Engineering Multi-scale Structure of the Knee Meniscus using Advanced 3D Nonwovens Fabrication

使用先进的 3D 非织造布制造技术设计膝盖半月板的多尺度结构

• 批准号: 10246257
• 负责人: Matthew B Fisher
• 金额: $ 15.71万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246257
• 关键词: 3-Dimensional; 3D Print; Aging; Air; Allografting; Anatomy; Architecture; Attenuated; Autologous Transplantation; Biological; Biology; Biomechanics; Biomimetics; Caliber; Cell Differentiation process; Cells; Cellular Infiltration; Characteristics; Clinical Treatment; Collagen; Collagen Fibril; Complex; Custom; Deposition; Electrospinning; Engineering; Extracellular Matrix; FDA approved; Fiber; Geometry; Goals; Implant; In Vitro; Infiltration; Injury; Intervertebral disc structure; Investigation; Joints; Knee; Knee Injuries; Knowledge; Ligaments; Mechanics; Medical; Meniscus structure of joint; Modeling; Molecular Weight; Morphology; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Outcome; Pathology; Patients; Physiological; Polymers; Population; Porosity; Prevention; Process; Production; Property; Rattus; Regenerative Medicine; Reporting; Reproducibility; Rotation; Shapes; Sheep; Soft Tissue Injuries; Speed; Stifle joint; Structure; Structure-Activity Relationship; Surface; Synovitis; Techniques; Technology; Tendon structure; Textiles; Tissue Engineering; Tissues; Translations; Transplantation; Work; articular cartilage; base; caprolactone; cartilage degradation; clinical application; design; fundamental research; implantation; in vivo; in vivo Model; mechanical properties; melting; meniscal tear; meniscus injury; multidisciplinary; novel; novel strategies; polycaprolactone; response; scaffold; sheep model; socioeconomics; subcutaneous; three dimensional structure

Abstract Meniscal tears are the most commonly reported knee injuries, and approximately 1 million surgeries involving the meniscus are performed annually in the US. Tissue engineering and regenerative medicine approaches are being actively pursued as potential alternatives to overcome limitations of current clinical treatments. Yet, the translation of these approaches to clinical application has been hampered by their limited ability to efficiently and reproducibly create physiologic-sized, patient-specific scaffolds featuring anisotropic structural and mechanical properties on the order of native meniscus. 3D printing can create scaffolds that replicate physiologic size and patient-specific geometry in a highly repeatable manner and with good handling characteristics for surgical implantation, yet, these fiber sizes are typically on the order of hundreds of microns, several orders of magnitude higher than the native tissue. On the other hand, nonwoven textiles approaches allow the fabrication of fibers on the scale of native collagen fibrils, but it is infeasible to create complex anatomical 3D geometries, such as that of the knee meniscus. The overall goal of this proposal is to investigate the ability of a new 3D nonwoven scaffold fabrication approach that synergistically integrates attributes of traditional nonwoven melt blowing and 3D printing to overcome these limitations and recapitulate complex anisotropic structural characteristics of the meniscus at multiple scales as a means to provide superior outcomes, in-vitro and in-vivo. We hypothesize that this 3D Melt Blowing (3DMB) approach can allow physiological fiber morphology (similar to other nonwovens such as electrospinning), while also enabling the creation of patient-specific meniscus 3D geometry via the customized rotating mandrel (similar to 3D printing). We further hypothesize that the resulting scaffold features will permit superior in-vivo outcomes, particularly, cell infiltration, new matrix production, and the prevention of cartilage degeneration via control of porosity and fiber size. Aim 1 is to determine the effect of the 3DMB process variables on polycaprolactone scaffold fibrous morphology and resulting ECM organization and biomechanical function using in-vitro, ex-vivo and sub- cutaneous in-vivo models. Additionally within this aim, a response surface function will be developed and validated to correlate cellular infiltration, collagen content, matrix alignment, and mechanics as a function of fiber diameter and scaffold porosity. Aim 2 is to assess the distribution of cellular infiltration and viability, aligned ECM formation and biomechanical function over 26 weeks in a sheep model for patient-specific 3D melt blown meniscus scaffolds of the leading-group determined from Aim 1 outcomes. This Aim will also provide the first one-on-one comparison between the characteristics of the 3DMB nonwoven and traditional 3D printed scaffolds, wherein there is an order of magnitude difference in the fiber morphologies. On completion, this project will provide fundamental knowledge about the micro- and macro-level process-structure-function relationships in meniscus-relevant scaffolds fabricated using our new 3DMB nonwovens approach, and will serve as a base technology of great significance allowing advances in the treatment of orthopaedic fibrous soft tissue injuries.

摘要 半月板撕裂是最常见的膝关节损伤报告，约有100万例手术涉及 在美国，每年都会进行半月板手术。组织工程与再生医学的研究方向 正在积极寻求作为潜在的替代方案，以克服目前临床治疗的局限性。然而， 这些方法转化为临床应用一直受到它们有限的能力的阻碍 高效、可重复地创建具有各向异性结构的生理大小、患者特定的支架 力学性能在天然半月板的数量级。3D打印可以创建复制的脚手架 生理尺寸和患者特定的几何形状，具有高度可重复性和良好的操控性 用于外科植入的特征，然而，这些纤维尺寸通常在数百微米量级， 比天然组织高出几个数量级。另一方面，非织造布接近 允许在天然胶原纤维的规模上制造纤维，但不能制造复合体 解剖的3D几何图形，例如膝盖半月板的几何图形。这项提案的总体目标是 研究一种新的协同集成的3D非织造支架制作方法的能力 传统非织造布熔喷和3D打印的属性克服了这些限制，并概括了 半月板在多个尺度上的复杂各向异性结构特征作为提供 无论是在体外还是在体内，结果都很好。我们假设这种3D熔喷(3DMB)方法可以 生理性纤维形态(类似于其他非织造布，如电纺)，同时也使 通过定制的旋转心轴创建特定于患者的半月板3D几何图形(类似于3D打印)。 我们进一步假设，由此产生的支架特征将允许更好的体内结果，特别是， 细胞渗透，新基质的产生，并通过控制孔隙率和软骨退变来防止软骨退化 纤维大小。目的1是确定3DMB工艺参数对聚己内酯支架纤维的影响 用体外、体外和亚生物力学方法研究细胞外基质的形态及其组织和生物力学功能 皮肤活体模型。此外，在此目标范围内，将开发响应面函数，并 经验证可将细胞渗透、胶原含量、基质排列和力学作为以下因素的函数 纤维直径和支架孔隙率。目标2是评估细胞渗透和活性的分布， 患者特异性3D的绵羊模型26周内对齐的ECM形成和生物力学功能 根据目标1的结果确定领先组的熔喷半月板支架。这一目标还将 首次对3DMB非织造布和传统3D的特性进行了一对一的比较 印刷支架，其中在纤维形态上存在数量级的差异。完工后， 本项目将提供有关微观和宏观层面的过程-结构-功能的基本知识 使用我们新的3DMB非织造布方法制作的半月板相关支架中的关系，并将 作为一项具有重要意义的基础技术，推动骨科纤维软组织治疗的进步 组织损伤。