Engineering biomimetic knee menisci with zonal and anisotropic variations

具有分区和各向异性变化的仿生膝关节半月板工程

• 批准号: 10425800
• 负责人: Kyriacos A Athanasiou
• 金额: $ 0.27万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425800
• 关键词: Address; Adhesions; Adhesives; Allogenic; American; Animals; Anisotropy; Biochemical; Biochemistry; Biological Assay; Biomechanics; Biomimetics; Cattle; Cell Culture Techniques; Cells; Characteristics; Chondroitin ABC Lyase; Clinical; Collagen; Complex; Cytology; Data; Disadvantaged; Engineering; Future; Generations; Goals; Growth; Histology; Human; Hydrostatic Pressure; Immunohistochemistry; Implant; Knee; LOXL2 gene; Laboratories; Magnetic Resonance Imaging; Mechanical Stimulation; Mechanics; Medial; Meniscus structure of joint; Methodology; Methods; Modeling; Molds; Molecular; Morphology; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Pathologic; Performance; Phase; Phenotype; Population; Positioning Attribute; Procedures; Production; Property; Reaction; Scanning Electron Microscopy; Serology; Sheep; Source; Stimulus; Stress; Structure-Activity Relationship; Surgical Models; Surgical sutures; System; Techniques; Technology; Testing; Time; Tissue Donors; Tissue Engineering; Tissues; Traction; Translations; Variant; cellular engineering; design; improved; in vitro testing; in vivo; innovation; lysophosphatidic acid; mechanical properties; mimetics; novel; preservation; repaired; sample fixation; scaffold; success; synergism; trait

PROJECT SUMMARY This proposal aims to tissue engineer an anisotropic neo-meniscus that also captures the regional variations present in the native tissue. Subsequently, allogeneic neo-meniscal constructs will be implanted in a leporine model to achieve both meniscus repair and replacement. It is hypothesized that: 1) regionally variant, anisotropic, meniscus-shaped constructs can be engineered by optimizing cell culture and scaffold-free culture conditions; 2) the strategic temporal application of multi-level stimuli (at cellular-, molecular-, and construct- levels) will allow for synergisms across the different levels of action to enhance the functional properties of the maturing neo-menisci; and 3) allogeneic constructs can be successfully implanted in a leporine model. These hypotheses will be tested via the following three specific aims: 1) To create an anisotropic neo-meniscus with regional variations mimicking native tissue; 2) to enhance functional and organizational properties of the neo- meniscus via multi-level exogenous stimulation synergized by temporal coordination; and 3) to develop surgical fixation techniques and implant the neo-menisci in the rabbit. Previously, the native meniscus was found to be highly anisotropic and regionally variant both morphologically and biomechanically, motivating our current tissue engineering approach to mimic these characteristics. Allogeneic leporine cells will be used to form organizationally and regionally mimetic neo-meniscal constructs in Aim 1; this goal will be accomplished via the use of novel spatial and temporally variant seeding techniques. The anisotropic and organizational properties of the engineered neo-meniscus will then be enhanced by manipulating molecular-, cellular-, and construct-level targets in Aim 2. Specifically, TGF-β1 and hydrostatic pressure will act on the cellular level to increase matrix production; lysophosphatidic acid and chondroitinase-ABC will be used to align and compact the matrix at the molecular level; and meniscus-specific mechanical stimulation will direct anisotropy at the construct level. In this proposal, to avoid the use of primary cells, we will investigate the use of passaged allogeneic cells toward in vivo repair and replacement of the meniscus (Aim 3). Upon successful demonstration of repair/replacement in the leporine model, we will determine methods to likewise expand sheep and human cells for future studies. This approach seeks to address the issue of tissue scarcity and aims to provide a solution to the complex problem of meniscus repair and replacement.

项目摘要 该建议旨在组织工程师各向异性的新囊肿，也捕获了区域变化 存在于天然组织中。随后，同种异体新歧视结构将被植入麻木 模型以实现半月板修复和更换。假设：1）区域变体， 各向异性，半月板形构建体可以通过优化细胞培养和无脚手架培养来设计 状况; 2）多级刺激的战略临时应用（在细胞，分子和构造上 级别）将允许在不同级别的作用层面上进行协同作用，以增强 成熟的Neo-Menisci； 3）可以将同种异体构建体成功植入麻风病模型。这些 假设将通过以下三个特定目的进行检验：1）与使用各向异性新杂种一起使用 模仿天然组织的区域变化； 2）增强新的功能和组织特性 通过临时协调协同的多级外源刺激通过多级外源刺激； 3）发展 手术固定技术和植入兔子中的新元学。以前，本地的半月板是 发现在形态和生物力学上都是高度各向异性和区域变体的，激励我们 当前的组织工程方法模仿这些特征。同种异体Lepoline细胞将用于 在AIM 1中形成组织和区域模仿的新阶段构造；这个目标将实现 通过使用新型的空间和暂时变体的播种技术。各向异性和组织 然后，通过操纵分子 - ，细胞和 AIM 2中的构造水平目标。具体来说，TGF-β1和静水压力将作用于细胞水平 增加基质产生；溶血磷脂酸和软骨蛋白酶-ABC将用于对齐和紧凑 分子水平的基质；和半月板特异性的机械刺激将指导各向异性 构造水平。在此提案中，为避免使用主要单元，我们将调查使用的使用 同种异体细胞朝体内修复和弯月面的替换（AIM 3）。成功演示 Lepoline模型中的维修/替代品，我们将确定同样扩展绵羊和人类的方法 细胞进行未来的研究。这种方法旨在解决组织稀缺问题，并旨在提供 解决半月板修复和更换的复杂问题。

项目成果

Engineering self-assembled neomenisci through combination of matrix augmentation and directional remodeling.

• DOI: 10.1016/j.actbio.2020.04.019
• 发表时间: 2020-06
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Gonzalez-Leon EA;Bielajew BJ;Hu JC;Athanasiou KA
• 通讯作者: Athanasiou KA