Transdermal Mechanical Loading for Cell Therapy-Based Bone Repair

用于基于细胞疗法的骨修复的透皮机械加载

基本信息

批准号：
9868891
负责人：
Yusuf M Khan
金额：
$ 34.1万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9868891
关键词：
3-Dimensional Acoustics Adipose tissue Alkaline Phosphatase Animal Model Belief Bone Regeneration Bone Tissue Bone Transplantation Calcium Signaling Calvaria Cell Survival Cell Therapy Cells Cellular biology Ceramics Clinical Collagen Computer Models Connecticut Data Defect Development Diagnostic radiologic examination Dinoprostone Encapsulated Engineering Environment Exposure to Fracture Gel Genes Goals Hydrogels Implant In Vitro Injections Injury Intention Laboratories Left Marrow Measurable Mechanics Methods Modeling Molecular Monitor Mus Musculoskeletal Operative Surgical Procedures Organ Transplantation Oryctolagus cuniculus Osteocalcin Osteogenesis PTGS2 gene Pathway interactions Phenotype Physiologic pulse Physiological Pliability Polymers Porifera Process Production Radiation Research Residencies Scientist Site Surgical incisions System Therapeutic Thick Time Tissue Engineering Traction Ultrasonography Universities Water Weight-Bearing state Work base bone bone healing cell behavior clinically relevant computer generated cost crosslink density design experience healing hydrogel scaffold implantation in silico in vivo mechanical load mechanical properties mineralization minimally invasive novel strategies osteopontin particle pre-clinical radiation effect repaired response sample fixation scaffold stem cells tissue repair tool

项目摘要

Cell therapy for bone repair combined with hydrogels, networks of crosslinked polymer chains with very high water content, is gaining in acceptance as a potential alternative to scaffold-based tissue engineering, especially for smaller scale defects that may be treatable through minimally invasive methods. Injecting cells into a bony defect with a small incision may be preferable to more invasive surgical procedures when clinically indicated. Once at the defect site the cells are left largely unperturbed within the hydrogel as the defect itself would require stabilization to permit healing, a requirement that goes against the therapeutic benefit of physically loading bone forming cells. It is this contradiction that has driven the work outlined in this proposal. Non-invasive, low-intensity pulsed ultrasound has been shown to be effective for transdermal treatment of fresh fractures (38% reduction in clinical and radiographic healing time) and fracture nonunions. While the mechanism through which LIPUS acts is poorly understood we have developed a highly tunable ultrasound system that demonstrates a measurable acoustic radiation force at clinically relevant ultrasound intensities and have shown this force to be capable of physically deflecting both cells and hydrogels. However, to date LIPUS-generated acoustic radiation force has not been paired with cell-loaded hydrogels for bone repair. The goal of this proposal is to combine LIPUS-generated acoustic radiation force and hydrogel-based cell therapy with the belief that both approaches together will enhance repair over either one alone. Using LIPUS- generated loading capable of imparting physical forces on cells, it is our intention to design hydrogel scaffolds that 1) are able to deliver encapsulated viable cells in vivo, 2) can be physically loaded by LIPUS generated acoustic radiation force after implantation and during the healing process and 3) can be modified to transfer varied physical forces from the hydrogel to cells such that healing would be optimized. The objectives of the present research are 1) to evaluate the effect of LIPUS-generated acoustic radiation force on cells embedded in hydrogels with increasing crosslinking densities, 2) to evaluate the effect of radiation force on cells encapsulated in collagen hydrogels of varying mechanical properties to determine the relationship between applied force and hydrogel stiffness on cell behavior, and 3) to use radiation force applied to hydrogels that have been loaded with cells and implanted in bone defect models. Implanted hydrogels containing cells will be loaded transdermally using acoustic radiation force. It is anticipated that the parameters defined in the in vitro studies will result in enhanced in vivo defect healing in hydrogels under acoustic radiation force when compared to either parameter alone.

与水凝胶、交联聚合物链网络相结合的骨修复细胞疗法水含量，作为基于支架的组织工程的潜在替代品正在获得越来越多的认可，特别是对于可以通过微创方法治疗的较小规模的缺陷。注射细胞临床上，通过小切口进入骨缺损可能比更具侵入性的外科手术更可取表明的。一旦到达缺陷部位，细胞在水凝胶内基本上不受干扰，就像缺陷本身一样需要稳定才能愈合，这一要求违背了治疗效果对骨形成细胞进行物理负载。正是这种矛盾推动了本提案中概述的工作。非侵入性、低强度脉冲超声波已被证明可有效用于透皮治疗新鲜骨折（临床和放射学愈合时间减少 38%）和骨折不愈合。虽然 LIPUS 的作用机制尚不清楚，我们开发了一种高度可调谐的超声波系统在临床相关的超声强度下展示可测量的声辐射力，并且已经证明这种力能够使细胞和水凝胶发生物理偏转。然而，迄今为止 LIPUS 产生的声辐射力尚未与细胞负载水凝胶配对用于骨修复。该提案的目标是将 LIPUS 产生的声辐射力与基于水凝胶的电池结合起来相信两种方法一起使用会比单独使用任何一种方法更能增强修复效果。使用 LIPUS- 产生的负载能够对细胞施加物理力，我们的目的是设计水凝胶支架 1) 能够在体内递送封装的活细胞，2) 可以通过 LIPUS 产生的物理负载植入后和愈合过程中的声辐射力和 3) 可以修改以转移水凝胶对细胞施加不同的物理力，从而优化愈合。本研究的目标是 1) 评估 LIPUS 产生的声辐射的效果随着交联密度的增加，对嵌入水凝胶中的细胞施加力，2) 评估效果对封装在不同机械性能的胶原水凝胶中的细胞施加辐射力，以确定施加的力和水凝胶刚度对细胞行为的关系，以及 3) 使用施加的辐射力已加载细胞并植入骨缺损模型的水凝胶。植入水凝胶含有细胞的细胞将使用声辐射力经皮加载。预计体外研究中定义的参数将导致水凝胶在体内缺陷愈合的增强与单独的任一参数相比时的声辐射力。