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: 10112931
• 负责人: Stephanie J Bryant
• 金额: $ 36.51万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112931
• 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; chemokine; design; digital; implantation; improved; injured; long bone; mechanical properties; microCT; mimetics; novel; pediatric patients; prevent; recruit; scaffold; skeletal; stem cell differentiation; stem cell migration; 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.

物理损伤占所有小儿骨折的30％，可能导致骨骼生长受损。物理 （或“生长板”）是儿童长骨头末端的软骨区域，负责纵向 骨生长。一旦损坏，来自下层下骨的间充质干细胞迁移到 受伤的物理，发生成骨，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，这对儿童来说是毁灭性的 仍在增长。当前的手术治疗涉及去除骨棒。该网站通常会填充 带有柔软的脂肪移植物或坚硬的，不可降解的塑料，两者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披露。那，这个项目的总体目标是 为了开发一种改进的治疗选择，该选项利用3D打印技术来设计生物学 板块软骨含有机械分级的3D僵硬结构，并用软软骨仿生 水凝胶。我们的假设是，生长板软骨的3D印刷仿生型可防止 切除站点通过其结构，简单地招募MSC来指导它们 具有软骨的占地适当的生理学提示，而不是成骨的谱系，并且可以防止 通过用软骨修复组织代替骨杆形成。长期印刷了3D 仿生型将允许物理损伤后正常的骨伸长。为了检验这一假设，我们已经开发了 R21阶段的两个目的，R33阶段的两个目标。在R21阶段，我们将（1）打印3D构造 模仿生长板软骨的形态和机械特性（AIM 1）和（2）评估 生长板软骨的3D印刷仿生型的能力，以防止兔模型中的骨棒形成 物理损伤（AIM 2）。在2年探索阶段的结论结束时，我们希望建立一个 通过3D打印技术设计的生长板软骨的新型仿生型，并确认了3D 印刷的刚性结构模仿生长板的结构并用软水凝胶填充，可防止骨棒 改革。在R33阶段，我们将（1）植入的3D印刷仿生剂中的评估软骨形成 通过募集内源性干细胞（AIM 3）和（2）在兔子损伤的兔子模型中构建 评估生长板软骨的3D印刷仿生型能够在A中纵向骨生长 物理损伤的兔模型，植入后1年随后进行。在三年的结论结束时 R33阶段，我们希望证明在骨棒切除后用3D打印填充现场 生长板软骨的仿生性可防止骨棒审查并支持软骨形成 最终在生长到骨骼成熟后转化为新骨骼。通过提供修复解决方案 正常的骨骼生长，这种3D印刷的生长板软骨的仿生型有可能翻译成 诊所改善受影响儿童的生活质量。

项目成果

Material properties and strain distribution patterns of bovine growth plate cartilage vary with anatomic location and depth.

• DOI: 10.1016/j.jbiomech.2022.111013
• 发表时间: 2022-03
• 期刊: JOURNAL OF BIOMECHANICS
• 影响因子: 2.4
• 作者: Fischenich, Kristine M.;Schneider, Stephanie E.;Neu, Corey P.;Payne, Karin A.;Ferguson, Virginia L.
• 通讯作者: Ferguson, Virginia L.

A 3D printed mimetic composite for the treatment of growth plate injuries in a rabbit model.

• DOI: 10.1038/s41536-022-00256-1
• 发表时间: 2022-10-19
• 期刊: NPJ REGENERATIVE MEDICINE
• 影响因子: 7.2
• 作者: Yu, Yangyi;Fischenich, Kristine M.;Schoonraad, Sarah A.;Weatherford, Shane;Uzcategui, Asais Camila;Eckstein, Kevin;Muralidharan, Archish;Crespo-Cuevas, Victor;Rodriguez-Fontan, Francisco;Killgore, Jason P.;Li, Guangheng;McLeod, Robert R.;Miller, Nancy Hadley;Ferguson, Virginia L.;Bryant, Stephanie J.;Payne, Karin A.
• 通讯作者: Payne, Karin A.

The heterogeneous mechanical properties of adolescent growth plate cartilage: A study in rabbit.

• DOI: 10.1016/j.jmbbm.2022.105102
• 发表时间: 2022-04
• 期刊: JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS
• 影响因子: 3.9
• 作者: Eckstein, Kevin N.;Thomas, Stacey M.;Scott, Adrienne K.;Neu, Corey P.;Hadley-Miller, Nancy A.;Payne, Karin A.;Ferguson, Virginia L.
• 通讯作者: Ferguson, Virginia L.

Microscale Photopatterning of Through-thickness Modulus in a Monolithic and Functionally Graded 3D Printed Part.

• DOI: 10.1002/smsc.202000017
• 发表时间: 2021-02
• 期刊: Small science
• 作者: A. C. Uzcategui;Callie I. Higgins;John E. Hergert;Andrew E. Tomaschke;Victor Crespo-Cuevas;V. Ferguson;S. Bryant;R. McLeod;J. Killgore