Annals of Biomedical Engineering, Vol. 37, No. 5, May 2009 (Ó 2009) pp. 847–859 DOI: 10.1007/s10439-009-9661-x Biomechanics: Cell Research and Applications for the Next Decade 1 2 3 4 5 DENNIS DISCHER, CHENG DONG, JEFFREY J. FREDBERG, FARSHID GUILAK, DONALD INGBER, 1 6 7 8 PAUL JANMEY, ROGER D. KAMM, GEERT W. SCHMID-SCHO¨ NBEIN, and SHELDON WEINBAUM 1University of Pennsylvania, Philadelphia, PA, USA; 2Pennsylvania State University, University Park, PA, USA; 3Harvard School of Public Health, Boston, MA, USA; 4Duke University, Durham, NC, USA; 5Harvard Medical School, Boston, MA, USA; 6MIT, Boston, MA, USA; 7University of California, San Diego, San Diego, CA, USA; and 8City College of New York, New York, NY, USA (Received 10 July 2008; accepted 21 February 2009; published online 4 March 2009) Abstract—With the recent revolution in Molecular Biology emerge through collective interactions within dynami- and the deciphering of the Human Genome, understanding cally coupled regulatory networks. Systems Biology of the building blocks that comprise living systems has presently emphasizes information transfer,17 but the advanced rapidly. We have yet to understand, however, how the physical forces that animate life affect the synthesis, three-dimensional geometries and physical forces that folding, assembly, and function of these molecular building play so large a role in biological structure and function blocks. We are equally uncertain as to how these building have yet to be fully taken into account. Indeed, with- blocks interact dynamically to create coupled regulatory out these biomechanical factors there would be no networks from which integrative biological behaviors form, no function, no life. emerge. Here we review recent advances in the field of Most diseases present as a complex genetic profile biomechanics at the cellular and molecular levels, and set 85,131 forth challenges confronting the field. Living systems work with multiple changes in molecular expression. and move as multi-molecular collectives, and in order to Nonetheless, a patient goes to the doctor’s office often understand key aspects of health and disease we must first be because of a mechanical defect in a tissue or organ: a able to explain how physical forces and mechanical structures new swelling or lump, pain due to nerve compression, contribute to the active material properties of living cells and tissues, as well as how these forces impact information stiffness that limits movement, edema caused by a leak processing and cellular decision making. Such insights will no of tissue bodily fluids, constricted blood flow or lymph doubt inform basic biology and rational engineering of flow, or obstructed airflow that restricts breathing. effective new approaches to clinical therapy. Cures and remedies are often judged successful by the patient only when such mechanical defects are reme- Keywords—Biomechanics, Cell, Mechanics, Rheology, Sig- died. In order to understand health-related and disease- naling, Force, Stress. related aspects of living systems—all of which work and move as multi-molecular collectives—we must first be able to explain how physical forces and mechanical structures contribute to the ‘active’ material properties INTRODUCTION of living cells and tissues, as well as how these forces impact information processing and cellular decision In this post-genomic era, the challenge that all areas making.50,71 Such insights will inform not only basic of biomedical research now face is to understand how biology but also rational engineering of effective new the molecules that are expressed go on to fold, approaches to clinical therapy. Here we discuss key assemble and function within the context of living cells, obstacles and major opportunities confronting the field tissues, and organs. Just as challenging is the question of biomechanics, as well as implications for the future of how complex biological characteristics subsequently of science, engineering, and healthcare. Address correspondence to Jeffrey J. Fredberg, Harvard School of Public Health, Boston, MA, USA. Electronic mail: discher@seas. HISTORICAL BACKGROUND upenn.edu, [email protected], [email protected], guilak@ duke.edu, [email protected], [email protected]. In the first half of the 20th century, D’Arcy upenn.edu, [email protected], [email protected], weinbaum@ccny. Thompson proposed that mechanical forces act as cuny.edu This is a white-paper developed by the Cell Mechanics working causative agents during tissue morphogenesis. At a group of the US National Committee on Biomechanics. time when the molecular basis of viscosity was being 847 0090-6964/09/0500-0847/0 Ó 2009 Biomedical Engineering Society 848 DISCHER et al. developed by Einstein,28 some of the earliest quanti- hydrodynamic flow-mediated tumor cell adhe- tative evidence of non-Newtonian viscosity emerged sion,67,114 loss of lung elasticity in emphysema,77,98,116 from studies of biological fluids Even though the excessive narrowing of airways in asthma,38 increased reality of molecules, as distinct from colloidal particles, wall stiffness in hypertension, enhanced rigidity and was still being contested, the unusual mechanical adhesion of red cells to the endothelium in malaria and properties of cytoplasm led to visionary proposals that sickle cell disease,65,73,94 and abnormal cellular mech- the cell contained a system of molecular filaments anotransduction in deafness as well as polycystic kid- (reviewed in Trepat et al.119). ney disease. There are numerous other examples in Clinicians recognized quite early the central impor- virtually all areas of medicine and surgery.56 Even in tance of physical forces in physiological control. Well- embryonic development and cancer, it is physical for- known examples include the effects of inspiratory ces, material flows, and differences in cellular pressure on lung function, hemodynamic shear stress mechanics that provide essential inputs in the program on vascular remodeling, compression on bone gener- that drives cell sorting, differentiation, growth and ation, and tension on skin aging. There is now the angiogenesis.58,89 In these cases, biomechanics recognition of pivotal roles played by physical forces in underlies the abilities of the cell, tissue or organ to genetic and cellular regulation, as well as in develop- carry out normal functions in health or to malfunction mental control.42 Interest in biomechanics has since in disease. grown exponentially and now includes researchers in a wide range of biological disciplines including molecu- lar biophysics, cell biology, developmental biology, PAST ACCOMPLISHMENTS IN CELL genetics and physiology, as well as mechanical engi- MECHANICS neering, materials science and nanotechnology. An essential aspect of biomechanics emerging from many lines of evidence is that cells are not only CURRENT STATUS OF THE FIELD exposed to forces, stresses, and tensions, but that they also actively generate their own. This and additional Even if they are not presented in the context of determinants are summarized in a few pertinent biomechanics, clinical therapies and cues to treat dis- examples. ease often rely directly upon biomechanics.56 Some are ancient, such as a mechanical support of the skin with Cardiovascular Cell Mechanics and Microcirculation a bandage in venous ulcers. Modern examples include stents, ventilators, and vasodilators/constrictors. A One of the most thorough analyses of the mechan- recent and intriguing example is the vacuum-assisted ical properties of living cells has been carried out on closure sponge100; application of cyclic suction to a the mammalian red blood cell, which is a uniquely non-healing wound is more effective at healing than simple structure with predominantly two compo- are two other FDA-approved therapeutics: platelet nents—a membrane with bending and shearing prop- derived growth factor (PDGF) or a tissue engineered erties that are dependent upon strain, strain rate, and implant with stem cells. Foams are used to close blood strain history, and a cytoplasm that in the normal red vessels during uncontrolled angiogenesis and venous cell is predominantly a Newtonian viscous fluid.16 ulcerations. Across a broad spectrum of disorders, Quantitative passive biomechanical models were better understanding of the biophysical basis of cellu- developed that serve to predict red cell motion and lar mechanotransduction seems likely lead to new deformation in a large number of in vivo situa- drug-based and nanotechnology-based therapeutics. tions.44,45,101,113 A key element of these models was the Some heart arrhythmias will almost certainly come to recognition that under the influence of membrane be treated with inhibitors of stress-sensitive ion chan- tension the lipid bilayer preserves membrane area nel, for example. within narrow limits. Discrete network models of the Microscopic changes in cell mechanics and extra- red blood cell membrane are increasingly taking into cellular matrix structure are expected to dysregulate account the particular load-bearing functions of spe- molecular mechanisms of mechanotransduction— cific proteins (e.g., flexible spectrin springs, and actin which is the process by which cells sense mechanical protofilament nodes) as well as the key role of prestress signals and convert them into chemical responses.4,5,42 for shape stability.121 Newly developed constitutive Examples include numerous developmental abnor- models for the red cell membrane show the full power malities (e.g., osteogenesis imperfecta)