Injectable Macroporous Matrices to Enhance Stem Cell Survival and Craniofacial Repair

可注射大孔基质增强干细胞存活和颅面修复

基本信息

批准号：
9264933
负责人：
Bogdan Conrad
金额：
$ 3.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-25 至 2019-03-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264933
关键词：
Address Adhesions Adipose tissue Affect Age Allografting Autologous Biochemical Biocompatible Materials Biology Biomimetics Blood Vessels Bone Matrix Bone Regeneration Bone Tissue Cell Proliferation Cell Survival Cell Therapy Cells Cephalic Collagen Communicable Diseases Congenital Abnormality Defect Deposition Development Dimensions Disease Economic Burden Engineering Engraftment Excision Extracellular Matrix Face Gelatin Growth Factor HA coating Harvest Human Hydrogels Hydroxyapatites In Situ In Vitro Individual Infiltration Inflammatory Injectable Injection of therapeutic agent Lead Ligands Mechanics Mesenchymal Differentiation Mesenchymal Stem Cells Minerals Modeling Morbidity - disease rate Mus Operative Surgical Procedures Organic solvent product Osteogenesis Outcome Patients Polymers Population Porosity Proteins Protocols documentation Reporting Shapes Site Societies Stem cells Stress Stromal Cells Structure Supporting Cell System Tissue Donors Tissue Engineering Tissue Grafts Tissues Traumatic injury United States Vascularization Work allogenic bone transplantation base bone bone loss cell type chemical property clinically relevant conventional therapy craniofacial craniofacial repair crosslink density design hydrophilicity immunogenicity improved in vivo in vivo regeneration interdisciplinary approach long bone materials science migration minimally invasive novel osteogenic physical property public health relevance repaired scaffold socioeconomics stem cell differentiation symposium tissue regeneration tissue repair

项目摘要

DESCRIPTION (provided by applicant): Bone loss affects millions of patients in the United States annually and can be caused by traumatic injury, inflammatory and infectious diseases, congenital malformation or oncologic resection. Conventional treatment often involves using autologous or allograft bone tissues, which is limited by donor site morbidity, insufficient donor tissue supply, and potential immunogenicity. Stem cell-based therapy offers a promising approach for the repair of bone loss such as cranial and long bone defects. However, a critical barrier to progress in the field is the lack of suitable cell carriers that can support stem cell survival, and guide vascularized and mineralized bone formation in situ without the addition of supraphysiological concentration of growth factors. To address the above challenges, my proposed multidisciplinary approach aims to validate the efficacy of microribbon-based scaffolds as a novel type of cell carrier for enhancing stem cell survival and mineralized bone matrix deposition in vivo using a mouse critical size cranial defect model. Our µRB- like hydrogels were fabricated by wet-spinning gelatin (digested collagen), the most abundant ECM matrix protein, into µRB-like structures, which can be crosslinked into a macroporous scaffold. The resulting hydrogels combine the injectability and cell-encapsulation ability of standard hydrogels with the macroporosity that facilitates faster vascular ingrowth, cell proliferation, adhesion, migration, and ECM deposition. This injectable system empowers minimally invasive surgery for a broad range of diseases. In our preliminary studies, µRB-based matrices markedly enhanced the survival of human adipose-derived stromal cells (ASCs) and accelerated tissue regeneration in vivo. Here I propose to further enhance the osteoinductivity and osteoconductivity of µRB-like hydrogels by tuning µRB stiffness, bulk stiffness and hydroxyapatite coating. I hypothesize that osteogenic differentiation of human mesenchymal stem cells (MSCs) in microribbon-based scaffolds can be enhanced by increasing the µRB stiffness and hydroxyapatite coating of microribbons. Furthermore, I hypothesize that increasing bulk stiffness of the scaffold will result in reduced matrix deposition due to decreasing pore size. Overall, the macroporosity of microribbon-based scaffolds would lead to enhanced cell survival, faster vascularization and enhanced bone tissue formation in vivo compared to convention biomaterials. The outcomes of the proposed work would lead to the development of new tissue engineering therapy for treating craniofacial and other large bony defects, and correspondingly reduce the associated socio-economical burden on society.

描述（由适用提供）：骨质流失每年影响美国数百万患者，可能是由创伤性损伤，炎症和传染病，先天性畸形或肿瘤学切除引起的。常规治疗通常涉及使用自体或同种异体移植骨组织，这些骨组织受供体部位的发病率，供体组织供应不足和潜在的免疫原性的限制。基于干细胞的疗法为修复骨质流失（例如颅骨和长骨缺损）提供了有希望的方法。但是，该领域进展的关键障碍是缺乏可以支持干细胞存活的合适细胞载体，并在不加入生长因子的超生理浓度的情况下引导血管化和矿化骨形成。为了应对上述挑战，我提出的多学科方法旨在验证基于微孔的支架作为一种新型细胞载体的效率，用于增强干细胞存活和使用小鼠临界大小颅底缺陷模型在体内增强干细胞存活和矿化骨基质沉积。我们的µRB样水凝胶是通过湿旋蛋白（消化的胶原蛋白）（最丰富的ECM基质蛋白）制成的，将其切成类似µRB的结构，可以将其交联成大孔脚手架。所得的水凝胶结合了标准水凝胶的注射性和细胞囊化能力与促进更快的血管内部，细胞增殖，粘合剂，迁移和ECM沉积的宏观质量。这种注射系统可为多种疾病提供最小的侵入性手术。在我们的初步研究中，基于µRB的矩阵显着增强了人脂肪衍生的基质细胞（ASC）和体内加速组织再生的存活。在这里，我建议通过调整µRB刚度，散装刚度和羟磷灰石涂层来进一步增强µRB样水凝胶的骨诱导和骨传导性。我假设通过增加微孔的µRB刚度和羟磷灰石涂层，可以增强基于微邻苯的支架中人类梅塞氏干细胞（MSC）的成骨分化。此外，我假设会导致脚手架的散装刚度增加在减小孔径降低的基质沉积中。总体而言，与惯例生物材料相比，基于微孔基的支架的宏观速度将导致细胞存活，更快的血管形成和体内骨组织形成增强。拟议工作的结果将导致开发新的组织工程疗法，用于治疗颅面和其他大键缺陷，并相应地减少了社会上相关的社会经济伯恩。