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Journal of Biomechanics

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Integrative biomechanics: A paradigm for clinical applications offundamental mechanics

Gerard A. Ateshian a,�, Morton H. Friedman b

a Department of Mechanical Engineering, Columbia University, New York, NY, USAb Department of Biomedical Engineering, Duke University, Durham, NC, USA

a r t i c l e i n f o

Article history:

Accepted 4 April 2009Integrative biomechanics uses biomechanics knowledge and methods at multiple scales and among

biological entities to address fundamental and clinical problems at the tissue and organ level. Owing to

Keywords:

Integrative biomechanics

Multiscale approaches

Clinical translation

90/$ - see front matter & 2009 Elsevier Ltd. A

016/j.jbiomech.2009.04.001

esponding author. Columbia University, Dep

, 500 W 120th St, MC4703, New York, NY 1002

12 854 3304.

ail address: ateshian@columbia.edu (G.A. Ate

a b s t r a c t

the large ranges of scale involved, integrative biomechanics is intrinsically multidisciplinary, extending

from molecular biophysics to contemporary engineering descriptions of kinematics and bulk constitu-

tive properties. Much of this integration is accomplished through multiscale models of the interactions

of interest. Applications can range from the development of new biological knowledge to the creation of

new technologies for clinical application.

In this white paper, the historical background of, and the rationale behind, integrative biomechanics

are reviewed, followed by a sampling of clinical advances that were developed using the integrative

approach. Refinements of many of these advances are still needed, and unsolved problems remain, in

genomic applications, developing improved interventional procedures and protocols, and personalized

medicine. Challenges to achieve these goals include the need for better models and the acquisition

and organization of the data needed to parameterize, validate and apply them. These challenges will be

overcome, because the advances in characterizing disease risk, personalization of care, and therapeutics

that will follow, demand that we continue to move forward in this exciting field.

& 2009 Elsevier Ltd. All rights reserved.

1 The members of the Summit panel whose deliberations form the basis of this

1. Introduction

‘‘Biomechanics is mechanics applied to biology’’ (Fung, 1981).These applications are diverse, extending from the developmentof new biological knowledge to the creation of new technologiesfor clinical application. The purpose of this white paper is tosummarize challenging new directions of research that aim tointegrate the various subfields of mechanics and biology, span-ning the hierarchy from the molecular to the organ level, in aneffort to create new clinical treatment modalities and improveexisting ones.

The intended audience is the rising generation of biomedicalengineers who will confront these challenges firsthand, and theircolleagues in the biological and clinical sciences who may come tobetter appreciate the demanding application of engineering analy-ses to biological systems, as well as their potential for improvingclinical treatments and our understanding of the etiology of vari-ous diseases.

ll rights reserved.

artment of Mechanical Engi-

7, USA. Tel.: +1212 854 8602;

shian).

This paper originated from a Biomechanics Summit organizedby the US National Committee on Biomechanics and held inKeystone CO, June 18–20, 2007.1 The purpose of the Summit was toidentify important medical and biological problems that could beaddressed by biomechanics, the barriers to their solution, and thesteps needed to overcome these barriers and realize the potentialof the discipline. Panels were organized generally according to ahierarchy of scale; the present panel addressed the issue of cross-scale research, coining the term ‘‘integrative biomechanics’’.

This paper follows the format of the Summit, beginning withthe historical foundation of integrative biomechanics. We thendiscuss this approach in greater detail, and review a sampling ofclinical advances that were developed using it. It is recognizedthat many of these advances can be improved through furtherapplication of integrative biomechanics, and new areas in which it

document were Gerard Ateshian (co-Chair, Columbia University), Stanley Berger

(University of California, Berkeley), C. Ross Ethier (Imperial College, London),

Morton Friedman (co-Chair, Duke University), Steven Goldstein (University of

Michigan), Jay Humphrey (Texas A&M University), Karl Jepsen (Mt. Sinai School of

Medicine), Andrew McCulloch (University of California, San Diego), James Moore

(Texas A&M University), John Tarbell (City University of New York), Charles Taylor

(Stanford University), David Vorp (University of Pittsburgh), and Savio Woo

(University of Pittsburgh).

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can be applied are discussed as well. The paper closes with asummary of the challenges that must be met to achieve thesegoals.

1.1. Historical background

Though biomechanics is a science whose roots can be tracedback to Aristotle, its recent history begins in the late Renaissance,as reviewed in Fung’s book (Fung, 1981). Today, the field owes itsprogress to the pioneering work of engineers and scientistsstarting in the 1960s and 1970s, a period that saw the applicationof rigorous engineering analyses to the study of biological tissues.In these early modern days, one of the most pressing needs was tocharacterize the mechanical properties of various tissues inrelation to their structure, to better understand their function. Itwas quickly appreciated that the elementary engineering analysesthat are conventionally taught to undergraduate students, andthat would normally suffice to describe conventional engineeringmaterials, were generally inadequate for modeling biologicaltissues.

In bone mechanics, for example, though bone behaved as alinear elastic material to within a reasonable approximation, itwas found to be anisotropic, exhibiting properties that variedconsistently with the spatial orientation of its microstructure(Bonfield and Grynpas, 1977; Katz, 1980; Townsend et al., 1975).Many soft tissues, such as cardiovascular and musculoskeletaltissues, were similarly observed to be anisotropic, often under-going large deformations during normal function, and to exhibitsignificant viscoelasticity (Demer and Yin, 1983; Huyghe et al.,1991; Johnson et al., 1994; Lim and Boughner, 1976; Mak, 1986;Westerhof and Noordergraaf, 1970; Woo et al., 1993; Yin et al.,1983). Blood and synovial fluid were observed to be non-Newtonian, with the latter exhibiting thixotropy (Chien et al.,1966; Safari et al., 1990). These material behaviors under normalloading conditions severely limit the applicability of traditionalmechanical analysis tools such as linear elasticity. This hasprovided both a challenge and an opportunity to biomechaniciansdeveloping undergraduate curricula to prepare the next genera-tion to push the field forward.

These material behaviors required the application of sophisti-cated theoretical frameworks of applied mechanics, often at theforefront of that field. In many cases, new formulations andframeworks were proposed, motivated by observations in biolo-gical tissues. These developments continue to this day; biologicaltissues exhibit some of the most complex material responsesknown to mechanicists, posing challenges that have not allbeen met. Modeling challenges unique to biological tissues havealso arisen in the area of active contraction, as observed forexample in cardiac and skeletal muscle (Guccione and McCulloch,1993; Guccione et al., 1993; Hunter et al., 1998,1992; Ma andZahalak, 1991), in growth and remodeling (Cowin, 1983; Hsu,1968; Humphrey, 2008; Rodriguez et al., 1994; Skalak et al.,1982), and in tissue engineering (Grodzinsky et al., 1997; Lemonet al., 2006).

Theoretical models have been driven by experimental observa-tions, but the development of new theories has also posed experi-mental challenges for characterizing ever more detailed materialstructures, properties, and responses under various conditions.Today, biomechanics is intricately tied to modern measurementtechniques, spanning scales from the molecular to the organ level.It often requires high-resolution spatio-temporal data for modeldevelopment, parameterization and evaluation. For clinical appli-cations, the preferred acquisition method is non-invasive. Suchmethods can generally provide anatomic and metabolic data,though invasive methods are also being developed to probe

material properties. Contemporary basic science investigationsoften require simultaneous measurements of biological responsesas well. Recent advances in the biological sciences have presentedunique opportunities for biomechanics investigation, such as theability to relate changes in biomechanical phenotype to specificgenetic alterations achieved via gene knockout or gene silencingtechniques.

Sophisticated computational techniques complement thesetheoretical and experimental tools, facilitating the biomechanicalanalyses critical to practical applications. The development offinite element and image processing methods specifically designedfor biological applications, the use of supercomputers to solve bio-mechanical problems with a minimum number of approximations,and the development of molecular modeling techniques are pro-viding a wide range of opportunities to translate advances infundamental biomechanics to the clinical arena.

These fundamental developments are at the foundation ofintegrative biomechanics.

1.2. Integrative biomechanics: multiscale approaches to translational

research

Biomechanics is an important component of biological proces-ses at the subcellular, cellular, tissue and organ levels. Integrativebiomechanics integrates biomechanics knowledge and methods atmultiple scales to address fundamental and clinical problems atthe tissue and organ level. Owing to the large ranges of scaleinvolved, integrative biomechanics is intrinsically multidiscip-linary, extending from biophysical studies of the mechanics ofbiological molecules to engineering descriptions of kinematicsand bulk constitutive properties. The integrative aspect of thisbranch of biomechanics emphasizes interactions among biologi-cal entities (as in physiological control) and examines individualentities at different scales (as in studies of the microstructuralbasis of macroscopic properties). These interactions are describedby multiscale biomechanical models that can relate higher-levelevents to lower-level mechanisms.

Although clinical disease is most clearly evident at the tissue andorgan level, it can involve any of several levels in the hierarchy ofscale; some conditions are initiated by a single gene mutation, othersby an acute alteration in organ function. Most commonly, multiplescales are involved in the disease process, either simultaneously orsequentially. This is understandable since the natural homeostaticstate of the organism, disturbances in which accompany disease,is expressed at multiple levels extending from regulation of geneexpression to physiologic control. The normal homeostatic state alsoincludes a mechanical homeostasis, which is also seen at scalesthat range from cytoskeletal reorganization under stress to systemicblood pressure regulation. Thus, in general, and specifically for bio-mechanical investigation, an integrative approach is the naturalapproach to understand human pathophysiology.

Many aspects of tissue and organ function, such as tissue adap-tation, remodeling, degradation and repair, are driven or regulatedby mechanical forces. Many diseases are characterized by a failureof these processes; for instance, cystic fibrosis is due primarilyto the impaired transport and flow of mucus, and cardiac eventsresult from inadequate blood flow and reduced myocardial con-tractility. A greater understanding of the role of mechanical forcesin modulating tissue and organ function, in health and disease,will lead to rational improvements in disease prevention, inter-vention and therapy.

Integrative biomechanics is application oriented, but relies onbasic knowledge at all levels of scale. As a consequence, integra-tive biomechanical investigation can identify important unsolvedproblems in basic biomechanics and biophysics, and provide the

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route whereby their solution can be translated into advances inclinical medicine. For instance, it has long been appreciated thatmechanical forces are involved in atherogenesis and subsequentacute events, and in the distinct hyperplastic response of thevessel wall to clinical interventions such as bypass grafts andstents. This understanding has prompted numerous basic studiesof the effects of mechanical stimuli on endothelial cells, smoothmuscle cells, and fibroblasts; the inflammatory response; andmechanotransduction at the molecular level. Heart valve inducedthrombosis has led to new investigations of the effects of fluidstresses on platelet activation. Biomechanical analyses of aneu-rysm development and rupture have focused research on cellularinvolvement in matrix turnover. Mechanical forces also play acritical role in bone modeling, remodeling and adaptation, afinding dating back to clinical observations in the late 19thcentury. Similar to the cardiovascular studies summarized above,the precise mechanism for transducing forces in bone into cellularsignals is an active topic of investigation, with a current focus onin vivo and in vitro studies examining the role of a variety ofmechanical conditions, including oscillatory shear, on osteocytesand related cells.

The solution of important problems in integrative biomecha-nics will lead to greater longevity, health, and quality of life. Assuggested above, a more rational approach to therapeutic inter-ventions will lead to further improvements in graft and stentdesign. The heart itself is another target of this approach; a betterunderstanding of cardiac mechanics, extending in scale from car-diomyocyte biology to the entire heart, will guide more rationalmanagement strategies and device designs for treating congestiveheart failure. Similarly, in the musculoskeletal system, the fragilityof bone that accompanies advanced age or disease results in anenormous health burden in terms of morbidity and societal costs.An improved biomechanical understanding of the role of theorganic and inorganic constituents of bone, their organizationalinteractions (at multiple scales), and their influence on cellularregulation may lead to new therapeutic approaches to strengthenbone or prevent fragility.

1.3. Past achievements of integrative biomechanics

There are already numerous examples of how integrative bio-mechanics has advanced clinical medicine. Several of these aresummarized briefly below, in approximate chronological order.Additional examples can be found in the AIMBE Hall of Fame,(http://www.aimbe.org/content/index.php?pid=127).

1.3.1. Artificial kidney

Once, kidney failure meant certain death. The advent of dia-lysis treatment to remove deadly impurities from the blood savedpatients’ lives. For some, dialysis has become a way station tothe long-term solution of a kidney transplant. But today, dialysisremains a time consuming process requiring the patient to beconnected to a large fixed piece of equipment. The design of thehemodialyzer required the application of the principles of mem-brane transport and fluid flow, as well as understanding of kidneyarchitecture and function at the cellular level; further work alongthese lines will be necessary to develop means for continuousdialysis of an ambulatory patient.

1.3.2. Vascular grafts and cardiopulmonary bypass

Surgery to bypass narrowed or blocked coronary arteries usingsynthetic grafts or healthy arteries or veins from other parts of thebody extends and improves the quality of life. This procedure wasmade possible with the development of the heart–lung machine,which allows the heart to be stopped during surgery—with the

machine taking over the job of providing oxygen to the blood andmoving blood through the body. The heart–lung machine andgrafting process required understanding of pulmonary oxygentransport and circulatory flow; thrombosis during oxygenationand further disease at the graft junction are prevented usingdesigns that are based on models of the local flow field and thecomplex biochemical and cellular processes that accompany clotformation and arterial disease. Further application of integrativebiomechanics in tissue engineering should lead to small-caliberblood vessels that remain patent longer than existing grafts.

1.3.3. Artificial heart valves

The development of replacement heart valves was an earlyexample of engineers and clinicians working together to restorecardiac function for patients facing incapacitation because theirown valves were failing. Over the years, engineers have developednew designs and materials that allow valves made with syntheticand natural materials to replace damaged or diseased valves.Valve designs have been optimized to maintain a lifelike flowthrough the valve, and to open promptly and close securely, whileminimizing trauma to the entrained red blood cells. Greaterunderstanding of the interaction of the fluid mechanical stressesthat accompany valve operation with blood cells, and the trans-duction of these stresses into blood trauma at the mechanical,functional and biological levels, will support the design of morelong-lasting valves that are less damaging to the fluid passingthrough them.

1.3.4. Angioplasty and vascular stents for coronary artery disease

Rational design and delivery of drug eluting stents require con-sideration of biomechanical events at many scales. These includetissue and structural level events such as the mechanical designof the stent itself, the shape and properties of the angioplastyballoon, and the mechanical response of the diseased arterialtissue to stent expansion, to smaller scale events such as theinteraction between the stent and the healing vessel wall, to thetransport of eluted drug from the stent and its interaction in acomplex mechanical environment with the biology of the resi-dent cells. Though considerable progress has been made in thedesign of drug eluting stents, long-term complications relatedto restenosis persist. These complications represent the types ofchallenges that may be addressed with integrative biomechanics.

1.3.5. Joint arthroplasty

Before the advent of artificial hip and knee joints, millions ofpeople – particularly the aged – lived with considerable pain andvery limited mobility as a result of degenerative joint diseases.Today, joint arthroplasty represents the primary clinical treat-ment for advanced joint degeneration, restoring function andproviding a return to nearly normal activities of daily living withremarkable success. Artificial replacements have been designedfor most diarthrodial joints in the body, as a result of close inter-actions between engineers and orthopaedic surgeons. However,joint replacements typically last between 10 and 20 years beforesignificant implant wear, loosening and failure occur. Due tosignificant bone loss, patients can tolerate at most two replace-ments for a given joint, thereby limiting this type of surgeryto subjects whose life expectancy does not exceed that of theimplant. Consequently, new treatment modalities need to bedeveloped for younger patients, such as improved artificial jointsand implantation procedures, or successful tissue engineeredosteochondral implants.

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1.3.6. Ligament surgery

Intracapsular ligament failures, such as failure of the anteriorcruciate ligament of the knee, are frequent injuries that lead tojoint instability and may promote osteoarthritis. Ligament repairsare commonly performed using tissue autografts, allografts, orartificial replacements. Biomechanical engineers and their phy-sician collaborators have played a critical role in assessing thefailure properties of native ligaments and their graft replace-ments, toward the goal of finding equivalent matches. They havealso provided the biomechanical analyses necessary to under-stand and exploit the effect of graft pre-tensioning on long-termjoint stability following surgery. Considerable progress has beenmade in this field, such as improving joint stability and restoringfunction. However, ligament repairs do not necessarily delay orprevent the progression of joint degeneration. An integrative bio-mechanics approach to this problem may be needed to improvethe long-term outcome of ligament surgery.

2. Long-term goals of integrative biomechanics research

Future opportunities for integrative biomechanics research canbe broadly classified in three categories.

2.1. Extension of the scale of integration to the genomic level

The biomechanics of organs and tissues depend at the smallestscale on the proportions and organization of the biomolecules –largely proteins – of which they are composed. The synthesis ofthese molecules is controlled at the level of the genome; hence,genomic events are critical determinants of the mechanical pro-perties and behavior of much larger structures. A long-term goalof what might be termed ‘‘mechanogenomics’’ is the integrationof genomics into the multiscale approach that is an essential char-acteristic of integrative biomechanics. This will allow us to usegenomic information to understand and predict individual differ-ences in tissue and organ function, paralleling the clinical use ofthis information to personalize medical care.

Furthermore, when we understand the relationship betweengene expression profiles and gross mechanical behavior, it may bepossible to use high-throughput screening to predict biomecha-nical function and intervene in a disease process, such as heartfailure, well before an untoward clinical event.

The effect of genomic processes on gross mechanics proceedsthrough protein interactions and cell biological mechanisms.Accordingly, the development of mechanogenomic understandingwill stimulate new work in these areas as well.

2.2. Develop rational design principles for lower cost, longer lived

and more effective interventions

An integrated understanding of the biomechanical basis ofdisease will allow the development and optimization of surgicalprocedures and nonsurgical protocols on a more rational basis,and will support the design of improved implantable and externaldevices. Interventions can more readily be made patient specificto produce better outcomes. Devices whose design is guided byprinciples based on integrative biomechanics will be more effec-tive and less likely to fail, leading to cost savings. For example,such interventions based on biomechanical understanding mayinclude:

�

An implantable intraocular lens that allows the full range ofaccommodation while restoring the visual transparency lostwhen a native lens is opacified by a cataract.

�

Stents and ventricular assist devices that are less subject torestenosis and thrombosis. � Customized soft tissue (e.g., arteries, cartilage, ligament, tendon)

surgical procedures that are guided by a better understandingof the specific stresses to which the repaired tissue will besubjected, and how they will adapt thereafter.

2.3. Provide mechanics-based guidance in patient care

We have already noted the close connection between integ-rative biomechanics and disease. This discipline is not only bestpositioned within biomechanics to address the causes of disease,it is also in the best position to provide guidance regarding ther-apy in those many instances in which mechanics is involved. Thisguidance can be specific to particular patients and based on bio-mechanical modeling of their particular situation. For example,areas of clinical care that can benefit from this approach include

�

Cardiovascular Medicine. The mechanical processes in cardio-vascular function are self-evident, and include the hemo-dynamics and solid mechanics of the circulation and heart.Integrative biomechanics can be used to: predict risk of athero-sclerosis and consequent coronary disease, stroke, claudicationand organ failure; guide surgical decisions and tool develop-ment in intracranial and aortic aneurysm management; quan-tify cardiac function in congestive heart failure; and designindividualized surgical procedures for arterial grafting and therepair of congenital cardiovascular defects. � Ophthalmology. Many processes in the eye rely on mechanical

events, and diseases of the eye can be addressed by integrativeapproaches to develop individualized therapy based on soundmechanics. In addition to cataracts, whose treatment can beimproved by designing an intraocular lens that allows accom-modation (mentioned above), these conditions include: glau-coma, which arises from defective fluid drainage from the eyeand which can be treated by implantation of devices designedto lower intraocular pressure into a target range specific tothe patient; strabismus, or ‘‘lazy eye’’, which can be due toan imbalance in the extraocular muscles acting on the eye;keratoplasty, the surgical alteration of the cornea to produce amore sharply focused image on the retina and which relies onpost-surgical corneal biomechanics; and severe myopia, whichleads to retinal tears and is caused by excessive growth of thesclera in development.

� Orthopaedics. The importance of biomechanics in orthopae-

dics needs no demonstration. Individualized biomechanicalanalysis is already used in prosthesis and implant design, butintegrative biomechanics can also be used to guide therapiesfor chronic conditions such as osteoarthritis, osteoporosis andcerebral palsy; as well as computer-aided surgical planningand robotics-assisted surgery.

3. Challenges to realize the potential of integrative biomechanics

The field of biomechanics has benefited from a long history offundamental advances, both in the basic engineering sciences andin the clinical realm. These advances have opened up a wide rangeof opportunities to intimately integrate biomechanics with clini-cal treatment in novel ways. However, as in all engineering ende-avors, the transition from a promising potential to its effective

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realization lies in the details of the implementation. To broadlyenhance the impact of integrative biomechanics on clinical prac-tice, a number of needs must be met, as outlined below.

3.1. Development of integrative biomechanical models

Engineers need analysis tools to assist them in the design ofsystems and processes. While researchers have the ability todevelop custom advanced tools for specific research applications,it is essential to make these tools available and accessible toclinicians so that they can exploit the most recent advances inbiomechanical analysis. In the traditional areas of solid mecha-nics, fluid mechanics and multi-body dynamics, a wide variety ofcommercial software programs are available to perform analysesof motion, deformation and stress. However, most of these exist-ing products are not specifically geared to biomechanics, and thusare unsuited to many important biological applications. Conse-quently, there is a major need to develop and disseminate moresuitable computational tools.

In cardiovascular mechanics, the ability to model solid–fluidinteractions, such as the pumping of blood by the contractingheart and the deformation and motion of heart valve leaf-lets or arteries, is a major challenge that has been partiallymet by a few research groups using custom-developed codes(Lemmon and Yoganathan, 2000; McQueen and Peskin, 2001;Peskin and McQueen, 1995; Prosi et al., 2004; Watton et al., 2007;Yoganathan et al., 1995; Zeng et al., 2003). Several investigatorshave used these technologies to analyze the state of stress inabdominal aortic and cerebral aneurysms (Fukushima et al.,1989; Perktold et al., 1988; Raghavan and Vorp, 2000; Ryan andHumphrey, 1999; Stringfellow et al., 1987; Wolters et al., 2005).Other investigators have modeled the electrophysiology of thecontracting heart under normal and pathological conditions(Hunter et al., 1992; McCulloch et al., 1992; Rogers and McCulloch,1994; Vetter and McCulloch, 2001). Integrating these approachesoffers great potential to analyze and predict alterations in cardiacoutput under various conditions and in the presence of disease.These tools would be valuable for both basic science and clinicalapplications, as well as in the design of heart valves, stents, andvascular grafts.

Most biological tissues are highly hydrated and experienceinterstitial fluid flow. The analysis of tissues using porous mediatheories has been highly successful, especially in the field ofcartilage mechanics (Lai et al., 1991; Mow et al., 1980), but also instudies of the intervertebral disc (Frijns et al., 1997; Yao and Gu,2006), arteries (Kenyon, 1976), heart (Yang et al., 1994), cornea(Bryant and McDonnell, 1998), and many other tissues. Somecommercial programs exist which can model deformation andflow in porous media, and their relatively widespread applica-tion is a testament to the need for such tools in biomechanicalapplications. At the research level, more sophisticated tools havealso been developed which can describe streaming and diffusionpotentials and currents, as well as osmotic pressure and solutetransport in deformable porous media (Frank and Grodzinsky,1987; Gu et al., 1998; Huyghe and Janssen, 1997; Lai et al., 1991).Based on fundamental principles of transport, these tools canuniquely provide insights into the biomechanics of biologicaltissues, and recent developments suggest that they can besuccessfully applied to cell mechanics as well. These tools meritmore widespread dissemination and application.

It is often said that biology is ultimately chemistry; however,chemistry can be modulated by mechanics. Alterations in molecu-lar conformation in response to mechanical signals are known tomodulate biochemical reactions at the cellular and subcellularlevels (Vogel and Sheetz, 2006). Molecular dynamics is a modeling

tool that has the potential to describe mechanotransduction at themolecular scale, although major computational challenges haverestricted its predictive powers to date. Nevertheless, even ifbiomechanical computations do not reach down to the molecularlevel, one of the critical needs of integrative biomechanics isthe ability to integrate multiscale analyses from the smallest tothe largest scale of interest. Thus, for instance in the heart, eventhough the computational analysis of a beating heart cannot pos-sibly model every cardiomyocyte, it is nonetheless important thatanalysis tools be developed to permit the local environment at thecellular level to be obtained from a more macroscopic description.Conversely, tools must also be developed to relate the responseof the entire heart to the contraction of specific cardiomyocytedomains.

One of the greatest challenges in the field of biomechanicsremains the analysis of tissue growth and remodeling. Thoughsignificant progress has been made in the mathematical founda-tions for describing growth and remodeling (Cowin, 1983; Hsu,1968; Humphrey, 2008; Rodriguez et al., 1994; Skalak et al., 1982),a consensus has not yet emerged, partly due to the complexityof describing evolving tissue configurations. An even greaterchallenge is the need to couple the mathematics of growthand remodeling to the biological, chemical and physical signalsthat trigger and regulate these events, and respond to them ina closed-loop feedback system. The field of bone mechanicshas seen extensive developments in this area, where models ofgrowth and remodeling have been used to predict alterationsin bone density and strength around prosthetic implants, andthereby to anticipate potential bone fractures and guide futureimplant designs (Huiskes and Boeklagen, 1989; Stolk et al., 2007).Significant progress has also been reported in the fields of vas-cular remodeling (Gleason and Humphrey, 2004; Humphrey andRajagopal, 2003) and cartilage growth (Dimicco and Sah, 2003;Klisch et al., 2003). A resolution of the mathematical challengesnoted above, and the development and dissemination of com-putational tools to describe growth and remodeling, remainimportant needs. These tools can subsequently be integratedwith analyses of biological signal transmission and mechano-transduction and with the models of fluid–solid interactions,porous media biomechanics and solute transport describedearlier. By simulating the complex biological events that underlietissue adaptation, remodeling, degradation, and repair, this suiteof techniques will support the testing of new hypotheses andthe development of new therapies, advancing both basic scienceand clinical medicine.

3.2. Acquisition of organ-level data to support integrative

biomechanical analysis

3.2.1. Computational tools for large-scale biomechanical analyses

Most commercial engineering software programs today arenot specifically geared for biomechanical analyses. For example,analyzing the deployment of an arterial stent, with the resultingdeformation of the arterial wall and alteration in blood flow, isnot a routine analysis available to the engineering designer.Examining the biomechanical response of an implanted tissueengineered graft, such as an osteochondral construct or a liga-ment in a diarthrodial joint, remains a complex task today.Computational tools that accommodate large-scale analyses ofcomplex biomechanical systems need to be made available tothe general engineering professional. These tools should beformulated to assist in the design and analysis of biomedicaldevices in situ; they should also facilitate the developmentof predictive tools to investigate the long-term outcome ofvarious treatment modalities, and the progression of diseases

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such as heart failure, atherosclerosis, aneurysms, osteoporosis,osteoarthritis, glaucoma, and other diseases driven partly bymechanics.

3.2.2. Higher spatially and temporally resolved in vivo

measurements of structure and function

Advances in non-invasive imaging technologies have provi-ded immense benefits to integrative biomechanics. For example,X-ray computed tomography, dual-energy X-ray absorptiometry,magnetic resonance imaging and ultrasound imaging are notonly useful clinical diagnostic tools; they also facilitate bio-mechanical analyses that can be used to predict the stressesaround endoprostheses and resulting bone resorption, estimatefracture failure risk from osteoporosis, compute the hemodyna-mic changes accompanying flow constrictions caused by athero-sclerosis, predict the risks of rupture of abdominal aneurysms,compute cardiac output in real-time, support surgical planning fororthopaedics and neurosurgery, predict brain deformation duringtumor-removal surgery, guide robotics-assisted surgery, and formany other applications.

However, limitations persist in the spatial and temporal reso-lution of these imaging methodologies that limit their potentialfor achieving more accurate biomechanical predictions of out-comes. For example, in vivo imaging of the cardiovascular systemis generally unable to resolve the structure of arterioles andcapillaries; thus computational fluid dynamic models to predictblood flow and blood pressure in the cardiovascular system mustrely on the application of a priori boundary conditions at theedges of the resolvable structures, resulting in a level of uncer-tainty that potentially compromises the accuracy of modelingpredictions, limiting their clinical application. A similar resolutionissue arises with respect to the lung and the modeling of alveoli.Likewise, while micro-computed tomography is able to resolveindividual bone trabeculae in the intervertebral body in smallanimal models, yielding a wealth of information for predictingthe fracture risk from osteoporosis, the resolutions achieved inthese animals have not yet been attained for clinical imaging inhumans.

Other challenges persist, most notably in the ability todirectly measure the mechanical properties of biological tissuesvia non-invasive methods, thereby providing the necessary datafor predicting biomechanical outcomes in organ systems on apatient-specific basis. Ultrasound techniques have the ability totransmit pressure waves across tissue walls and thereby to applymechanical loads to soft tissues non-invasively; if the profileof the transmitted pressure wave could be predicted accurately,and the resulting tissue deformation measured precisely, suchmethods could potentially produce useful measurements of softtissue mechanical properties. However, many technical obstaclesremain to achieve this goal. The development of creative metho-dologies that build upon existing imaging modalities to producereliable measurements of mechanical properties would open upnew avenues for integrative biomechanics.

3.2.3. Animal models relevant to human disease and amenable

to high-throughput analysis

Many animal models of human disease have been developed.Some of these diseases are induced by alterations in diet, localizedor systemic delivery of biochemical agents, or localized mecha-nical alterations, such as arterial flow constrictions or soft tissuetransections, in a manner thought to simulate the natural initia-tion and progression of these diseases in humans. However, manydiseases which alter the normal biomechanical function of load-bearing organs and tissues have unknown causes or catalysts,often originating at the genome level. Molecular alterations via

gene knockout or gene silencing techniques offer tremendouspotential for investigating the influence of genetic factors on thestructure and biomechanical function of organs and tissues, aswell as enhancing our overall understanding of the interactionof mechanics and biology. The continued development of animalmodels relevant to human disease, that are suitable for high-throughput analysis and whose biomechanical function canreasonably be extrapolated to man, represents a major need.

3.3. Development of supporting databases

Extensive databases are needed to inform and validate bio-mechanical models and serve as benchmarks for the developmentof novel biomedical devices, drugs and biologicals, and clinicalprocedures. Research efforts in biomechanics over the past severaldecades have produced a wealth of data that has been dissemi-nated mostly via peer-reviewed archival papers. However, unlikethe more traditional engineering disciplines or the biological andpharmaceutical sciences, few bioengineering handbooks and data-bases have been published that attempt to collect this dispersedbiomechanics information into organized and centralized databasesources.

For example, there are few compilations of the materialproperties and biochemical composition of biological tissues inhumans and other animal species, in health or disease, and as afunction of age or disease progression, despite the wealth of dataavailable in the literature. A recognized challenge is that materialproperties are presented in the context of a selected constitutiverelation for the tissue; given the complex biomechanical behaviorof most biological tissues, few definitive constitutive relationshave emerged to date, and published studies often advance dif-ferent models with incompatible properties. In many cases, theconstitutive models used to describe biological tissues are notincorporated into existing commercial modeling tools, makingthem available only to a selected group of investigators.

The development of such databases will represent an impor-tant milestone in the field of integrative biomechanics, facilitatingand marking the transition from a mostly research-oriented ende-avor to a mature discipline that strives to translate its advancesto clinical applications. Professional societies with an interest inbiomedical engineering or biomechanics may choose to take thelead in establishing such databases to further encourage profes-sional development in this field.

3.4. Promotion of a multidisciplinary approach to patient-specific

treatment

The development of biomedical devices and computational toolsfor patient-specific treatment is anchored in the close partnershipof engineers, clinicians, and biomedical scientists that provides themultidisciplinary expertise required to employ patient treatmentmodalities successfully.

This type of partnership needs to be nurtured at an early stageof training in these various professions. In the early days of bio-medical engineering, these successful interactions occurred at theinitiative of highly motivated individuals who had the vision tobridge beyond their traditional disciplines. Today it is importantto formalize these interactions and not leave them to chance,to help establish broader and more ambitious partnerships thatcan significantly advance medical practice. Novice biomedicalengineers must learn to focus their problem solving skills onclinically relevant challenges, while clinicians can benefit froma better understanding of the broad class of problems wherebiomedical engineers may contribute their skills.

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4. Concluding remarks

Technological advances have progressed rapidly over therecent decades. Many concepts that would have been dismissedas science fiction twenty years ago have become reality. Thepower of computational tools, the ability to miniaturize devices,the decreased cost and improved accuracy of non-invasive imag-ing technology, and the willingness of many clinicians to adoptnovel approaches such as robotic-assisted surgery, promise signif-icant improvements in clinical care and outcomes. To fully realizethis promise, it will be necessary to understand more fully thanwe do today the sequence of events that translate genetic pre-disposition and environmental influences into clinical states. Thisneed for integration is a challenge and an opportunity for bio-mechanics, because mechanics is integral to biological events atall levels of scale. In the previous pages, we have outlined but afew of the past successes of integrative biomechanics and thetechnological challenges facing this discipline today. These chal-lenges will be overcome, because the advances in characterizingdisease risk, personalization of care, and therapeutics that willfollow, demand that we continue to move forward in this excitingfield.

Conflict of interest statement

The authors do not have any conflicts of interest with regard tothis opinion survey and the materials contained herein.

Acknowledgments

The authors are grateful to C.R. Ethier, S.A. Goldstein,J.D. Humphrey and J.E. Moore for their contributions of text forthis document. The careful review of the entire document bypanelists C.R. Ethier and J.D. Humphrey is particularly appreciated.

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