Enhanced Tendon Healing through Growth Factor and Cell Therapies

描述（由申请人提供）：在美国，每年大约有300亿美元花费在肌肉骨骼损伤上。肌腱和韧带损伤几乎占这些损伤的一半。在上肢，手部屈肌腱损伤通常需要手术重建，并导致长期残疾。较差的临床结果通常是由于早期修复部位失败和肌腱与其周围滑膜鞘之间形成粘连。我们的目标是开发治疗方案，以防止修复部位失败，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/或滑膜鞘外源细胞向修复部位的延伸。在迁移的细胞填充到修复部位并合成细胞外基质之前，修复的机械性能不会得到改善。然而，肌腱表面细胞的增殖和外源性血管的长入可导致肌腱与其鞘之间的粘连形成，并伴有指指功能的丧失。先前的研究表明，密集结缔组织的愈合可以通过生长因子和细胞为基础的治疗来增强。我们之前的研究表明，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囊胞内屈肌腱。本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动和强度。为了验证这一假设，我们将研究自体脂肪源性间充质干细胞治疗对滑膜内屈肌腱愈合的影响，无论是否使用生长因子。一种新型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的分化，一种肌腱生长因子将与干细胞结合并传递到修复中。为了在愈合过程中增强活动范围，一种抗粘连生长因子会

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.