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

腓骨损伤占所有儿童骨折的30%，并可能导致骨骼生长受损。骨赘 (或称为生长板)是儿童长骨末端的一个软骨区域，负责纵向 骨骼生长。一旦受损，软骨下骨中的间充质干细胞就会迁移到 损伤的骨赘，进行成骨，并形成不需要的骨组织，称为“骨条”。这可以 导致角形畸形或完全停止纵向骨骼生长，这对儿童是毁灭性的， 仍在增长。目前的外科治疗包括移除骨条。该网站经常被填满 使用柔软的脂肪移植或硬的、不可降解的塑料，这两者都提供了导致崩溃的不完美的解决方案 分别是切除部位或生物材料的移位。因此，这个项目的总体目标是 开发一种改进的治疗方案，利用3D打印技术设计一种仿生生长 含有机械分级3D刚性结构的平板软骨，填充有软软骨仿生材料 水凝胶。我们的假设是，3D打印的生长板软骨仿生体可以防止软骨塌陷 切除部位通过其结构，同时招募间充质干细胞引导它们通过 地带性合适的物理化学线索，成软骨的，而不是成骨的，谱系和预防 通过用软骨修复组织取代它来形成骨棒。因此，长期的3D打印 仿生技术将使骨赘损伤后正常的骨骼伸长。为了验证这一假设，我们开发了 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构造 模拟生长板软骨的形态和力学性能(目标1)和(2)评估 3D打印的生长板软骨仿生体在兔实验性骨质疏松症模型中防止骨条形成的能力 骨赘损伤(目标2)。在为期两年的探索阶段结束时，我们预计将建立一个 通过3D打印技术设计的新型仿生生长板软骨证实，一种3D 模拟生长板的印刷僵硬结构，并填充柔软的水凝胶防止骨条 宗教改革。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 通过募集内源性干细胞构建兔生长板损伤模型(目标3)，和(2) 评估3D打印的生长板软骨仿生模型实现骨纵向生长的能力 建立兔生长板损伤模型，植入后随访1年。在为期3年的课程结束时 R33期，我们希望已经演示了用3D打印机填充骨条切除后的部位 生长板软骨的仿生阻止了骨棒的形成，并支持软骨的形成，即 最终在生长到骨骼成熟后转化为新的骨骼。通过提供解决方案来恢复 正常的骨骼生长，这种3D打印的生长板软骨仿生模型有可能转化为 该诊所旨在改善受影响儿童的生活质量。

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.