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：
10330538
负责人：
Yusuf M Khan
金额：
$ 34.75万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330538
关键词：
3-Dimensional Acoustics Adipose tissue Alkaline Phosphatase Animal Model Belief Bone Tissue Bone Transplantation Calcium Signaling Calvaria Cell Survival Cell Therapy Cells Cellular biology Ceramics Clinical Collagen Computer Models Connecticut Data Defect Development 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 Universities Water Weight-Bearing state Work base bone bone healing bone repair 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 radiological imaging repaired response sample fixation scaffold stem cells tissue repair tool translational potential ultrasound

3-Dimensional Acoustics Adipose tissue Alkaline Phosphatase Animal Model Belief Bone Tissue Bone Transplantation Calcium Signaling Calvaria Cell Survival Cell Therapy Cells Cellular biology Ceramics Clinical Collagen Computer Models Connecticut Data Defect Development 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 Universities Water Weight-Bearing state Work base bone bone healing bone repair 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 radiological imaging repaired response sample fixation scaffold stem cells tissue repair tool translational potential ultrasound

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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.

用于骨修复的细胞疗法与水凝胶，交联聚合物链网络结合很高水含量正在接受，作为基于脚手架的组织工程的潜在替代方案，特别是对于较小的尺度缺陷，可以通过微创方法治疗。注射细胞在临床上，在带有小切口的骨缺陷中，可能比更具侵入性的手术程序更可取表明的。一旦在缺陷部位需要稳定才能允许康复，这是违背治疗益处的要求物理上加载骨形成细胞。正是这种矛盾推动了该提议中概述的工作。非侵入性，低强度脉冲超声已被证明可有效新鲜骨折（临床和射线照相愈合时间降低了38％）和骨折骨折。而 Lipus行为的机制知之甚少，我们开发了高度可调的超声在临床相关的超声强度和已经证明了这种力能够物理地偏转细胞和水凝胶。但是，迄今为止 Lipus生成的声辐射力尚未与负载的细胞水凝胶配对以进行骨修复。该提案的目的是结合Lipus生成的声学辐射力和基于水凝胶的细胞疗法相信两种方法都可以加强对任何一种方法的维修。使用Lipus- 产生的负载能够在细胞上赋予物理力，这是我们设计水凝胶支架的意图 1）能够在体内传递封装的可行细胞，2）可以通过生成的脂肪在物理上加载植入后和愈合过程中的声学辐射力和3）可以修改以转移从水凝胶到细胞的各种物理力，可以优化愈合。本研究的目标是1）评估Lipus生成的声学辐射的影响嵌入水凝胶中的细胞对交联密度增加，2）评估封装在不同机械性能的胶原凝胶中的细胞上的辐射力，以确定施加力和水凝胶刚度在细胞行为上的关系，3）使用施加辐射力到已加载细胞并植入骨缺损模型的水凝胶。植入水凝胶包含细胞将使用声辐射力透射加载。预计体外研究中定义的参数将导致体内缺陷在水凝胶下的缺陷愈合与单独的两个参数相比，声学辐射力。