3D Printed Biomimetic Bioglass-Gradient Matrices for ACL Reconstruction

用于 ACL 重建的 3D 打印仿生生物玻璃梯度矩阵

• 批准号: 10654089
• 负责人: Vipuil Kishore
• 金额: $ 44.98万
• 依托单位: FLORIDA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654089
• 关键词: 3D Print; Acceleration; Affect; Anterior Cruciate Ligament; Architecture; Autologous Transplantation; Biochemical; Bioglass; Biomimetics; Biophysics; Bone Transplantation; Cell Differentiation process; Cell Lineage; Cells; Clinical; Collagen; Collagen Fiber; Complex; Connective Tissue; Cues; Degenerative polyarthritis; Dose; Failure; Female; Femur; Fiber; Fibrocartilages; Functional Regeneration; Goals; Health Care Costs; Heterogeneity; Implant; In Vitro; Inflammatory Response; Ink; Joints; Knee joint; Length; Ligaments; Magnetism; Mechanics; Methodology; Minerals; Modeling; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Outcome Measure; Patients; Performance; Phase; Phenotype; Play; Predisposition; Printing; Process; Production; Raman Spectrum Analysis; Reconstructive Surgical Procedures; Reporting; Role; Rotator Cuff; Scheme; Side; Site; Techniques; Technology; Teenagers; Tendon structure; Tissue Engineering; Tissue Grafts; Tissues; Training; Transforming Growth Factor beta; Up-Regulation; Viscosity; anterior cruciate ligament healing; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; articular cartilage; bone; bone strength; cell motility; clinical translation; cost; design; dosage; early onset; efficacy evaluation; graft failure; healing; implantation; improved; indexing; innovation; interfacial; joint function; male; mineralization; musculoskeletal injury; novel; scaffold; sex; success; tibia; undergraduate student

Project Summary Anterior cruciate ligament (ACL) is a band of connective tissue that connects the femur and the tibia and plays a crucial role in stabilizing the knee joint. ACL ruptures are very serious musculoskeletal injuries with poor self-healing capability and often mandate surgical intervention to restore normal joint function. Over 175,000 ACL reconstruction (ACLR) surgeries are performed in the US each year with over 17 billion dollars in lifetime healthcare costs. While viable graft choices are available, graft failure is reported in 10% of cases. In addition, 1 in 5 teenage athletes reinjure their ACL. Long-term consequences of ACLR include limited mobility of the affected joint and early onset of osteoarthritis in up to 80% of patients. Further, sex-based differences in healing outcomes have been reported with females more susceptible to ACL re-tear compared to males. Poor integration of the ACL graft at the bone-ligament interface (i.e., enthesis) is reported to be the main reason for suboptimal graft performance and high graft failure rates. Tissue engineering of the graft-tissue interface is a promising alternative solution to overcome the limitations of existing graft choices and improve the clinical outcome post ACLR. In this realm, recreating the heterogeneity in composition, architecture and cell phenotype of the native enthesis post ACLR is deemed to be critically important for improving graft-bone integration, facilitating reliable load transfer, and restoring long-term normal ACL function. Towards this goal, we propose to develop a novel continuous gradient-based construct that combines multiple biophysical and biochemical cues on a single platform to guide functional regeneration of the ACL enthesis. We hypothesize that spatial presentation of tissue-specific cues will promote cell migration, stimulate multilineage differentiation and matrix remodeling, improve graft integration, and enable functional healing of enthesis post ACLR. Using support from the first period of this R15 project, we delivered a continuous biomimetic Bioglass-gradient integrated collagen matrix (BioGIM) that emulates the composition of the mineralized gradient of the native enthesis. This renewal application has three specific aims. In Aim 1 studies, 3D printing will be combined with a magnetic alignment approach in a 4D printing scheme to orient collagen fibers and achieve > 90% collagen alignment index in BioGIMs. Aligned collagen can provide topographical cues to guide ligamentous differentiation on pure collagen side of the BioGIM. In Aim 2 studies, TGF-β1 dosage and delivery strategy will be optimized to attain reliable fibrocartilaginous matrix formation on the BioGIM interface. In addition, multi-lineage cell differentiation and matrix remodeling along the BioGIM will be assessed. In Aim 3 studies, 4D printed BioGIM flaps will be integrated onto ends of a tendon autograft and implanted in rabbits. Autograft without BioGIM will serve as clinical control and unoperated healthy rabbits will be the positive control. Three weeks post implantation, outcomes measured will include mechanical strength of the bone-ligament interface, typification of de novo matrix remodeling, and inflammatory response. Successful completion of proposed studies is critical for clinical translation of the novel BioGIM flap for ACL reconstruction.

项目摘要 前交叉韧带（ACL）是连接股骨和胫骨的结缔组织。 在稳定膝关节方面起着至关重要的作用。 ACL破裂是非常严重的肌肉骨骼损伤，较差 自我修复能力和经常要求手术干预以恢复正常的关节功能。超过175,000 ACL重建（ACLR）手术在美国每年进行，一生超过170亿美元 医疗保健费用。尽管有可行的移植选择，但在10％的病例中报告了移植物衰竭。另外，1 在5名少年运动员中，重新攻击了他们的ACL。 ACLR的长期后果包括受影响的活动有限 多达80％的患者的关节和早期骨关节炎发作。此外，基于性别的康复结果差异 据报道，与男性相比，女性更容易受到ACL的敏感。整合不良 据报道，骨膜界面的ACL移植物是次优移植物的主要原因 性能和高年级失败率。图形组织界面的组织工程是有望的替代方案 解决现有移植物选择的局限性并改善ACLR后临床结果的解决方案。在这个 领域，重现本地衰落柱的组成，结构和细胞表型的异质性 ACLR被认为对于改善移植物骨整合至关重要，支持可靠的负载转移， 并恢复长期正常ACL功能。为了实现这一目标，我们建议开发一种持续的小说 基于梯度的结构，在单个平台上结合了多个生物物理和生化线索来指导 ACL源的功能再生。我们假设组织特异性提示的空间表现将 促进细胞迁移，刺激多节分区分和基质重塑，改善移植物的整合， 并在ACLR后实现分孔的功能愈合。利用此R15项目的第一阶段的支持，我们 提供了一个连续的仿生型野生型矿物梯度综合胶原蛋白基质（BioGim），该基质模仿 天然灌感的矿化梯度的组成。该更新应用具有三个特定目标。 在AIM 1研究中，3D打印将与4D打印方案中的磁对齐方式结合在一起 东方胶原蛋白纤维并在BioGims中达到> 90％的胶原蛋白对齐指数。对齐胶原蛋白可以提供 地形提示，以指导BioGim纯胶原蛋白侧的韧带分化。在AIM 2研究中， TGF-β1剂量和递送策略将被优化，以在上获得可靠的纤维化基质基质形成 BioGim界面。此外，沿BioGim的多段细胞分化和基质重塑将 被评估。在AIM 3研究中，4D印刷的BioGim襟翼将集成到肌腱自体移植的末端和 植入兔子。没有生物元的自体移植将用作临床控制和不手术的健康兔子 成为积极对照。植入后三周，测量的结果将包括机械强度 骨膜界面，从头基质重塑的典型和炎症反应。成功的 拟议研究的完成对于新型BioGim瓣的临床翻译至关重要。

项目成果

In vitro characterization of xeno-free clinically relevant human collagen and its applicability in cell-laden 3D bioprinting.

• DOI: 10.1177/0885328220959162
• 发表时间: 2021-03
• 期刊: JOURNAL OF BIOMATERIALS APPLICATIONS
• 影响因子: 2.9
• 作者: Schmitt, Trevor;Kajave, Nilabh;Cai, Huan Huan;Gu, Linxia;Albanna, Mohammad;Kishore, Vipuil
• 通讯作者: Kishore, Vipuil

Bioglass incorporated methacrylated collagen bioactive ink for 3D printing of bone tissue.

• DOI: 10.1088/1748-605x/abc744
• 发表时间: 2021-02-26
• 期刊: Biomedical materials (Bristol, England)
• 作者: Kajave NS;Schmitt T;Nguyen TU;Gaharwar AK;Kishore V
• 通讯作者: Kishore V