Endothelial cell specification at the osteogenic and angiogenic interface in cranial bone tissue engineering

颅骨组织工程中成骨和血管生成界面的内皮细胞规范

基本信息

批准号：
10618247
负责人：
XINPING ZHANG
金额：
$ 53.11万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2020-09-03 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618247
关键词：
Address Affect Aging Allografting Arteries Autologous Transplantation BMX gene Binding Biological Markers Blood Vessels Blood capillaries Bone Regeneration Bone Tissue Cardiovascular system Cells Cephalic Clinical Coupling Defect Development Embryonic Development Endothelial Cells Endothelium Engineering Excision Genetic Goals Hypoxia Hypoxia Inducible Factor Hypoxia Pathway Image Imaging technology Implant Infection Knowledge Label Laser Scanning Microscopy Mediating Metabolic Metaphysis Modeling Molecular Profiling Morphology NADH Natural regeneration Nature Nicotinamide adenine dinucleotide Orthopedic Procedures Osteoblasts Osteogenesis Oxidation-Reduction Oxygen PECAM1 gene Pathway interactions Perfusion Play Population Regulation Resolution Role Series Site Specific qualifier value Tamoxifen Time Tissue Engineering Tissues Trauma Vascularization Veins Venous angiogenesis blood vessel development bone bone loss bone reconstruction bone repair craniomaxillofacial fluorescence lifetime imaging gain of function genetic approach genetic manipulation hypoxia inducible factor 1 imaging approach improved inducible Cre insight intravital imaging long bone loss of function migration mouse model multi-photon nanofiber novel osteogenic overexpression postnatal reconstruction regenerative repair model repaired response scaffold success tissue oxygenation tissue repair transcriptome sequencing tumor two-photon vascular bed vascular tissue engineering

项目摘要

Abstract Repair and reconstruction of bone loss due to tumor resection, trauma and infection remains a significant clinical challenge. Worldwide, autografts or allografts are used in approximately 3 million orthopaedic procedures annually, of which 6% are craniomaxillofacial in nature. Bone tissue engineering has been hailed as the ultimate solution for replacing bone autograft in repair of bone defects. However, the long-term success of bone tissue engineering is impeded by inadequate vascularization of the engineered construct. The current lack of progress in vascularization of tissue engineered scaffold is attributed to our incomplete understanding of angiogenesis and vascular beds in bone repair and regeneration. A functional blood vessel network consists of arteries, veins and a capillary interface that connects arterial and venous microvessels for proper vascular perfusion. While the specification of arterial and venous endothelium has been well studied during early embryonic development, the postnatal regulation of arterial and venous expansion and specification at capillary level during repair and regeneration is poorly understood. A series of recent studies have suggested that hypoxia affects the endothelial cell (EC) specification at the osteogenic and angiogenic interface in development and aging. Genetic manipulation of the hypoxia inducible factor 1 (HIF-1) pathway markedly affects the formation of specific subsets of capillary vessels, termed Type H (CD31highEmcnhigh) vessels that couple to OSX+ osteoblasts at the long bone metaphysis. To gain a better understanding of the critical role of hypoxia at the osteogenic and angiogenic interface in repair and regeneration, we established a series of novel imaging approaches that permit high resolution, quantitative, and functional analyses of capillary vessels that couple to Col (I) 2.3 GFP+ osteoblasts at a cranial bone defect site. Utilizing these novel imaging approaches in a layer-by-layer enabled, nanofiber-mediated cranial defect repair model, we demonstrate that osteogenesis- dependent angiogenesis consists of morphologically and functionally distinct CD31+Emcn+ and CD31+Emcn- vessels. Examination of blood vessel type distribution and bone regeneration demonstrates differential angiogenic responses and contrasting distributions of CD31+Emcn+ and CD31+Emcn- vessels associated with Col I (2.3) GFP+ osteoblasts, new bone and non-bone forming tissue, suggesting that EC specification at the capillary level is a key component of osteogenesis-dependent angiogenesis in bone repair and regeneration. Based on these findings, we propose to examine the effects of hypoxia on EC specification and the impact of dysregulation of EC specification on bone formation during cranial defect repair and regeneration. Three complementary Aims will combine imaging, genetic and engineering approaches to defining the osteogenesis- dependent EC specification and the role of hypoxia in repair and regeneration. The success of our study will provide novel insights into mechanisms of osteogenesis and angiogenesis in repair, potentially offering novel translational targets for bone regeneration.

抽象的由于肿瘤切除，创伤和感染而导致的骨质流失的修复和重建仍然是显着的临床挑战。全球，自体移植或同种异体移植物用于大约300万个骨科每年的程序，其中6％的性质是颅颌面。骨组织工程已被誉为作为替换骨骼缺陷修复骨自体移植的最终解决方案。但是，长期成功工程构建体的血管形成不足会阻碍骨组织工程的作用。电流组织工程脚手架的血管形成缺乏进展归因于我们不完整的理解骨修复和再生中的血管生成和血管床。功能性血管网络包括连接动脉和静脉微血管的动脉，静脉和毛细管界面的适当血管灌注。虽然在早期已经对动脉和静脉内皮的规范进行了很好的研究胚胎发育，毛细管时动脉和静脉膨胀的产后调节维修和再生期间的水平知之甚少。一系列最近的研究表明缺氧会影响内皮细胞（EC）的规格发展和衰老。低氧诱导因子1（HIF-1）途径的遗传操纵明显影响毛细血管血管的特定子集的形成，称为H型H（CD31Highemcnhigh）血管夫妇在长的骨冲导分析处夫妇到OSX+成骨细胞。为了更好地了解在修复和再生中的成骨和血管生成界面上的缺氧，我们建立了一系列新颖的允许对毛细管血管进行高分辨率，定量和功能分析的成像方法在颅骨缺陷部位，夫妇到Col（I）2.3 GFP+成骨细胞。利用这些新颖的成像方法纳米纤维介导的颅骨缺陷修复模型启用了一层层次，我们证明了骨生成 - 依赖性血管生成由形态和功能上不同的CD31+EMCN+和CD31+EMCN-组成船只。血管类型分布和骨再生的检查表明差异 CD31+EMCN+和CD31+EMCN-血管的血管生成反应和对比分布与 Col I（2.3）GFP+成骨细胞，新骨和非骨形成组织，表明EC规范在毛细血管水平是骨修复和再生中成骨依赖性血管生成的关键组成部分。基于这些发现，我们建议检查缺氧对EC规范的影响以及在颅骨缺陷修复和再生过程中，EC规范的EC规范失调。三互补的目标将结合成像，遗传和工程方法来定义成骨 - 依赖的EC规范以及缺氧在修复和再生中的作用。我们研究的成功将对修复中成骨的机制和血管生成的机制提供新的见解，并有可能提供新颖骨再生的翻译目标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Periosteum Mimetic Coating on Structural Bone Allografts via Electrospray Deposition Enhances Repair and Reconstruction of Segmental Defects.

DOI：
10.1021/acsbiomaterials.0c00421
发表时间：
2020-11-09
期刊：
ACS biomaterials science & engineering
影响因子：
5.8
作者：
Zhuang Z;John JV;Liao H;Luo J;Rubery P;Mesfin A;Boda SK;Xie J;Zhang X
通讯作者：
Zhang X

Doctors vs. Nurses: Understanding the Great Divide in Vaccine Hesitancy among Healthcare Workers.

DOI：
10.1109/bigdata55660.2022.10020853
发表时间：
2022-12-01
期刊：
Proceedings : ... IEEE International Conference on Big Data. IEEE International Conference on Big Data
影响因子：
0
作者：
Ahamed, Sajid Hussain Rafi;Shakil, Shahid;Luo, Jiebo
通讯作者：
Luo, Jiebo

Fabrication of channeled scaffolds through polyelectrolyte complex (PEC) printed sacrificial templates for tissue formation.