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

骨骺损伤占所有儿科骨折的30%，可导致骨骼生长受损。生长骨骺板 (or，“生长板”）是儿童长骨末端的软骨区域，负责纵向 骨骼生长一旦受损，来自底层软骨下骨的间充质干细胞迁移到软骨中。 受伤的骺板经历骨生成，并形成不需要的骨组织，称为“骨棒”。这可以 导致角畸形或完全停止纵向骨生长，这对 仍在增长目前的手术治疗包括去除骨棒。该网站往往是填补要么 用软脂肪移植物或硬的不可降解塑料，这两种方法都提供了不完美的解决方案，导致崩溃 切除部位或生物材料的移位。因此，本项目的总体目标是 开发一种改进的治疗方案，利用3D打印技术设计仿生生长 含有填充有软软骨仿生物的机械分级3D刚性结构的板软骨 水凝胶。我们的假设是，生长板软骨的3D打印仿生物可以防止塌陷， 切除部位通过其结构，同时招募MSC， 区域适当的生理化学线索，软骨，而不是成骨，谱系，并防止 通过用软骨修复组织替代骨棒形成。因此，长期的3D打印 仿生将允许骨骺损伤后的正常骨伸长。为了验证这一假设，我们开发了 R21阶段有两个目标，R33阶段有两个目标。在R21阶段，我们将（1）打印一个3D结构 模拟生长板软骨的形态和机械特性（目的1）和（2）评估生长板软骨的生物学特性。 生长板软骨的3D打印仿生物在兔模型中防止骨棒形成的能力 骨骺损伤（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，并证实了3D 印刷的硬结构模仿生长板的结构，并填充有软水凝胶， 改革。在R33阶段，我们将（1）评估植入的3D打印仿生材料中的软骨形成， 通过募集内源性干细胞在骨骺损伤的兔模型中构建（目的3），和（2） 评估生长板软骨的3D打印仿生物在骨组织中实现纵向骨生长的能力。 兔骨骺损伤模型，植入后随访1年。在3年结束时， R33阶段，我们希望已经证明，用3D打印的 生长板软骨的仿生学防止骨杆再形成并支持软骨形成， 最终在生长至骨骼成熟后转化为新骨。通过提供解决方案来恢复 正常的骨骼生长，这种生长板软骨的3D打印仿生有可能被转化为 诊所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.