Aetiology of pressure ulcers

Aetiology of pressure ulcers
Sandra Loerakker
October, 2007
BMTE 07.39
Promotor: prof. dr. ir. F.P.T. Baaijens
Coach: dr. ir. C.W.J. Oomens
Eindhoven University of Technology
Department of Biomedical Engineering
Section Materials Technology
Division Biomechanics and Tissue Engineering
Contents
1 General information
1.1 Prevalence and costs of pressure ulcers . . . . . . . . . . . . . . . . . . .
1.2 Classification systems . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3 Risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2
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4
2 Mechanical loading
2.1 Pressure, shear and friction . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Internal stress state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Magnitude and duration of loading . . . . . . . . . . . . . . . . . . . . .
6
6
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9
3 Damage pathways
3.1 Localized ischemia . . . . . .
3.2 Ischemia/reperfusion injury .
3.3 Impaired lymphatic drainage
3.4 Sustained deformation of cells
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4 Discussion
4.1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Focus questions for our research . . . . . . . . . . . . . . . . . . . . . . .
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Bibliography
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Chapter 1
General information
1.1
Prevalence and costs of pressure ulcers
Pressure ulcers are localized areas of tissue necrosis that tend to develop when soft tissue
is compressed between a bony prominence and an external surface for a prolonged period
of time [58]. They occur in situations where people are subjected to sustained mechanical
loads and are particularly common in subjects who are bedridden or wheelchair-bound.
Prevalence figures remain very high; e.g. in a recent Dutch prevalence study it was
shown that the prevalence of pressure ulcers was 15.4% in university hospitals, 11.8% in
general hospitals, 18.3% in nursing homes and 8.4% in home care [47]. Especially spinal
cord injury (SCI) patients are at risk for developing pressure ulcers, since prevalence
rates for this group are much higher. For SCI patients, the occurrence of pressure ulcers
is among the most common long-term secondary medical complications [50]. According
to Dinsdale, the incidence of pressure ulcers in paraplegic and quadriplegic patients
ranges from 25% to 85% [24]. In addition, Garber and Rintala found that a large part
(56%) of the ulcers in SCI patients are grade IV pressure ulcers (most severe, see section
1.2) [27]. These ulcers usually start in deep tissues over bony prominences and are hard
to detect before they reach the skin surface.
Besides the fact that pressure ulcers are very painful for patients themselves, they
also represent a huge financial burden for health care in Western countries. In the
Netherlands, more than 1% of the total health care budget is spent on prevention and
treatment of pressure ulcers or the prolonged hospital stay once a pressure ulcer has
developed. Here, pressure ulcers are the third costliest disorder, after cancer and cardiovascular diseases [55].
1.2
Classification systems
There are different systems to classify pressure ulcers. The system adopted by the European Pressure Ulcer Advisory Panel (EPUAP) consists of four grades in which each
grade is defined by the anatomic limit of tissue damage, see table 1.1 [23] and figure
1.1. This classification system can be used to evaluate the anatomic depth of tissue
2
Chapter 1. General information
1.2. Classification systems
Table 1.1: Classification system of the EPUAP [23].
Grade
Grade I
Short description
Non-blanchable erythema of
intact skin
Grade II
Abrasion or blister
Grade III
Superficial ulcer
Grade IV
Deep ulcer
Definition
A discolouration of the skin,
warmth, oedema, induration or
hardness may also be used as indicators, particularly on individuals
with darker skin.
A partial loss in the thickness of the
skin involving epidermis, dermis, or
both.
A full loss in the thickness of the
skin involving damage necrosis of
subcutaneous tissue that may extend down to, but not through, underlying fascia.
An extensive destruction, tissue
necrosis, or damage to muscle,
bone, or supporting structures with
or without full loss in the thickness
of the skin.
destruction, but is also erroneously used in reverse order to monitor the healing process
of an ulcer [49, 59]. This is not correct, for as stage IV ulcers granulate progressively
to a shallower depth, they do not replace the structural layers of muscle, subcutaneous
fat, and dermis before they reepithelialize [49]. Furthermore, the inter- and intrarater
reliability of the EPUAP classification system appeared both to be low for nurses. Misclassification of pressure ulcers can then lead to inadequate preventive and therapeutic
measures and suboptimal nursing care [23]. Besides the fact that the system cannot
be used for monitoring wound healing, it also focusses only on visible signs of skin or
underlying tissues, so ulcers that initiate in deeper tissues, e.g. near bony prominences,
are not recognized until they reach the skin and instantly become a grade IV ulcer [25].
Ankrom et al. also mentioned that the published literature did not offer consensus on
how to describe, diagnose, or treat pressure-related deep tissue injury under intact skin
[2]. Recently, the National Pressure Ulcer Advisory Panel (NPUAP) updated their classification system and also added deep tissue injury as a distinct pressure ulcer in this
updated system [6].
3
Chapter 1. General information
1.3. Risk assessment
Figure 1.1: Schematic representation of the four grades of pressure ulcers [1]. A grade I ulcer is
characterized by a discoloration of the skin, a grade II ulcer by partial loss in thickness of the skin, a
grade III ulcer by full loss in thickness of the skin, and a grade IV ulcer by extensive destruction of
muscle, bone, or supporting structures with or without full loss in the thickness of the skin.
1.3
Risk assessment
There are two major factors associated with the risk of developing pressure ulcers: the
amount and duration of exposure to pressure and the ability of the tissue to tolerate
the pressure [5], see figure 1.2. The primary cause of pressure ulcer development is
the exposure to pressure; without a mechanical load no pressure ulcer will develop.
However, the ability of the tissue to withstand mechanical loading determines whether
or not a person will develop a pressure ulcer due to a certain loading. The exposure to
pressure is influenced by the mobility, activity and sensory perception of a patient and
tissue tolerance for pressure is influenced by intrinsic and extrinsic factors [5]. Intrinsic
factors are related to the individual, e.g. age, smoking, incontinence, weight and body
temperature. Extrinsic factors are related to the environment, e.g. contact surface and
temperature and humidity of the environment.
In clinical practice, these risk factors are used in risk assessment scales to identify
patients at risk of developing pressure ulcers. Many different risk assessment scales exist,
but the value of these scales in predicting the risk of pressure ulcer development remains
questionable. For example, Schoonhoven et al. tested three commonly used scales (the
Norton, Braden and Waterlow scales) and concluded that the use of the outcomes of
these risk assessment scales to decide on preventive measures leads to ineffective and
inefficient treatment for most patients [75]. Moreover, these scales cannot be used for
SCI patients, since they are always classified as high risk patients. Still, they may stay
free of ulcers for a long time, and suddenly develop an ulcer in a very short period.
4
Chapter 1. General information
1.3. Risk assessment
Figure 1.2: Conceptual schema which accounts for the relative contributions of the duration and
intensity of pressure and the tolerance for pressure.
5
Chapter 2
Mechanical loading
2.1
Pressure, shear and friction
Mechanical loading that can lead to the development of pressure ulcers not only consists
of pressure; shear and friction are also mentioned to be important [24, 69]. It is believed
that shear and friction mainly cause superficial ulcers, while pressure usually leads to
deep tissue destruction, especially in soft tissues over bony prominences [13]. In practice
however, it is difficult to have conditions of pure pressure, and impossible to develop
pure shear [3]. For example, the application of pressure by means of a piston leads to a
shear stress near the piston edge [4], and the absence of pressure during the application
of shear will promote slip [3].
Not all kinds of mechanical load are equally damaging for biological tissues. Hydrostatic pressure does not have a large influence on the development of pressure ulcers,
since divers can work at large depths without developing pressure ulcers [8, 53, 81].
Localized pressure on the other hand, causes deformation of the tissues and blockage of
blood vessels, and is therefore far more damaging [20]. Furthermore, Nola and Vistnes
found that, by applying pressure on skin and muscle tissue over bone in rats, that more
ulceration appeared in the muscle layer than in the skin [54]. They therefore concluded
that muscle was more sensitive to pressure than skin and subcutaneous tissue. Salcido
et al. also observed that lesions occurred first in the muscle rather than in the skin when
applying pressure to the trochanteric region of rats [74]. However, instead of being more
sensitive to mechanical loading than skin, the muscle tissue in these studies could also
be subjected to higher loadings than the superficial layers, see also section 2.2. This
would also explain the earlier occurrence of ulceration in muscle tissue.
An applied shearing load does not lead to large tissue destruction, e.g. Bennett and
Lee found that externally applied pressure was approximately twice as effective as applied shear in reducing pulsatile blood flow [3]. However, the combination of pressure and
shear is very damaging, e.g. at a sufficiently high level of shear, the pressure necessary
to produce occlusion was only half that when little shear was present [3]. Furthermore,
Dinsdale found that friction also increases the susceptibility to skin ulceration, since
the presence of friction decreased the amount of pressure necessary to produce ulcers in
6
Chapter 2. Mechanical loading
2.2. Internal stress state
paraplegic swine [24].
The amount and distribution of external pressure, shear and friction during sitting or
lying is influenced by several factors. Firstly, the body configuration has a large influence
on the applied mechanical loading [35]. In addition, the properties of the cushion or
mattress material play an important role. Finally, the individual characteristics also
affect the kind and distribution of mechanical loading. For example, in sitting on a hard,
slick seat, paraplegic, geriatric, and ill subjects develop roughly three times the median
shear load experienced by normal subjects in skin lateral to the ischial tuberosities [3].
Furthermore, by investigating the effects of seated posture and body orientation on the
pressure distribution and shear forces acting at the body-seat interface, Hobson found
that individuals with SCI have significantly higher maximum pressures than nondisabled
subjects in all postures that were studied [35].
2.2
Internal stress state
In clinical practice, the interface pressures between the body and the supporting surface
are measured to assess the mechanical load that is applied to the body and thereby the
risk of developing pressure ulcers. Interface pressures are however not a good measure to
estimate the risk for deep pressure ulcers, since they do not provide information about
the stress state in deeper tissue layers. For example, it was shown by numerical models
[20, 31, 45, 46, 57, 80, 82, 86] and physical models [17, 67] that stresses and strains are
not uniform within the tissues. Moreover, the nature of the external loading does not
result in the same kind of loading within the tissues, which is illustrated in figure 2.1.
Figure 2.1: Schematic drawing of a uniaxial compression test. Solid and dotted lines show the undeformed and deformed configurations, respectively [56].
In this figure, a uniform axial compression is applied to an object. When small
rectangular part the object is observed as in situation a, then the deformation of the
small part is similar to the macroscopic deformation, and the object only experiences
compression. However, if the small part is rotated as in situation b, then it experiences
compression as well as shear. In fact, for each material point a configuration can be
7
Chapter 2. Mechanical loading
2.2. Internal stress state
found in which only compressive or tensile stresses and strains are present, as well as
a configuration in which the maximum shear strain is reached. Thus, although the
macroscopic deformation was compressive, it results in pressure and shear in the tissue
[56]. Furthermore, since hydrostatic pressure is relatively harmless to biological tissues,
the harmfull stress is presumably a form of shear [20].
Several numerical studies in which soft tissues are compressed, showed that stresses
and strains in the muscle layer adjacent to bony prominences are much higher than
those near the surface [31, 45, 46, 57], see also figure 2.2. In addition, the mechanical
state of the tissue can change over time [48]. Moreover, Linder-Ganz et al. showed that
stresses and strains in muscle are less homogeneous than in fat, and that muscle tissue
was also subjected to tensile stress where fat was not [46]. Furthermore, the study of
Oomens et al. showed that the highest shear strains occurred in fat [57]. However, Sun
et al. reported that the maximum shear stresses occurred in muscle tissue and within
skin, and that they were significantly higher than in fat [80].
(a)
(b)
Figure 2.2: Two examples of finite element models that show that stresses and strains are higher near
bony prominences than near the surface. a) Deformed mesh of buttock model of Oomens et al. with
von Mises stress [57]. b) Principle compressive strains in deep tissues under the ischial tuberosities of a
healthy subject, modeled by Linder-Ganz et al. [46].
The internal stress state in the tissues depends on several factors. Firstly, the cushion
properties have an influence on the stresses and strains within the tissues [57, 67]. For
example, Oomens et al. mentioned that a change in cushion properties mainly influences
the shear strains in the fat layer [57]. Furthermore, Linder-Ganz and Gefen showed that
a change in mattress stiffness led to larger changes in contact pressure and shear than
in peak internal stresses [45]. Secondly, the mechanical properties of the tissues also
affect the stress and strain distribution. For example, a higher Young’s modulus in
the model of Chow and Odell resulted in smaller deformations and a more uniform
stress distribution [20]. Mechanical properties of tissues can change when cell becomes
damaged. It was found by Gefen et al. and Linder-Ganz and Gefen that damaged
8
Chapter 2. Mechanical loading
2.3. Magnitude and duration of loading
muscle tissue becomes stiffer [31, 45]. This increase in muscle stiffness leads to higher
stresses in the injured muscle parts in the numerical model of Gefen et al., and these
stresses were then transferred to adjacent tissue that was not yet injured [31]. Finally,
the shape of a bony prominence also influences the internal stress state. This was shown
by the physical buttock model of Candadai and Reddy, which consists of a PVC gel (soft
tissue) molded around a wooden core (bone), in which two shapes of bone were tested
[17]. Furthermore, a theoretical analysis of Gefen showed that the size of the injured
muscle area and the time for injury onset depended on the radius of curvature of the
bony prominence [30].
It is clear that the internal stress state is nonuniform in the tissues that are subjected
to a mechanical load. However, the internal distribution of stresses and strains does not
directly determine whether or not a pressure ulcer will develop at certain locations. This
also depends upon the load threshold of the individual tissues.
2.3
Magnitude and duration of loading
Besides the mechanical loading of tissues, the time of exposure also plays an important
role in the development of pressure ulcers. The influence of both factors was studied in
animal models. In 1942, Groth applied pressure to the posterior ischii of rabbits, and
found that an inverse relationship existed between the minimum pressure and minimum
duration required to produce a pressure ulcer [33]. Husain confirmed the shape of this
relationship by applying pressures of 100 to 600 mmHg to the legs of normal rats for
1 to 6 hours [37]. In 1959, Kosiak applied pressures ranging from 100 to 550 mmHg
for periods of 1 to 12 hours to the femoral trochanter and ischial tuberosity of dogs.
This also revealed an inverse relationship between the minimum pressure and time that
lead to ulceration of tissue [39]. In 1981, Daniel et al. subjected the greater femoral
trochanter of pigs to pressures of 30 to 1000 mmHg for periods of 2 to 18 hours, which
also resulted in a hyperbolic pressure-time curve [21]. In 1976, a similar hyperbolic curve
was produced for humans by Reswick and Rogers, who used comments of physicians,
nurses and therapists, pressure measurements, and controlled tests on volunteers [70].
A large variation however exists between the threshold values found in different studies,
see figure 2.3(a). This is due to diversity in experimental conditions, animal models,
loading methods and locations of load application [77].
The shape of the curve was also determined by Sacks, who used dimensional analysis
to determine a relationship between the required pressure to produce an ulcer, and the
physical properties of the tissue, the blood flow through it, and the time of exposure [73].
This analysis showed that the pressure was a function of t−4/3 . If a linear relation was
assumed between the pressure and t−4/3 , a fit of the equation to the data of Kosiak [39]
and Reswick and Rogers [70] resulted in a good agreement for both experiments [73].
9
Chapter 2. Mechanical loading
2.3. Magnitude and duration of loading
(a)
(b)
Figure 2.3: a) Pressure versus time curves determined by different studies. Time/pressure combinations
above the curves result in tissue breakdown [77]. b) Adapted pressure versus time curve determined by
Linder-Ganz et al. [44].
The hyperbolic pressure-time curve implies that loads that are applied for very short
times would not lead to tissue damage. To investigate if this was true, Linder-Ganz et
al. also applied varying loads for short durations and showed that high loads could lead
to damage instantly [44]. The pressure-time curve as proposed previously is therefore
probably not complete, and shows a more sigmoidal shape when short duration data
are also included, see figure 2.3(b). This means that for short exposures (less than 1
hour) and also for long exposures (over 2 hours) the magnitude of the pressure is the
most important factor for causing cell death; the exposure time has little or no effect.
However, for the intermediate exposures (between 1 and 2 hours) pressure and time
both are important factors [44].
The pressure-time relationship was also investigated for paraplegic animals. Groth
[33] and Kosiak [40] studied the response of paraplegic animals when compared to normals. Both found no significant differences in susceptibility. Daniel et al. however
noted that the animal model of Groth was probably experimented too soon following
transection of the spinal cord, thereby precluding the tissue atrophy characteristic of the
clinical condition [22]. Probably this also holds for the animal model of Kosiak. Daniel
et al. therefore waited six weeks after transection of the spinal cords before using his
paraplegic pigs. They found that the pressure-time curve for paraplegic pigs was also
hyperbolic, but the magnitude of the variables was greatly reduced. Spinal-transected
animals would therefore develop pressure sores at lower magnitudes of pressure and after
a shorter time than normal animals. The difference between the results was attributed
to tissue atrophy, which would lead to increased interface pressures between the support
surface and the soft tissues overlying bony prominences [22].
10
Chapter 3
Damage pathways
Although it is known that sustained mechanical loading is the primary cause of pressure
ulcers, the underlying pathways whereby mechanical loading leads to tissue breakdown
are hardly understood. At the moment theories involve:
• Localized ischemia;
• Ischemia/reperfusion injury;
• Impaired lymphatic drainage;
• Sustained deformation of cells.
These four theories will be described in the following sections.
3.1
Localized ischemia
Ischemia is often considered to be the most important factor in the development of
pressure ulcers [21, 39, 40]. When a mechanical load is applied to the body, blood
vessels in the loaded tissue can collapse, thereby stopping blood flow and depriving the
tissue of its oxygen and nutrients supply. In 1930, Landis studied the blood pressure
within a capillary loop in healthy human fingernail beds using a microinjection technique,
and found that an average pressure of 32 mmHg was sufficient to close the capillaries
[43]. The validity of this value should however be questioned, since the capillaries were
cannulated , which could have resulted in lower pressure readings as the bleeding vessels
were not full or enclosed. Furthermore, capillary pressures can rise during mechanical
loading due to autoregulation, in which case higher external pressures are needed to close
the blood vessels [3, 81]. Finally, capillary closure depends on local pressure gradients
across the vessel wall and not just on interface pressures [13]. Still, the capillary closing
pressure found in Landis’ study is frequently used in clinical practice as a threshold for
tissue damage, where care is taken to avoid interface pressures higher than 32 mmHg.
External pressures that are high enough to close blood vessels will lead to ischemia,
which initiates a series of chemical and pH imbalances, accompanied by enhanced generation of injurious free radical species. The damage produced by short periods of ischemia
11
Chapter 3. Damage pathways
3.1. Localized ischemia
tends to be reversible if the circulation is restored, but cells subjected to long episodes
of ischemia become irreversibly damaged and die [71]. In general, muscle appears to be
tolerant of ischemia for up to 4 hours, fat up to 13 hours, and skin up to 24 hours at
normothermia [7]. Ceelen et al. developed a finite element model that describes deformation, diffusion of oxygen and damage in a cross-section of skeletal muscle tissue [18].
They investigated whether the cessation of oxygen consumption in dead cells could be
beneficial for the remaining cells in the tissue, and if a change in mechanical properties
upon cell death had an influence on damage development in other cells. The results
showed that when cells stopped consuming oxygen after cell death, further cell death is
delayed or even prevented. This effect is larger after more cells have died, because the
amount of extra oxygen available for the other cells increases, and is more pronounced
at lower compression levels, since at high compression levels there is already hardly any
oxygen available, and therefore the little amount of extra oxygen hardly has any effect.
A change in mechanical properties of cells upon cell death, in this study it was assumed
that dead cells were less stiff, eventually led to delayed cell death at high compression
levels. At low compression levels or when only a few cells had already died, no change
of mechanical properties of dead cells resulted in slower cell death.
During ischemia, cells have to switch from aerobic to anaerobic metabolism due to
the lack of oxygen. Anaerobic metabolism results in the generation of lactic acid which
leads to a decrease in intracellular pH. The depletion of glucose and accumulation of
lactic acid which decreases the intracellular pH both lead to cell death. For example,
Gawlitta et al. showed that glucose deprivation and acidification in C2C12 murine
myoblasts resulted in increased cell death [29].
Figure 3.1: Schematic overview of the changes that occur during ischemia [71].
12
Chapter 3. Damage pathways
3.2. Ischemia/reperfusion injury
Intracellular ion concentrations also change during ischemia. Due to the lack of ATP,
the Na+ /K+ ion exchanges becomes inactive, which subsequently leads to the activation
of the Na+ /H+ ion exchanger. When intracellular acidosis threatens, it pumps H+ out
of the cell in exchange for Na+ to maintain proper intracellular pH. The increase in
intracellular Na+ then leads to activation of the Na+ /Ca2+ ion exchanger, enhancing
calcium entry. Since calcium pumps are ATP dependent and cannot pump the excess
Ca2+ out of the cell anymore, calcium accumulates in the cells. High calcium concentrations in ischemic cells activate phospholipase A2 , leading to degradation of membrane
phospholipids and the consequent release of free fatty acids and lysophospholipids. These
are both potent mediators of inflammation and lysophospholipids also act as detergents
that solubilize cell membranes. The combination of electrolyte imbalance and increased
permeability of the cell membrane causes cell swelling [71]. Figure 3.1 gives a schematic
overview of the changes that occur during ischemia.
The rise in intracellular calcium concentration during ischemia was confirmed by
Boffi et al. who examined intracellular calcium levels in mouse-derived C2C12 myotubes
with inhibition of glycolytic and oxidative metabolism as ischemic condition [9]. On the
other hand, Smith et al. found that the total tissue calcium contents of preischemic
and end ischemic canine gracilis muscle were similar and started to increase after the
ischemic period during reperfusion. They therefore concluded that calcium influx is a
feature of reperfusion rather than the ischemic interval [76]. Furthermore, when the cell
membrane ionic pumps become depressed, more ions enter the cells than leave them.
This leads to osmosis of water into the cells and thus causes intracellular edema [34, 51].
Although ischemia will eventually lead to tissue death, it is probably not the only
cause of pressure ulcers. One reason for this is that pressure ulcers can develop within
two hours, whereas tissues can withstand ischemia for longer times. Furthermore, ischemia alone fails to explain why higher tissue pressures can create ulcers after a short
period of ischemia, whereas lower pressures, which still create an ischemic state, need
longer periods to cause the identical lesion [60].
3.2
Ischemia/reperfusion injury
Tissue can also become damaged when the blood flow in the tissue is restored after
an ischemic period. Ischemia and reperfusion of skeletal muscle can trigger a series
of deleterious phenomena in tissue, such as cell edema, increased permeability in the
microcirculation, induction of the no-reflow phenomenon, free oxygen radical production,
electrolytic changes in mitochondria, cytosolic calcium overload, and degradation of
membrane phospholipids [32].
After a relatively short ischemic period, the blood flow is temporarily higher than
under normal circumstances. This increased blood flow after occlusion is called reactive
hyperemia. It is a consequence of a local regulatory mechanism whereby the arterioles
are dilated and the resistance to blood flow is reduced [51]. Ikebe et al. investigated
the relationship between the duration of ischemia and the subsequent reperfusion blood
flow in rats [38]. They found increased reperfusion blood flow after 90 minutes and
13
Chapter 3. Damage pathways
3.2. Ischemia/reperfusion injury
3 hours of ischemia, but after 6 hours of ischemia there was no significant increase in
postischemic blood flow. This is called the “no-reflow phenomenon” and is probably
caused by cellular swelling, thrombosis, and white cell plugging in capillaries, which
increases the resistance in the microcirculation [85]. The incidence of no flow depends
on the severity of both the ischemic insult and the subsequent reperfusion injury [38].
During reperfusion oxygen is provided to the tissues, which combines with the free
radical species generated during ischemia to form reactive oxygen species (ROS) [71].
When present in excess they damage the endothelium, attracting platelets and granulocytes, stimulating stasis of blood flow and thrombosis, further decreasing blood flow and
thereby stimulating the development of tissue necrosis [36]. The superoxide anion (O−
2)
is produced principally by leaks in mitochondrial electron transport or as part of the
inflammatory response, see figure 3.2. In the case of phagocytic inflammatory cells, activation of a plasma membrane oxidase produces O−
2 , which is then converted to hydrogen
peroxide H2 O2 and eventually to other ROS. H2 O2 is also produced directly by a number of oxidases in cytoplasmic peroxisomes. By itself, H2 O2 is not particularly injurious,
but when produced in excess, it is converted to hydroxyl radicals (• OH). In neutrophils,
myeloperoxidase transforms H2 O2 to the potent radical hypochlorite (OCl− ), which is
lethal for microorganisms and cells.
Figure 3.2: Mechanisms by which reactive oxygen species are generated from molecular oxygen and
then detoxified by cellular enzymes. CoQ = coenzyme Q; GPX = glutathione peroxidase; SOD =
superoxide dismutase. [71].
Hydroxyl radicals are formed by (1) the radiolysis of water, (2) the reaction of H2 O2
with ferrous iron (Fenton reaction), and (3) the reaction of O−
2 with H2 O2 (Haber-Weiss
reaction). The hydroxyl radical is the most reactive molecule, and there are several
mechanisms by which it can damage macromolecules [71]:
• Lipid peroxidation: The hydroxyl radical removes a hydrogen atom from the
unsaturated fatty acids of membrane phospholipids, a process that forms a free
14
Chapter 3. Damage pathways
3.2. Ischemia/reperfusion injury
lipid radical, which subsequently initiates a chain reaction. The destruction of the
unsaturated fatty acids of phospholipids results in a loss of membrane integrity.
• Protein interactions: Hydroxyl radicals may also attack proteins. As a result
of oxidative damage, proteins eventually undergo degradation.
• DNA damage: DNA is an important target of hydroxyl radicals. If the oxidative
damage is sufficiently extensive, the cell dies.
The major enzymes that convert ROS to less reactive molecules are superoxide dismutase (SOD), catalase and glutathione peroxidase. SOD converts O−
2 to H2 O2 and O2 .
Catalase in one of the two enzymes that complete the dissolution of O2 by eliminating
H2 O2 and therefore its potential conversion to • OH. Glutathione peroxidase (GPX) catalyzes the reduction of H2 O2 and lipid peroxides in mitochondria and the cytosol, see
figure 3.2. GPX uses reduced glutathione (GSH) as a cofactor, producing two molecules
of oxidized glutathione (GSSG) for every molecule of H2 O2 reduced to water. GSSG
is reduced to GSH by glutathione reductase [71]. In tissues undergoing oxidative stress
the amounts of these enzymes decrease, so during reperfusion the oxygen free radicals
are not buffered, or are buffered to a lesser degree [36]. Furthermore, retinoids, the
precursors of vitamin A, are lipid soluble and function as chain-breaking antioxidants.
Vitamin C is water soluble and reacts directly with O2 , • OH, and some products of lipid
peroxidation. Vitamin E blocks free-radical chain reactions. Since it is fat soluble, it
exerts its activity in lipid membranes, protecting them against lipid peroxidation [71].
Houwing et al. showed that pretreatment with vitamin E prevents damage caused by
pressure applied to the femoral trochanters of pigs to a large extent. Vitamin E did
not prevent oxidative stress during pressure application, but it did prevent the excess
production of oxygen free radicals and hydrogen peroxide during reperfusion [36].
It is hypothesized that the reperfusion phase after an ischemic period is more damaging to tissues than ischemia itself. Peirce et al. subjected rats to different numbers
of ischemia/reperfusion (I/R) cycles (2 hours of ischemia and 0.5 hour of reperfusion),
varied the duration of the ischemic insult, and compared ischemia-induced injury with
I/R-injury [65]. They found that tissue injury increased with an increasing number of
I/R cycles and duration of ischemia, and moreover that when the total extent of ischemia was constant, a greater number of reperfusion events during that period resulted
in increased tissue damage. It was therefore concluded that the reperfusion phase of
the I/R cycle is an important component of the total injury produced. Tsuji et al. subjected mice to two different loading protocols and used the functional capillary density
as a measure for tissue damage [83]. The total duration of compression was equal for
both groups, but the first group received four cycles of 2 hours compression and 1 hour
release, while the second group was exposed to a continuous compression of 8 hours.
The results showed that the cyclic compression-release procedure significantly decreased
functional capillary density as compared to continuous compression, from which they
concluded that repetition of the ischemia-reperfusion cycle was more damaging than a
single prolonged ischemic insult, see figure 3.3(a). Furthermore, when applying pressure
to the skin immediately above the greater femoral trochanters of pigs, Houwing et al.
15
Chapter 3. Damage pathways
3.3. Impaired lymphatic drainage
found that early signs of damage in the muscles and subcutaneous tissue appeared only
after a reperfusion time of one to two hours and not during the ischemic period [36].
Since I/R injury is more damaging than ischemia alone, it was investigated if gradual reperfusion was better than complete reperfusion at once. Durrani et al. isolated
the left renal artery and vein of rats [26]. Microclamps were applied for 45 minutes
and released at once in one groups and gradually in another group. Although there
were no significant differences between both groups in the malondialdehyde (MDA) and
myeloperoxidase (MPA) levels, which are indicators of lipid peroxidation and polymorphonuclear infiltration, respectively, histopathologic scoring showed less tissue damage
in the gradual reperfusion group when compared to the conventional reperfusion group.
Ikebe et al. regulated the postischemic blood flow in rats by the administration of LNMMA (nitric oxide synthase inhibitor) to investigate alterations in the viability and
contractile function of the skeletal muscle [38]. They found that muscle viability of the
L-NMMA-treated group was significantly better, which suggests that excessive blood
flow during reperfusion deteriorates skeletal muscle contractile function. Ünal et al. investigated the gradual reperfusion in a rat hind limb model and tried to elucidate its
potential beneficial effect [84]. Their results showed that the MDA and MPO levels were
significantly larger in the conventional reperfusion group than in the control and gradual
reperfusion groups. There was no significant difference between the levels in the control
and gradual reperfusion groups. Inflammatory cell infiltration and loss of striation of
the muscle were also noticeably less in the gradual reperfusion group than those of the
conventional reperfusion group.
(a)
(b)
Figure 3.3: Effects of reperfusion. a) Percentage of microcirculatory injury is higher after four ischemiareperfusion cycles than after continuous compression with the same duration of ischemia [83]. b) The
tissue damage of group II rats (conventional reperfusion) is significantly higher than the damage in
group III rats (gradual reperfusion). Group I was a control group (without ischemia) [84].
3.3
Impaired lymphatic drainage
Ischemia and I/R injury cannot be the only factors contributing to the development
of pressure ulcers. If oxygen would be the only factor, then all pressure intensities
that cause capillary closure should produce ulceration in the same duration, which is
16
Chapter 3. Damage pathways
3.3. Impaired lymphatic drainage
in contrast to the measured inverse relation between pressure and duration required to
produce ulcers [66]. It is believed that the lymphatic system can also play an important
role [42, 41, 52, 66]. The lymphatic system functions as an “overflow mechanism” to
return excess proteins and excess fluid volume from the tissue spaces to the circulation.
Therefore, it plays a central role in controlling: (1) the concentration of proteins in
the interstitial fluids, (2) the volume of interstitial fluid, and (3) the interstitial fluid
pressure [34].
During mechanical loading, the lymphatics can collapse, thereby obstructing lymph
flow. This leads to an accumulation of waste products. Miller and Seale investigated the
relation between the external pressure and lymph clearance in dogs [52]. They found a
nonlinear rise in lymph flow with increasing pressure until a critical closing pressure was
reached. At this point, the flow ceased. The increase in flow with increasing external
pressure was believed to be caused by the increased translymphatic pressure drop at
larger external pressures, which promotes increasing flow into the lymphatics. Therefore,
as pressure increases, so does flow, until the external pressure collapses the vessel. At
an applied pressure of 60 mmHg, some animals showed relatively large clearance levels
indicating enhanced lymph flow. Others showed reduced lymph flow indicating the onset
of vessel closure, which implied that the critical closing pressure might be at or near 60
mmHg, see figure 3.4.
Figure 3.4: Lymph flow per unit tissue volume as a function of applied pressure. Lymph flow increases
with pressure until a critical closing pressure is reached. Some data at 60 mmHg show vessel closure and
some show enhanced flow, indicating that the critical closing pressure may be at or near 60 mmHg [52].
It is also hypothesized that the application of mechanical loads impairs the contractility of the lymphatic vessels. Krouskop et al. postulated that hypoxia caused by
external loading leads to damage of lymphatic smooth muscle which in turn results in
the loss of lymph motility and impaired lymph flow [42, 41].
Another hypothesis implies that when interstitial fluid is squeezed out of a region,
direct contact of cells (fibroblasts) may induce contact stresses. These may in turn cause
contact inhibition or even rupture and interrupt collagen synthesis. Furthermore, if the
external pressure is removed, the interstitial fluid pressure might become small enough
17
Chapter 3. Damage pathways
3.4. Sustained deformation of cells
to cause capillary bursting, edema and lymphatic damage [66].
The lymphatic flow was also studied by means of mathematical models. For example,
Reddy et al. offered a phenomenological theory to explain the formation of pressure
ulcers [66]. They considered a cylinder of tissue and assumed that the flow in connective
tissue can be described with Darcy’s law. They found that the product of the interstitial
fluid pressure and time was constant for a reduction in interstitial fluid volume, which
might lead to tissue damage. Since this inverse relationship is in correspondence with
other studies in which the relationship between pressure intensity and load duration
required to create ulcers was investigated, it was concluded that interstitial fluid flow
could play a significant role in the mechanisms responsible for this inverse relationship,
and therefore also in tissue breakdown.
In a later study, Reddy and Patel developed a mathematical model to simulate
lymph flow through the terminal lymphatics under different physiological conditions
[68]. Blood pressure and protein concentration in the capillary formed the upstream
boundary conditions and the pressure in the adjacent contractile lymphatic was taken
as the downstream boundary condition. Results showed that the flow increased with
increasing stiffness of the terminal lymphatic vessel wall, increasing stiffness of the anchoring filaments, and increasing hydraulic conductivity of the terminal lymphatic vessel
wall and blood capillary wall. Also, the flow through the terminal lymphatics increased
during edema, which was simulated by increasing the capillary pressure. Furthermore,
the results showed that the flow through the terminal lymphatics is due to periodic fluctuations in interstitial fluid pressure and due to the suction mechanisms of the adjacent
contractile lymphatics.
3.4
Sustained deformation of cells
Recently, it was hypothesized that sustained deformation of cells could also be a cause
of pressure ulcers [12, 13, 11, 72]. Cell deformation influences local membrane stresses,
volume changes, and the cytoskeleton organization, which may be involved in early cell
damage [12, 11].
The role of deformation in the development of tissue damage was investigated by
several researchers. Peeters et al. developed a single cell loading device to monitor the
biomechanical response of skeletal muscle cells under sustained compression [61]. During
compression the volume of the cell remained constant, but the surface area of the cell
increased, which was probably caused by stretching of the cell membrane. In a later
study, Peeters et al. also found that the deformation of the cells was anisotropic, since
the cells deformed from an elliptical to a more circular shape [62]. It was suggested that
this anisotropic deformation was due to the preferred orientation of actin filaments. With
this loading device, the mechanical and failure properties of attached muscle cells were
also determined [63], as well as the viscoelastic properties of the cells [64]. Bouten et al.
developed a three-dimensional in vitro model system, consisting of muscle cells seeded
and cultured in agarose [12]. Cylindrical constructs cultured up to day 12 were subjected
to 20% gross strain for periods of 1, 2, 4, 12, and 24 h. For all straining periods the
18
Chapter 3. Damage pathways
3.4. Sustained deformation of cells
total percentage of cell damage appeared to be significantly higher in strained constructs
than in unstrained controls. In addition, Breuls et al. developed a compression device to
simultaneously compress tissue engineered muscle constructs with circular, impermeable
glass indenters [14]. Results showed that dead cells were highly localized below the
indenter and that higher strains led to earlier damage initiation. Furthermore, Gawlitta
et al. exposed tissue engineered muscle constructs to different combinations of hypoxia
and deformation, and found that deformation had decremental effects on tissue viability,
but that hypoxia had no additional effect within 22 hours [28].
The effect of deformation on tissue damage was also studied in animal models. Bosboom et al. investigated the location of damage development by applying compressive
loading to the tibialis anterior muscle of rats [10]. They reported that besides histology,
also MRI can be used to find locations of damage, since increased signal intensities in
T2-weighted MR images correlated with damage determined by histological examination. Stekelenburg et al. also examined muscle damage after compressive loading of rat
tibialis anterior muscle with T2-weighted MRI in combination with histological examination [78]. In contrast to the study of Bosboom et al. [10], the loading procedure in
this study also took place in the MR scanner, so the exact indentation of the muscle
could be observed, see figure 3.5.
Figure 3.5: Transversal T2-weighted-sum images taken before loading (A), during loading (B), and
immediately after unloading (C). The TA muscle is indicated by the white line in A [78].
In the muscle underneath the indenter a necrotic region was observed, which was
assumed to be caused by the large deformation that pulled the muscle fibers apart.
It was also noted that T2 values in slices distal to the indenter were higher than in
slices proximal to the indenter. This was probably due to a different perfusion status of
the tissue, since the large indentation presumably led to the collapse of blood vessels,
whereas in the tissue proximal to the indentor the perfusion was hardly affected during
loading. The difference in amount of affected volume largely disappeared during the
first hour after unloading, which indicates that the effect of ischemia was reversible
within the muscle tissue. However, it was also noted that ischemia might accelerate or
increase tissue damage. In a later study, Stekelenburg et al. studied muscle damage in
rat tibialis anterior muscle during ischemia by applying a cuff around the thigh, and
during ischemia and deformation using an indentor applied to the muscle. This revealed
that ischemia alone only led to reversible damage, whereas the combination of ischemia
19
Chapter 3. Damage pathways
3.4. Sustained deformation of cells
and deformation was far more damaging [79].
Breuls et al. developed a multilevel finite element model to investigate local cell
deformations in engineered tissue constructs, subjected to macroscopic loads [16]. The
results showed that there were large differences in strain energy density within the microstructure at one macroscopic point, indicating that individual cells can experience
deformations which highly exceed the macroscopic deformation. Therefore, it should be
questioned whether cell damage due to deformation can be evaluated based on macroscopic deformations. Breuls et al. also used this multilevel finite element approach
to model the development of tissue damage in muscle tissue which is compressed over
a bony prominence [15]. In this study, a damage law was derived from in vitro experiments with tissue engineered skeletal muscle constructs to evaluate tissue damage
[14]. It was reported that muscle damage started at locations deep within the muscle
tissue layer, where shear strains were largest. A parameter study also showed that a
lower cell stiffness resulted in an increased area of tissue damage and a faster damage
growth. Furthermore, related to the animal experiments of Stekelenburg et al., Ceelen
et al. developed dedicated two-dimensional finite element models of the hind limbs of
rats used in the experiments to investigate the strain state of the muscle. The results of
these models show a correlation between the location of damage and local strain [19],
see figure 3.6.
Figure 3.6: Left and middle: maximum shear strains in finite element models of Ceelen et al. based
on two experiments of Stekelenburg et al.. Locations of damage (x) in MR images are superimposed on
the image. Right: number of damaged and undamaged pixels against maximum shear strain. [19]
20
Chapter 4
Discussion
4.1
Summary
Pressure ulcers are caused by sustained mechanical loading; without a mechanical loading no pressure ulcer will develop. External loading of the tissues leads to a nonuniform
internal stress and strain state. This internal mechanical state depends on the magnitude of the applied loading, type of external loading (pressure, shear, friction), and the
mechanical and geometrical properties of the tissues. In addition, the time of exposure
to mechanical loading also plays an important role in the development of tissue damage.
On the other hand, the ability of the tissue to withstand mechanical loading determines
whether a certain loading will lead to the development of an ulcer or not.
Both the mechanical loading and patient susceptibility are influenced by intrinsic and
extrinsic factors. Intrinsic factors are related to the individual, e.g. with age, mobility,
weight, posture, incontinence and nutritional state. Extrinsic factors are related to the
environment, e.g. with nursing, the contact surface, nutrition, and the temperature and
humidity of the environment. In clinical practice, these risk factors are used in risk
assessment scales to identify patients at risk of developing pressure ulcers. However, the
value of these scales remains questionable. Moreover, SCI patients are always identified
as high risk patients, while they may stay free of ulcers for a long time, and suddenly
develop an ulcer in a very short period. Risk assessment scales can therefore not be
used in this group of patients.
The underlying pathways whereby mechanical loading leads to tissue breakdown are
hardly understood. At the moment theories involve:
• Localized ischemia
Mechanical loading can lead to the collapse of blood vessels, thereby stopping blood
flow and depriving the tissue of its oxygen and nutrients supply. Furthermore,
ischemia initiates a series of chemical and pH imbalances. In general, muscle
tissue appears to be tolerant of ischemia for 4 hours, fat up to 13 hours, and skin
up to 24 hours [7].
21
Chapter 4. Discussion
4.2. Focus questions for our research
• Ischemia/reperfusion injury
When the blood flow to the tissues is restored after ischemia, oxygen combines
with free radical species generated during ischemia to form reactive oxygen species,
that also cause cell damage. It is hypothesized that the reperfusion phase is more
damaging than ischemia alone. For example, when the total extent of ischemia
is constant, a larger number of reperfusion events during that period results in
increased tissue damage [65, 83]. Furthermore, gradual reperfusion leads to less
tissue damage when compared to conventional reperfusion [26, 84].
• Impaired lymphatic drainage
During mechanical loading, the lymphatics can also collapse, which leads to an
accumulation of waste products. The exact contribution of this effect to the onset
of tissue damage is however unclear.
• Sustained deformation of cells
Cell deformation influences local membrane stresses, volume changes, and the
cytoskeletal organization, which may be involved in cell damage [12, 11]. In fact,
it was shown in an animal model that ischemia in combination with deformation
of cells was more damaging than ischemia alone [79]. In addition, a computer
model also shows that there is a correlation between local tissue deformation and
damage in the animal model [19].
4.2
Focus questions for our research
At this moment, by combining the results of the animal model of Stekelenburg et al.
[78, 79] with dedicated finite element models [19], it is already studied whether there
is a correlation between local tissue deformation and damage. Since the local tissue
deformation is important for the development of tissue damage, it would also be interesting to investigate how the internal mechanical state of tissues depends on variations
in mechanical and/or geometrical properties of tissues among individuals. Furthermore,
it will be studied how the internal mechanical state is influenced by changes in material
and geometrical properties as a result of disease.
It is also known that a certain mechanical loading will not lead to the same amount
of damage in each individual, i.e. some individuals are more to susceptible to develop
pressure ulcers than others. Therefore, if a certain relation between local tissue deformation and damage can be derived from the animal experiments, it is important to
investigate whether such a relation is the same for each animal or not. If it is similar,
then the local tissue deformation probably is the main trigger for the development of
tissue damage, and thus the susceptibility of an individual to develop a pressure ulcer is
mainly a mechanical issue. Otherwise, also other factors play a role in this process, e.g.
lack of tissue repair, bad tissue perfusion, and altered metabolism. It would therefore be
interesting to compare the relations between tissue deformation and damage of subjects
with a similar (patho)physiological state, and also to compare these results with a group
of subjects with a different (patho)physiological state.
22
Chapter 4. Discussion
4.2. Focus questions for our research
D
The overall goal of this project is to develop a biosensor system on the basis of
biochemical markers to detect deep tissue injury at an early stage. To achieve this
goal, it is important to know at which moment it is necessary to adopt preventive
measures to prevent deep tissue injury, and at which moment it is too late. This is
illustrated in figure 4.1. In situation a, the amount of tissue damage D increases until
the load is removed at time ta . At this moment, there is no significant tissue damage
yet (D < Dmin ) and the tissue will return to its original status. In situation b, there is
much more damage (Dmin < D < Dmax ) and preventive measures are needed to enable
the damaged tissue to heal again. In situation c, the amount or degree of damage has
passed a critical value (D > Dmax ), after which it is expected that tissue damage will
continue to increase even if the load is removed. Probably, it is not easy to detect tissue
damage by visual inspection before it has reached damage criterion Dmax . A biosensor
system should therefore be able to detect tissue damage in the range Dmin < D < Dmax .
An important question for our research is therefore: what are the amounts or kinds of
skeletal muscle damage corresponding with Dmin and Dmax ?
Furthermore, biochemical markers have to be chosen that are released upon skeletal
muscle damage. With respect to these markers, it should be investigated how specific
they are for skeletal muscle damage and also how large the minimal amount of damage
is that can be detected with these markers. A theoretical model may also be developed
to gain more insight into the kinetics of these biomarkers in injured skeletal muscle.
c
too late
Dmax
b
take preventive
measures
Dmin
a
ta
too early
tb
tc
t
Figure 4.1: Illustration of how tissue damage is expected to change in time due to mechanical loading.
Below a certain damage criterion Dmin , the damage is not considered to be significant. Above damage
criterion Dmax tissue damage is expected to increase even if the load is removed. Between these two
criteria, preventive measures can probably lead to healing of the tissue.
23
Bibliography
[1] http://webpages.charter.net/nursing project/images/progression-of-a-decubitisulcer.jpg.
[2] M. A. Ankrom, R. G. Bennett, S. Sprigle, D. Langemo, J. M. Black, D. R. Berlowitz,
and C. H. Lyder. Pressure-related deep tissue injury under intact skin and the
current pressure ulcer staging systems. Adv. Skin Wound. Care, 18(1):35–42, 2005.
[3] L. Bennett and B. Y. Lee. Pressure versus shear in pressure sore causation. In
B. L. Lee, editor, Chronic ulcers of the skin., pages 39–56. McGraw-Hill, 1985.
[4] L. Bennett and B. Y. Lee. Vertical shear existence in animal pressure threshold
experiments. Decubitus., 1(1):18–24, 1988.
[5] N. Bergstrom. Patients at risk for pressure ulcers and evidence-based care for
pressure ulcer prevention. In D. L. Bader, C. V. C. Bouten, D. Colin, and C. W. J.
Oomens, editors, Pressure ulcer research; current and future perspectives., pages
35–50. Springer-Verlag, 2005.
[6] J. Black, M. Baharestani, J. Cuddigan, B. Dorner, L. Edsberg, D. Langemo, M. E.
Posthauer, C. Ratliff, and G. Taler. National pressure ulcer advisory panel’s updated pressure ulcer staging system. Urol. Nurs., 27(2):144–50, 156, 2007.
[7] F. W. Blaisdell. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc. Surg., 10(6):620–630, 2002.
[8] M. R. Bliss. Aetiology of pressure sores. Rev. Clin. Gerontol., 3:379–397, 1993.
[9] F. M. Boffi, J. Ozaki, N. Matsuki, M. Inaba, E. Desmaras, and K. Ono. Effects of
chemical ischemia on purine nucleotides, free radical generation, lipids peroxidation
and intracellular calcium levels in c2c12 myotube derived from mouse myocytes. J.
Vet. Med. Sci., 64(6):483–488, 2002.
[10] E. M. Bosboom, C. V. Bouten, C. W. Oomens, F. P. Baaijens, and K. Nicolay.
Quantifying pressure sore-related muscle damage using high-resolution mri. J. Appl.
Physiol, 95(6):2235–2240, 2003.
[11] C. V. Bouten, R. G. Breuls, E. A. Peeters, C. W. Oomens, and F. P. Baaijens. In
vitro models to study compressive strain-induced muscle cell damage. Biorheology,
40(1-3):383–388, 2003.
24
Bibliography
Bibliography
[12] C. V. Bouten, M. M. Knight, D. A. Lee, and D. L. Bader. Compressive deformation
and damage of muscle cell subpopulations in a model system. Ann. Biomed. Eng,
29(2):153–163, 2001.
[13] C. V. Bouten, C. W. Oomens, F. P. Baaijens, and D. L. Bader. The etiology of
pressure ulcers: skin deep or muscle bound? Arch. Phys. Med. Rehabil., 84(4):616–
619, 2003.
[14] R. G. Breuls, C. V. Bouten, C. W. Oomens, D. L. Bader, and F. P. Baaijens.
Compression induced cell damage in engineered muscle tissue: an in vitro model to
study pressure ulcer aetiology. Ann. Biomed. Eng, 31(11):1357–1364, 2003.
[15] R. G. Breuls, C. V. Bouten, C. W. Oomens, D. L. Bader, and F. P. Baaijens. A
theoretical analysis of damage evolution in skeletal muscle tissue with reference to
pressure ulcer development. J. Biomech. Eng, 125(6):902–909, 2003.
[16] R. G. Breuls, B. G. Sengers, C. W. Oomens, C. V. Bouten, and F. P. Baaijens.
Predicting local cell deformations in engineered tissue constructs: a multilevel finite
element approach. J. Biomech. Eng, 124(2):198–207, 2002.
[17] R. S. Candadai and N. P. Reddy. Stress distribution in a physical buttock model:
effect of simulated bone geometry. J. Biomech., 25(12):1403–1411, 1992.
[18] K. K. Ceelen, C. W. Oomens, and F. P. Baaijens. Microstructural analysis
of deformation-induced hypoxic damage in skeletal muscle. Biomech. Model.
Mechanobiol., 2007.
[19] K.K. Ceelen, 2007.
[20] W. W. Chow and E. I. Odell. Deformations and stresses in soft body tissues of a
sitting person. J. Biomech. Eng., 100:79–87, 1978.
[21] R. K. Daniel, D. L. Priest, and D. C. Wheatley. Etiologic factors in pressure sores:
an experimental model. Arch. Phys. Med. Rehabil., 62(10):492–498, 1981.
[22] R. K. Daniel, D. Wheatley, and D. Priest. Pressure sores and paraplegia: an
experimental model. Ann. Plast. Surg., 15(1):41–49, 1985.
[23] T. Defloor, L. Schoonhoven, V. Katrien, J. Weststrate, and D. Myny. Reliability
of the european pressure ulcer advisory panel classification system. J. Adv. Nurs.,
54(2):189–198, 2006.
[24] S. M. Dinsdale. Decubitus ulcers: role of pressure and friction in causation. Arch.
Phys. Med. Rehabil., 55(4):147–152, 1974.
[25] J. Donnelly. Should we include deep tissue injury in pressure ulcer staging systems?
the npuap debate. J. Wound. Care, 14(5):207–210, 2005.
25
Bibliography
Bibliography
[26] N. K. Durrani, R. Yavuzer, V. Mittal, M. M. Bradford, C. Lobocki, and B. Silberberg. The effect of gradually increased blood flow on ischemia-reperfusion injury in
rat kidney. Am. J. Surg., 191(3):334–337, 2006.
[27] S. L. Garber and D. H. Rintala. Pressure ulcers in veterans with spinal cord injury:
a retrospective study. J. Rehabil. Res. Dev., 40(5):433–441, 2003.
[28] D. Gawlitta, W. Li, C. W. Oomens, F. P. Baaijens, D. L. Bader, and C. V. Bouten.
The relative contributions of compression and hypoxia to development of muscle
tissue damage: an in vitro study. Ann. Biomed. Eng, 35(2):273–284, 2007.
[29] D. Gawlitta, C. W. Oomens, D. L. Bader, F. P. Baaijens, and C. V. Bouten.
Temporal differences in the influence of ischemic factors and deformation on the
metabolism of engineered skeletal muscle. J. Appl. Physiol, 103(2):464–473, 2007.
[30] A. Gefen. Risk factors for a pressure-related deep tissue injury: a theoretical model.
Med. Biol. Eng Comput., 45(6):563–573, 2007.
[31] A. Gefen, N. Gefen, E. Linder-Ganz, and S. S. Margulies. In vivo muscle stiffening under bone compression promotes deep pressure sores. J. Biomech. Eng,
127(3):512–524, 2005.
[32] P. C. Grisotto, A. C. dos Santos, J. Coutinho-Netto, J. Cherri, and C. E. Piccinato.
Indicators of oxidative injury and alterations of the cell membrane in the skeletal
muscle of rats submitted to ischemia and reperfusion. J. Surg. Res., 92(1):1–6,
2000.
[33] K. E. Groth. Klinische Beobachtungen und experimentelle studien ber die Entstehung des Dekubitus. 1942.
[34] A. C. Guyton and J. E. Hall. Textbook of Medical Physiology. 9th edition, 1996.
[35] D. A. Hobson. Comparative effects of posture on pressure and shear at the bodyseat interface. J. Rehabil. Res. Dev., 29(4):21–31, 1992.
[36] R. Houwing, M. Overgoor, M. Kon, G. Jansen, B. S. van Asbeck, and J. R. Haalboom. Pressure-induced skin lesions in pigs: reperfusion injury and the effects of
vitamin e. J. Wound. Care, 9(1):36–40, 2000.
[37] T. Husain. An experimental study of some pressure effects on tissues, with reference
to the bed-sore problem. J. Pathol. Bacteriol., 66(2):347–358, 1953.
[38] K. Ikebe, T. Kato, M. Yamaga, J. Hirose, T. Tsuchida, and K. Takagi. Increased
ischemia-reperfusion blood flow impairs the skeletal muscle contractile function. J.
Surg. Res., 99(1):1–6, 2001.
[39] M. Kosiak. Etiology and pathology of ischemic ulcers. Arch. Phys. Med. Rehabil.,
40(2):62–69, 1959.
26
Bibliography
Bibliography
[40] M. Kosiak. Etiology of decubitus ulcers. Arch. Phys. Med. Rehabil., 42:19–29, 1961.
[41] T. A. Krouskop. A synthesis of the factors that contribute to pressure sore formation. Med. Hypotheses, 11(2):255–267, 1983.
[42] T. A. Krouskop, N. P. Reddy, W. A. Spencer, and J. W. Secor. Mechanisms of
decubitus ulcer formation–an hypothesis. Med. Hypotheses, 4(1):37–39, 1978.
[43] E. M. Landis. Micro-injection studies of capillary blood pressure in human skin.
Heart, 15:209–228, 1930.
[44] E. Linder-Ganz, S. Engelberg, M. Scheinowitz, and A. Gefen. Pressure-time cell
death threshold for albino rat skeletal muscles as related to pressure sore biomechanics. J. Biomech., 39(14):2725–2732, 2006.
[45] E. Linder-Ganz and A. Gefen. Mechanical compression-induced pressure sores in rat
hindlimb: muscle stiffness, histology, and computational models. J. Appl. Physiol,
96(6):2034–2049, 2004.
[46] E. Linder-Ganz, N. Shabshin, Y. Itzchak, and A. Gefen. Assessment of mechanical
conditions in sub-dermal tissues during sitting: a combined experimental-mri and
finite element approach. J. Biomech., 40(7):1443–1454, 2007.
[47] LPZ-projectgroep, 2007.
[48] A. F. Mak, L. Huang, and Q. Wang. A biphasic poroelastic analysis of the flow
dependent subcutaneous tissue pressure and compaction due to epidermal loadings:
issues in pressure sore. J. Biomech. Eng, 116(4):421–429, 1994.
[49] J. Maklebust. Policy implications of using reverse staging to monitor pressure ulcer
status. Adv. Wound. Care, 10(5):32–35, 1997.
[50] W. O. McKinley, A. B. Jackson, D. D. Cardenas, and M. J. DeVivo. Long-term
medical complications after traumatic spinal cord injury: a regional model systems
analysis. Arch. Phys. Med. Rehabil., 80(11):1402–1410, 1999.
[51] C. C. Michel and H. Gillott. Microvascular mechanisms in stasis and ischaemia. In
D. L. Bader, editor, Pressure sores: clinical practice and scientific approach., pages
153–163. McMillan Press, 1990.
[52] G. E. Miller and J. Seale. Lymphatic clearance during compressive loading. Lymphology, 14(4):161–166, 1981.
[53] O. W. Neumark. Deformation, not pressure, is the prime cause of pressure sores.
Care. Sci. Pract., 1:41–43, 1981.
[54] G. T. Nola and L. M. Vistnes. Differential response of skin and muscle in the
experimental production of pressure sores. Plast. Reconstr. Surg., 66(5):728–733,
1980.
27
Bibliography
Bibliography
[55] Health Council of the Netherlands. Health council of the netherlands: pressure
ulcers. Report, 1999.
[56] C. Oomens. Perspectives of numerical modelling in pressure ulcer research. In
D. L. Bader, C. V. C. Bouten, D. Colin, D. Colin, and C. W. J. Oomens, editors,
Pressure ulcer research; current and future perspectives., pages 149–159. SpringerVerlag, 2005.
[57] C. W. Oomens, O. F. Bressers, E. M. Bosboom, C. V. Bouten, and D. L. Blader.
Can loaded interface characteristics influence strain distributions in muscle adjacent
to bony prominences? Comput. Methods Biomech. Biomed. Engin., 6(3):171–180,
2003.
[58] National Pressure Ulcer Advisory Panel. Pressure ulcers prevalence, cost and risk
assessment: consensus development conference statement. Decubitus., 2(2):24–28,
1989.
[59] National Pressure Ulcer Advisory Panel. Position on reverse staging of pressure
ulcers. Adv. Wound. Care, 8(6):32–33, 1995.
[60] L. C. Parish, P. Lowthian, and J. A. Witkowski. The decubitus ulcer: many questions but few definitive answers. Clin. Dermatol., 25(1):101–108, 2007.
[61] E. A. Peeters, C. V. Bouten, C. W. Oomens, and F. P. Baaijens. Monitoring the
biomechanical response of individual cells under compression: a new compression
device. Med. Biol. Eng Comput., 41(4):498–503, 2003.
[62] E. A. Peeters, C. V. Bouten, C. W. Oomens, D. L. Bader, L. H. Snoeckx, and F. P.
Baaijens. Anisotropic, three-dimensional deformation of single attached cells under
compression. Ann. Biomed. Eng, 32(10):1443–1452, 2004.
[63] E. A. Peeters, C. W. Oomens, C. V. Bouten, D. L. Bader, and F. P. Baaijens.
Mechanical and failure properties of single attached cells under compression. J.
Biomech., 38(8):1685–1693, 2005.
[64] E. A. Peeters, C. W. Oomens, C. V. Bouten, D. L. Bader, and F. P. Baaijens.
Viscoelastic properties of single attached cells under compression. J. Biomech.
Eng, 127(2):237–243, 2005.
[65] S. M. Peirce, T. C. Skalak, and G. T. Rodeheaver. Ischemia-reperfusion injury in
chronic pressure ulcer formation: a skin model in the rat. Wound. Repair Regen.,
8(1):68–76, 2000.
[66] N. P. Reddy and G. V. Cochran. Interstitial fluid flow as a factor in decubitus ulcer
formation. J. Biomech., 14(12):879–881, 1981.
[67] N. P. Reddy, H. Patel, G. V. Cochran, and J. B. Brunski. Model experiments
to study the stress distributions in a seated buttock. J. Biomech., 15(7):493–504,
1982.
28
Bibliography
Bibliography
[68] N. P. Reddy and K. Patel. A mathematical model of flow through the terminal
lymphatics. Med. Eng Phys., 17(2):134–140, 1995.
[69] S. M. Reichel. Shearing force as a factor in decubitus ulcers in paraplegics. J. Am.
Med. Assoc., 166(7):762–763, 1958.
[70] J. B. Reswick and J. E. Rogers. Experience at rancho los amigos hospital with
devices and techniques that prevent pressure sores. In R. M. Kenedi and J. M.
Cowden, editors, Bedsore biomechanics, pages 301–310. The Macmillan Press, 1st
edition, 1976.
[71] E. Rubin, F. Gorstein, R. Rubin, R. Schwarting, and D. Strayer. Rubin’s pathology: clinicopathologic foundations of medicine. Lippincott Williams & Wilkins, 4th
edition, 2005.
[72] T. J. Ryan. Cellular responses to tissue distortion. In D. L. Bader, editor, Pressure
sores: clinical practice and scientific approach., pages 141–152. McMillan Press,
1990.
[73] A. H. Sacks. Theoretical prediction of a time-at-pressure curve for avoiding pressure
sores. J. Rehabil. Res. Dev., 26(3):27–34, 1989.
[74] R. Salcido, J. C. Donofrio, S. B. Fisher, E. K. LeGrand, K. Dickey, J. M. Carney,
R. Schosser, and R. Liang. Histopathology of pressure ulcers as a result of sequential
computer-controlled pressure sessions in a fuzzy rat model. Adv. Wound. Care,
7(5):23–4, 26, 28, 1994.
[75] L. Schoonhoven, J. R. Haalboom, M. T. Bousema, A. Algra, D. E. Grobbee, M. H.
Grypdonck, and E. Buskens. Prospective cohort study of routine use of risk assessment scales for prediction of pressure ulcers. BMJ, 325(7368):797, 2002.
[76] A. Smith, G. Hayes, A. Romaschin, and P. Walker. The role of extracellular calcium
in ischemia/reperfusion injury in skeletal muscle. J. Surg. Res., 49(2):153–156, 1990.
[77] A. Stekelenburg, C. Oomens, and D. Bader. Compression-induced tissue damage:
animal models. In D. L. Bader, C. V. C. Bouten, D. Colin, D. Colin, and C. W. J.
Oomens, editors, Pressure ulcer research; current and future perspectives., pages
187–204. Springer-Verlag, 2005.
[78] A. Stekelenburg, C. W. Oomens, G. J. Strijkers, K. Nicolay, and D. L. Bader.
Compression-induced deep tissue injury examined with magnetic resonance imaging
and histology. J. Appl. Physiol, 100(6):1946–1954, 2006.
[79] A. Stekelenburg, G. J. Strijkers, H. Parusel, D. L. Bader, K. Nicolay, and C. W.
Oomens. Role of ischemia and deformation in the onset of compression-induced deep
tissue injury: Mri-based studies in a rat model. J. Appl. Physiol, 102(5):2002–2011,
2007.
29
Bibliography
Bibliography
[80] Q. Sun, F. Lin, S. Al-Saeede, L. Ruberte, E. Nam, R. Hendrix, and M. Makhsous.
Finite element modeling of human buttock-thigh tissue in a seated posture. Summer
Bioengineering Conference, 2005.
[81] D. Thompson. A critical review of the literature on pressure ulcer aetiology. J.
Wound. Care, 14(2):87–90, 2005.
[82] B. A. Todd and J. G. Thacker. Three-dimensional computer model of the human
buttocks, in vivo. J. Rehabil. Res. Dev., 31(2):111–119, 1994.
[83] S. Tsuji, S. Ichioka, N. Sekiya, and T. Nakatsuka. Analysis of ischemia-reperfusion
injury in a microcirculatory model of pressure ulcers. Wound. Repair Regen.,
13(2):209–215, 2005.
[84] S. Ünal, S. Ozmen, Y. DemIr, R. Yavuzer, O. LatIfoglu, K. Atabay, and M. Oguz.
The effect of gradually increased blood flow on ischemia-reperfusion injury. Ann.
Plast. Surg., 47(4):412–416, 2001.
[85] J. R. Urbaniak, A. V. Seaber, and L. E. Chen. Assessment of ischemia and reperfusion injury. Clin. Orthop. Relat Res., (334):30–36, 1997.
[86] J. D. Zhang, A. F. Mak, and L. D. Huang. A large deformation biomechanical
model for pressure ulcers. J. Biomech. Eng., 119(4):406–408, 1997.
30