Exosome-mediated Craniofacial Bone Tissue Engineering by Controlled Release

外泌体介导的颅面骨组织工程控释

基本信息

批准号：
10373020
负责人：
William Benton Swanson
金额：
$ 5.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10373020
关键词：
3-Dimensional Attention Biocompatible Materials Biological Biological Assay Biomimetics Blood Vessels Bone Marrow Bone Regeneration Bone Transplantation Calcium Calvaria Cell Differentiation process Cells Cellularity Clinical Data Defect Dental Implants Dentition Dentures Disease Edentulous Mouth Elderly Electron Microscopy Electrophoresis Encapsulated Engineering Gene Expression Genes Goals Guided Tissue Regeneration Health Histology Implant Implantation procedure In Vitro Infiltration Inflammatory Response Instruction Kinetics Laboratories Maxilla Mediating Membrane Lipids Mesenchymal Stem Cells Messenger RNA Methods MicroRNAs Microfluidic Microchips Microspheres Minerals Modality Molecular Morbidity - disease rate Morphology Mus Natural regeneration Nature Oral cavity Osteoblasts Osteogenesis Outcome Particle Size Patients Phenotype Polymers Property Proteins RNA Regenerative capacity Scanning Electron Microscopy Site Spectrometry Stem cell transplant Stromal Cells Surface Technology Therapeutic Time Tissue Engineering Tissues Trauma Trehalose Ultracentrifugation Wound models base biomaterial compatibility bone bone healing bone quality controlled release copolymer craniofacial bone craniofacial complex delivery vehicle disease transmission exosome experimental study healing in vivo in vivo Model light scattering mechanical properties microCT mineralization molecular carrier nanoindentation novel osteogenic particle preservation regenerative repaired scaffold self assembly small molecule standard of care stem cell differentiation stem cell therapy submicron success

项目摘要

Abstract Healthy bone is critically important to systemic health. Of relevance to the craniofacial complex, dental implants require that empty sockets are filled with bone prior to implant placement and restoring dentition. Bone quality and bone amount are strongly correlated with both the short- and long-term success of dental implants. Biomaterials-based bone regeneration is promising to circumvent shortcomings of bone grafting. These biomaterials can be functionalized with instructive components which guide tissue regeneration. Exosomes, thought to be nature's endogenous biomolecule delivery platform, are particularly interesting because of their innate biocompatibility and capacity to communicate with cells to modulate their phenotype. Recent in vitro data suggests that exosomes derived from mineralizing MC3T3 pre-osteoblasts are able to induce mineralization in naive bone marrow stromal cells. However, engineering a means for their efficient therapeutic delivery in vivo, in a clinically and biologically relevant manner is a challenge in exosome-mediated therapy. The overall therapeutic goal of this project is to exploit the regenerative capacity of endogenous mesenchymal stem cells by mimicking the natural secretion of exosomes with a polymeric tissue engineering construct. My preliminary data suggests that polymeric self-assembly via a tunable biodegradable copolymer can encapsulate exosomes, which are released in a sustained fashion over time. My central hypothesis is that controlled release of osteogenic exosomes from a polymer matrix will promote craniofacial bone healing. The specific aims are to 1) develop a well-controlled fabrication method which allows incorporation of an exosome-releasing modality into a three-dimensional tissue engineering construct; 2) evaluate the integrity of the bioactive exosome contents during encapsulation and release, and their ability to cause phenotype changes in downstream cells; and 3) validate the technology invented herein in two in vivo models of craniofacial bone regeneration. The outcomes of the proposed experiments will demonstrate a means for the encapsulation and controlled delivery of exosomes from a polymer matrix, causing craniofacial bone regeneration without stem cell transplantation. Effective exosome encapsulation and release strategies, which preserve their biologic activity, are critical to advancing the field of exosome-mediated clinical therapies, which can be applied to the regeneration of many tissue types.

抽象的健康的骨骼对于全身健康至关重要。与颅面复合体、牙种植体相关要求在植入种植体和恢复牙列之前用骨填充空牙槽。骨质量骨量和骨量与牙种植体的短期和长期成功密切相关。基于生物材料的骨再生有望克服骨移植的缺点。这些生物材料可以通过指导组织再生的指导成分进行功能化。外泌体，被认为是自然界的内源性生物分子传递平台，由于其先天的生物相容性以及与细胞沟通以调节其表型的能力。最近的体外数据表明，源自矿化 MC3T3 前成骨细胞的外泌体能够诱导幼稚骨髓基质细胞中的矿化。然而，设计一种有效治疗的方法以临床和生物学相关的方式进行体内递送是外泌体介导的治疗中的一个挑战。该项目的总体治疗目标是利用内源性间充质的再生能力通过使用聚合物组织工程结构模拟外泌体的自然分泌来培养干细胞。我的初步数据表明，通过可调节的可生物降解共聚物进行聚合物自组装可以封装外泌体，随着时间的推移以持续的方式释放。我的中心假设是从聚合物基质中控制释放成骨外泌体将促进颅面骨的形成康复。具体目标是 1）开发一种控制良好的制造方法，允许结合外泌体释放方式进入三维组织工程结构； 2）评估完整性封装和释放过程中的生物活性外泌体含量及其引起表型的能力下游细胞的变化； 3) 在两个体内模型中验证本文发明的技术颅面骨再生。拟议实验的结果将展示一种方法从聚合物基质中封装和控制外泌体的递送，导致颅面骨无需干细胞移植即可再生。有效的外泌体封装和释放策略，保留其生物活性对于推进外泌体介导的临床治疗领域至关重要可应用于多种组织类型的再生。