Tissue Regeneration by Biophysical Signaling

通过生物物理信号传导进行组织再生

• 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
• 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

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）：组织工程的传统方法集中在生化鸡尾酒上，将细胞引导到组织特异性结果。在某些情况下，机械力也已被利用。然而，还有一篇重要的文献详细介绍了生物物理信号在组织发育和组织再生中的作用，迄今为止尚未将其纳入组织工程领域。发育生物学领域已经跟踪了生物物理因子的作用，例如膜电压电势和离子通量，在组织再生，在伤口愈合，胚胎模式中以及在许多其他关键组织中的事件中。这些数据提供了确定组织特异性结果的膜电位和细胞行为之间的明确联系。但是，许多分子细节仍不清楚，这种新型的细胞控制方式尚未大写以推动组织再生。本提案的重点是通过专门研究骨骼和脂肪组织再生，发育和图案的生物物理调节来填补这一空白。我们将利用3D人体组织系统进行骨骼和脂肪组织。目的是确定在AIM＃1的组织再生，AIM＃2中的组织发育以及AIM＃3中的组织发展的背景下，在组织再生的背景下，生物物理因子（例如膜电位）的实用性。我们将将膜电位在组织再生和形成中的作用与使用传统生化鸡尾酒作为对照的作用。在最后一个目标中，我们将通过3D光学上可调的脚手架系统介导的离子转运的光激活调节来关注组织结局的空间控制，以在体外产生组织模式，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全新的方法，用于调节体外组织形成，在许多再生医学领域都有意义。理解和利用生物电信信号对非驱散细胞的组织结局的作用将为组织再生的基本控制提供新的见解，以及在体外和体内产生复杂模式发展的新颖方法。 公共卫生相关性：在组织工程领域对组织再生的生物物理控制的剥削实际上是未开发的领域，尽管在发育生物学方面进行了广泛的研究，这些研究清楚地表明了在组织/器官发育和再生期间膜潜能和内源性电场变化的重要性。因此，该程序的目的是确定膜电位调节的信号对骨骼和脂肪组织再生，形成和图案的影响。该程序的结果将是一种全新的组织形成和控制的方法，对体内的再生产生了重大影响。有或没有传统的生化控​​制，对这些强大的生物物理控制的合理调节将使组织发育和功能更加控制。基于发展生物学的原则，拟议的研究的进步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洞悉组织生长和再生的基本控制机制，从而为当前的组织工程范式提供新的视角。这样的理解还将定义一组特征良好的药理和分子遗传学工具，以实现复杂的组织模式的新方法。