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

• 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
• 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

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，每年数以万计的肌腱缺陷的修复以恢复相关关节的运动范围。自体移植是主要选择；但是，供体现场发病率和供应限制是重大问题。同种异体移植/异种移植物可能会引起免疫反应。外国人体对合成聚合物的反应是一个重要的缺点。加快肌腱修复，使早期动员和降低失败率的再生解决方案通过降低治疗成本非常重要。由于缺乏统一机械鲁棒性，伸缩率和能够通过手术使维修部位整合的形式，肌腱重建面临多个挑战。在R21项目的一部分支持下，我们开发了一种新颖的方法来制造电化学上排列的胶原蛋白（ELAC）螺纹，其织物方向，堆积密度和机械性能与天然肌腱的胶原相匹配。 ELAC诱导间充质干细胞（MSC）的肾脏分化，并在编织支架中的MSC合成胶原I阳性的基质和肌腱特异性tenomodulin分子。 ELAC在体内具有生物相容性，并分解成肌腱样纤维组织。 ELAC的降解速率与肌腱的缓慢修复率相匹配。因此，ELAC是一个独特的生物活性和机械胜任的平台，可以维修肌腱，而无需添加生长因子。拟议的研究将检验以下假设：基于ELAC的再生策略修复的肌腱间隙缺陷的生物力学将与自体移植所实现的相匹配或超过。第一个目的将优化ELAC的地形和体外调节过程，以最大程度地提高机构ELAC支架中MSC的肾脏。具体而言，Sub-aim 1.1将研究底物压实，比对和刚度在引起观察到的作用 终结反应。骨髓衍生的MSC将种植在随机与对齐，电压与凝胶形式的纹理上，以及在六个数量级（1 kPa至1000 MPa）上调制的矩阵刚度值，这是ELAC独有的范围覆盖率。 SUB AIM 1.2研究将优化细胞播种密度并调用机械刺激，以评估应变振幅和应变速率的影响，以进一步增强体外肾脏的作用。第二个目标将通过使用编织的ELAC支架来改善关键大小肌腱缺陷的修复结果。将采用兔肌腱缺陷模型。治疗组将包括自体移植修复，ELAC支架（有或没有细胞）以及GAP缺失为阴性对照。结果指标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。在大型动物模型中，阐明基于材料和体外条件的线索在使用兔子模型的肾脏作用和深入验证其优点验证其优点将为对这一新型生物材料的临床前评估铺平道路。如果ELAC的表现至少与自动移植一样好，那么与自体移植相关的成本和发病率将被消除。 ELAC将通过恢复关节运动范围和通过 消除修订手术。