Novel Biomaterials as Sealants for Applications in Annulus Fibrosus Repair

描述(申请人提供)：下腰痛通常与椎间盘退行性变(IVD)有关，是患者就诊的最常见的身体状况。目前还没有可接受的生物材料可用于修复IVD的小纤维环(AF)缺陷，这些缺陷可能与针刺生物制剂或椎间盘造影术、椎间盘突出症切除手术或其他小病变和AF撕裂有关。这些类型的缺陷与加速的IVD退化有关。该培训基金的总体目标是评估与开发用于小型房颤修复的有前途的生物材料密封剂相关的基本生物力学和生物学。房颤修复封闭剂的成功与否取决于其机械性能、细胞相容性以及在复杂的机械和化学环境中发挥作用的能力。这项培训资助包括对房颤组织密封剂及其与天然房颤组织的相互作用进行机械和生物学评估，以优化体外生物材料和原位评估生物材料。有效的AF密封胶的设计必须具有可调的材料性能、促进细胞渗透、具有强大的粘接能力，并且可以注射以填补各种缺陷。所提出的两种凝胶是染料木素交联纤维蛋白凝胶(fib-gen)和羧甲基纤维素水凝胶(CMC)。体外优化(目标1)包括测试每种凝胶的多种密封剂配方，以匹配本地牛房颤组织的机械硬度，在与本地牛房颤双层结构中创建强大的粘附性，并促进细胞种子凝胶上的细胞存活和细胞增殖。原位评估(目标2)是使用一种新的受载共聚焦显微镜成像技术在微观水平上评估封闭剂-组织界面，评估修复后椎体运动节段双轴力学性能的机械恢复，以及使用器官培养技术评估封闭剂-组织界面对细胞生长和运输的影响。总体假设是，房颤粘接密封剂可以优化为细胞相容，具有与天然房颤组织相当的机械强度，并能够将受损运动节段的生物力学行为恢复到未损伤状态。这项研究战略的拟议目标是对培训计划的补充，该培训计划包括培训模块，包括生物材料表征和开发(使用CMC和Fib-gen配方)、细胞和分子生物学(使用细胞存活和增殖测试)、显微镜和成像(使用粘合剂和组织界面的微型成像和应变图)，以及临床和翻译研究(使用临床相关缺陷的应用和修复交付)。 公共卫生相关性：腰椎间盘退变被认为在腰痛的表现中起主要作用。这笔培训补助金将发展、优化和评估 新型水凝胶生物材料，用作封闭剂，用于对IVD的病理条件进行微创外科干预。补充科学的培训目标 旨在使申请者发展新的和重要的新技术技能，扩大和建立她以前的生物医学工程背景，为她的独立研究生涯做好准备。

DESCRIPTION (provided by applicant): Low back pain is often associated with degeneration of the intervertebral disc (IVD) and represents the most common physical condition for which patients visit their doctor. There are currently no acceptable biomaterials available to repair small annulus fibrosus (AF) defects of the IVD that might be associated with needle injection of biologics or discography, discectomy procedures for herniations, or other small lesions and AF tears. These types of defects are linked with accelerated IVD degeneration. The overall goal of this training grant is to evaluate fundamental biomechanics and biology associated with the development of promising biomaterial sealants for small AF repairs. The success of a sealant for AF repair depends on its mechanical properties, cytocompatibility, and its ability to function in a complex mechanical and chemical environment in situ. This training grant involves mechanical and biological assessments of AF tissue sealants and their interactions with native AF tissue in order to optimize the biomaterial in vitro and to evaluate the biomaterial in situ. Effective AF sealants must be designed to have tunable material properties, promote cell infiltration, have strong adhesive capabilities, and be injectable to fill a variable range of defets. The two gels proposed are a genipin cross- linked fibrin gel (fib-gen) and carboxymethylcellulose hydrogel (CMC). The in vitro optimization (Aim 1) is comprised of testing multiple sealant formulations of each gel in shear to match the mechanical stiffness of native bovine AF tissue, to create strong adhesive properties in bilayered constructs with native bovine AF, and to promote cell viability and cell proliferation on cell-seeded gels. The in situ assessments (Aim 2) are to assess the sealant-tissue interface at the microscale level using a novel confocal microscopy imaging technique under loading, to evaluate mechanical restoration of biaxial mechanical properties in a vertebral motion segment following repair, and to assess the sealant-tissue interface for cell growth and transport using organ culture techniques. The overall hypothesis is that an AF adhesive sealant can be optimized to be cytocompatible, of comparable mechanical strength as native AF tissue, and capable of restoring biomechanical behaviors of injured motion segments to the uninjured state. The proposed aims of this research strategy complement a training plan comprised of training modules that include Biomaterials Characterization and Development (with CMC and fib-gen formulation), Cell and Molecular Biology (with cell viability and proliferation testing), Microscopy and Imaging (with microscale imaging and strain mapping of adhesive and tissue interfaces), and Clinical and Translational Research (with application of clinically relevant defects and delivery of repair). PUBLIC HEALTH RELEVANCE: Intervertebral disc degeneration is thought to play a major role in the manifestation of low back pain. This training grant will develop, optimize and evaluate novel hydrogel biomaterials for their use as sealants to be used in minimally invasive surgical interventions for pathological conditions of the IVD. Training goals that complement the scientific aims allow the applicant to develop novel and important new technical skills that expand and build off her prior biomedical engineering background to prepare her for an independent research career.