Engineering Tendon Grafts for Better Outcomes

工程肌腱移植以获得更好的结果

• 批准号: 9120306
• 负责人: Chunfeng Zhao
• 金额: $ 58.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-07 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120306
• 关键词: Accounting; Adhesions; Adopted; Allografting; Amputation; Animal Model; Attenuated; Autologous; Autologous Transplantation; Award; Biocompatible; Bone Marrow; Canis familiaris; Carbodiimides; Cell Density; Cell Therapy; Cells; Chemical Engineering; Chemicals; Cicatrix; Clinical; Clinical Research; Data; Digit structure; Economic Burden; Emergency department visit; Engineering; Exhibits; Fingers; Flexor; Freeze Drying; Funding; Goals; Hand; Harvest; Health; Hyaluronic Acid; Impaired wound healing; Implant; In Vitro; Inferior; Joints; Liquid substance; Lubricants; Measurable; Mechanics; Medical; Methods; Modeling; Modification; Mononuclear; Natural regeneration; Operative Surgical Procedures; Organ; Outcome; Patients; Preparation; Procedures; Property; Research Proposals; Second Look Surgery; Source; Stromal Cells; Structure; Surface; Synovial Fluid; Techniques; Tendon Injuries; Tendon structure; Testing; Therapeutic Agents; Time; Tissue Engineering; Tissues; Translating; Transplantation; Trauma; clinical application; clinical practice; clinically relevant; clinically significant; cost; disability; economic impact; functional loss; functional outcomes; hand rehabilitation; improved; improved functioning; improved outcome; in vitro Model; in vivo; in vivo Model; lubricin; migration; minimal risk; novel; novel therapeutics; reconstruction; research study

DESCRIPTION (provided by applicant): Flexor tendon injuries are one of the most common and difficult-to-treat hand traumas causing considerable functional loss and economic burden. Hand traumas are estimated to account for over 10% of total emergency department visits. For the past half-century, flexor tendon reconstruction has been a major surgical procedure to restore hand function following flexor tendon injuries. However, clinical outcomes remain frustratingly unsatisfactory and are marred by a high rate of complications, including adhesion and poor digit function following reconstruction. These unacceptable outcomes often result in multiple surgical revisions or even finger amputations that further prolong patient disability and increase medical costs. The overall goal of this project is to develop a clinically-applicable engineered tendon graft that could become an off-the-shelf, functionally superior alternative to the conventional tendon graft. In the first award period, we have developed strategies to improve the surface quality of the graft tendons using carbodiimide derivatized hyaluronic acid and lubricin, two important lubricating molecules. We found that this modification enhanced tendon gliding ability, decreased adhesions, and improved digit function using either extrasynovial autograft (clinical standard) or intrasynovial allograft (attractive alternative) transplantation. Encouragingly, our experiments in an in vitro model have allowed us to successfully enhance graft tendons using chemically modified native synovial fluid (SF) from joints, which is readily available and clinically applicable. Therefore, in this renewal, we will advance our project to test our hypothesis that synovialization of extrasynovial autograft using chemically modified autologous SF will improve the outcome of flexor tendon reconstruction in a clinically-relevant canine in vivo model as proposed in Specific Aim 1. If successful, this technique can be quickly translated to clinical practice, since both chemical modification and autologous synovial fluid can be safely applied clinically to tendon autograft. This technique can also be adopted in transplantation of other organs where adhesions are problematic. Furthermore, in an ex vivo model, we have developed a novel cell-based therapy that has potential to accelerate allograft regeneration, overcoming the slow revitalization we have encountered in the first funding period. Therefore in Specific Aim 2, we will combine chemical and tissue engineering approaches to synovialize and revitalize intrasynovial allograft tendon to generate a functionally superior alternative to the conventional tendon graft for flexor tendon reconstruction. If successful, these techniques can also be rapidly applied to clinical application since allograft tendons could be available off-the-shelf and revitalized and synovialized from patient's own joint fluid and cells. Considering the clinical significance of flexor tendon reconstruction, our novel and feasible approaches, supportive preliminary studies, reasonable hypotheses, and measurable outcomes, we are confident this proposal will be successful and has a significant clinical impact.

描述（由申请人提供）：屈肌腱损伤是最常见和最难治疗的手外伤之一，造成相当大的功能损失和经济负担。据估计，手外伤占急诊总就诊量的10%以上。在过去的半个世纪里，屈肌腱重建一直是屈肌腱损伤后恢复手部功能的主要外科手术。然而，临床结果仍然令人沮丧地不令人满意，并受到高并发症发生率的影响，包括重建后的粘连和手指功能差。这些不可接受的结果往往导致多次手术翻修，甚至手指截肢，进一步延长患者的残疾和增加医疗费用。本项目的总体目标是开发一种临床适用的工程化肌腱移植物，该移植物可能成为传统肌腱移植物的现成的、功能上上级的替代品。 在第一个奖项期间，我们已经制定了战略，以改善移植肌腱的表面质量，使用碳二亚胺衍生的透明质酸和润滑素，两个重要的润滑分子。我们发现，这种改良增强肌腱滑动能力，减少粘连，并改善手指功能，无论是滑膜外自体移植（临床标准）或滑膜内同种异体移植（有吸引力的替代）移植。令人鼓舞的是，我们在体外模型中的实验使我们能够使用来自关节的化学修饰的天然滑液（SF）成功地增强移植肌腱，这是容易获得的和临床适用的。因此，在本次更新中，我们将推进我们的项目，以检验我们的假设，即使用化学修饰的自体SF对滑膜外自体移植物进行滑膜化将改善临床相关犬体内模型中屈肌腱重建的结果，如具体目标1中所述。如果成功，这种技术可以迅速转化为临床实践，因为化学修饰和自体滑液都可以安全地应用于临床肌腱自体移植。该技术也可用于粘连有问题的其他器官的移植。此外，在离体模型中，我们开发了一种新的基于细胞的疗法，该疗法有可能加速同种异体移植物再生，克服了我们在第一个资助期遇到的缓慢再生。因此，在特定目标2中，我们将联合收割机化学和组织工程方法对滑膜内同种异体肌腱进行滑膜化和再生，以产生功能上级传统肌腱移植物的替代方法，用于屈肌腱重建。如果成功的话，这些技术也可以迅速应用于临床应用，因为同种异体肌腱可以从现成的供应商获得，并从患者自己的关节液和细胞中再生和滑膜化。考虑到屈肌腱重建的临床意义，我们新颖可行的方法，支持性的初步研究，合理的假设和可衡量的结果，我们相信这个建议将是成功的，并具有重大的临床影响。