA微球内部释放 掺入软骨细胞种子的水凝胶构建体中促进机械功能性软骨的生长 组织和赋予细胞因子保护的方式，类似于与外部补充的Dex观察到的细胞因子保护 培养基。我们的团队已经确认了脂肪组织的体内功效 工程应用。通过局部dex的交付，可以使用浓度来实现这些好处 是通过注射临床给药采用的数量级。建立在这个有前途的基础上 查找并进一步实现该策略基于细胞的软骨修复的临床翻译的潜力， 我们提出以下全局假设：从内部释放DEX的聚合物微球的掺入 细胞种子的水凝胶构建体将保护构建体免受细胞因子暴露和 在炎症环境中改善软骨修复。