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Bioengineering Models of Deep Tissue InjuryAmit Gefen, PhD
For patients permanently confined to a wheelchair or a bed,
pressure ulcers are a major health risk. Pressure ulcers typically
appear in soft tissues enveloping bony prominences (eg, the
ischial tuberosities), which are compressed by body weight
against the supporting surfaces. In patients with central ner-
vous system disorders, the combination of immobility, which
imposes unrelieved tissue compression and shear stresses, and
the lack or dysfunction of a pain ‘‘alarm’’ sensation creates the
conditions for local prolonged tissue ischemia. Excessive pro-
longed tissue deformation from the bone’s compression also
causes cell death, leading to a pressure ulcer.1 However,
ischemia is traditionally considered the primary factor in pres-
sure ulcer etiology.2 Muscle tissue, the most vascularized tissue
layer between the bone and skin during sitting and the tissue
with the highest metabolic demand, is reported to have the
lowest tolerance to mechanical compression.3 Accordingly, in
the recent years, it was recognized that pressure ulcers can
develop in muscles that pad bony prominences without any
external indication of deep tissue necrosis during the early
stages of injury.1,4–6 Therefore, the 2005 Consensus Meeting of
the US National Pressure Ulcer Advisory Panel (NPUAP) in-
troduced a new term, deep tissue injury (DTI), to classify this
potentially life-threatening form of pressure ulcer, which is
characterized by necrotic muscle tissue under intact skin. The
current NPUAP’s definition of a ‘‘suspected DTI’’ is ‘‘Purple or
maroon localized area of discolored intact skin or blood-filled
blister due to damage of underlying soft tissue from pressure
and/or shear. The area may be preceded by tissue that is
painful, firm, mushy, boggy, warmer, or cooler as compared to
adjacent tissue (http://www.npuap.org).
Pressure ulcers and DTI do not develop spontaneously in
animals, making basic research and applied research work
more difficult. Special models need to be developed and veri-
fied to study the etiology of DTI and to design preventive or
protective measures. The purpose of this review is to describe
the frontier of biomedical research on DTI, with an emphasis
on up-to-date computer modeling, imaging strategies, and
cellular and tissue engineering methods. These new research
tools allow well-defined, carefully controlled studies of tissue
viability under prolonged loading, which was impossible until a
few years ago. The discoveries made using these methods are
expected to boost the understanding of DTI and lead to the de-
velopment of improved medical protocols and preventive equip-
ment for susceptible patients. Although the pathomechanics of
DTI is discussed here from a bioengineering perspective, the
physiologic mechanisms of injury and the clinical relevance are
comprehensively addressed. For readers with a nonengineering
background, a Glossary of Engineering Terms is provided.
ANIMAL MODELSAnimal models of pressure ulcers have been used since the
early 1950s,7 but during the last few years, modeling tech-
nology improved when animal models started being used with
sophisticated computer models,8–10 and small-animal magnetic
resonance imaging (MRI)11–14 became feasible. These inte-
grated approaches allow better characterization of the mechan-
ical conditions in deep muscle tissue that lead to DTI.
Animal models reported in the literature of pressure ulcer
research are rats,8–15 rabbits,16 dogs,17 and pigs.3,18 Of these,
the rat is by far the most commonly used, in part because the
physiology, metabolism, and pharmacologic response of rat
muscles are well documented in the literature.15 Also, experi-
ments with rats cost less, which allows studies of a relatively
large number of them.15 Most DTI studies of rat models used
Sprague-Dawley8–10 or Brown Norway strains.11–14 An im-
portant advantage of rats as a model of pressure ulcers in deep
muscles is that pressures applied to the surface of the animal’s
skin correspond closely to the internal mechanical compression
stress that consequently develops in the muscle tissue.10
Specifically, computer simulations using the finite element
(FE) method showed that in rat limb anatomy, differences
between external (skin) pressures and internal (muscle) com-
pression stresses are negligible (<5%) for external pressures of
less than 40 kPa (300 mmHg) andf10% for external pressures
of more than 40 kPa.10 Peak deep muscle tissue compression
stresses in sitting humans were recently reported to be 32 F 9
kPa (mean F standard deviation).19 Hence, rats are a good
model to study DTI affecting muscle tissues in humans because
magnitudes of internal stresses in the rat’s muscle tissues can
be adequately controlled during experiments.10
To cause the onset of a pressure ulcer in the animal’s leg
muscle, all recent studies used a rigid indenter driven by an
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Amit Gefen, PhD, is a Senior Lecturer in the Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel. Acknowledgments: This work was
supported in part by the Slezak Super Center for Cardiac Research and Biomedical Engineering at Tel Aviv University and by the Internal Research Fund of Tel Aviv University. Submitted
February 22, 2007; accepted in revised form April 18, 2007.
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elastic spring,8–10,12–14 pressurized air,11,18,20,21 or a motor.15,22
This differs from Husain’s fundamental study of rats as pressure
ulcer models,7 in which a pressure calf was used to load the
tissues. Before indenting the leg tissues to produce a pressure
ulcer, some studies induced paraplegia in rats by sectioning the
spinal cord23 because paralyzed humans showed lower capil-
lary pressures than normals,24 and thus, it was hypothesized
that paralyzed animals may be more susceptible to ischemia and
pressure necrosis. In the studies of DTI affecting the rat’s
muscles (eg, the gluteus, tibialis anterior, gastrocnemius, ham-
strings, or gracilis), the skin may be reflected9,10 or not.8,11–15,20–22
Pressure magnitudes delivered to the animal’s tissues are often
selected to reproduce pressures or internal tissue stresses
shown to occur in humans through interface pressure measure-
ments during sitting or computational modeling of load
transfer in deep tissues during sitting.8–10 The classic method
used to determine whether tissues remained viable after pres-
sure delivery is histological staining.3,7–10,21,22 Hematoxylin and
eosin was used in several studies to demonstrate the loss of
cross-striation in striated muscle postcompression and infiltra-
tion of macrophagic immune cells.7,20–22 More recently,
phosphotungstic acid hematoxylin8–10 and Gomori trichrome13
were used for staining because they can demonstrate muscle
cell death 1 hour or less after pressure is removed, whereas
hematoxylin and eosin staining cannot identify tissue damage
until 24 hours after compression.22
Because histology is a labor-intensive and destructive method
of assessing the viability of muscle tissue after applying pres-
sure, a small-animal MRI system for monitoring the onset and
progression of ulcers was recently introduced.11–14 The major
advantage of MRI studies is their ability to characterize the
evolution of tissue damage with time, which allows the incorpo-
ration of reperfusion effects in the experimental protocol.11–14
In these studies, T2-weighted high-resolution images of the
rat’s tibialis anterior muscle showed regions of muscle damage
1 to 24 hours after indentation of the limb at pressures of 150
kPa (1125 mm Hg) or 50 kPa (375 mm Hg).11–14 The location
and area of the higher T2-weighted MRI signal intensity co-
incided with the location and extent of damage determined by
histology, which showed necrosis and disorganization of mus-
cle fibers 1 to 4 hours after load removal and inflammatory
response 20 hours after load removal.11–14 An important ad-
vantage of high-resolution MRI imaging is that it allows direct
measurements of the internal local deformations in muscle
tissue during indentation and simultaneous monitoring of tis-
sue damage by means of MRI tagging.14 Also, MRI perfusion
measurements can demonstrate local tissue perfusion, and
magnetic resonance spectroscopy allows biochemical evalua-
tion of the tissue during and after loading.14 It is also possible to
couple an FE model of the animal’s leg to the experiment to
further study the mechanical stresses corresponding to internal
tissue deformations measured by MRI tagging.14
COMPUTER MODELSAlthough animal models are efficient for studying the
pathobiology of DTI affecting muscle tissue, they generally do
not allow correlation of the pathobiology with the internal
mechanical conditions in human tissues that lead to ulcer
formation (eg, distributions of muscle tissue deformations and
mechanical stresses). For the study of these mechanical con-
ditions, computer modeling, particularly modeling using the FE
method of stress analysis, is a very powerful approach.8,9,25–32
Computer simulation, ‘‘the third method of science,’’ allows
many experiments at a substantially lower cost than any human
or animal studies. Unlike real-world experiments, numerical
experiments allow isolation of each factor affecting the me-
chanical conditions leading to ulceration, for example, the
curvature of the ischial tuberosities, the thickness of the muscle
layer, the stiffness of each tissue involved, and the stiffness and
thickness of wheelchair cushions or bed mattresses (Figure 1).
Figure 1.
SCHEME OF COMPUTER MODELING APPROACH USED IN
THE MUSCULOSKELETAL BIOMECHANICS LABORATORY
AT TEL AVIV UNIVERSITY TO STUDY DEEP TISSUE INJURY
IN THE GLUTEUS MUSCLES
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With increases in computer power, computer models in
pressure ulcer research and DTI research in particular are
becoming more and more realistic in representing the human
anatomy and the mechanical behavior of tissues. Chow and
Odell,25 Todd and Thacker,26 Oomens et al,29 Kuroda and
Akimoto,31 Linder-Ganz and Gefen,8,9 and Sun et al32
developed FE models of the buttock that analyzed the bone-
muscle interactions during sitting or lying. All studies
concluded that complicated deformation and stress distri-
butions are formed in the deep tissues of the buttock and
that peak tissue stresses (compression, shear) appear in deep
muscle tissue adjacent to bony prominences. Another con-
clusion was that providing an accurate evaluation of local
muscle loading from interface pressure measurements alone
is extremely difficult. That is because of the complicated inter-
nal tissue loading patterns, which were manifested not only in
anatomically realistic models,8,19 but also in models that rep-
resented the anatomy of the human buttock using a relatively
simple geometry (eg, an axisymmetric rigid half-cylinder or
half-sphere to represent the ischium).25,29,31 The focal stresses
and deformations in muscle tissue around bony prominences
were shown to intensify if some muscle elements were
considered to stiffen after injury, as shown in animal models,8,9
or if some gap was introduced between the ischial bone and
partially necrotic muscle, as documented in patients.31
The focal mechanical stresses and deformations shown to
develop in deep tissues during prolonged sitting or lying sug-
gest that the mechanical state of muscle tissue in DTI and the
tissue’s response to loading should be studied not only at the
organ (ie, whole muscle) level, but also at a microscopic level,
at the sites of localized elevated loading. Accordingly, the me-
chanical conditions in muscle tissue at the macroscopic and
microstructural levels in individual muscle fibers were studied
by Breuls et al.30,33 In these studies, muscle cell deformations
were predicted from detailed FE analyses of the microstructure
of skeletal muscle, consisting of a population of cells embedded
in extracellular matrix. When subjected to compression loads,
the model showed that this microstructural heterogeneity in
skeletal muscle had a substantial influence on local cell defor-
mations, which were shown to be larger than macroscopic
deformations of the continuum.33 Muscle cells also deformed
into complex shapes under compression, causing highly non-
uniform deformations in individual muscle cells.33 When local
load-time threshold curves were introduced into the model to
simulate changes in muscle cell viability under loading (based
on cell culture experiments described later),34 it was demon-
strated that intramuscular cellular density and the bone-muscle
contact stresses strongly affect the extent and distribution of
DTI.30 Use of such computer simulations to study the me-
chanical conditions at the microstructural levels of skeletal
muscle subjected to bone compression in DTI requires knowl-
edge of the tolerance of individual cells or cell cultures to
continuously delivered deformation and stress.30 Hence, cell
and tissue culture models were developed, as described in the
following section.
CELL AND TISSUE CULTURE MODELSAlthough ischemia and hypoxia in compressed muscle tissue
are traditionally considered to be the dominant causes of pres-
sure necrosis in DTI, recent evidence from cell and tissue
culture studies indicates that cellular deformation from bone
compression is also an important cause.1,34–38 Under ade-
quately controlled toxic conditions, studies in isolated muscle
cells and tissue cultures allow a separation of the effects of
cellular deformation from effects of hypoxia and ischemia.
Such separation of effects is generally not feasible in an ani-
mal model, in vivo.
To determine the relationship between compressive defor-
mation and muscle cell death and to study the roles of cell-cell
interactions, cell-matrix interactions, and tissue geometry in
this process, Bouten et al35 reported the development of several
in vitro models. These models were designed using a
hierarchical approach from single myoblast cell studies to
myoblast cell monolayers and up to 3D agarose constructs
seeded with myoblasts.35 In all these setups, compression was
delivered using specially designed loading devices, and cell
deformation was visualized with confocal microscopy. Cell
damage was assessed with viability tests, including vital
microscopy, histologic, and biochemical analyses. Single-cell
compression studies were able to demonstrate changes in the
shape of compressed myoblasts (from mice) under confocal
microscopy.34 It was shown that myoblastic cells are nearly
incompressible (ie, they do not change their volume while
being compressed), but their surface area tends to increase with
the level of compression stress.34 These models confirmed at
different levels of structural hierarchy that muscle cell
deformation is an important trigger for pressure necrosis. Cell
or tissue culture loads that caused deformations of more than
20% resulted in a significant increase in cell damage with time
of compression compared with controls.35,36 In a later study,
using the DNA nick-translation method, Bouten et al36 found
that this increase resulted primarily from apoptosis.
To extend these findings to a more realistic representation of
muscle tissue without considering the function of the blood and
lymphatic vessels, Breuls et al37 developed an in vitro model
system of engineered skeletal-muscle tissue constructs for
studying the effect of compressive loading on cell viabil-
ity. Compression of these engineered muscle tissue constructs
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revealed that most cells died in 1 to 4 hours at clinically relevant
deformation percentages (shortening of the constructs by 30%–
50%) and that higher deformations led to earlier cellular
damage initiation. Also, the uniform distribution of dead mus-
cle cells across the constructs suggested that sustained defor-
mation was the principal cause of cell death.37
Taken together, these studies approach the establishment of
an injury threshold for muscle tissue at a cellular level. This
adds on existing injury thresholds for muscle tissue at the organ
level10 and is highly useful for DTI computer modeling because
it allows a determination of the effects of local mechanical
stress or deformation levels in the tissue on the viability of cells
contained in that region.30
CONCLUSIONSThe etiology and biomechanics of DTI are still poorly under-
stood, but in recent years, major progress has taken place. It
has been recognized that DTI is distinct from other pressure
ulcers in that it originates in deep muscle tissue around the
contact region between muscle and bony prominences (par-
ticularly the ischial tuberosities or sacrum). Because the site of
initial injury is muscle tissue, and if untreated, the injury prog-
resses to other tissues, the focus of research in recent years has
been the tolerance of skeletal muscle tissue to prolonged com-
pression. Major landmarks in research work include (1) im-
provement of computer models of sitting and lying humans to
incorporate a better detailed anatomy and a more realistic
representation of the mechanical behavior of human tissues in
the simulations, particularly regarding the extrapolation from
internal mechanical loading in tissues to the onset of biologic
damage; (2) establishment of tissue injury thresholds for skele-
tal muscle when subjected to transverse compression (ie, a
compression load applied perpendicularly to the direction of
muscle fibers) at the scales of individual myofibers and tissue
cultures; (3) coupling of animal models with computer models
of the animal experiments to better characterize the mechanical
conditions in deep muscles during the onset and progression of
a DTI; and (4) introduction of small-animal MRI imaging
methods to monitor the onset and progression of ulceration in
muscles of animal models in real-time. Some of the pros and
cons of these recently introduced DTI modeling approaches are
detailed in Table 1.
It is expected that, in the near future, these research steps will
allow the establishment of improved clinical criteria and
protective means for managing patients with spinal cord injury
or lesions and other susceptible patients. However, to achieve
this practical aim, further research is needed to determine the
unique mechanical conditions in the muscles of these patients
by means of computer modeling coupled with animal modeling
and cell and tissue culture methods.
GLOSSARY OF ENGINEERING TERMSPressure and StressPressure on a surface equals the force acting normal to a sur-
face, per unit area of the surface. Units of pressure are there-
fore provided as force (in newtons) per area (in meter squared);
N/m2 is defined as 1 Pa. Pressures are also specified in milli-
meters of mercury (mm Hg), and 1 mm Hg is 133.3 Pa, or
0.1333 kPa. Pressures applied on the skin tend to compress
underlying tissue layers. An interface pressuremap of wheelchair
sitting indicates how the normal contact forces between the
patient’s buttock and wheelchair support are distributed across
the contact area.
TABLE 1.
ADVANTAGES AND DISADVANTAGES OFANIMAL MODELS, COMPUTER MODELS,AND CELL AND TISSUE CULTURE MODELSIN STUDIES OF DEEP TISSUE INJURY
Advantages Disadvantages
Animalmodels
Represent true complexityof DTI in vivo.
Difficult to isolate andquantify contribution ofindividual injury factors(such as ischemia or tissuedeformation) to the overalltissue damage.
Allow correlations betweenmechanical loads andbiological damage.
May be costly andlabor-intensive.
Computermodels
Allow noninvasiveevaluation of mechanicalconditions in deep tissues.
Biological conditions intissues, such as tissueviability, cannot be directlyderived.Control of model
parameters (geometry,tissue mechanicalproperties) is relativelyeasy, and parameters canbe adjusted to studypatient-specific cases.
Only possible to obtain dataon mechanical conditions intissues (stress, deformation).Difficult to reproduce thecomplexity of mechanicalbehavior of living humantissues.Many ‘‘virtual’’
experiments can be madein a short time at low cost.
Simulation results may besensitive to modelassumptions (geometry,mechanical properties oftissues, interface betweentissue layers, and externalmechanical loads).
Cell andtissueculturemodels
Provide biological data(particularly cell viability),not just mechanicalconditions in tissues.
Only partial representationof complexity of DTI in vivo,eg, difficult to include bloodflow effects.
Better able to isolateeffects of individual factorsinvolved in DTI (such ashypoxia, tissuedeformation) than animalmodels.
May be costly andlabor-intensive.
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Stress is the force acting through an object, per unit of cross-
sectional area of the object. Units of stress are the same as
those of pressure (Pa, kPa, and mm Hg). In fact, pressure is a
special variety of stress. However, stress is a more complex
quantity than pressure because it varies with both the direction
and the surface it acts on. Stresses that act to shorten an object
are called compression stresses. Stresses that act to lengthen an
object are called tension stresses. Shear stresses act parallel to a
surface and tend to deform rectangular objects to the shape of a
parallelogram. Thus, the most general definition of a shear
stress is that it acts to change the angles of an object. Pressure
is a special type of stress called normal stress, that is, a stress
that acts perpendicularly to a surface. Pressure and shear
stresses acting on the skin during sitting or lying can contribute
to the local internal stress in deeper tissues. Stresses are typi-
cally maximized in deep muscle tissues adjacent to the bony
prominences, such as the ischial tuberosities and sacrum.8,9
The Elastic ModulusThe elastic modulus equals the ratio between a stress applied
to deform an object and the relative deformation caused by
that stress. It is a property of the material (tissue) and does
not depend on the geometry. A higher elastic modulus means
that a larger force (or stress) is needed to deform the material;
thus, a stiffer material will be characterized by a higher elas-
tic modulus. The elastic modulus of cortical bone is around
10 million kPa, and that of trabecular bone is an order of
magnitude lower.8 The elastic modulus of a skeletal muscle,
when compressed in a direction perpendicular to the direc-
tion of muscle fibers, is about 2 kPa.39 Hence, for practical
purposes, the ischial tuberosities can be considered as being
completely rigid when compressing the compliant underlying
muscle tissue.
During wheelchair sitting or prolonged lying in bed,
soft tissue layers (skin, fat, and muscle) are compressed be-
tween the supports and the bony prominences. Because each
tissue type has a different elastic modulus, each tissue layer
deforms to a different extent, and shear stresses occur along
the boundaries between tissue layers. This effect is particu-
larly pronounced at the interface between the bone and
muscle, where the elastic modulus of bone is more than
6 orders of magnitude higher than that of the underlying
muscles.8,9,39
The Finite Element Method for Analysis ofDeep Tissue LoadsThe FE method of stress analysis in biomechanics is based on
dividing complex anatomical structures, such as the human
buttock, into small tissue elements with a simpler geometry
(eg, bricks, tetrahedrons, or hexahedrons), which are connected
through common nodes. The equations of mechanical equili-
brium are analyzed for each element, and displacement
information in an element is transferred to neighboring
elements through the shared nodes in an iterative calculation
process that eventually provides the distribution of internal
tissue deformations and stresses in the whole anatomic
structure. Review of the general-purpose FE method of
analysis, the differential equations of element equilibrium,
and the methods of programming an FE problem are outside
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