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. 2013 May 7;12(2):202–209. doi: 10.1111/iwj.12082

Establishment of a novel rat model for deep tissue injury deterioration

Yunita Sari 1,2,†, Takeo Minematsu 1,†, Lijuan Huang 1, Hiroshi Noguchi 3, Taketoshi Mori 3, Gojiro Nakagami 1, Takashi Nagase 1, Makoto Oe 1, Junko Sugama 4, Kotaro Yoshimura 5, Hiromi Sanada 1,✉
PMCID: PMC7950563  PMID: 23651215

Abstract

Deep tissue injuries (DTIs) can become significant problems because of their rapid deterioration into deep pressure ulcers. Presently, no animal model of DTI deterioration has been developed. By concentrating pressure and shear stress in deep tissues while minimising pressure and shear stress in the overlying skin, we produced an effective rat model of DTI deterioration. Two‐dimensional finite element method (FEM) simulated the distribution of pressure and shear stress under several pressure‐loading conditions. FEM showed that concentrated shear stress in deep tissue with minimum shear stress in the overlying skin could be created by using a prominence and a cushion, respectively. On the basis of the results of FEM analysis, we selected suitable conditions for testing the rat DTI deterioration model. The compressed area was macroscopically observed until day 13, and histopathologic analysis via haematoxylin and eosin (H&E) staining was performed on days 3, 7 and 13. H&E staining showed that the distribution of tissue damage was similar to the predicted FEM results. Deep ulceration and tissue damage extending from deep tissues to the overlying skin and surrounding tissues were observed in the DTI deterioration model, which are similar to the clinical manifestations of DTI deterioration. In conclusion, a representative DTI deterioration model was established by concentrating high shear stress in deep tissues while minimising shear stress in the overlying skin. This model will allow a better understanding of the mechanisms behind DTI deterioration and the development of preventative strategies.

Keywords: Deep tissue injury, Deterioration, Finite element method, Rat, Shear stress

Introduction

Pressure ulcers (PUs) are a common complication in hospitals and nursing homes. Approximately 2·5 million PUs are treated in acute care facilities alone every year, with an estimated cost of $11 billion in the USA 1, 2, 3. Severe PUs, which include deep tissue damage, are more devastating than superficial ulcers because of high mortality due to infections and other complications and reduced patient quality of life 4. Previous studies have suggested that deep tissue injury (DTI) is part of the pathogenesis of severe PUs 5, 6.

DTI is a recently categorised type of PU, and is considered to originate from deep tissue damage that expands outwards to the overlying skin (bottom‐up theory), whereas conventional PUs originate in superficial tissues and extend to deeper structures 7. The National Pressure Ulcer Advisory Panel (NPUAP) classified DTI as a unique form of PU in the new staging system 8. In the clinical setting, DTI causes significant problems as it shows the stage I‐like appearance only in the initial phase, rapidly deteriorating to stages III and IV despite optimum treatment 6, 9.

This characteristic of rapid deterioration of DTI into severe PUs has attracted many clinicians to study DTI. Some researchers have reported the pathophysiological aspects of DTI formation 10, 11, 12, 13, 14, 15, 16, 17. However, in clinical settings, the more important problem with DTI is lesion deterioration, rather than lesion formation. This is because a large number of DTI cases are due to unavoidable conditions such as a multi‐hour surgery or unconsciousness due to cerebral infarction or drugs 6, 9.

Previously, our research group proposed the detection of DTI by ultrasonography 18, 19 and the detection of creatine phosphokinase in wound exudates 20. Other groups have carried out similar research 10, 21, 22, 23. While these efforts will allow the establishment of convenient and non‐ invasive detection methods for DTI formation in the future, they require a method to prevent DTI deterioration to be therapeutically effective.

Up to now, studies of DTI deterioration have been limited. One of the primary reasons for this has been a lack of an effective animal model for DTI deterioration, which hampers studies of its mechanism and prevention. While many researchers have studied DTI formation using in vitro engineered muscle 11, 12, 13 and animal models 14, 15, 16, 17, 24, 25, 26, none of these produced DTI deterioration, defined as progression of tissue damage from deep to superficial tissues and expanding damage to surrounding normal tissue.

Previously, we analysed the histological and pathophysiological changes of deep skeletal muscle after pressure loading 27 to determine if damage to deeper tissues could mimic lesions found in DTI deterioration. Whole flank skin of rat including deep skeletal muscle was compressed at 1 and 10 kg/3 cm2 by the modified method of Sugama et al. 28. The tissue damage of deep muscle was identified in both groups on post‐wounding day (PWD) 1 and expanded to the surrounding tissues until PWD 3 in the 10 kg group. All wounds healed without ulceration by PWD 14. The expression and activation (translocation to nucleus) of hypoxia‐inducible factor 1 (HIF1) were increased in the muscle tissues of the 10 kg group. These results suggested that DTI deterioration could be simulated by severe compression of skeletal muscle.

To establish a novel rat model for DTI deterioration, we used both modelling and histopathologic analysis. We first used finite element method (FEM) to simulate the distribution of pressure and shear stress in compressed skin tissue under several conditions. Then, we analysed the pathologic alteration of compressed rat skin in selected conditions.

Methods

Finite element analysis

To establish an animal model for DTI deterioration, we started with the conventional rat PU model 28, where a metal plate is inserted subperitoneally and the overlying skin is compressed by an indenter (Figure 1A). We hypothesised that a DTI deterioration model could be created by altering the metal plate to include a prominence that concentrates the force in the deep tissues, as well as the use of a soft cushion, to protect the overlying layer of skin from damage. We designed three types of plates: a flat plate without a prominence, a plate with rounded prominence and a plate with trapezoidal prominence. FEM analysis was conducted to estimate which type of plates would be best for establishment of DTI deterioration rat model. Simulations using narrow and wide indenters with and without cushions were performed for each plate (Figure 1B).

Figure 1.

IWJ-12082-FIG-0001-b

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(A) Conventional pressure ulcer model by Sugama et al. 28. (B) Two‐dimensional geometric design for finite element analysis.

Pressure and shear stress distributions of skin tissues compressed between metal plates with and without prominences as well as with and without soft cushions were simulated by FEM using Easy‐Sigma 2D Lite software (Geoscience Research Laboratory, Tokyo, Japan). Analysis was performed in two dimensions, with the basic parameters of FEM including geometry, material properties and boundary conditions assigned as follows.

Geometry

The diameter and height of the rounded and trapezoidal prominences were 23 and 5 mm, respectively. A rectangle with a width of 5 cm and a height of 1 cm was used to represent skin tissue. To simplify the model, human skin was assumed to be a single layer. The soft cushion was 5 cm in diameter and 2 mm thick. The diameter of the pressure‐loading indenter was set to 2 cm (narrow) and 5 cm (wide). For finite element analysis, all geometry was meshed. As geometry was assumed to be symmetrical, we simulated only half of the total geometric figure (Figure 1B).

Material properties

According to previous research, the Young's modulus was 0·34 MPa and the Poisson ratio was 0·48 for skin 29. The plate, prominence and pressure‐loading device were made of stainless steel, with a Young's modulus of 19 700 MPa and a Poisson ratio of 0·48 30. The cushion was assigned a Young's modulus of 0·01 MPa and a Poisson ratio of 0·49.

Boundary condition

Boundary condition of the symmetry axis was horizontally but not vertically constrained. The model base was both horizontally and vertically constrained. Shear stress was evaluated in the horizontal direction at the centreline of the pressure‐loading device and the stainless plate.

Sensitivity analysis

To examine the effects of biological variations in anatomy and mechanical properties on the strain and stress distributions, the simulations to determine the best model (Figure 1) were repeated using several skin thicknesses (from 8 to 15 mm) and varying Young's moduli (from 0·034 to 3·4).

Animals

Fifty‐one 6‐month‐old male Wistar rats with a body weight of 450–500 g were purchased from Japan SLC (Shizuoka, Japan) and maintained under controlled light (12‐hour light and 12‐hour dark) and temperature (25°C ± 2°C) conditions, with free access to food and water. Experimental protocols were approved by the Animal Research Committee of The University of Tokyo and all animals were treated according to guidelines established by the Japanese Association for Laboratory Animal Sciences (1987).

Wounding and wound management

One day before wounding, the hair of each rat was shaved. The next day, rats were anaesthetised via intraperitoneal injection of pentobarbital sodium (30 mg/kg body weight) and two 2‐cm sagittal incisions were created 5 cm apart into the abdomen, using a scalpel. A metal plate, either with or without a rounded prominence (Figure 2A), was inserted through the incisions into the abdomen and 10 kg/3 cm2 pressure was applied by a 1‐cm diameter indenter for 8 hours. After relieving the pressure, the metal plate was removed and the incisions sutured. A hydrocolloid dressing (ConvaTec, Tokyo, Japan) was applied to the compressed area and the incisions and was changed daily. During dressing changes, wounds were cleansed with normal saline, observed and photographed by digital camera (DSC‐T100, Sony, Tokyo, Japan).

Figure 2.

IWJ-12082-FIG-0002-b

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Plate with rounded prominence used for animal experiments (A), and apparatus for producing the deep tissue injury (DTI) deterioration rat model based on finite element method (FEM) analysis (B).

On the basis of the results of FEM analysis, we selected suitable conditions for testing the rat DTI deterioration model. The rounded prominence (diameter: 2·3 cm and height: 5 mm) was attached to the metal plate. The 5‐mm‐thick felt, representing an overlying soft cushion, was placed on the surface of skin for protection of superficial layers of skin from damage. A hard rubber pad was laid over the felt to distribute pressure to a wider area (Figure 2B). This protocol was tested in 19 rats (deterioration group). Controls included a flat group (without a prominence or cushion, similar to the conventional PU model, n = 17) and a prominence group (with a prominence but lacking a cushion, n = 15).

Macroscopic evaluation of wounds

Two wound, ostomy and continence (WOCN)‐certified nurses blindly and randomly evaluated the severity of all wounds from photographs and classified them into superficial or deep PUs.

Histological analysis

Tissue samples on PWDs 3, 7 and 13 were individually harvested, fixed with 4% paraformaldehyde and embedded in paraffin. Tissue samples were cut into 5‐µm‐thick sections and stained with haematoxylin and eosin (H&E). In the dermis, the denaturation of collagen fibres and the presence of inflammatory cells were compared among groups. In the muscle tissues, muscle degeneration, regeneration, necrosis and the presence of inflammatory cells were compared.

Results

FEM analysis

Shear stress distributions for the skin, estimated by FEM, are shown in Figure 3. When pressure was directly applied to the skin, shear stresses concentrated immediately below the indenter and just above the metal plate under the skin (Figure 3A). The inclusion of a prominence induced drastic increases in shear stresses (compression stress) on the centre of the prominence and a slight shear stress in the opposite direction (tensile stress) on the slope of the prominences (Figure 3B,C). Additionally, higher tensile stresses appeared on the edge of the trapezoidal prominence (Figure 3C). The use of soft cushions remarkably reduced the intensity of shear stress in the surface of compressed skin (Figure 3D). However, considerable shear stress still remained on the overlying skin just below the indenter when the rounded prominence was used (Figure 3E). It is noted that the soft cushion increased the tensile stress slightly above the slope of round prominence and substantially above the edge of trapezoidal prominence (Figure 3F). When the contact areas of the indenter were made wider, the shear stress on surface of the skin was remarkably decreased in the rounded prominence model (Figure 3H), although considerable tensile stress on the edge of trapezoidal prominence remained (Figure 3I).

Figure 3.

IWJ-12082-FIG-0003-c

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Distribution of shear (left) and pressure stresses (right) in the compressed skin tissue estimated with finite element analysis. The lower right scale represents the intensity of the shear stress (red: compression stress and blue: tensile stress).

Pressure stresses were relatively higher in upper parts than lower parts of the skin in every model (Figure 3J–R). The plates containing a prominence increased the intensity of pressure stresses in skin tissues (Figure 3K,L). Interestingly, the soft cushion did not substantially decrease pressure stresses (Figure 3M–O). The wider indenter resulted in a redistribution of pressure stress; however, the concentration of pressure stress on the edge of the trapezoidal prominence was increased (Figure 3P–R).

To determine the sensitivity of this method to anatomic and mechanical variation, the simulations of the round prominence, wider indenter and soft cushion model were performed using several skin thicknesses and different values for Young's modulus of skin (Figure 4). Increased skin thickness and Young's modulus resulted in reduced shear stress, whereas decreased values resulted in higher shear stress. The distribution of shear stress, especially the localised shear stress above the centre of the prominence, was found in all tested conditions.

Figure 4.

IWJ-12082-FIG-0004-c

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Distribution of shear stress in the round prominence, soft cushion and wide indenter model was estimated using finite element analysis under the different conditions of skin thickness (upper panels) and of Young's modulus (lower panels).

Macroscopic evaluation of rat wounds

On the basis of the FEM results, we compared three types of models: the flat group (with neither a prominence nor a cushion), the prominence group (with a rounded prominence but without a cushion) and the deterioration group (with a rounded prominence and a cushion).

Macroscopic observations are shown in Figure 5. Just after the pressure was released, a dark red colour was observed in the prominence and flat groups, while a bright red colour was detected in the deterioration group, suggesting that the cushion reduced damage of the superficial dermis. On PWD 1, wound surfaces turned from white to tan in the deterioration and prominence models, while the surface colour was similar to the surrounding skin in the flat group, suggesting that the colour change was due to damage of the deep tissue by the prominence. On PWD 3, the wound surfaces became yellow in the deterioration and prominence groups, with no change in the flat group. Wounds of the flat group had completely healed by PWD 9; in contrast, in the deterioration and prominence groups, wound edges started to detach from the wound beds on PWD 9 and deep ulcers were formed by PWD 11. Wound areas in the deterioration group were relatively larger than those in the prominence group. On PWDs 0 and 7, all wounds in the three groups were classified as a superficial ulcer. On day 9, 60% of the wounds were classified as deep ulcers in the deterioration group, whereas all wounds in the prominence group were still classified as superficial. In the flat group, all wounds were healed on PWD 9. All wounds in the deterioration group were classified as deep ulcers on PWDs 11 and 13, whereas in the prominence group, 60% and 80% of wounds were classified as deep ulcers on PWDs 11 and 13, respectively.

Figure 5.

IWJ-12082-FIG-0005-c

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Macroscopic observations of deep tissue injury (DTI) deterioration in the rat models. Bar = 1 cm.

Histologic analysis of wounds

On PWD 3, collagen fibres were severely denatured in the prominence and flat groups, whereas only slight denaturation was observed in the deterioration group. Epidermal lesions were not observed in any groups. Inflammatory cells, primarily polymorphonuclear cells, were mostly detected in the prominence and flat groups, whereas they were rare in the deterioration group (Figure 6B,E,H). The deterioration and prominence groups showed severe tissue degeneration and slight inflammation within the skeletal muscle layer compared with the flat group (Figure 6C,F,I).

Figure 6.

IWJ-12082-FIG-0006-c

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Histology of wounds on post‐wounding day (PWD) 3. Whole‐section images were recorded under low magnification (A, D and G). Infiltration of inflammatory cells and tissue denaturation were observed under higher magnification in the dermis (B, E and H) and deep muscle layers (C, F and I). Scale bars = 2 mm in A, D and G; 50 µm in the other panels.

On PWD 7, the area of inflammation was obvious, even at low magnification (Figure 7A,D,G). Inflammation was primarily distributed in the deep muscle layer in the deterioration group (Figure 7A), whereas it also extended to the dermis in the prominence and flat groups (Figure 7D,G). High‐magnification images indicated that inflammation of the dermis was most severe in the prominence group (Figure 7B,E,H), and inflammation, degeneration and necrosis of muscle were similar in the prominence and deterioration groups (Figure 7C,F,I).

Figure 7.

IWJ-12082-FIG-0007-c

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Compressed and surrounding skin and subcutaneous tissue harvested on post‐wounding day (PWD) 7. Whole‐section images were recorded under lower magnification (A, D and G). The infiltration of inflammatory cells and tissue denaturation were observed under higher magnification in the dermis (B, E and H) and deep muscle layer (C, F and I). Scale bars = 2 mm in A, D and G; 50 µm in the other panels.

On PWD 13, tissue necrosis in the dermis and deep muscle tissues progressed and was enlarged in the deterioration and prominence groups, whereas wounds in the flat group had healed (Figure 8A,D,G). Severe inflammation and tissue degradation were observed around the necrotic tissue in the dermis and muscle layers in the deterioration and prominence groups (Figure 8B,C,E,F).

Figure 8.

IWJ-12082-FIG-0008-c

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Compressed and surrounding skin and subcutaneous tissues harvested on post‐wounding day (PWD) 13. Whole‐section images were recorded under lower magnification (A, D and G). Infiltration of inflammatory cells and tissue denaturation were observed under higher magnification in the dermis (B, E and H) and deep muscle layer (C, F and I). Scale bars = 2 mm in A, D and G; 50 µm in the other panels.

Discussion

In this study, we developed a novel rat model for DTI deterioration. All the rats in the deterioration group developed symptoms of DTI deterioration. Histologic analysis showed that the tissue damage originated from the deep muscle layer and extended to the surrounding tissues and the dermis. This model will help in understanding the pathophysiology of DTI and the development of novel treatments to prevent the DTI deterioration.

FEM was used to simulate the distribution of pressure and shear stresses in compressed skin tissue. These occlude blood flow by direct compression, bending and pinching of blood vessels that run perpendicular to the skin surface 24, 31. Previous studies have shown that shear stress contributes to blood vessel occlusion more than pressure stress 32. Therefore, we decided to emphasise the shear stress distribution in the FEM analysis in developing the DTI deterioration model, despite the substantially different distributions of pressure and shear stresses. Relatively high shear stress localised in two regions, immediately below the indenter and just above the plate under direct compression (Figure 3A,B) and above the prominence using a wider indenter and soft cushion (Figure 3H). Variation of anatomic and mechanical properties of skin did not affect the distribution of shear stress (Figure 4). In animal experiments, similar distributions of necrotic tissue and inflammation were identified by H&E staining of PWD 7 tissues, indicating the importance of inner shear stress following tissue damage due to compression.

The NPUAP officially defined suspected DTI as a ‘localised purple or maroon area of discoloured 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 with adjacent tissue’ 8. Macroscopically, compressed skin showed yellow, purple and whitish colour in both the deterioration and prominence groups on PWD 1. However, the different character of redness immediately after compression between the deterioration and prominence groups suggested a different pathology in these groups. The appearance of the prominence group was relatively dark red, whereas the deterioration group was a much brighter red. It is speculated that the dark red colour reflected bleeding in the skin due to tissue damage. Moreover, histological findings on PWD 3 showed that the denaturation of dermal collagen and the infiltration of inflammatory cells were extensive in the prominence group, whereas these findings were unusual in the deterioration group. Therefore, only the deterioration group meets the NPUAP definition of DTI.

Regardless of the use of a cushion, deep ulceration of the compressed area was identified in the deterioration and prominence groups. However, histologic analysis showed the different origins of tissue damage between the deterioration and prominence groups. The tissue damage originated only from deep tissue in the deterioration group, but from both the deep tissues and superficial dermis in the prominence group. These results indicate that the deterioration group is the most appropriate for the DTI deterioration model, and the prominence group represents a different pathophysiology from DTI deterioration 9.

Interestingly, the wound size in the deterioration group was remarkably larger than that in the prominence group just after pressure loading, although the use of the cushion should absorb the compression force 33. Oomens et al. 34 performed FEM analysis to estimate the effect of cushion properties on the strain distribution in buttock skin, which consisted of four layers, including bone, muscle, fat and skin. Their results showed that a soft cushion to reduce interface pressure led to high deformation of skeletal muscle near the bone. Our FEM analysis predicts a similar increase of tensile stress above the slope of the rounded prominence. Therefore, we speculate that the material properties of the cushion were the cause of the larger wound in the deterioration group.

To date, no study has shown the mechanisms of DTI deterioration. We previously showed the association of hypoxia with damage of skeletal muscle in PU model rats 27. Severe pressure loading on flank skin induced increases in muscle damage from PWDs 1 to 3. During this period, the elevated expression and activation of HIF1 were observed in skeletal muscles. HIF1 is a multifunctional transcription factor that plays a central role in cellular response to hypoxia 35. HIF1 can initiate hypoxia‐mediated apoptosis 36, 37 and upregulate matrix metalloproteinases 38, 39. These apoptotic and/or proteolytic roles of HIF1 might be a part of the mechanism of DTI deterioration.

In conclusion, we successfully established a rat model for DTI deterioration, in which shear stresses in deep tissues were increased by the use of a rounded prominence and the overlying skin was protected by the use of a cushion, based on our FEM simulations. The model rats develop a superficial PU‐like ulcer during the initial phase and develop a deep ulcer by PWD 11. We expect that this model will help clarify the mechanisms of DTI deterioration and allow for development of novel treatments to prevent DTI deterioration.

Acknowledgement

This work was supported by Grant‐in‐Aid for Scientific Research (C) from Japan Society for the Promotion of Science.

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