Tendon-Bone Construct Tissue Engineering for Extremity Reconstuction

用于四肢重建的肌腱-骨结构组织工程

• 批准号: 8971507
• 负责人: James Chang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971507
• 关键词: Accidents; Allografting; Anatomy; Animal Model; Area; Athletic Injuries; Biocompatible; Biocompatible Materials; Biological Assay; Biological Preservation; Biomechanics; Biomedical Engineering; Blood Platelets; Body Temperature; Bone Regeneration; Bone Tissue; Bone Transplantation; Cadaver; Caring; Cell Proliferation; Cell Survival; Cells; Clinical; Complex; DNA; Defect; Degenerative Disorder; Distal; Early Mobilizations; Extracellular Matrix Proteins; Fatty acid glycerol esters; Flexor; Gel; Goals; Grant; Healed; Histology; Human; Human Development; Hydrogels; Immunohistochemistry; Implant; In Situ; In Situ Hybridization; In Vitro; Injury; Lead; Limb structure; Liquid substance; Measurement; Medical; Methods; Migration Assay; Military Personnel; Modeling; Molecular; Motion; Operating Rooms; Operative Surgical Procedures; Outcome; Patients; Phalanx; Plasma; Postoperative Period; Powder dose form; Process; Production; Proliferating; Property; Protocols documentation; Rattus; Rehabilitation therapy; Research; Resected; Resolution; Roentgen Rays; Rotator Cuff; Rupture; Sampling; Seeds; Site; Soldier; Solid; Solutions; Stem cells; Structure; Supplementation; Surgeon; Surgical sutures; Survival Rate; System; Techniques; Tendon structure; Testing; Time; Tissue Banking; Tissue Banks; Tissue Engineering; Tissues; Training; Translating; Translations; Upper Extremity; Veterans; achilles tendon; anterior cruciate ligament rupture; base; biomaterial compatibility; bone; bone healing; bone strength; calcaneum; cell motility; clinical application; combat; healing; human tissue; improved; in vivo; injured; joint function; microCT; migration; novel; public health relevance; reconstitution; reconstruction; repaired; tissue culture

 DESCRIPTION (provided by applicant): When soldiers and Veterans injure their extremities, tendons are likely to be disrupted. Without intact tendon-bone units, extremities cannot function properly. These injuries may be mid-substance tendon ruptures, or tears at the tendon-bone interface (TBI). The most difficult aspect of tendon reconstruction is adequate healing of this interface with bone. To date, the healing process of the TBI is poorly understood. The goals of this project are to determine the cellular and molecular mechanisms of TBI healing, and to develop tissue engineered TBI constructs that can be used for extremity reconstruction. It is hypothesized that tissue-engineered composite constructs consisting of tendon and bone would allow reconstruction with tendon-to-tendon and bone-to-bone healing. This would be faster and stronger, thus offering earlier mobilization and improved outcomes. Because there is a paucity of research on the process of TBI healing and tissue engineered TBI composite constructs, the following research objectives are proposed: The initial objective is to use an animal model of TBI healing based on the rat Achilles tendon to develop tendon-bone constructs. Decellularization of rat Achilles tendon-calcaneal bone segments and reseeding with adipoderived stem cells (ASCs) will be performed to create tissue engineered composite constructs. This process will be optimized with platelet-rich plasma (PRP) supplementation and the use of a novel tendon hydrogel as a carrier. The hydrogel is produced from decellularized tendon powder, is reconstituted into liquid form, and becomes a solid, yet porous gel at body temperature. It is hypothesized that the strength of bone-bone healing and tendon-tendon healing will exceed that of tendon-bone healing. Furthermore, repairs made with reseeded TBI grafts would be stronger than repairs performed with decellularized TBI grafts. In order to test this, tissue engineered rat Achilles TBI constructs will be re-implanted to assess fo short-term and long-term biocompatibility and repair strength. Techniques to assess healing will include immunohistochemistry, in situ hybridization, MTS measurement of tendon and bone-tendon junction biomechanical strength, high resolution Xray, and micro CT. Lastly, the ultimate goal would be translation to the production of human TBI composite grafts for clinical use in the reconstruction of extremity injuries. Human tissue engineered TBI constructs will be created based on optimized decellularization and reseeding techniques from the previous objectives. The specific anatomic structure to be produced initially is the distal phalanx-flexor tendon graft. The strength of native versus decellularized composite grafts will be tested. This proposal will ultimately allow the development of human composite TBI grafts for use in the reconstruction of traumatic and degenerative conditions of the extremities in soldiers and Veterans.

 描述（由申请人提供）： 当士兵和退伍军人受伤时，肌腱可能会受到干扰。没有完整的肌腱骨单位，四肢无法正常运行。这些损伤可能是固定肌腱破裂，也可能是肌腱骨界面（TBI）的撕裂。肌腱重建最困难的方面是与骨骼的界面进行足够的愈合。迄今为止，TBI的康复过​​程知之甚少。该项目的目标是确定TBI愈合的细胞和分子机制，并开发可用于肢体重建的组织工程TBI构建体。假设由肌腱和骨骼组成的组织工程复合构造将允许通过肌腱到螺纹刺激和骨对骨愈合进行重建。这将是更快，更强大的，因此提供了早期的动员和改善的结果。由于对TBI愈合过程和组织工程TBI复合构建体的过程缺乏研究，因此提出了以下研究目标：最初的目标是使用基于大鼠acchilles肌腱的TBI愈合模型来开发肌腱骨构建体。将进行大鼠肌腱 - 卡尔卡纳骨骨段的脱落和用脂肪构成干细胞（ASC）恢复以创建组织工程复合构建体。该过程将用富含血小板的血浆（PRP）补充和使用新型肌腱水凝胶作为载体进行优化。水凝胶是由脱细胞肌腱粉产生的，将其重构为液态，并在体温下变成固体但多孔的凝胶。假设骨骨愈合和肌腱 - 螺孔愈合的强度将超过肌腱骨愈合的强度。此外，用回收的TBI移植物进行的维修要比用脱细胞的TBI移植物进行的维修更强。为了测试这一点，将重新插入组织设计的大鼠阿基里斯TBI构建体，以评估短期和长期生物相容性和修复强度。评估愈合的技术将包括免疫组织化学，原位杂交，MTS测量肌腱和骨 - 螺旋连接生物力学强度，高分辨率XRay和Micro CT。最后，最终目标是将人类TBI复合移植物的产生转化为临床在肢体损伤重建中的使用。人体组织工程TBI构建体将基于以前目标的优化脱细胞和恢复技术创建。最初要产生的特定解剖结构是远端phanx-flexor肌腱移植物。 将测试天然与脱细胞复合移植物的强度。该提案最终将允许人类复合TBI移植物的发展用于重建士兵和退伍军人肢体的创伤和退化条件。