Engineering mechanical-electrical cell microenvironment in myocardium using advanced biomaterials

心血管疾病是当前全球范围内导致人类死亡的首要原因, 心肌组织工程的发展为心血管疾病的治疗, 尤其是心肌组织再生修复提供了最有潜力的解决方案.心血管疾病的发生发展与细胞力--电微环境的变化密切相关. 近十几年, 随着先进生物材料和微纳生物制造技术的发展, 越来越多的研究表明, 细胞力--电微环境的调控对工程化心肌组织的成熟和功能化以及心肌组织再生修复具有重要意义. 本文首先阐明了在体心肌细胞所处力学微环境的生物学基础以及电信号的传导过程, 包括正常和疾病状态下心肌细胞所处的力--电微环境.其次调研了用于心肌组织工程的先进生物材料的研究现状.最后总结用于基底硬度与应力应变细胞微环境以及细胞电学微环境的构建和调控, 以及细胞对力--电微环境的生物学响应.%     

基于先进生物材料的心肌细胞力–电微环境体外构建

心血管疾病是当前全球范围内导致人类死亡的首要原因,心肌组织工程的发展为心血管疾病的治疗,尤其是心肌组织再生修复提供了最有潜力的解决方案.心血管疾病的发生发展与细胞力–电微环境的变化密切相关.近十几年,随着先进生物材料和微纳生物制造技术的发展,越来越多的研究表明,细胞力–电微环境的调控对工程化心肌组织的成熟和功能化以及心肌组织再生修复具有重要意义.本文首先阐明了在体心肌细胞所处力学微环境的生物学基础以及电信号的传导过程,包括正常和疾病状态下心肌细胞所处的力–电微环境.其次调研了用于心肌组织工程的先进生物材料的研究现状.最后总结用于基底硬度与应力应变细胞微环境以及细胞电学微环境的构建和调控,以及细胞对力–电微环境的生物学响应.     

力敏感受体介导细胞功能调控的力学生物学研究

细胞膜是细胞与外部环境进行物质与能量交换的界面,是调节细胞正常生命活动的重要结构基础.细胞膜上力敏感受体可通过力学作用方式参与并影响细胞的力信号转导等功能.整合素和钙黏素是细胞膜上典型的力敏感受体,可介导细胞与细胞周围基质或邻近细胞发生力学作用,并将力学刺激信号转导为生化信号,进而激活细胞内一系列应答反应,最终影响细胞生长、分化、增殖、凋亡和迁移等功能.力敏感受体介导细胞功能调控研究已成为探索细胞主动响应外界复杂力学微环境的力学生物学机制的关键,为进一步深入认识生理和病理状态下细胞功能变化规律,为揭示疾病的发生、发展机制提供重要的力学生物学理论与实验依据.本文总结了力敏感受体介导细胞功能调控的国内外研究进展;介绍了黏附界面处典型力敏感受体的结构和功能;总结了这些力敏感受体参与的细胞力信号感知与响应的数理模型;概述了细胞通过力敏感受体进行力学信号转导的过程;介绍了黏附介导细胞功能调控的力学生物学过程和机制;简述了体外构建模拟细胞力学微环境中细胞-细胞外基质和细胞-细胞力学相互作用的技术;指出了力敏感受体介导细胞功能调控的力学生物学研究发展趋势和未来方向.     

肿瘤及其微环境的力学问题

肿瘤微环境包括肿瘤细胞、间质细胞、细胞外基质等.其在肿瘤的生长和发展过程中起着关键作用.肿瘤的微环境与正常组织的微环境有着显著的不同.肿瘤中的压应力对微环境有着多方面的影响, 例如, 可调控血管与淋巴管的功能, 造成代谢异常和间质高压, 压缩间隙基质, 增大药物输运的困难, 促进间质细胞变异并诱导肿瘤细胞转移. 因此, 肿瘤中的力学因素引起了广泛关注.本文总结了肿瘤及其微环境力学问题的研究进展, 讨论了肿瘤微环境中应力产生、药物输运、肿瘤转移等问题, 介绍了肿瘤微环境正常化的策略及其对肿瘤治疗的意义.      

Biomechanics of stem cells

干细胞生物力学作为生物力学的重要分支和前沿学科,近年来在力学-生物学、力学-化学耦合等方面取得了重大进展,已成为生物力学乃至生物医学工程最活跃的领域之一,并对发生物学、干细胞生物学、组织修复、再生医学等相关领域产生重要影响.干细胞具有独特的力学性质,可感知、传递、转导和响应生理力学微环境的改变,从而调控干细胞的生长、分化等功能,体现出典型的力学-生物学耦合特征.本文将对干细胞的力学性质与细胞力学模型、在体力学环境对干细胞生长和分化的影响、干细胞对外界力学刺激的响应等方面加以综述.     

干细胞的生物力学研究

干细胞生物力学作为生物力学的重要分支和前沿学科,近年来在力学-生物学、力学-化学耦合等方面取得了重大进展,已成为生物力学乃至生物医学工程最活跃的领域之一,并对发育生物学、干细胞生物学、组织修复、再生医学等相关领域产生重要影响.干细胞具有独特的力学性质,可感知、传递、转导和响应生理力学微环境的改变,从而调控干细胞的生长、分化等功能,体现出典型的力学-生物学耦合特征.本文将对干细胞的力学性质与细胞力学模型、在体力学环境对干细胞生长和分化的影响、干细胞对外界力学刺激的响应等方面加以综述.     

多物理场耦合作用分析的近场动力学理论与方法

广义来说, 近场动力学(peri-dynamics,PD)是假设每个物质点在承受一定范围内的非接触相互作用下,研究整个物理系统演化过程的理论,为涉及非连续和非局部相互作用的问题提供了一个统一的数学框架,具有广泛的适用性.在简要介绍诸多工程对于多物理场模型和数值计算软件的迫切需求后,针对现有商用软件在处理结构非连续演化问题时遇到的瓶颈,引入近场动力学理论和方法. 概述近场动力学固体力学模型,系统阐述近场动力学扩散模型和近场动力学多物理场耦合建模的研究现状和进展,主要涉及电子元器件、电子封装和岩土工程领域的多物理场耦合建模,包括热--力、湿--热--力、热--氧、热--力--氧、力--电、热--电、力--热--电、多孔介质的水--力流固相互作用等非耦合、半耦合与完全耦合模型,强调发展耦合方程数值解法的重要性.最后对扩散问题和多物理场耦合问题的近场动力学理论模型、数值算法和工程应用做进一步展望.      

Review of peridynamics for multi-physics coupling modeling

广义来说, 近场动力学(peri-dynamics,PD)是假设每个物质点在承受一定范围内的非接触相互作用下,研究整个物理系统演化过程的理论,为涉及非连续和非局部相互作用的问题提供了一个统一的数学框架,具有广泛的适用性.在简要介绍诸多工程对于多物理场模型和数值计算软件的迫切需求后,针对现有商用软件在处理结构非连续演化问题时遇到的瓶颈,引入近场动力学理论和方法. 概述近场动力学固体力学模型,系统阐述近场动力学扩散模型和近场动力学多物理场耦合建模的研究现状和进展,主要涉及电子元器件、电子封装和岩土工程领域的多物理场耦合建模,包括热--力、湿--热--力、热--氧、热--力--氧、力--电、热--电、力--热--电、多孔介质的水--力流固相互作用等非耦合、半耦合与完全耦合模型,强调发展耦合方程数值解法的重要性.最后对扩散问题和多物理场耦合问题的近场动力学理论模型、数值算法和工程应用做进一步展望.     

CD44-配体相互作用的生物力学与功能调控

作为一种广谱表达的细胞粘附分子, I型跨膜糖蛋白CD44(cluster of differentiation 44)参与细胞增殖、分化、迁移, 血管生成等生物学过程,对于介导细胞信号转导, 调节组织稳态等功能具有关键作用. 特别地,CD44-选择素、CD44 -透明质酸相互作用介导的细胞粘附动力学在经典炎症反应、肿瘤转移或组织特异的肝脏免疫中具有重要作用.该综述分别从细胞层次粘附动力学、二维与三维条件下的分子层次反应动力学、原子层次微观结构以及胞内信号转导通路等方面综述了CD44 -选择素、CD44 -透明质酸相互作用的研究进展及尚待回答的生物力学问题.力学、物理因素对生命活动的不可或缺性逐渐被研究者们接受,力学医学、力学免疫学、力学组学等新概念相继提出. 生理、病理条件下,CD44 -配体相互作用介导的细胞粘附必将受到血流剪切、基底硬度等力学、物理微环境的调控,但是其调控机制还远不清楚. 基于此,本文就CD44 -配体相互作用相关的未来研究方向做出展望, 主要包括:力学、物理因素如何调控CD44 -配体相互作用介导的细胞粘附动力学及其内在机制;CD44 -配体相互作用反应动力学的力学调控规律及结构基础是什么;以及力学作用下CD44 -配体相互作用原子层次的微观结构如何发生动态演化.本文可为深入理解CD44 -配体相互作用的生物学功能及其结构功能关系提供线索.      

骨组织细胞的力学调控研究

力学环境是影响骨组织细胞形成、增殖和功能成熟的一个重要因素. 骨细胞是力学感受细胞, 将力学信号传递给效应细胞; 成骨细胞、破骨细胞为力学效应细胞, 使骨形成和骨吸收处于动态平衡以维持骨力学稳定性. 目前对骨组织细胞间力学调控的机理仍不甚清楚. 综述了骨组织细胞力学生物学作用和细胞间力学调控的一些相关问题. 在概述了成骨细胞、骨细胞和破骨细胞的生物学特性基础上,阐述了骨重建力学调控理论,成骨细胞、骨细胞和破骨细胞生物力学效应和细胞间力学调控最新研究进展. 最后对骨组织细胞三维网络间力学调控研究做出展望.     

ADVANCES IN EXPERIMENTAL APPROACHES FOR INVESTIGATING CELL AGGREGATE MECHANICS

Cells tend to form hierarchy structures in native tissues.Formation of cell aggregates in vitro such as cancer spheroids and embryonic bodies provides a unique means to study the mechanical properties and biological behaviors/functions of their counterparts in vivo.In this paper,we review state-of-the-art experimental approaches to assess the mechanical properties and mechanically-induced responses of cell aggregates in vitro.These approaches are classified into five categories according to loading modality,including micropipette aspiration,centrifugation,compression loading,substrate distention,and fluid shear loading.We discussed the advantages and disadvantages of each approach,and the potential biomedical applications.Understanding of the mechanical behavior of cell aggregates provides insights to physical interactions between cells and integrity of biological functions,which may enable mechanical intervention for diseases such as atheromatosis and cancer.     

垂直入射弹性波在压电体单侧接触界面上的传播特性

弹性波与压电材料接触界面的相互作用问题是工程应用中常见而复杂的问题,入射波足够强会引起界面出现滑移和分离,但滑移和分离的边界未知,边界条件具有非线性特性。通过Fourier分析,将混合边值问题的求解转化为非线性代数方程,利用软件通过迭代修正的方法进行了求解;给出3种状态边界的求解,分析入射波强度、外加应力及电场对界面状态的影响,并对高频谐波的特性进行分析,通过实例对理论推导进行验证,结果显示:入射波强度、外加荷载和电场的大小及摩擦因数均会影响到界面,通过改变这些条件可以控制界面状态,另外检测高频谐波的信号也可以反映界面状态。     

Computational Optogenetics: A Novel Continuum Framework for the Photoelectrochemistry of Living Systems

Electrical stimulation is currently the gold standard treatment for heart rhythm disorders. However, electrical pacing is associated with technical limitations and unavoidable potential complications. Recent developments now enable the stimulation of mammalian cells with light using a novel technology known as optogenetics. The optical stimulation of genetically engineered cells has significantly changed our understanding of electrically excitable tissues, paving the way towards controlling heart rhythm disorders by means of photostimulation. Controlling these disorders, in turn, restores coordinated force generation to avoid sudden cardiac death. Here, we report a novel continuum framework for the photoelectrochemistry of living systems that allows us to decipher the mechanisms by which this technology regulates the electrical and mechanical function of the heart. Using a modular multiscale approach, we introduce a non-selective cation channel, channelrhodopsin-2, into a conventional cardiac muscle cell model via an additional photocurrent governed by a light-sensitive gating variable. Upon optical stimulation, this channel opens and allows sodium ions to enter the cell, inducing electrical activation. In side-by-side comparisons with conventional heart muscle cells, we show that photostimulation directly increases the sodium concentration, which indirectly decreases the potassium concentration in the cell, while all other characteristics of the cell remain virtually unchanged. We integrate our model cells into a continuum model for excitable tissue using a nonlinear parabolic second order partial differential equation, which we discretize in time using finite differences and in space using finite elements. To illustrate the potential of this computational model, we virtually inject our photosensitive cells into different locations of a human heart, and explore its activation sequences upon photostimulation. Our computational optogenetics tool box allows us to virtually probe landscapes of process parameters, and to identify optimal photostimulation sequences with the goal to pace human hearts with light and, ultimately, to restore mechanical function.     

A generic approach towards finite growth with examples of athlete's heart, cardiac dilation, and cardiac wall thickening

The objective of this work is to establish a generic continuum-based computational concept for finite growth of living biological tissues. The underlying idea is the introduction of an incompatible growth configuration which naturally introduces a multiplicative decomposition of the deformation gradient into an elastic and a growth part. The two major challenges of finite growth are the kinematic characterization of the growth tensor and the identification of mechanical driving forces for its evolution. Motivated by morphological changes in cell geometry, we illustrate a micromechanically motivated ansatz for the growth tensor for cardiac tissue that can capture both strain-driven ventricular dilation and stress-driven wall thickening. Guided by clinical observations, we explore three distinct pathophysiological cases: athlete's heart, cardiac dilation, and cardiac wall thickening. We demonstrate the computational solution of finite growth within a fully implicit incremental iterative Newton-Raphson based finite element solution scheme. The features of the proposed approach are illustrated and compared for the three different growth pathologies in terms of a generic bi-ventricular heart model.     

Non-contact tensile viscoelastic characterization of microscale biological materials

Many structures and materials in nature and physiology have important “meso-scale” structures at the micron length-scale whose tensile responses have proven difficult to characterize mechanically. Although techniques such as atomic force microscopy and micro- and nano-identation are mature for compression and indentation testing at the nano-scale, and standard uniaxial and shear rheometry techniques exist for the macroscale, few techniques are applicable for tensile-testing at the micrometre-scale, leaving a gap in our understanding of hierarchical biomaterials. Here, we present a novel magnetic mechanical testing (MMT) system that enables viscoelastic tensile testing at this critical length scale. The MMT system applies non-contact loading, avoiding gripping and surface interaction effects. We demonstrate application of the MMT system to the first analyses of the pure tensile responses of several native and engineered tissue systems at the mesoscale, showing the broad potential of the system for exploring micro- and meso-scale analysis of structured and hierarchical biological systems.     

复杂微力－电系统的细微尺度力学

现代高新技术的崛起,提出了大量新的经典力学所不能完全包容的力学问题。这将是现代应用力学发展的巨大动力。微电子技术中微电子材料、器件、系统和微电子－机械系统（ｍｉｃｒｏｅｌｅｃｔｒｏ－ｍｅｃｈａｎｉｃａｌｓｙｓｔｅｍ,ＭＥＭＳ）所组成的复杂微力－电系统,是跨世纪发展的新科技方向,本文简要介绍了复杂微力,电系统的工业技术背景和发展;综述了这一领域存在的力学问题,主要讨论细微尺度下的结构力学与破坏力学。并评介与展望了这一新的力学领域的研究状况和发展趋势。      

MULTISCALE MECHANICS OF BIOLOGICAL AND BIOLOGICALLY INSPIRED MATERIALS AND STRUCTURES

The world of natural materials and structures provides an abundance of applications in which mechanics is a critical issue for our understanding of functional material properties. In particular, the mechanical properties of biological materials and structures play an important role in virtually all physiological processes and at all scales, from the molecular and nanoscale to the macroscale, linking research fields as diverse as genetics to structural mechanics in an approach referred to as materiomics. Example cases that illustrate the importance of mechanics in biology include mechanical support provided by materials like bone, the facilitation of locomotion capabilities by muscle and tendon, or the protection against environmental impact by materials as the skin or armors. In this article we review recent progress and case studies, relevant for a variety of applications that range from medicine to civil engineering. We demonstrate the importance of fundamental mechanistic insight at multiple time- and length-scales to arrive at a systematic understanding of materials and structures in biology, in the context of both physiological and disease states and for the development of de novo biomaterials. Three particularly intriguing issues that will be discussed here include： First, the capacity of biological systems to turn weakness to strength through the utilization of multiple structural levels within the universality-diversity paradigm. Second, material breakdown in extreme and disease conditions. And third, we review an example where the hierarchical design paradigm found in natural protein materials has been applied in the development of a novel hiomaterial based on amyloid protein.     

Biaxial Mechanical Evaluation of Planar Biological Materials

A fundamental goal in constitutive modeling is to predict the mechanical behavior of a material under a generalized loading state. To achieve this goal, rigorous experimentation involving all relevant deformations is necessary to obtain both the form and material constants of a strain-energy density function. For both natural biological tissues and tissue-derived soft biomaterials, there exist many physiological, surgical, and medical device applications where rigorous constitutive models are required. Since biological tissues are generally considered incompressible, planar biaxial testing allows for a two-dimensional stress-state that can be used to characterize fully their mechanical properties. Application of biaxial testing to biological tissues initially developed as an extension of the techniques developed for the investigation of rubber elasticity [43, 57]. However, whereas for rubber-like materials the continuum scale is that of large polymer molecules, it is at the fiber-level (∼1 μm) for soft biological tissues. This is underscored by the fact that the fibers that comprise biological tissues exhibit finite nonlinear stress-strain responses and undergo large strains and rotations, which together induce complex mechanical behaviors not easily accounted for in classic constitutive models. Accounting for these behaviors by careful experimental evaluation and formulation of a constitutive model continues to be a challenging area in biomechanics. The focus of this paper is to describe a history of the application of biaxial testing techniques to soft planar tissues, their relation to relevant modern biomechanical constitutive theories, and important future trends. This revised version was published online in July 2006 with corrections to the Cover Date.