Use Of Adipose Derived Stem Cells For Engineering Of Ligament Tissue

描述(由申请人提供)： 摘要：前十字韧带断裂是膝关节最常见的韧带损伤之一，常见于VA患者。在美国，每年大约有10.2万例需要手术。前交叉韧带是膝关节的重要稳定器，它的完整性是许多日常生活和体育活动所必需的。在许多退伍军人中，前交叉韧带对于高尔夫和垒球等娱乐体育活动是必要的，在一些患者的日常生活活动中是必要的，包括步行。当受伤时，它的缺失会导致膝关节不稳定，为了避免症状性不稳定，经常需要改变活动度。此外，有证据表明，如果不治疗，膝关节会恶化。因此，前交叉韧带损伤的治疗旨在恢复膝关节的稳定性，以防止继发的半月板和关节软骨损伤而导致的复发不稳定的相关并发症。目前对前交叉韧带断裂的治疗需要使用移植物进行重建，因为损伤的前交叉韧带几乎没有愈合能力。目前的移植选择包括使用自体移植(从另一个未受伤的膝盖部位获得的组织)或同种异体移植(从身体捐赠者获得的组织)。由于使用这些移植物的固有缺点，使用组织工程化的前交叉韧带移植物替代品将是有利的。我们目前正在研究在体外实现这一点的方法，以便稍后在体内植入。该项目的总体目标是开发一种方法，在合成支架上种植自体细胞，在合适的条件下体外培养细胞种子构建物，并最终将其植入膝关节韧带重建。这种方法可以极大地改变膝关节韧带损伤的治疗方法，避免目前使用自体和同种异体移植组织所遇到的缺点和风险。该项目将利用一种新型的生物反应器，将种植有人类脂肪来源干细胞的电纺纤维制成的聚合物支架在体外受到机械刺激和生长因子的影响，作为产生新的韧带组织的初步步骤，这些组织随后可以被植入用于韧带重建。我们希望最终能设计出用于重建前交叉韧带的强韧的新寡聚体，避免因使用自体和同种异体移植物而增加的并发症。此外，这种组织工程学方法可能会缩短此类手术后康复所需的时间。 公共卫生相关性： 项目描述对退伍军人医疗保健的潜在影响：由于退伍军人管理局患者群体中需要手术重建的膝关节韧带损伤很常见，因此这项提议有可能直接影响退伍军人的生活，从而提高退伍军人管理局提供的服务质量。虽然目前重建前交叉韧带的方法在恢复膝关节稳定性方面是成功的，但外科重建有许多副作用和风险，主要是由于重建损伤韧带所需的移植物的使用。事实上，许多患有这种损伤的退伍军人被拒绝为这一问题进行手术，因此必须减少他们的体力活动水平，因为移植物收获引起的发病率风险是没有道理的，而且目前没有足够的同种异体移植供所有有这种问题的人使用。仅在退伍军人管理局，在过去的6年里，就进行了150多次前交叉韧带重建。因此，这项建议可以改善退伍军人前交叉韧带损伤的管理。此外，本研究建立的韧带和肌腱组织工程的基本方法也可直接应用于肌腱或韧带组织缺失或缺失的其他常见临床问题。这些问题包括肩部(肩袖)和膝盖(股四头肌和膝盖骨)肌腱断裂，这在VA患者群体中也很常见。此外，本研究的结果还可应用于其他结缔组织的工程设计，包括其他肌腱、筋膜和皮肤。因此，这项提议最终可能会大幅提高退伍军人的生活质量。

DESCRIPTION (provided by applicant): Abstract: Rupture of the anterior cruciate ligament (ACL) is one of most common ligament injuries of the knee and is often seen in the VA patient population. There are approximately 102,000 cases requiring surgery each year in the United States. The ACL is an important stabilizer of the knee and its integrity is required for many activities of daily living and sporting activities. In many veterans, the ACL is necessary for recreational sporting activities such as golf and softball and in some patients it is necessary for activities of daily living including walking. When injured, its absence leads to knee instability and often necessitates activity modifications in order to avoid symptomatic instability. In addition, there is evidence to suggest the knee joint will deteriorate if left untreated. Thus, the treatment of ACL injuries is aimed at restoring knee stability to prevent the associated complications of recurrent instability with subsequent damage to the menisci and articular cartilage. Current treatments for ACL ruptures require the use of grafts for reconstruction because the injured ACL has little healing capacity. Current graft options include the use of either autografts (tissue obtained from another uninjured part of the knee) or allografts (tissue obtained from a cadaver donor). Because of the inherent disadvantages with the use of these grafts, it would be advantageous to use a tissue- engineered ACL graft substitute. We are currently investigating ways that this could be accomplished in vitro for later implantation in vivo. The overall goal of this project is to develop a method for seeding a synthetic scaffold with autologous cells, cultivating the cell seeded construct under appropriate conditions in vitro and ultimately implanting it for knee ligament reconstruction. This approach could vastly change the treatment of knee ligament injuries and avoids the disadvantages and risks encountered with the current use of autograft and allograft tissue. This project will utilize a novel bioreactor in which polymer scaffolds created with electrospun fibers seeded with human adipose derived stem cells will be subjected to mechanical stimuli and growth factors in vitro as a preliminary step towards generating neoligament tissue which could later be implanted for ligament reconstruction. We hope to eventually engineer strong neoligaments for ACL reconstruction and the added morbidity associated with the use of autografts and allografts could be avoided. In addition, such a tissue engineering approach could potentially shorten the time necessary for rehabilitation following this type of surgery. PUBLIC HEALTH RELEVANCE: Project Narrative Potential Impact on Veterans Health Care: Because knee ligament injuries which require surgical reconstruction are common in the VA patient population, this proposal has the potential to directly influence the lives of veterans and thereby enhance the quality of services provided by the VA. Although current methods for ACL reconstruction are successful at restoring stability to the knee, there are many side effects and risks to surgical reconstruction due primarily to the use of a graft which is needed to rebuild the injured ligament. In fact, many veterans with this injury are denied surgery for this problem and thus must decrease their physical activity level because the risk of morbidity from the graft harvest is not justified and there are not enough allografts currently available for everyone with this problem. At our VA institution alone, over 150 ACL reconstructions have been performed over the last 6 years. Thus, this proposal can improve the management of ACL injuries in veterans. In addition, basic methods of ligament and tendon tissue engineering developed in this study could be directly applied to other common clinical problems in which tendon or ligament tissue is absent or deficient. These problems include shoulder (rotator cuff) and knee (quadriceps and patellar) tendon ruptures, which are also common in the VA patient population. Furthermore, the results of this research could be applied to engineering of other connective tissues including other tendons, fascia, and skin. Thus, this proposal could ultimately result in substantial improvements in the quality of life of veterans.