ARTICLE IN PRESS

Journal of Biomechanics 42 (2009) 14441451

Contents lists available at ScienceDirect

Journal of Biomechanics
journal homepage: www.elsevier.com/locate/jbiomech
www.JBiomech.com

Integrative biomechanics: A paradigm for clinical applications of

fundamental mechanics
Gerard A. Ateshian a,, Morton H. Friedman b
a
b

Department of Mechanical Engineering, Columbia University, New York, NY, USA

Department of Biomedical Engineering, Duke University, Durham, NC, USA

a r t i c l e in f o

a b s t r a c t

Article history:
Accepted 4 April 2009

Integrative 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
the large ranges of scale involved, integrative biomechanics is intrinsically multidisciplinary, extending
from molecular biophysics to contemporary engineering descriptions of kinematics and bulk constitutive 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. Renements 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 eld.
& 2009 Elsevier Ltd. All rights reserved.

Keywords:
Integrative biomechanics
Multiscale approaches
Clinical translation

1. Introduction
Biomechanics is mechanics applied to biology (Fung, 1981).
These applications are diverse, extending from the development
of new biological knowledge to the creation of new technologies
for clinical application. The purpose of this white paper is to
summarize challenging new directions of research that aim to
integrate the various subelds of mechanics and biology, spanning the hierarchy from the molecular to the organ level, in an
effort to create new clinical treatment modalities and improve
existing ones.
The intended audience is the rising generation of biomedical
engineers who will confront these challenges rsthand, and their
colleagues in the biological and clinical sciences who may come to
better appreciate the demanding application of engineering analyses to biological systems, as well as their potential for improving
clinical treatments and our understanding of the etiology of various diseases.

 Corresponding author. Columbia University, Department of Mechanical Engineering, 500 W 120th St, MC4703, New York, NY 10027, USA. Tel.: +1 212 854 8602;
fax: +1 212 854 3304.
E-mail address: ateshian@columbia.edu (G.A. Ateshian).

0021-9290/$ - see front matter & 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jbiomech.2009.04.001

This paper originated from a Biomechanics Summit organized

by the US National Committee on Biomechanics and held in
Keystone CO, June 1820, 2007.1 The purpose of the Summit was to
identify important medical and biological problems that could be
addressed by biomechanics, the barriers to their solution, and the
steps needed to overcome these barriers and realize the potential
of the discipline. Panels were organized generally according to a
hierarchy of scale; the present panel addressed the issue of crossscale research, coining the term integrative biomechanics.
This paper follows the format of the Summit, beginning with
the historical foundation of integrative biomechanics. We then
discuss this approach in greater detail, and review a sampling of
clinical advances that were developed using it. It is recognized
that many of these advances can be improved through further
application of integrative biomechanics, and new areas in which it

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

summary of the challenges that must be met to achieve these
goals.

1.1. Historical background

Though biomechanics is a science whose roots can be traced
back to Aristotle, its recent history begins in the late Renaissance,
as reviewed in Fungs book (Fung, 1981). Today, the eld owes its
progress to the pioneering work of engineers and scientists
starting in the 1960s and 1970s, a period that saw the application
of rigorous engineering analyses to the study of biological tissues.
In these early modern days, one of the most pressing needs was to
characterize the mechanical properties of various tissues in
relation to their structure, to better understand their function. It
was quickly appreciated that the elementary engineering analyses
that are conventionally taught to undergraduate students, and
that would normally sufce to describe conventional engineering
materials, were generally inadequate for modeling biological
tissues.
In bone mechanics, for example, though bone behaved as a
linear elastic material to within a reasonable approximation, it
was found to be anisotropic, exhibiting properties that varied
consistently with the spatial orientation of its microstructure
(Boneld and Grynpas, 1977; Katz, 1980; Townsend et al., 1975).
Many soft tissues, such as cardiovascular and musculoskeletal
tissues, were similarly observed to be anisotropic, often undergoing large deformations during normal function, and to exhibit
signicant 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 uid were observed to be nonNewtonian, with the latter exhibiting thixotropy (Chien et al.,
1966; Safari et al., 1990). These material behaviors under normal
loading conditions severely limit the applicability of traditional
mechanical analysis tools such as linear elasticity. This has
provided both a challenge and an opportunity to biomechanicians
developing undergraduate curricula to prepare the next generation to push the eld forward.
These material behaviors required the application of sophisticated theoretical frameworks of applied mechanics, often at the
forefront of that eld. In many cases, new formulations and
frameworks were proposed, motivated by observations in biological tissues. These developments continue to this day; biological
tissues exhibit some of the most complex material responses
known to mechanicists, posing challenges that have not all
been met. Modeling challenges unique to biological tissues have
also arisen in the area of active contraction, as observed for
example in cardiac and skeletal muscle (Guccione and McCulloch,
1993; Guccione et al., 1993; Hunter et al., 1998,1992; Ma and
Zahalak, 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; Lemon
et al., 2006).
Theoretical models have been driven by experimental observations, but the development of new theories has also posed experimental challenges for characterizing ever more detailed material
structures, properties, and responses under various conditions.
Today, biomechanics is intricately tied to modern measurement
techniques, spanning scales from the molecular to the organ level.
It often requires high-resolution spatio-temporal data for model
development, parameterization and evaluation. For clinical applications, the preferred acquisition method is non-invasive. Such
methods can generally provide anatomic and metabolic data,
though invasive methods are also being developed to probe

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material properties. Contemporary basic science investigations

often require simultaneous measurements of biological responses
as well. Recent advances in the biological sciences have presented
unique opportunities for biomechanics investigation, such as the
ability to relate changes in biomechanical phenotype to specic
genetic alterations achieved via gene knockout or gene silencing
techniques.
Sophisticated computational techniques complement these
theoretical and experimental tools, facilitating the biomechanical
analyses critical to practical applications. The development of
nite element and image processing methods specically designed
for biological applications, the use of supercomputers to solve biomechanical problems with a minimum number of approximations,
and the development of molecular modeling techniques are providing a wide range of opportunities to translate advances in
fundamental biomechanics to the clinical arena.
These fundamental developments are at the foundation of
integrative biomechanics.

1.2. Integrative biomechanics: multiscale approaches to translational

research
Biomechanics is an important component of biological processes at the subcellular, cellular, tissue and organ levels. Integrative
biomechanics integrates biomechanics knowledge and methods at
multiple scales to address fundamental and clinical problems at
the tissue and organ level. Owing to the large ranges of scale
involved, integrative biomechanics is intrinsically multidisciplinary, extending from biophysical studies of the mechanics of
biological molecules to engineering descriptions of kinematics
and bulk constitutive properties. The integrative aspect of this
branch of biomechanics emphasizes interactions among biological entities (as in physiological control) and examines individual
entities at different scales (as in studies of the microstructural
basis of macroscopic properties). These interactions are described
by multiscale biomechanical models that can relate higher-level
events to lower-level mechanisms.
Although clinical disease is most clearly evident at the tissue and
organ level, it can involve any of several levels in the hierarchy of
scale; some conditions are initiated by a single gene mutation, others
by an acute alteration in organ function. Most commonly, multiple
scales are involved in the disease process, either simultaneously or
sequentially. This is understandable since the natural homeostatic
state of the organism, disturbances in which accompany disease,
is expressed at multiple levels extending from regulation of gene
expression to physiologic control. The normal homeostatic state also
includes a mechanical homeostasis, which is also seen at scales
that range from cytoskeletal reorganization under stress to systemic
blood pressure regulation. Thus, in general, and specically for biomechanical investigation, an integrative approach is the natural
approach to understand human pathophysiology.
Many aspects of tissue and organ function, such as tissue adaptation, remodeling, degradation and repair, are driven or regulated
by mechanical forces. Many diseases are characterized by a failure
of these processes; for instance, cystic brosis is due primarily
to the impaired transport and ow of mucus, and cardiac events
result from inadequate blood ow and reduced myocardial contractility. A greater understanding of the role of mechanical forces
in modulating tissue and organ function, in health and disease,
will lead to rational improvements in disease prevention, intervention and therapy.
Integrative biomechanics is application oriented, but relies on
basic knowledge at all levels of scale. As a consequence, integrative biomechanical investigation can identify important unsolved
problems in basic biomechanics and biophysics, and provide the

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route whereby their solution can be translated into advances in

clinical medicine. For instance, it has long been appreciated that
mechanical forces are involved in atherogenesis and subsequent
acute events, and in the distinct hyperplastic response of the
vessel wall to clinical interventions such as bypass grafts and
stents. This understanding has prompted numerous basic studies
of the effects of mechanical stimuli on endothelial cells, smooth
muscle cells, and broblasts; the inammatory response; and
mechanotransduction at the molecular level. Heart valve induced
thrombosis has led to new investigations of the effects of uid
stresses on platelet activation. Biomechanical analyses of aneurysm development and rupture have focused research on cellular
involvement in matrix turnover. Mechanical forces also play a
critical role in bone modeling, remodeling and adaptation, a
nding dating back to clinical observations in the late 19th
century. Similar to the cardiovascular studies summarized above,
the precise mechanism for transducing forces in bone into cellular
signals is an active topic of investigation, with a current focus on
in vivo and in vitro studies examining the role of a variety of
mechanical conditions, including oscillatory shear, on osteocytes
and related cells.
The solution of important problems in integrative biomechanics will lead to greater longevity, health, and quality of life. As
suggested above, a more rational approach to therapeutic interventions will lead to further improvements in graft and stent
design. The heart itself is another target of this approach; a better
understanding of cardiac mechanics, extending in scale from cardiomyocyte biology to the entire heart, will guide more rational
management strategies and device designs for treating congestive
heart failure. Similarly, in the musculoskeletal system, the fragility
of bone that accompanies advanced age or disease results in an
enormous health burden in terms of morbidity and societal costs.
An improved biomechanical understanding of the role of the
organic and inorganic constituents of bone, their organizational
interactions (at multiple scales), and their inuence on cellular
regulation may lead to new therapeutic approaches to strengthen
bone or prevent fragility.
1.3. Past achievements of integrative biomechanics
There are already numerous examples of how integrative biomechanics has advanced clinical medicine. Several of these are
summarized briey 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. Articial kidney
Once, kidney failure meant certain death. The advent of dialysis treatment to remove deadly impurities from the blood saved
patients lives. For some, dialysis has become a way station to
the long-term solution of a kidney transplant. But today, dialysis
remains a time consuming process requiring the patient to be
connected to a large xed piece of equipment. The design of the
hemodialyzer required the application of the principles of membrane transport and uid ow, as well as understanding of kidney
architecture and function at the cellular level; further work along
these lines will be necessary to develop means for continuous
dialysis of an ambulatory patient.
1.3.2. Vascular grafts and cardiopulmonary bypass
Surgery to bypass narrowed or blocked coronary arteries using
synthetic grafts or healthy arteries or veins from other parts of the
body extends and improves the quality of life. This procedure was
made possible with the development of the heartlung machine,
which allows the heart to be stopped during surgerywith the

machine taking over the job of providing oxygen to the blood and
moving blood through the body. The heartlung machine and
grafting process required understanding of pulmonary oxygen
transport and circulatory ow; thrombosis during oxygenation
and further disease at the graft junction are prevented using
designs that are based on models of the local ow eld and the
complex biochemical and cellular processes that accompany clot
formation and arterial disease. Further application of integrative
biomechanics in tissue engineering should lead to small-caliber
blood vessels that remain patent longer than existing grafts.

1.3.3. Articial heart valves

The development of replacement heart valves was an early
example of engineers and clinicians working together to restore
cardiac function for patients facing incapacitation because their
own valves were failing. Over the years, engineers have developed
new designs and materials that allow valves made with synthetic
and natural materials to replace damaged or diseased valves.
Valve designs have been optimized to maintain a lifelike ow
through the valve, and to open promptly and close securely, while
minimizing trauma to the entrained red blood cells. Greater
understanding of the interaction of the uid mechanical stresses
that accompany valve operation with blood cells, and the transduction of these stresses into blood trauma at the mechanical,
functional and biological levels, will support the design of more
long-lasting valves that are less damaging to the uid passing
through them.

1.3.4. Angioplasty and vascular stents for coronary artery disease

Rational design and delivery of drug eluting stents require consideration of biomechanical events at many scales. These include
tissue and structural level events such as the mechanical design
of the stent itself, the shape and properties of the angioplasty
balloon, and the mechanical response of the diseased arterial
tissue to stent expansion, to smaller scale events such as the
interaction between the stent and the healing vessel wall, to the
transport of eluted drug from the stent and its interaction in a
complex mechanical environment with the biology of the resident cells. Though considerable progress has been made in the
design of drug eluting stents, long-term complications related
to restenosis persist. These complications represent the types of
challenges that may be addressed with integrative biomechanics.

1.3.5. Joint arthroplasty

Before the advent of articial hip and knee joints, millions of
people particularly the aged lived with considerable pain and
very limited mobility as a result of degenerative joint diseases.
Today, joint arthroplasty represents the primary clinical treatment for advanced joint degeneration, restoring function and
providing a return to nearly normal activities of daily living with
remarkable success. Articial replacements have been designed
for most diarthrodial joints in the body, as a result of close interactions between engineers and orthopaedic surgeons. However,
joint replacements typically last between 10 and 20 years before
signicant implant wear, loosening and failure occur. Due to
signicant bone loss, patients can tolerate at most two replacements for a given joint, thereby limiting this type of surgery
to subjects whose life expectancy does not exceed that of the
implant. Consequently, new treatment modalities need to be
developed for younger patients, such as improved articial joints
and implantation procedures, or successful tissue engineered
osteochondral implants.

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1.3.6. Ligament surgery

Intracapsular ligament failures, such as failure of the anterior
cruciate ligament of the knee, are frequent injuries that lead to
joint instability and may promote osteoarthritis. Ligament repairs
are commonly performed using tissue autografts, allografts, or
articial replacements. Biomechanical engineers and their physician collaborators have played a critical role in assessing the
failure properties of native ligaments and their graft replacements, toward the goal of nding equivalent matches. They have
also provided the biomechanical analyses necessary to understand and exploit the effect of graft pre-tensioning on long-term
joint stability following surgery. Considerable progress has been
made in this eld, such as improving joint stability and restoring
function. However, ligament repairs do not necessarily delay or
prevent the progression of joint degeneration. An integrative biomechanics approach to this problem may be needed to improve
the long-term outcome of ligament surgery.

2. Long-term goals of integrative biomechanics research

Future opportunities for integrative biomechanics research can
be broadly classied in three categories.

 Stents and ventricular assist devices that are less subject to

restenosis and thrombosis.

 Customized soft tissue (e.g., arteries, cartilage, ligament, tendon)

surgical procedures that are guided by a better understanding
of the specic stresses to which the repaired tissue will be
subjected, and how they will adapt thereafter.

2.3. Provide mechanics-based guidance in patient care

We have already noted the close connection between integrative biomechanics and disease. This discipline is not only best
positioned within biomechanics to address the causes of disease,
it is also in the best position to provide guidance regarding therapy in those many instances in which mechanics is involved. This
guidance can be specic to particular patients and based on biomechanical modeling of their particular situation. For example,
areas of clinical care that can benet from this approach include

 Cardiovascular Medicine. The mechanical processes in cardio-

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

The biomechanics of organs and tissues depend at the smallest
scale on the proportions and organization of the biomolecules
largely proteins of which they are composed. The synthesis of
these molecules is controlled at the level of the genome; hence,
genomic events are critical determinants of the mechanical properties and behavior of much larger structures. A long-term goal
of what might be termed mechanogenomics is the integration
of genomics into the multiscale approach that is an essential characteristic of integrative biomechanics. This will allow us to use
genomic information to understand and predict individual differences in tissue and organ function, paralleling the clinical use of
this information to personalize medical care.
Furthermore, when we understand the relationship between
gene expression proles and gross mechanical behavior, it may be
possible to use high-throughput screening to predict biomechanical function and intervene in a disease process, such as heart
failure, well before an untoward clinical event.
The effect of genomic processes on gross mechanics proceeds
through protein interactions and cell biological mechanisms.
Accordingly, the development of mechanogenomic understanding
will 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 of
disease will allow the development and optimization of surgical
procedures and nonsurgical protocols on a more rational basis,
and will support the design of improved implantable and external
devices. Interventions can more readily be made patient specic
to produce better outcomes. Devices whose design is guided by
principles based on integrative biomechanics will be more effective and less likely to fail, leading to cost savings. For example,
such interventions based on biomechanical understanding may
include:

 An implantable intraocular lens that allows the full range of

accommodation while restoring the visual transparency lost
when a native lens is opacied by a cataract.

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vascular function are self-evident, and include the hemodynamics and solid mechanics of the circulation and heart.
Integrative biomechanics can be used to: predict risk of atherosclerosis and consequent coronary disease, stroke, claudication
and organ failure; guide surgical decisions and tool development in intracranial and aortic aneurysm management; quantify cardiac function in congestive heart failure; and design
individualized surgical procedures for arterial grafting and the
repair of congenital cardiovascular defects.
Ophthalmology. Many processes in the eye rely on mechanical
events, and diseases of the eye can be addressed by integrative
approaches to develop individualized therapy based on sound
mechanics. In addition to cataracts, whose treatment can be
improved by designing an intraocular lens that allows accommodation (mentioned above), these conditions include: glaucoma, which arises from defective uid drainage from the eye
and which can be treated by implantation of devices designed
to lower intraocular pressure into a target range specic to
the patient; strabismus, or lazy eye, which can be due to
an imbalance in the extraocular muscles acting on the eye;
keratoplasty, the surgical alteration of the cornea to produce a
more sharply focused image on the retina and which relies on
post-surgical corneal biomechanics; and severe myopia, which
leads to retinal tears and is caused by excessive growth of the
sclera in development.
Orthopaedics. The importance of biomechanics in orthopaedics needs no demonstration. Individualized biomechanical
analysis is already used in prosthesis and implant design, but
integrative biomechanics can also be used to guide therapies
for chronic conditions such as osteoarthritis, osteoporosis and
cerebral palsy; as well as computer-aided surgical planning
and robotics-assisted surgery.

3. Challenges to realize the potential of integrative biomechanics

The eld of biomechanics has beneted from a long history of
fundamental advances, both in the basic engineering sciences and
in the clinical realm. These advances have opened up a wide range
of opportunities to intimately integrate biomechanics with clinical treatment in novel ways. However, as in all engineering endeavors, the transition from a promising potential to its effective

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realization lies in the details of the implementation. To broadly

enhance the impact of integrative biomechanics on clinical practice, 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 of
systems and processes. While researchers have the ability to
develop custom advanced tools for specic research applications,
it is essential to make these tools available and accessible to
clinicians so that they can exploit the most recent advances in
biomechanical analysis. In the traditional areas of solid mechanics, uid mechanics and multi-body dynamics, a wide variety of
commercial software programs are available to perform analyses
of motion, deformation and stress. However, most of these existing products are not specically geared to biomechanics, and thus
are unsuited to many important biological applications. Consequently, there is a major need to develop and disseminate more
suitable computational tools.
In cardiovascular mechanics, the ability to model soliduid
interactions, such as the pumping of blood by the contracting
heart and the deformation and motion of heart valve leaflets or arteries, is a major challenge that has been partially
met 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 investigators
have used these technologies to analyze the state of stress in
abdominal aortic and cerebral aneurysms (Fukushima et al.,
1989; Perktold et al., 1988; Raghavan and Vorp, 2000; Ryan and
Humphrey, 1999; Stringfellow et al., 1987; Wolters et al., 2005).
Other investigators have modeled the electrophysiology of the
contracting heart under normal and pathological conditions
(Hunter et al., 1992; McCulloch et al., 1992; Rogers and McCulloch,
1994; Vetter and McCulloch, 2001). Integrating these approaches
offers great potential to analyze and predict alterations in cardiac
output under various conditions and in the presence of disease.
These tools would be valuable for both basic science and clinical
applications, as well as in the design of heart valves, stents, and
vascular grafts.
Most biological tissues are highly hydrated and experience
interstitial uid ow. The analysis of tissues using porous media
theories has been highly successful, especially in the eld of
cartilage mechanics (Lai et al., 1991; Mow et al., 1980), but also in
studies 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. Some
commercial programs exist which can model deformation and
ow in porous media, and their relatively widespread application is a testament to the need for such tools in biomechanical
applications. At the research level, more sophisticated tools have
also been developed which can describe streaming and diffusion
potentials and currents, as well as osmotic pressure and solute
transport 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 can
uniquely provide insights into the biomechanics of biological
tissues, and recent developments suggest that they can be
successfully applied to cell mechanics as well. These tools merit
more widespread dissemination and application.
It is often said that biology is ultimately chemistry; however,
chemistry can be modulated by mechanics. Alterations in molecular conformation in response to mechanical signals are known to
modulate biochemical reactions at the cellular and subcellular
levels (Vogel and Sheetz, 2006). Molecular dynamics is a modeling

tool that has the potential to describe mechanotransduction at the

molecular scale, although major computational challenges have
restricted its predictive powers to date. Nevertheless, even if
biomechanical computations do not reach down to the molecular
level, one of the critical needs of integrative biomechanics is
the ability to integrate multiscale analyses from the smallest to
the largest scale of interest. Thus, for instance in the heart, even
though the computational analysis of a beating heart cannot possibly model every cardiomyocyte, it is nonetheless important that
analysis tools be developed to permit the local environment at the
cellular level to be obtained from a more macroscopic description.
Conversely, tools must also be developed to relate the response
of the entire heart to the contraction of specic cardiomyocyte
domains.
One of the greatest challenges in the eld of biomechanics
remains the analysis of tissue growth and remodeling. Though
signicant progress has been made in the mathematical foundations 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 complexity
of describing evolving tissue congurations. An even greater
challenge is the need to couple the mathematics of growth
and remodeling to the biological, chemical and physical signals
that trigger and regulate these events, and respond to them in
a closed-loop feedback system. The eld of bone mechanics
has seen extensive developments in this area, where models of
growth and remodeling have been used to predict alterations
in bone density and strength around prosthetic implants, and
thereby to anticipate potential bone fractures and guide future
implant designs (Huiskes and Boeklagen, 1989; Stolk et al., 2007).
Signicant progress has also been reported in the elds of vascular remodeling (Gleason and Humphrey, 2004; Humphrey and
Rajagopal, 2003) and cartilage growth (Dimicco and Sah, 2003;
Klisch et al., 2003). A resolution of the mathematical challenges
noted above, and the development and dissemination of computational tools to describe growth and remodeling, remain
important needs. These tools can subsequently be integrated
with analyses of biological signal transmission and mechanotransduction and with the models of uidsolid interactions,
porous media biomechanics and solute transport described
earlier. By simulating the complex biological events that underlie
tissue adaptation, remodeling, degradation, and repair, this suite
of techniques will support the testing of new hypotheses and
the development of new therapies, advancing both basic science
and 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 are
not specically geared for biomechanical analyses. For example,
analyzing the deployment of an arterial stent, with the resulting
deformation of the arterial wall and alteration in blood ow, is
not a routine analysis available to the engineering designer.
Examining the biomechanical response of an implanted tissue
engineered graft, such as an osteochondral construct or a ligament in a diarthrodial joint, remains a complex task today.
Computational tools that accommodate large-scale analyses of
complex biomechanical systems need to be made available to
the general engineering professional. These tools should be
formulated to assist in the design and analysis of biomedical
devices in situ; they should also facilitate the development
of predictive tools to investigate the long-term outcome of
various 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 by
mechanics.
3.2.2. Higher spatially and temporally resolved in vivo
measurements of structure and function
Advances in non-invasive imaging technologies have provided immense benets to integrative biomechanics. For example,
X-ray computed tomography, dual-energy X-ray absorptiometry,
magnetic resonance imaging and ultrasound imaging are not
only useful clinical diagnostic tools; they also facilitate biomechanical analyses that can be used to predict the stresses
around endoprostheses and resulting bone resorption, estimate
fracture failure risk from osteoporosis, compute the hemodynamic changes accompanying ow constrictions caused by atherosclerosis, predict the risks of rupture of abdominal aneurysms,
compute cardiac output in real-time, support surgical planning for
orthopaedics and neurosurgery, predict brain deformation during
tumor-removal surgery, guide robotics-assisted surgery, and for
many other applications.
However, limitations persist in the spatial and temporal resolution of these imaging methodologies that limit their potential
for achieving more accurate biomechanical predictions of outcomes. For example, in vivo imaging of the cardiovascular system
is generally unable to resolve the structure of arterioles and
capillaries; thus computational uid dynamic models to predict
blood ow and blood pressure in the cardiovascular system must
rely on the application of a priori boundary conditions at the
edges of the resolvable structures, resulting in a level of uncertainty that potentially compromises the accuracy of modeling
predictions, limiting their clinical application. A similar resolution
issue arises with respect to the lung and the modeling of alveoli.
Likewise, while micro-computed tomography is able to resolve
individual bone trabeculae in the intervertebral body in small
animal models, yielding a wealth of information for predicting
the fracture risk from osteoporosis, the resolutions achieved in
these animals have not yet been attained for clinical imaging in
humans.
Other challenges persist, most notably in the ability to
directly measure the mechanical properties of biological tissues
via non-invasive methods, thereby providing the necessary data
for predicting biomechanical outcomes in organ systems on a
patient-specic basis. Ultrasound techniques have the ability to
transmit pressure waves across tissue walls and thereby to apply
mechanical loads to soft tissues non-invasively; if the prole
of the transmitted pressure wave could be predicted accurately,
and the resulting tissue deformation measured precisely, such
methods could potentially produce useful measurements of soft
tissue mechanical properties. However, many technical obstacles
remain to achieve this goal. The development of creative methodologies that build upon existing imaging modalities to produce
reliable measurements of mechanical properties would open up
new 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, localized
or systemic delivery of biochemical agents, or localized mechanical alterations, such as arterial ow constrictions or soft tissue
transections, in a manner thought to simulate the natural initiation and progression of these diseases in humans. However, many
diseases which alter the normal biomechanical function of loadbearing organs and tissues have unknown causes or catalysts,
often originating at the genome level. Molecular alterations via

1449

gene knockout or gene silencing techniques offer tremendous

potential for investigating the inuence of genetic factors on the
structure and biomechanical function of organs and tissues, as
well as enhancing our overall understanding of the interaction
of mechanics and biology. The continued development of animal
models relevant to human disease, that are suitable for highthroughput analysis and whose biomechanical function can
reasonably be extrapolated to man, represents a major need.

3.3. Development of supporting databases

Extensive databases are needed to inform and validate biomechanical models and serve as benchmarks for the development
of novel biomedical devices, drugs and biologicals, and clinical
procedures. Research efforts in biomechanics over the past several
decades have produced a wealth of data that has been disseminated mostly via peer-reviewed archival papers. However, unlike
the more traditional engineering disciplines or the biological and
pharmaceutical sciences, few bioengineering handbooks and databases have been published that attempt to collect this dispersed
biomechanics information into organized and centralized database
sources.
For example, there are few compilations of the material
properties and biochemical composition of biological tissues in
humans and other animal species, in health or disease, and as a
function of age or disease progression, despite the wealth of data
available in the literature. A recognized challenge is that material
properties are presented in the context of a selected constitutive
relation for the tissue; given the complex biomechanical behavior
of most biological tissues, few denitive constitutive relations
have emerged to date, and published studies often advance different models with incompatible properties. In many cases, the
constitutive models used to describe biological tissues are not
incorporated into existing commercial modeling tools, making
them available only to a selected group of investigators.
The development of such databases will represent an important milestone in the eld of integrative biomechanics, facilitating
and marking the transition from a mostly research-oriented endeavor to a mature discipline that strives to translate its advances
to clinical applications. Professional societies with an interest in
biomedical engineering or biomechanics may choose to take the
lead in establishing such databases to further encourage professional development in this eld.

3.4. Promotion of a multidisciplinary approach to patient-specic

treatment
The development of biomedical devices and computational tools
for patient-specic treatment is anchored in the close partnership
of engineers, clinicians, and biomedical scientists that provides the
multidisciplinary expertise required to employ patient treatment
modalities successfully.
This type of partnership needs to be nurtured at an early stage
of training in these various professions. In the early days of biomedical engineering, these successful interactions occurred at the
initiative of highly motivated individuals who had the vision to
bridge beyond their traditional disciplines. Today it is important
to formalize these interactions and not leave them to chance,
to help establish broader and more ambitious partnerships that
can signicantly advance medical practice. Novice biomedical
engineers must learn to focus their problem solving skills on
clinically relevant challenges, while clinicians can benet from
a better understanding of the broad class of problems where
biomedical engineers may contribute their skills.

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4. Concluding remarks
Technological advances have progressed rapidly over the
recent decades. Many concepts that would have been dismissed
as science ction twenty years ago have become reality. The
power of computational tools, the ability to miniaturize devices,
the decreased cost and improved accuracy of non-invasive imaging technology, and the willingness of many clinicians to adopt
novel approaches such as robotic-assisted surgery, promise significant improvements in clinical care and outcomes. To fully realize
this promise, it will be necessary to understand more fully than
we do today the sequence of events that translate genetic predisposition and environmental inuences into clinical states. This
need for integration is a challenge and an opportunity for biomechanics, because mechanics is integral to biological events at
all levels of scale. In the previous pages, we have outlined but a
few of the past successes of integrative biomechanics and the
technological challenges facing this discipline today. 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
eld.

Conict of interest statement

The authors do not have any conicts of interest with regard to
this 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 for
this document. The careful review of the entire document by
panelists C.R. Ethier and J.D. Humphrey is particularly appreciated.
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