Functional Fluid Flow Regulated Bone Regeneration

功能性流体流量调节骨再生

基本信息

批准号：
8307695
负责人：
Yi-Xian Qin
金额：
$ 34.6万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307695
关键词：
3-Dimensional Affect Animal Model Biochemistry Bioreactors Birds Blood Circulation Blood Vessels Bone Marrow Stem Cell Bone Regeneration Bone Substitutes Bone Surface Bone Tissue Bone Transplantation Cell Culture Techniques Cell Differentiation process Cell Proliferation Cell Survival Cell Transplantation Cells Clinical Cultured Cells Defect Dose Endosteum Engineering Environment Equation Finite Element Analysis Fourier Transform Frequencies Goals Growth Healed Health Healthcare Histology Homing Immature Bone In Vitro Knowledge Liquid substance Marrow Measures Mechanics Mediating Mediator of activation protein Modality Modeling Muscle Natural regeneration Nutrient Operative Surgical Procedures Osteoblasts Osteogenesis Osteopenia Outcome Oxygen Patients Perfusion Periosteum Permeability Phase Physiologic calcification Physiological Porosity Quality of life Recruitment Activity Regulation Relative (related person)Role Signal Transduction Solid Spatial Distribution Stimulus Synchrotrons Techniques Tissue Engineering Tissue Grafts Uncertainty Vascularization Waste Products base bone bone cell bone healing calcification design fluid flow healing implantation improved in vivo mineralization novel novel strategies osteogenic osteoporosis with pathological fracture pressure response scaffold shear stress stem cell differentiation tissue regeneration tissue repair ulna

项目摘要

DESCRIPTION (provided by applicant): Traumatic and osteoporotic fractures, critical/large defects and nonunion represent a significant burden in health care and affects quality of life for these patients. Tissue engineering approaches show promise as bone substitutes, and have been particularly successful in vitro in a bioreactor environment. The major challenge of tissue engineered regeneration is to maintain viability of cells in vivo and to rebuild vascular networks capable of delivering oxygen and nutrients while removing waste products after the implantation. Recently, a new cell homing approach has shown promising results in recruiting endogenous cells and then regeneration without cell transplantation. To accelerate cell homing and maintain cell viability in vivo, functional bone fluid flow induced by mechanical loading has been shown to be a critical regulator in initiating and mediating bone surface and osteonal adaptation. Dynamic fluid flow through porous constructs will exert increased fluid shear stress to promote in vivo cell differentiation and mineralization. Using oscillatory pressurized marrow fluid flow and muscle-bone interface stimuli, small magnitude fluid pressure (10-60 mmHg) with relative high frequency and short daily duration (10min) was found to initiate new bone formation and mitigate increased intracortical porosities caused by disuse osteopenia. It is essential to establish a functional dynamic fluid flow environment within the in vivo porous bone large defect and maintain an active fluid flow for bone regeneration. Thus, we will examine the general hypothesis that functional mechanotransduction regulated by dynamic bone fluid flow, with optimized intensity and rate, is essential and responsible for in vivo tissue regeneration, cellular differentiation, and osteogenic mineralization in critical defect healing. The ultimate gol is to generate an oscillatory fluid pressure gradient in the critical defect and the scaffold, servng as an in vivo bioreactor to promote functional fluid flow, vascular circulation, and osteogenesis. The outcomes will improve our understanding of how an optimized fluid flow environment enhances cellular viability and mineralization, and the importance of mechanotransduction in tissue repair and regeneration particularly under in vivo conditions. It is expected that this project will provide a novel approach to regulate bone formation via in vivo fluid flow stimuli, an improve our knowledge of critical signals for dynamic mechanotransduction in accelerating bone formation and mineralization in tissue regeneration, which will be ultimately used for clinical tissue repair. PUBLIC HEALTH RELEVANCE: Bone critical defects resultant from traumatic and osteoporotic fractures are major health problems. These patients have limited options, such as early surgical interventions with bone grafts with uncertainties in calcification and nonunion. Tissue engineering represents promising potentials, but requires large scale in vitro cell proliferation and differentiation. This project is expected to generate a new paradigm in bone tissue engineering by promoting osteogenic response and vascularization via enhanced in vivo dynamic fluid flow perfusion in the constructs to regulate and accelerate regeneration. Such approaches may accelerate in vivo healing and ultimately enhance clinical tissue repair through further design of novel non-invasive stimulator from the outcome of this application.

描述（由申请人提供）：外伤性和骨质疏松性骨折、严重/大的缺损和骨不连给医疗保健带来了重大负担，并影响这些患者的生活质量。组织工程方法显示出作为骨替代品的前景，并且在体外生物反应器环境中特别成功。组织工程再生的主要挑战是维持体内细胞的活力并重建能够输送氧气和营养物质的血管网络，同时清除植入后的废物。最近，一种新的细胞归巢方法在招募内源细胞然后无需细胞移植即可再生方面显示出有希望的结果。为了加速细胞归巢并维持体内细胞活力，机械负荷诱导的功能性骨液流动已被证明是启动和介导骨表面和骨适应的关键调节剂。通过多孔结构的动态流体流动将施加增加的流体剪切应力，以促进体内细胞分化和矿化。使用振荡加压骨髓液流和肌肉骨界面刺激，发现相对较高频率和较短的每日持续时间（10分钟）的小幅度流体压力（10-60 mmHg）可以启动新骨形成并减轻由废用性骨质减少引起的皮质内孔隙度增加。在体内多孔骨大缺损内建立功能性动态流体流动环境并维持骨再生的活跃流体流动至关重要。因此，我们将研究一般假设，即动态骨液流以优化的强度和速率调节的功能性机械转导对于关键缺损愈合中的体内组织再生、细胞分化和成骨矿化至关重要并负责。最终目标是在关键缺损和支架中产生振荡流体压力梯度，作为体内生物反应器来促进功能性流体流动、血管循环和成骨。这些结果将提高我们对优化的流体流动环境如何增强细胞活力和矿化的理解，以及机械转导在组织修复和再生中的重要性，特别是在体内条件下。预计该项目将提供一种通过体内流体流动刺激调节骨形成的新方法，提高我们对动态力转导在加速骨形成和组织再生中矿化的关键信号的认识，最终将用于临床组织维修。公众健康相关性：外伤性和骨质疏松性骨折导致的骨严重缺陷是主要的健康问题。这些患者的选择有限，例如对钙化和不愈合不确定的骨移植进行早期手术干预。组织工程具有广阔的前景，但需要大规模的体外细胞增殖和分化。该项目有望通过增强结构中的体内动态流体流动灌注来调节和加速再生，从而促进成骨反应和血管化，从而在骨组织工程中产生新的范例。这些方法可以加速体内愈合，并最终通过根据本申请的结果进一步设计新型非侵入性刺激器来增强临床组织修复。