Stem Cell-laden Hyaluronic Acid Gels for Cartilage Repair: In Vivo Translation

用于软骨修复的干细胞透明质酸凝胶：体内翻译

• 批准号: 8456453
• 负责人: Matthew B Fisher
• 金额: $ 3.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2013-12-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456453
• 关键词: Acute; Adult; Affect; Allografting; Animal Model; Animals; Appearance; Autologous; Autologous Transplantation; Benchmarking; Biochemical; Biological Models; Biomechanics; Cartilage; Cartilage injury; Cells; Characteristics; Chondrocytes; Chondrogenesis; Clinical; Clinical Treatment; Complex; Cues; Data; Defect; Degenerative polyarthritis; Development; Family suidae; Gel; Goals; Gold; Growth Factor; Healed; Hyaluronic Acid; Hydrogels; In Vitro; Injury; Joints; Laboratories; Lead; Measures; Mechanics; Mentors; Mesenchymal Stem Cells; Modeling; Molecular; Molecular and Cellular Biology; Motion; Nature; Orthopedics; Performance; Physical environment; Property; Replacement Arthroplasty; Research; Research Training; Role; Stem cells; Surface; System; Techniques; Time; Tissue Engineering; Tissues; Training; Translations; Work; articular cartilage; base; career; cartilage repair; density; experience; healing; imaging modality; implantation; improved; in vivo; in vivo Model; novel; osteochondral tissue; pre-clinical; public health relevance; repaired; restoration; scaffold; success; treatment strategy

DESCRIPTION (provided by applicant): Intrinsic repair of articular cartilage damage is unsatisfactory, largely due to its avascular nature and demanding physical environment. Various reconstructive techniques have not yet succeeded in restoring the complex mechanical properties of articular cartilage. Tissue engineering approaches have been pursued in the laboratory setting with results on the order of the native tissue. However, in vitro and in vivo daa suggest that increased tissue maturity may limit the ability to integrate with cartilage explants. Thus, these data indicate that "static" measures of construct maturity upon implantation (e.g. compressive modulus) may not be the best indicators of in vivo success. Alternatively, time-dependent increases in these properties in vitro (i.e. positive maturation rates) may provide a better indicator of success in vivo. Thus, the overall goal of this application is to take a "trajectory-based" approach to cartilage tissue engineering to determine the importance of in vitro culture parameters on the performance of tissue engineered constructs in vivo. To accomplish this objective, the PI will train under a unique team of mentors and will utilize a successful tissue engineering approach using a novel hydrogel combined with adult mesenchymal stem cells (MSCs). Once optimized, this approach will be implemented in a large animal model. Using this model system, we will 1) optimize in vitro formation and maturation of constructs made from porcine MSC- seeded HA hydrogels to establish baseline maturation trajectories, 2) compare mechanisms to accelerate construct maturation in vitro (increase trajectories), and 3) evaluate the role of maturation trajectories on construct properties and integration to the surrounding cartilage using both in vitro and in vivo models. Analysis will include cellular, histological, biochemical, and biomechanical measures of construct maturation. Successful completion of this project will represent a marked advance in the restoration of cartilage after injury, and will provide a novel treatment strategy for a debilitating condition affecting millions of people. This represents a shift in the paradigm away from the gold standard benchmark of cartilage TE constructs (i.e. properties similar to native tissue). Instead, we focus on "priming" the constructs, and then allowing them to appropriately remodel and integrate in vivo to restore normal function. Moreover, the unique experience gained will greatly benefit the PI's burgeoning career in orthopaedic research with a strong focus on translational models for tissue engineering.

描述(申请人提供)：关节软骨损伤的内在修复并不令人满意，这主要是由于其无血管的性质和苛刻的物理环境。各种重建技术尚未成功地恢复关节软骨的复杂力学性能。组织工程方法已经在实验室环境中进行了探索，结果达到了天然组织的数量级。然而，体外和体内的DAA表明，组织成熟度的增加可能会限制与软骨移植的整合能力。因此，这些数据表明，植入后“静态”测量结构成熟度(例如压缩弹性系数)可能不是体内成功的最佳指标。或者，这些特性在体外随时间的增加(即正成熟率)可能提供更好的体内成功指标。因此，这项应用的总体目标是采用基于轨迹的方法进行软骨组织工程，以确定体外培养参数对体内组织工程构建物性能的重要性。为了实现这一目标，PI将在一个独特的导师团队下进行培训，并将利用一种成功的组织工程方法，使用一种新型水凝胶与成人间充质干细胞(MSCs)相结合。一旦优化，这种方法将在大型动物模型中实施。使用这个模型系统，我们将1)优化猪MSC-HA水凝胶构建物的体外形成和成熟，以建立基线成熟轨迹，2)比较促进体外构建成熟的机制(增加轨迹)，以及3)使用体外和体内模型评估成熟轨迹对构建特性和与周围软骨整合的作用。分析将包括构建成熟的细胞、组织学、生化和生物力学测量。该项目的成功完成将代表着损伤后软骨恢复方面的显著进步，并将为影响数百万人的衰弱疾病提供一种新的治疗策略。这代表着从软骨TE构造的黄金标准基准(即类似于天然组织的特性)的范式的转变。取而代之的是，我们专注于“启动”这些构造，然后允许它们在体内适当地重塑和整合，以恢复正常的功能。此外，获得的独特经验将极大地有利于PI在骨科研究领域的蓬勃发展，并将重点放在组织工程的翻译模型上。