Enhanced Tendon Healing through Growth Factor and Cell Therapies

描述(由申请者提供)：在美国，每年约有300亿美元用于肌肉骨骼损伤。肌腱和韧带损伤几乎占这些损伤的一半。在上肢，手部屈肌腱损伤经常需要手术重建，并导致长期残疾。不良的临床结果通常是由于早期修复部位失效以及肌腱与其周围滑膜之间形成粘连所致。我们的目标是开发治疗方案，以防止修复部位的失败，并减少滑膜内肌腱修复后粘连的形成。屈肌腱的早期愈合依赖于肌腱表面细胞的迁移和/或外部细胞从滑膜鞘向修复部位的延伸。直到迁移细胞聚集在修复部位并合成细胞外基质，修复的机械性能才会改善。然而，肌腱表面细胞的增殖和外在血管的内生可导致肌腱与其鞘之间的粘连形成，并伴随着手指功能的丧失。先前的研究表明，致密结缔组织的愈合可以通过生长因子和基于细胞的治疗来增强。我们以前的研究表明，持续输送生长因子PDGF-BB可以改善屈肌腱修复后的活动范围。其他研究表明，成体干细胞可以促进滑膜外肌腱、关节软骨和其他组织的愈合。然而，很少有人应用这种方法来修复细胞稀少的滑膜内屈肌腱。这项研究的中心假设是，细胞/生长因子联合治疗可以改善滑膜内屈肌腱修复后的滑行和力量。为了验证这一假设，我们将检验自体脂肪来源的间充质干细胞治疗，在注射生长因子和不注射生长因子的情况下，对滑膜内屈肌腱愈合的影响。将使用一种新型的纳米纤维支架，能够控制细胞和生长因子的输送。为了在愈合过程中促进干细胞分化，一种弹性生长因子将与干细胞结合并输送到修复过程中。为了在愈合过程中增强活动范围，抗粘连生长因子将 与弹性生长因子和干细胞结合并交付修复。将确定间充质干细胞应用的效果，并将评估使用间充质干细胞和生长因子共同治疗的影响。结果将直接用于屈肌腱的临床修复，并广泛适用于其他解剖部位的肌腱和韧带修复。 与公共健康相关：在美国，肌肉骨骼损伤的治疗每年导致300亿美元的医疗费用。这些损伤中约有一半涉及肌腱和韧带。以生长因子和细胞为基础的治疗有可能促进广泛结缔组织损伤的愈合。我们的长期目标是应用生长因子和细胞疗法解决方案，以积极影响肌腱修复的临床结果。

DESCRIPTION (provided by applicant): Approximately 30 billion dollars are spent on musculoskeletal injuries in the United States each year. Tendon and ligament injuries represent almost half of these injuries. In the upper extremity, flexor tendon wounds to the hand often require surgical reconstruction and lead to prolonged disability. Poor clinical outcomes typically result from early repair-site failure and the formation of adhesions between the tendon and its surrounding synovial sheath. Our goal is to develop therapeutic solutions to prevent repair-site failure and to reduce adhesion formation following intrasynovial tendon repair. Early healing of flexor tendons relies on the migration of tendon surface cells and/or the extension of extrinsic cells from the synovial sheath to the repair site. The mechanical properties of the repair do not improve until migrating cells populate the site and synthesize extracellular matrix. The proliferation of cells on the tendon surface and the ingrowth of extrinsic vessels, however, can lead to adhesion formation between the tendon and its sheath, with associated loss of digital function. Prior studies have shown that the healing of dense connective tissues can be enhanced via growth factor- and cell-based therapies. Our previous studies demonstrated that sustained delivery of the growth factor PDGF-BB can improve range of motion after flexor tendon repair. Others have shown that adult stem cells can enhance healing in extrasynovial tendons, articular cartilage, and other tissues. However, few have applied this approach to repair pauci-cellular intrasynovial flexor tendons. The central hypothesis of this study is that a combined cell/growth factor therapy can improve gliding and strength of intrasynovial flexor tendons following repair. To test this hypothesis, we will examine the effects of autologous adipose derived mesenchymal stem cell therapy, with and without growth factor administration, on intrasynovial flexor tendon healing. A novel nanofiber scaffold capable of controlling the delivery of cells and growth factors will be used. In an effort to promote stem cell differentiatio during healing, a tenogenic growth factor will be combined with stem cells and delivered to the repair. In an effort to enhance range of motion during healing, an anti-adhesive growth factor will be combined with a tenogenic growth factor and stem cells and delivered to the repair. The effects of mesenchymal stem cell application will be determined and the impact of co-treatment using both mesenchymal stem cells and growth factors will be evaluated. Results will be directly translatable to clinical repair of flexor tendons and broadly applicable to tendon and ligament repair at other anatomic sites. PUBLIC HEALTH RELEVANCE: Treatment of musculoskeletal injuries results in 30 billion dollars in healthcare costs in the United States each year. Approximately half of these injuries involve tendons and ligaments. Growth factor- and cell- based therapy has the potential to improve healing for a broad range of connective tissue injuries. Our long-term goal is to apply growth factor and cell therapy solutions in order to positively affect the clinical outcomes of tendon repair.