Tendon Tissue Engineering by Electrochemically Aligned Collagen Bioscaffolds

通过电化学排列胶原生物支架进行肌腱组织工程

基本信息

批准号：
9247755
负责人：
Ozan Akkus
金额：
$ 53.5万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-08 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247755
关键词：
Allografting Animal Model Articular Range of Motion Autologous Autologous Transplantation Biocompatible Materials Biology Biomechanics Biometry Cells Cicatrix Collagen Collagen Type I Cues Defect Early Mobilizations Engineering Face Failure Foreign-Body Reaction Frequencies Gel Gold Growth Factor Histopathology Immune response In Vitro Inflammatory Response Interdisciplinary Study Joints Marrow Mechanical Stimulation Mechanics Mesenchymal Differentiation Mesenchymal Stem Cells Methods Modeling Molecular Morbidity - disease rate Morphology Operative Surgical Procedures Oryctolagus cuniculus Outcome Outcome Measure Output Patients Periodicity Physiological Polymers Procedures Process Production Quality of life Role Side Site Solid Stem cells System Tendon Injuries Tendon structure Testing Textiles Texture The Sun Tissue Engineering Tissues Treatment Cost Validation Xenograft procedure adult stem cell base biomaterial compatibility conditioning cost crosslink density healing improved improved outcome in vivo infraspinatous muscle injured mechanical properties novel pre-clinical public health relevance reconstruction regenerative repaired response scaffold standard care treatment group

项目摘要

DESCRIPTION (provided by applicant): Repair of massive tendon defects occur in tens of thousands annually in the U.S. alone to restore the range of motion of involved joints. Autografts are the primary choice; however, donor site morbidity and limits in supply are significant issues. Allografts/xenografts may elicit immune response. Foreign body reaction to synthetic polymers is a significant drawback. Regenerative solutions expediting tendon repair, enabling earlier mobilization and reducing failure rates would be highly significant by reducing treatment costs. Tendon reconstruction faces multiple challenges due to the absence of a bioscaffold which unifies mechanical robustness, tenoinductivity and a form that enables integration to the repair site surgically. Supported in part by a R21 project, we developed a novel method to fabricate electrochemically aligned collagen (ELAC) threads whose fabric orientation, packing density and mechanical properties match those of the native tendon. ELAC induces tenogenic differentiation of mesenchymal stem cell (MSC) topographically and MSCs in woven scaffolds synthesize a matrix that is positive of collagen I and the tendon-specific tenomodulin molecule. ELAC is biocompatible in vivo and resolves into a tendon-like fibrous tissue. The degradation rate of ELAC matches the slow repair-rate of tendon. Therefore, ELAC is a unique bioactive and mechanically competent platform with the potential to repair tendon without the addition of growth factors. The proposed studies will test the hypothesis that the biomechanics of the tendon gap defects repaired by ELAC-based regenerative strategies will match or exceed that is attained by autografts. The first aim will optimize ELAC topography and in vitro conditioning processes to maximize tenogenesis of MSCs in woven ELAC scaffolds. Specifically, Sub-Aim 1.1 will study the roles of substrate compaction, alignment and stiffness in eliciting the observed tenogenic response. Marrow- derived MSCs will be seeded on textures of random vs. aligned, electrocompacted vs. gel form, and matrix stiffness values modulated over six orders of magnitude (1 kPa to 1000 MPa), a range coverage that is unique to ELAC. Sub Aim 1.2 studies will optimize cell seeding density and invoke mechanostimulation to assess effects of strain amplitude and strain rate towards further enhancement of tenogenesis in vitro. The second aim will improve the repair outcome on critical sized tendon defects by using woven ELAC scaffolds. A rabbit infraspinatus tendon defect model will be employed. The treatment groups will include autograft repair, ELAC scaffolds (with and without cells) and gap-defect as the negative control. Outcome measures will include repair biomechanics, types of de novo matrix molecules, inflammatory response and healing morphology. Elucidation of material-based and in vitro conditioning based cues in tenogenesis and in depth validation of its merits using the rabbit model will pave the way for a preclinical assessment of this novel biomaterial in large animal models. If ELAC performs at least as good as autografts the costs and morbidity associated with autografts will be eliminated. ELAC will benefit patients by restoring joint range of motion and by eliminating revision surgeries.

描述（由申请人提供）：仅在美国每年就有数以万计的大规模肌腱缺损修复手术，以恢复相关关节的运动范围。自体移植是首选；然而，供体部位的发病率和供应限制是重大问题。同种异体移植物/异种移植物可能引发免疫反应。对合成聚合物的异物反应是一个显着的缺点。再生解决方案可以通过降低治疗成本来加速肌腱修复、实现早期活动并降低失败率，从而具有非常重要的意义。由于缺乏将机械鲁棒性、肌腱感应性和能够通过手术整合到修复部位的形式相结合的生物支架，肌腱重建面临着多重挑战。在 R21 项目的部分支持下，我们开发了一种新颖的方法来制造电化学排列胶原蛋白 (ELAC) 线，其织物方向、堆积密度和机械性能与天然肌腱相匹配。 ELAC 在形态上诱导间充质干细胞 (MSC) 的肌腱分化，并且编织支架中的 MSC 合成 I 型胶原蛋白和肌腱特异性肌腱调节蛋白分子呈阳性的基质。 ELAC 在体内具有生物相容性，可分解成肌腱样纤维组织。 ELAC的降解速度与肌腱的缓慢修复速度相匹配。因此，ELAC 是一种独特的生物活性和机械能力平台，具有在不添加生长因子的情况下修复肌腱的潜力。拟议的研究将检验以下假设：基于 ELAC 的再生策略修复肌腱间隙缺陷的生物力学将与自体移植物所达到的效果相匹配或超过。第一个目标是优化 ELAC 形貌和体外调节过程，以最大限度地提高编织 ELAC 支架中 MSC 的肌腱形成。具体来说，子目标 1.1 将研究基材压实、对齐和刚度在引发观察到的结果中的作用肌腱反应。骨髓来源的 MSC 将接种在随机与排列、电致密与凝胶形式的纹理上，并且基质刚度值调制超过六个数量级（1 kPa 至 1000 MPa），这是 ELAC 独有的范围覆盖范围。子目标 1.2 研究将优化细胞接种密度并调用机械刺激来评估应变幅度和应变速率对进一步增强体外肌腱形成的影响。第二个目标是通过使用编织 ELAC 支架来改善临界尺寸肌腱缺损的修复结果。将采用兔冈下肌腱缺损模型。治疗组将包括自体移植修复、ELAC 支架（有和没有细胞）和间隙缺陷作为阴性对照。结果测量将包括修复生物力学、从头基质分子的类型、炎症反应和愈合形态。阐明肌腱发生中基于材料和基于体外条件的线索，并使用兔子模型深入验证其优点，将为在大型动物模型中对这种新型生物材料进行临床前评估铺平道路。如果 ELAC 的性能至少与自体移植一样好，则与自体移植相关的成本和发病率将被消除。 ELAC 将通过恢复关节活动范围和消除修复手术。