Treatment of pediatric physeal injuries using a 3D printed biomimetic of growth plate cartilage

使用 3D 打印仿生生长板软骨治疗儿童骺损伤

• 批准号: 9926114
• 负责人: Stephanie J Bryant
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926114
• 关键词: 3-Dimensional; 3D Print; Affect; Age; Appearance; Area; Biocompatible Materials; Biomimetics; Bone Growth; Bone Lengthening; CCL25 gene; Cartilage; Chemicals; Child; Childhood; Chondrocytes; Chondrogenesis; Clinic; Clinical Management; Complex; Cues; Deformity; Development; Encapsulated; Engineering; Epiphysial cartilage; Excision; Extracellular Matrix; Fatty acid glycerol esters; Fracture; Goals; Growth; Histology; Hydrogels; Impairment; Implant; Injury; Lead; Left; Location; Measures; Mechanics; Mesenchymal Stem Cells; Minerals; Modeling; Morphology; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Phase; Printing; Property; Quality of life; Recurrence; Signal Transduction; Site; Stromal Cell-Derived Factor 1; Structure; Technology; Testing; Thick; Time; Tissues; Translating; Work; bone; cartilage repair; cartilaginous; cell motility; chemokine; design; digital; implantation; improved; injured; long bone; mechanical properties; microCT; mimetics; novel; pediatric patients; prevent; recruit; scaffold; skeletal; stem cell differentiation; stem cells; subchondral bone; tissue repair

Physeal injuries account for 30% of all pediatric fractures and can result in impaired bone growth. The physis (or, “growth plate”) is a cartilage region at the end of children's long bones that is responsible for longitudinal bone growth. Once damaged, mesenchymal stem cells from the underlying subchondral bone migrate into the injured physis, undergo osteogenesis, and form unwanted bony tissue, referred to as a “bony bar”. This can lead to angular deformities or completely halt longitudinal bone growth, which is devastating for children that are still growing. Current surgical treatments involve the removal of the bony bar. The site is often filled either with a soft fat graft or a hard, non-degradable plastic, both of which offer imperfect solutions leading to collapse of the resection site or the dislodgement of the biomaterial, respectively. Thus, the overall goal of this project is to develop an improved treatment option that utilizes 3D printing technology to engineer a biomimetic of growth plate cartilage containing mechanically-graded 3D stiff structures in-filled with a soft cartilage biomimetic hydrogel. Our hypothesis is that a 3D printed biomimetic of growth plate cartilage prevents collapse at the resection site through its structure and simultaneously recruits MSCs to direct them through zonally appropriate physiochemical cues to a chondrogenic, not osteogenic, lineage and prevents bony bar formation by replacing it with a cartilaginous repair tissue. Thus, long-term the 3D printed biomimetic will allow normal bone elongation after physeal injury. To test this hypothesis, we have developed two aims for the R21 phase and two aims for the R33 phase. In the R21 phase, we will (1) print a 3D construct that mimics the morphology and mechanical properties of growth plate cartilage (Aim 1) and (2) evaluate the ability of a 3D printed biomimetic of growth plate cartilage to prevent bony bar formation in a rabbit model of physeal injury (Aim 2). At the conclusion of the 2-year exploratory phase, we expect to have established a novel biomimetic of growth plate cartilage designed through 3D printing technology and confirmed that a 3D printed stiff structure mimicking that of the growth plate and infilled with a soft hydrogel prevents bony bar reformation. In the R33 phase, we will (1) assess cartilage formation in the implanted 3D printed biomimetic construct in a rabbit model of physeal injury through the recruitment of endogenous stem cells (Aim 3), and (2) evaluate the ability of a 3D printed biomimetic of growth plate cartilage to enable longitudinal bone growth in a rabbit model of physeal injury, which is followed for 1 year after implantation. At the conclusion of the 3-year R33 phase, we expect to have demonstrated that filling the site after bony bar resection with a 3D printed biomimetic of growth plate cartilage prevents bony bar reformation and supports cartilage formation that is eventually converted into new bone following growth to skeletal maturity. By providing a solution to restore normal bone growth, this 3D printed biomimetic of growth plate cartilage has the potential to be translated into the clinic to improve the quality of life of affected children.

骺板损伤占所有儿童骨折的 30%，并可能导致骨骼生长受损。 （或“生长板”）是儿童长骨末端的软骨区域，负责纵向生长 一旦受损，软骨下骨的间充质干细胞就会迁移到骨中。 受伤的骺板，进行成骨，并形成不需要的骨组织，称为“骨棒”。 导致成角畸形或完全停止纵向骨骼生长，这对于患有以下疾病的儿童来说是毁灭性的： 目前的手术治疗包括切除骨棒，该部位通常被填充。 使用柔软的脂肪移植物或坚硬的不可降解塑料，这两种方法都提供了导致塌陷的不完美解决方案 因此，该项目的总体目标是。 开发一种改进的治疗方案，利用 3D 打印技术来设计仿生生长 板软骨包含机械分级的 3D 刚性结构，内部填充软软骨仿生材料 我们的假设是，3D 打印的生长板软骨仿生材料可以防止塌陷。 通过其结构来识别切除部位，同时招募 MSC 引导它们通过 对软骨形成（而非成骨）谱系具有适当的生理化学线索，并预防 通过用软骨修复组织替代骨棒来形成骨棒，从而实现长期的 3D 打印。 为了检验这一假设，我们开发了仿生技术。 R21 阶段的两个目标和 R33 阶段的两个目标 在 R21 阶段，我们将 (1) 打印 3D 结构。 模拟生长板软骨的形态和机械特性（目标 1）和（2）评估 3D 打印生长板软骨仿生体防止兔子模型中骨棒形成的能力 在为期 2 年的探索阶段结束时，我们期望建立一个 通过3D打印技术设计的新型生长板软骨仿生体，并证实3D 模仿生长板的印刷刚性结构并填充柔软的水凝胶可防止骨棒 在 R33 阶段，我们将 (1) 评估植入的 3D 打印仿生体中的软骨形成。 通过招募内源干细胞构建兔骺损伤模型（目标 3）和（2） 评估生长板软骨 3D 打印仿生体实现纵向骨生长的能力 兔骺损伤模型，植入后随访 1 年，3 年结束时进行随访。 R33 阶段，我们希望能够证明，用 3D 打印的材料填充骨棒切除术后的部位 生长板软骨的仿生可防止骨棒重组并支持软骨形成 通过提供恢复溶液，最终在生长到骨骼成熟后转化为新骨。 正常骨骼生长，这种生长板软骨的 3D 打印仿生材料有潜力转化为 该诊所旨在改善受影响儿童的生活质量。