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Biorheology 39 (2002) 510 5IOS Press

From biomechanics to mechanobiologyJ.-F. Stoltz and X. WangCell and Tissue Engineering and Mechanics, LEMTA - UMR 7563 CNRS-INPL-UHP and IFR 111

Bioengineering CNRS-UHP-INPL-CHU, Faculty of Medicine, Brabois, 54500 Vandoeuvre-ls-Nancy,

France

Abstract. Biomechanics can be defined as the application of mechanical concepts to the living world, and various fields ofresearch have been developed such as the mechanics of movement, ergonomics, the mechanical properties of cells and tissues,and the relationship between physiology and applied forces. In this paper, the authors give, through several examples, an outlineof these approaches and their potential biomedical applications, as in tissue remodelling, cell and tissue engineering and thedevelopment of biotissues.

Keywords: Mechanobiology, biomechanics, stress, cell, tissue, remodelling

Bold ideas, unjustified expectations and speculations constitute our only means for comprehending

nature K. Kopper

1. Biomechanics: What definitions?

Everything should be made as simple as possible but not simpler Albert Einstein

Etymologically, biomechanics may be defined as mechanics applied to the living world. However,this definition is too vast and imprecise. It is also limiting, because it does not include physiological orpathological effects induced by the application of mechanical forces. Three approaches (more or lesscomplete) allow us to define the fields of biomechanics.

The first one proposes to find, by application of mechanical laws, solutions to problems in medicine,biology, ergonomics and athletics.

The second one envisages studies of the mechanical properties of cells and tissues in considering thecomplexity of the structures being studied, for example, the properties of cardiac muscle, blood vesselsand blood in the microcirculation.

The third one, more recent and no doubt more integrative, is interested not only in the mechanicalproperties of objects being studied through their structures, but also in their biological functions and inphysiopathological consequences. This approach demands not only the resolution of fundamental prob-

lems and the development of models, but also the most recent knowledge in molecular biology, genomicsand cell biology. This new approach which seems to be quite promising for its potential applications incell and tissue engineering, can be called mechanobiology.

*Address for correspondence: Prof. J.-F. Stoltz, Cell and Tissue Engineering and Mechanics, LEMTA - UMR 7563 CNRS-INPL-UHP and IFR 111 Bioengineering CNRS-UHP-INPL-CHU, Faculty of Medicine, Brabois, 54500 Vandoeuvre-ls-Nancy,France. Tel.: +33 3 83 59 26 41 / +33 3 83 15 37 79; Fax: +33 3 83 59 26 43 / +33 3 83 15 37 56; E-mail: [email protected], [email protected].

0006-355X/02/$8.00 2002 IOS Press. All rights reserved


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6 J.-F. Stoltz and X. Wang / From biomechanics to mechanobiology

2. Biomechanics: An old history but a modern science

. . . mechanical science is of all the noblest and most useful, seeing that by means of this all animate

bodies which have movement perform all their action. Leonardo da Vinci

Throughout the ages, mankind has exhibited a strong interest in explaining the behaviour of livingbodies, no doubt because of the importance of the challenge. Today the development of biomechanics,evoked by Aristotle (384322 BC) in his work De motus animalium, requires complementary researchin physics, chemistry, mechanics, biology, medicine and surgery. In fact, it is very difficult to imagine atheoretical approach without any reference to experiments.

Historically we can distinguish different phases in the development of biomechanics, just as in anyother scientific domain. Over more than 20 centuries the studies in biomechanics remained descriptive.Only with the evolution of sciences in 17th and 18th centuries did quantitative approaches and the firstapplications touching on instrumentation, and the concepts of implantable biomaterials and ergonomics

come into being. The revolution of knowledge in biology brought about by genetics and molecular biol-ogy at the end of the 20th century, and recent progress in physical instrumentation such as atomic forcemicroscopy, confocal fluorescence microscopy and laser tweezers to name a few, has again raised interestfor a new biomechanics and its applications as in biotissue engineering and cell and tissue therapy.

Great names illuminate the history of biomechanics. Without being exhaustive, one can cite AristotlesTreatise on the movement of animals, Archimedes (287212 BC), and Galien on anatomy. These peoplewere without any doubt the first biomechanicians.

The Renaissance was one of the most prosperous periods for the sciences. There was Leonardo daVinci (14521519) and his work on human body movement, Galileo (15641642), a physician beforebeing a physicist, William Harvey (15781658) and his fundamental work on blood circulation, whowas also the first to pose the problem of microcirculation when he wrote How does the blood manageto traverse the porosities of the flesh on its way from arteries to veins?

The 17th and 18th centuries were particularly rich in works on physiomechanics. Malpighi (16281694) described the capillaries and red blood cells (at the beginning confused with fat particles), vanLeeuwenhoek who completed the work of Malpighi, and Holes (16771761) who measured blood pres-sure.

It was in 19th century that the first physio-mechanical and rheological approaches were described.Thus, Jean Marie Lonard Poiseuille (17991869) can be considered as one of the pioneers of the modernphysiomechanics. It was on the basis of Poiseuilles experiments that Hagen proposed the classical lawon flow in a small circular tube which has generally been used in textbooks of physiology to describe themicrocirculation. These studies constitute the beginning of almost one century of research in biorheologyand biomechanics, and show the complexity of biological systems, in particular that of blood.

The term biomechanics appears to have been used for the first time in 1887 by M. Benedikt (ber

Mathematische Morphologie und Biomechanik). Among the outstanding achievements of this period, wecan cite the work of Wolff on the adaptability of a bone tissue, Fhraeus on microcirculation, Bernsteinon movement, and more recently, the work of Alan Burton, Al Copley, George Scott-Blair, Syoten Oka,Alex Silberberg, Gustav Born, Yuan-cheng Fung, Richard Skalak, Shu Chien, Van Mow, Savio Woo, etc.

Finally, the discovery of some important physiological mechanisms (Vane and Moncada for theprostaglandins, and Furchgott for nitric oxide, both works crowned by Nobel prizes) allows us to betterunderstand the role of local mechanical stresses on cell physiology and tissue remodelling.


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J.-F. Stoltz and X. Wang / From biomechanics to mechanobiology 7

This brief historical review covering the last 25 centuries shows the evolution of Aristotles initialpreoccupation, which was reconsidered during the centuries leading to the modern concept of bioengi-neering.

3. Classical biomechanics: Movement and ergonomics

The analysis of bodily motion and its modelling helps us not only to understand the movement ofdifferent structures and to design machines to test implantable materials, but also to improve the phys-ical performance of organs through a better understanding of their limitations. Such a biomechanicalapproach plays an important role, for example, in the re-establishment of motor functions through un-derstanding musculoskeletal problems, and in the redistribution of stresses by using a plantary orthesisto re-establish posture equilibrium. In the workplace, biomechanics touches especially on ergonomics asin the optimisation of work stations. This widely employed biomechanical approach brings together animportant scientific community around sports medicine and the technology of healthcare (readaptation,

implantable prosthesis, surgery).

4. Tissue and cell mechanics: Physiological models

In the second half of the 20th century, biomechanics was applied to explain and to model the behaviourof organs, tissues, and more recently, cells. It is not surprising that these developments have been slow,because a fluid or a Hookean solid is generally an abstraction when we consider the behaviour of a tissueor a cell. Thus we have long known that blood is a non-Newtonian fluid, but research of physiologicallyacceptable models has gone beyond the classical knowledge on the behaviour of colloidal suspensions.

4.1. Necessity of models

Good mathematical models dont start with the mathematics, but with a deep study of certain natural

phenomena. Stephen Smale (1930)

The extremely complex biological systems present different types of heterogeneity. On the one hand,there are different shapes, dimensions, and constitutive elements; on the other hand, there is variabilityin time and in space. But through an appropriate selection of biological parameters of a system to bestudied, the contribution of mechanics to the understanding of the physiology of organs, tissues, andcells has been demonstrated. For example in hemomechanics, the particulate nature of blood, a complexsuspension of deformable and non-spherical particles, and of its vascular interface have been consideredin order to understand complex blood flow in the microcirculation, and mass transfer in the capillarycirculation. In large vessels, the role of local singular flows at bifurcations, stenoses and aneurysmshave been considered in order to understand the occurrence of the pathological processes of thrombosisand atherosclerosis. Certainly the heterogeneity of scale must also be considered in hemomechanicsor in studies of other fluids and tissues. An organ is macroscopic compared to that of its constitutivecells which in their turn are dimensionally different form their constitutive macromolecules or theirenvironmental matrix components.

These problems of scale and structure, known to be fundamental since the 1960s, are inseparable fromreliable biomechanical approaches which would permit us to link molecules to microscale structures and


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to entire tissues. For example, the work of Alan Burton (1959) on enzymatic digestion of arterial tissuehelped to elucidate the role of vascular matrix components (elastin and collagen) on its mechanicalproperties.

According to Fung, research in biomechanics needs the integration of different data: Detailed structure of tissue and its matrix; Morphometric data on constitutive elements; Knowledge of mechanical properties of the constitutive elements and of their structure with and

without loading.

It is in this spirit that studies have been developed on pulmonary parenchyma, on heart and blood vessels,and on cartilage and bone.

4.2. Cell mechanics: A developing field

Basically, all tissues and organs are composed of assemblages of cells. Experimental studies of their

mechanical properties remain a delicate problem. Recent developments of non or little invasive physicaltechniques such as the cell scanner, biphotonic confocal microscopy, fluorescence spectroscopy, lasertweezers, and magnetocytometry, permits reliable measurements in cell mechanics to be made. We referto measurements of cell aggregation and adhesion, local micromechanical behaviour, the effects of thecell cycle and division, and the phenomenon of polarisation.

5. Mechanobiology, mechanotransduction and tissue remodelling

Cells of the living body are always exposed to mechanical stresses which can vary from several Pa(shear stress at the vessel wall) to millions of Pa (stress on hip cartilage). Only very recently has it

been admitted that these stresses can influence all organ and cell functions (physiology, synthesis, geneexpression), just as biochemical factors do.One of the early observations which remained forgotten for a long time is that of Wolff, a German

surgeon, in 1892 on bone adaptability. He wrote every change in the form and function of bone or oftheir functions alone is followed by certain definitive changes in their internal architecture and equally

definitive secondary alterations in their external conformation in accordance with mathematical laws.Thus, he defined the phenomenon of todays well known tissue remodelling.

In fact, cell mechanics, being at the interface of physics and biology, has experienced a conceptualrevolution in the last 20 years accompanied by the development of molecular biology, genomics, andalso bioengineering, with the possibility of measuring forces of the order of pico-Newtons and deforma-tions of the order of nanometers. We are now capable of investigating the relationships between localmechanical parameters and cell functions (the concept of mechanobiology). It has been shown that mostcells are not only sensitive to mechanical forces in their environment, but also to the origin and historyof the mechanical loading. Although the biological effects of mechanical forces on certain cells are rel-atively well described, the mechanisms involved in these phenomena still remain unclear. In fact, howdoes one explain the passage from a mechanical stimulus to a physiological process as in the secretionand expression of a receptor, or activation of a gene, knowing that the effects are not always the same ondifferent cell types, even for the same function? Conceptually, it is accepted today that these phenomenatake place in 4 steps:


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J.-F. Stoltz and X. Wang / From biomechanics to mechanobiology 9

1. Mechanical coupling, which generally implies the transformation of applied forces into detectablestimuli by cells or the induction of a physical phenomenon. For example, pressure on a bone caninduce a fluid flow in the canicular system and an electrokinetic potential.

2. Mechanotransduction corresponding to the action of induced stimuli on specific structures. Today,different hypotheses have been proposed and they constitute the subject of a large number of studieseither in mechanics or in biology, such as cytoskeleton restructuring, specific receptor localizationand receptors related to functional proteins (G protein, ionic channels, existence of mechanosensi-tive elements).

3. Signal transduction, which means the passage of intracellular physiological signals.4. Cell response including gene regulation, release of autocrine or paracrine factors and specific re-

ceptor expression.

It should be noted that although steps 3 and 4 have been well elucidated for certain cell types and func-tions, the understanding of steps 1 and 2 still needs the development of models and specific experimentalapproaches for every cell type studied.

6. Cell and tissue engineering: Emergent technology and industry

At the present time, research in mechanobiology finds applications mainly in vascular, cardiac andosteoarticular fields. Recent reports show that mechanical consequence is specific for the system beingconsidered. Furthermore, mechanical stresses are involved in tissue physiology, for example, the produc-tion of extracellular matrix (cartilage), and some specific secretions such as NO and prostaglandins inendothelial cells under flow.

These new findings can lead to the development of the concept of biotissue which means substitutingtissues made in vitro, based on bioreabsorbable (or no) scaffolds and on cells cultured in a mechanical en-vironment similar to the in vivo physiological conditions (vessel, cartilage, bone). It is estimated that this

new biomedical industry will reach a market turnover of more than 50 billion US dollars in the year 2020.6.1. Cardiovascular tissue engineering

Presently, research in this field is aimed at various targets such as myocardiac grafts and biovessels. In2000, the autologous graft of leg skeletal myoblast cultures in a patient suffering from a major cardiacinsufficiency, has opened the door for new applications of cell therapy. In fact, this first therapy attemptedto demonstrate that grafted muscle cells could become functional muscle fibres under the appropriatebiochemical and mechanical environment.

In the vascular field, the group of Robert Nerem in Atlanta (Georgia Tech/Emory University) is devel-oping vascular substitutes in vitro using cultures of smooth muscle cells and vascular endothelial cells ina collagen gel under physiological flow conditions.

6.2. Cartilage engineering

Cartilage is an interfacial tissue composed of only one cell type, the chondrocyte, and an autosynthe-sized matrix. Its properties are a function of its mechanical environment. A large number of studies aimto make cartilage in vitro with chondrocytes cultured in an initial matrix of polymers (hyaluronic acid)and under a physiologically compatible pressure. Clinical applications of such cultured tissue could seethe light of day in the not too distant future.


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There are still many cell and tissue therapies targeted by researchers, which need further investigationson the effect of the mechanical environment and on the quality of cell and tissue grafts (for example:mesenchymal cells, hematopoietic stem cells, bone tissues).

7. Conclusion

An unique point of view is always wrong. Paul Valry

Like any other biomedical discipline which wants to be credible, biomechanics must come to a betterunderstanding of pathological situations (e.g., thrombosis, atherosclerosis, arthrosis). That is why fu-ture evolution of the science necessitates interdisciplinary links between mechanics, physics, chemistry,molecular biology and genomics. Research in these fields will lead to implantable biotissues and to newcell therapies in the near future.

However, a large number of unknowns still exist, giving full meaning to the thought of the philosopherH. Michaux in the last century:

Any science creates new ignorance

Any conscious creates a new unconscious

Any new acquisition creates a new void

General bibliography on biomechanics and mechanobiology

N. Akkas, Biomechanics of active movement and deformation of cells, NATO ASI series serie H: Cell Biology, Springer-

Verlag, New York, Berlin 42 (1990), 524 pp.

A.A. Biewener, Biomechanics Structures and Systems, IRL Press at Oxford University Press, New York, 1992, 290 pp.

H.J. Bereiter, O.R. Anderson and W.E. Reif, Cytomechanics. The Mechanical Basis of Cell Form and Structure, Springer-

Verlag, New York, Berlin, 1987, 294 pp.

C.G. Caro, T.J. Pedley, R.C. Schroter and W.A. Seed, The Mechanics of the Circulation, Oxford University Press, New York,Toronto, 1978, 527 pp.

J. Enderle, S. Blanchard and J. Bronzino, Introduction to Biomedical Engineering, Academic Press, London, 2000, 1062 pp.

H.M. Frost, An Introduction to Biomechanics, Charles C. Thomas, Springfield, 1971, 151 pp.

Y.C. Fung, Biomechanics: Mechanical Properties of Living Tissues, Springer-Verlag, New York, Berlin, 1981, 433 pp.

Y.C. Fung, K. Hayushi and Y. Seguchi, Progress and New Directions of Biomechanics, Meta Press, Tokyo, 1989, 444 pp.

T. Hianik and V.I. Passechnik, Biolayer Lipid Membranes: Structure and Mechanical Properties, Kluwer Academic Publishers,

Dordrecht, London, 1995, 436 pp.

M.Y. Jaffrin and F. Goubel, Biomcanique des Fluides et des Tissus, Masson, Paris, 1997, 454 pp.

R.P. Lanza, R. Langer and W.L. Chick, Principles of Tissue Engineering, Academic Press, London, 1997, 808 pp.

A. Larcan and J.F. Stoltz, Micocirculation et Hmorheologie, Masson, Paris, 1970, 273 pp.

R.B. Martin, D.B. Bun and N.A. Sharley, Skeletal Tissue Mechanics, Springer-Verlag, New York, Berlin, 1998, 392 pp.

A. Silberberg, ed., Perspectives in Biorheology (Festschrift for A.L. Copley), Pergamon Press, New York, 1981, 422 pp.

J.F. Stoltz and P. Drouin, Hemorheology and Diseases, Doin, Paris, 1980, 709 pp.

J.F. Stoltz, New trends in Biorheology, Biorheology 30 (1993), 305322.

J.F. Stoltz, M. Singh and P. Riha, Hemorheology in Practice, IOS Press, Amsterdam, 1999, 128 pp.

J.F. Stoltz, ed., Mechanobiology: Cartilage and Chondrocyte, Biorheology 37 (2000), 1190.

J.R. Vane, G.V.R. Born and D. Welzel, The Endothelial Cell in Health and Disease, Schattauer, Stuttgart, 1995, 203 pp.

S.L.Y. Woo and Y. Seguchi, Tissue Engineering, The American Society of Mechanical Engineers, BED, 1989, 146 pp.

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