Tissue Regeneration by Biophysical Signaling

通过生物物理信号传导进行组织再生

基本信息

批准号：
8119480
负责人：
DAVID L. KAPLAN
金额：
$ 32.37万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119480
关键词：
Action Potentials Address Adipose tissue Alkaline Phosphatase Area Behavior Biochemical Biological Models Bioreactors Bone Marrow Bone Regeneration Bone Tissue Calcium Cartilage Cell Proliferation Cell membrane Cells Cellular Membrane Chemicals Collagen Type I Comparative Study Complex Cues Data Defect Deposition Development Developmental Biology Differentiation and Growth Disease model Embryo Engineering Environment Event Fiber Focus Groups Genetic Transcription Goals Growth Histocompatibility Testing Human Immigration In Vitro Ion Channel Ion Transport Ions Laboratories Lasers Ligaments Light Limb Development Limb structure Link Literature Lower Organism Mature Bone Mechanics Mediating Membrane Membrane Potentials Mesenchymal Stem Cells Modality Modeling Molds Molecular Molecular Genetics Morphogenesis Musculoskeletal System Natural regeneration Optics Organ Organism Outcome Pathway interactions Patients Pattern Pattern Formation Phase Preclinical Drug Evaluation Process Rana Reagent Recording of previous events Regenerative Medicine Regulation Research Reverse Transcriptase Polymerase Chain Reaction Role Running Scaffolding Protein Signal Transduction Signaling Molecule Site Source Staging Staining method Stains Stem cells Structure Support System System Time Tissue Engineering Tissue Model Tissues Universities Variant Work Wound Healing Zebrafish base bone bone sialoprotein cell behavior cell type electric field expectation human tissue improved in vivo in vivo regeneration insight limb regeneration novel novel strategies oil red O photonics programs public health relevance regenerative repaired restoration scaffold soft tissue spinal cord regeneration success tissue regeneration tool voltage

项目摘要

DESCRIPTION (provided by applicant): Traditional approaches to tissue engineering have focused on biochemical cocktails to direct cells toward tissue-specific outcomes; in some cases mechanical forces have also been utilized. However, there is also a significant literature that details the role of biophysical signaling during tissue development and tissue regeneration, which has not yet been incorporated into the field of tissue engineering to date. The field of developmental biology has tracked the role of biophysical factors, such as membrane voltage potential and ion fluxes, during tissue regeneration, in wound healing, in embryonic patterning, and in many other critical tissue- related events. These data provide a clear link between membrane potential and cell behavior that determine tissue-specific outcomes. However, many molecular details are still unclear and this novel cell control modality has not been capitalized upon to advance tissue regeneration. The focus of the present proposal is to fill this void by specifically studying biophysical regulation of bone and adipose tissue regeneration, development and patterning. We will utilize 3D human tissue systems for bone and adipose tissue. The goal is to determine the utility of biophysical factors, such as membrane potential, on tissue-specific outcomes in the context of tissue regeneration in Aim #1, tissue development in Aim #2, and tissue patterning in Aim #3. We will compare the role of membrane potential during tissue regeneration and formation to the use of traditional biochemical cocktails as the controls. In the last aim, we will focus on spatial control of tissue outcomes via light-activated regulation of ion transport, mediated via a 3D optically-addressable scaffold system, to generate tissue patterns in vitro, analogous to morphological control during limb development. The outcome of the proposed study will be an entirely new approach to the regulation of tissue formation in vitro, with implications in many areas of regenerative medicine. Understanding and exploiting the role of bioelectrical signals on tissue outcomes in non-excitable cells will provide new insight into fundamental control of tissue regeneration, as well as novel approaches toward generating complex pattern development in tissues both in vitro and in vivo. PUBLIC HEALTH RELEVANCE: Exploitation of biophysical control of tissue regeneration is virtually unexplored territory in the field of tissue engineering, despite extensive studies in developmental biology that have clearly shown the importance of changes in membrane potential and endogenous electric fields during tissue/organ development and regeneration. Thus, the goal of this program is to determine the impact of membrane potential-regulated signaling on bone and adipose tissue regeneration, formation, and patterning. The outcome of this program would be an entirely new approach to tissue formation and control in vitro, with major implications for regeneration in vivo. Rational modulation of these powerful biophysical controls, with or without more traditional biochemical controls, will allow greater control of tissue development and function. Building upon principles from developmental biology, progress from the proposed studies will have a profound impact on the field of tissue engineering. Understanding the role of biophysical factors on tissue behavior will yield insight into fundamental control mechanisms underlying tissue growth and regeneration, offering a new perspective to the current tissue engineering paradigm. Such an understanding will also define a set of well-characterized pharmacological and molecular-genetic tools to enable novel approaches to complex tissue patterning.

描述（由申请人提供）：传统的组织工程方法侧重于生化混合物来引导细胞产生组织特异性结果；在某些情况下，还使用了机械力。然而，还有一篇重要文献详细介绍了生物物理信号在组织发育和组织再生过程中的作用，但迄今为止尚未纳入组织工程领域。发育生物学领域追踪了生物物理因素（例如膜电压和离子通量）在组织再生、伤口愈合、胚胎模式以及许多其他关键组织相关事件中的作用。这些数据提供了膜电位和决定组织特异性结果的细胞行为之间的明确联系。然而，许多分子细节仍不清楚，并且这种新颖的细胞控制方式尚未被利用来促进组织再生。本提案的重点是通过专门研究骨和脂肪组织再生、发育和模式的生物物理调节来填补这一空白。我们将利用 3D 人体组织系统来处理骨骼和脂肪组织。目标是确定生物物理因素（例如膜电位）在目标 #1 中的组织再生、目标 #2 中的组织发育和目标 #3 中的组织模式化背景下对组织特异性结果的效用。我们将比较膜电位在组织再生和形成过程中的作用与使用传统生化鸡尾酒作为对照的情况。在最后一个目标中，我们将重点关注通过 3D 光学可寻址支架系统介导的离子传输的光激活调节对组织结果的空间控制，以在体外生成组织模式，类似于肢体发育过程中的形态控制。拟议研究的结果将是一种在体外调节组织形成的全新方法，对再生医学的许多领域都有影响。了解和利用生物电信号对非兴奋细胞组织结果的作用将为组织再生的基本控制提供新的见解，以及在体外和体内组织中产生复杂模式发展的新方法。公共健康相关性：利用组织再生的生物物理控制实际上是组织工程领域中尚未探索的领域，尽管发育生物学的广泛研究已经清楚地表明组织/器官发育和再生过程中膜电位和内源电场变化的重要性。因此，该项目的目标是确定膜电位调节信号对骨和脂肪组织再生、形成和模式的影响。该计划的成果将是一种全新的体外组织形成和控制方法，对体内再生具有重大影响。对这些强大的生物物理控制的合理调节，无论有或没有更传统的生化控制，都将能够更好地控制组织发育和功能。基于发育生物学的原理，拟议研究的进展将对组织工程领域产生深远的影响。了解生物物理因素对组织行为的作用将深入了解组织生长和再生的基本控制机制，为当前的组织工程范例提供新的视角。这种理解还将定义一套特征明确的药理学和分子遗传学工具，以实现复杂组织模式化的新方法。