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(a) Schematic representation of the experimental setup. The EpiDerm culture is surrounded by medium and loaded with an indenter with additional weights. (b) Schematic representation of the numerical set-up with the geometry of the EpiDerm culture (gray) and the medium (white). The dashed-dotted line is the axi-symmetry line.
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Pressure ulcer risk assessment might be optimized by incorporating the soft tissue reaction to mechanical loading in the currently used risk assessment scales. Cytokines, like IL-1alpha, IL-1RA, IL-8, and TNF-alpha, might be used to determine this tissue reaction, since they are released after 24 h of mechanical loading of epidermal equivalents. In...
Contexts in source publication
Context 1
... pressure of 150 mmHg (20 kPa) was applied on top of EpiDerm cultures for various loading times (1,2,4,6,8,16, and 24 h). As depicted in Fig. 1a, this pressure was applied using indenters and additional weights, 5 which were carefully loaded onto the top of the EpiDerm cul- tures to prevent damage from impact loading. Unloaded cultures were analyzed at the same time points and were used as control. After each loading period, all the sur- rounding medium was collected and stored ...
Context 2
... plate with a diameter of 35 mm. The thickness of the EpiDerm culture was determined to be on average 100 lm and due to the dimensions of the cell culture insert was located 1 mm above the bottom of the plate. The medium volume that was added in the experiments filled the well till a height of 1 mm. Therefore, a two-dimensional model, as shown in Fig. 1b, with its axi-symmetric axis per- pendicular to the center of the well, was used as geometry for the simulations. The EpiDerm culture and the medium were modeled using 40 and 200 ele- ments, ...
Context 3
... the numerical results a conversion was required. In the experiment 900 lL medium was 1, 2, 4, 6, 8, 16, and 24 h). * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001 compared to the unloaded control group (0 mmHg). ...
Context 4
... aim of the present study was to evaluate the pressure-time regulation of the cyto- kines IL-1a, IL-1RA, IL-8, and TNF-a. Epidermal equivalents were, therefore, subjected to either 0 or 150 mmHg in a custom-built loading device for vari- ous loading periods (1, 2, 4, 6, 8, 16, and 24 h). Numerical simulations were performed to estimate the temporal release of cytokines from the keratinocytes inside the culture, based on their measured values in the medium. ...
Context 5
... to the dimensions of the experimental setup (Fig. 1a), the loading of 150 mmHg was applied in the middle of the EpiDerm culture, resulting in nonuni- form deformation of the total culture. Histological examination revealed that the damage beneath the indenter was more severe than the damage adjacent to the indenter, which is comparable to indentation experiments with a skeletal muscle ...
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... Tumour Necrosis Factor-α (TNF-α) have also been analysed pre-and post-loading, but revealed less consistent trends [138], although there were reported increases after the onset of structural tissue damage [223]. ...
... However, markers studied include IL-6 and TNF-α, which have not been analysed in this research. Ratios of IL-6 and TNF-α have been analysed pre-and post-loading in previous research, but IL-6 revealed less consistent trends than IL-1α [138], and a significant increase in TNF-α was only evident after the onset of structural tissue damage [223]. ...
The residual limb tissues of an individual with below knee amputation form a critical loaded interface with the prosthetic limb. In the early stages of rehabilitation, residual limb tissues have not been conditioned to support loading and are vulnerable to damage. This impacts upon quality of life and can lead to rejection of the prosthesis. Bioengineers have established an array of measurements to understand the pathogenesis of soft tissue damage and assess multiple aspects of tissue tolerance during loading. However, to date, there is a scarcity of literature utilising these techniques to evaluate the residual limb-socket interface, resulting in a lack of evidence-based practice to prevent socket sores. A protocol for applying representative mechanical loading on lower limb tissues was developed with a cohort of volunteers without amputation. This involved incremental pressure application through a pneumatic cuff and an array of measurements before, during and after this loaded period to characterise the response of the underlying skin and soft tissues. The protocol was then applied to a cohort of participants with unilateral transtibial amputation. In order to evaluate intrinsic factors (soft tissue composition), Magnetic Resonance Imaging was used to visualise tissue composition and gross soft tissue deformation and a MyotonPROTM device was used to estimate tissue stiffness. Transcutaneous oxygen and carbon dioxide tensions were measured, and inflammatory biomarkers were collected at sites relevant to prosthetic load transfer, each of which reflected compromise to the skin tissues. MRI revealed increased adipose infiltrating muscle tissue in residual limbs (median 2.5 %, range 0.2 - 8.9 %) compared to intact limbs (median ≤ 1.7 %, range 0.1 - 5.1 %), indicating muscle atrophy post-amputation. This effect was reduced significantly in the contralateral limbs of those individuals with greater socket use (r = -0.88, p <0.01), indicative of adaptation post-activity. During prescribed loading, cuff pressure at the highest inflation of 60 mmHg resulted in mean interface pressures ranging from 66.2 - 83.6 mmHg. In the majority of cases, residual limbs displayed less compressive strain when loaded compared to intact limbs, the differences being statistically significant at a number of tested sites (median strains -6 to 2 % vs. 4 to 13 %, respectively). Cuff loading was observed to produce a transient compromise to tissue viability, reflected in a reduction in transcutaneous oxygen tension and an upregulation of inflammatory biomarkers, suggesting a degree of local ischaemia and inflammation, respectively. In most cases, reduced ischaemia and inflammatory biomarker upregulation was observed in residual limbs compared to intact limbs, suggesting enhanced tolerance to loading. Nonetheless there was considerable variation within the heterogeneous cohort of participants with amputation. These studies represent a first-of-kind evaluation of residual limb tissue tolerance to representative prosthetic loads involving tissue characterisation and physiological monitoring. This experimental approach could be implemented to identify individual susceptibility to tissue damage which, in turn, could help inform appropriate rehabilitation programmes to maintain health of tissue during prosthetic rehabilitation. Furthermore, development of these techniques into real-time portable measurements would support both prosthetic users and prosthetists to assess in-socket tissue health, leading to more informed management of residual limb tissues.
... Well-known DAMPs in the epidermis are interleukin-1α (IL-1α), interleukin-33 (IL-33), human mobility group box-1 (HMGB1), ATP, and DNA strains [14]. IL-1α is an early marker of mechanically induced skin damage in the skin, because it is rapidly released from the keratinocytes when they are injured [15,16] and can be used as a marker to assess the loaded skin status [17][18][19]. The effect of DM and DNP on DAMP production of the human skin in humans is, as far as we know, not well studied yet. ...
Background:
Shear is a major risk factor in the development of diabetic foot ulcers, but its effect on the skin of patients with type 2 diabetes mellitus (DM) remains to be elucidated. The aim was to determine skin responses to shear in DM patients with and without diabetic polyneuropathy (DNP).
Methods:
The forearm skin was loaded with 14.5 N shear (+2.4 kPa pressure) and with 3.5 kPa pressure for 30 minutes in 10 type 2 DM patients without DNP, 10 type 2 DM patients with DNP, and 10 healthy participants. A Sebutape collected IL-1α (measure of tissue damage). A laser Doppler flowmeter measured cutaneous blood cell flux (CBF) as a measure of the reactive hyperaemic skin response.
Findings:
Reactive hyperaemia and IL-1α release was significantly increased after shear loading in all three groups and was higher compared to the responses to pressure loading. The reactive hyperaemic response after shear loading was impaired in patients with type 2 DM compared to healthy participants but did not differ between patients with and without DNP. The reactive hyperaemic response was negatively correlated with the blood glucose level but did not correlate with the DNP severity score.
Interpretation:
Shear is important in the development of tissue damage, but the reparative responses to shear are impaired in patients with type 2 DM. DNP was not associated with altered skin responses, suggesting that the loss of protective sensation to sense shear to skin remains a key factor in the development of diabetic foot ulcers in patients with DNP.
... The Sebutape method can be utilised to assess the tissue response at the protein level and, in fact, it has been widely used for early detection of pressure ulcers [9]. Especially interleukin-1α (IL-1α) is considered as a novel biomarker for this purpose since the pro-inflammatory cytokine IL-1α was found to be significantly increased upon skin loading [10], and its measurement allowed for accurate monitoring of the skin response to both pressure and shear [11]. This approach is promising because the skin response can be captured non-invasively; however, the inflammatory response of the skin is not a specific predisposing status to pressure ulcers. ...
The development of pressure ulcers is associated with four different pathways: ischemia, ischemia-reperfusion injury, impaired interstitial fluid flow and lymphatic drainage, and cell deformation. For prediction of pressure ulcer development, it is important to detect the tissue response involved in the pathways at the molecular level. However, non-invasive techniques for detecting this tissue response are not available. This study aimed to demonstrate that the secretion of the candidate marker proteins in pressure-loaded mouse skin can be detected by skin blotting, and to propose a novel direct skin assessment method for predicting pressure ulcer development. We created three different tissue damage models: early stage pressure ulcers, blanchable erythema and intact skin. We confirmed the pathways involved in the pressure ulcer development by histological analyses in the pressure ulcer model. Interleukin-1α (IL-1α), vascular endothelial growth factor C (VEGF-C) and heat shock protein 90α (HSP90α) were expressed in the pressure ulcer model at a significantly different level compared to the blanchable erythema or intact skin during the time course. Detecting the secretion of these novel biomarkers by skin blotting can be a useful method for non-invasive prediction of pressure ulcer development.
... For example the pro-inflammatory cytokine IL-1α was reported to be up-regulated over category I pressure ulcers [2]. Moreover, the IL-1α expression was significantly increased upon skin loading [1,6] and, more recently, was reported to be sensitive to monitor the skin response when subjected to both pressure and shear [7]. In addition, with respect to device-related PUs, IL-1α was elevated with increasing loading duration on spine boards [11], strap tension of ventilation masks [19] [20]. ...
Pressure ulcers (PUs) are a major burden to both patients, carers and the healthcare system. It is therefore important to identify patients at risk and detect pressure ulcers at an early stage of their development. The pro-inflammatory cytokine IL-1α is a promising indicator of tissue damage. The aim of this study was to compare the temporal skin response, by means of IL-1α expression, to different loading regimens and to investigate the presence of individual variability. The sacrum of eleven healthy volunteers was subjected to two different loading protocols. After a baseline measurement, the left and right side of the sacrum were subjected to continuous and intermittent loading regimen, respectively, at a pressure of 100 mmHg. Data was collected every 20 min, allowing for a total experimental time of 140 min. Sebum, collected at ambient conditions using Sebutape, was analyzed for the pro-inflammatory cytokine IL-1α. Most robust results were obtained using a baseline normalization approach on individual data. The IL-1α level significantly changed upon load application and removal (p<0.05) for both loading regimens. Highest IL-1α ratio increase, 3.7-fold, was observed for 1 h continuous loading. During the refractory periods for both loading regimen the IL-1α levels were still found to be up-regulated compared to baseline (p<0.05). The IL-1α level increased significantly for the two initial loading periods (p<0.05), but stabilized during the final loading period for both loading regimens. Large individual variability in IL-1α ratio was observed in the responses, with median values of 1.91 (range 1.49–3.08), and 2.52 (range 1.96–4.29), for intermittent and continuous loading, respectively, although the differences were not statistically significant. Cluster analysis revealed the presence of two distinct sub-populations, with either a low or high response to the applied loading regimen. The measurement after the first loading period proved to be representative for the subsequent measurements on each site. This study revealed that trends in normalized IL-1α provided an early indicator for tissue status following periods of mechanical loading and refractory unloaded conditions. Additionally, the observed individual variability in the response potentially identifies patients at risk of developing PUs.
... Regardless of humidity, CPAP resulted in an increased physiologic response in the form of cytokine release, which may be an early indication of skin damage. 33 To the best of our knowledge, ours was the first study that investigated the in vivo impact of humidified CPAP on the potential for developing facial pressure ulcers. The use of humidification with CPAP disrupted the skin barrier function as evidenced by the rise in transepidermal water loss. ...
BACKGROUND: The use of noninvasive ventilation masks is known to cause damage to facial skin tissue, which affects both the efficacy of the intervention and the patient's quality of life. The use of humidification with noninvasive ventilation is a common practice, but its relative role in the development of facial pressure ulcers has not been fully studied.
METHODS: A crossover cohort design was used in this study, with 15 healthy volunteers. Each volunteer randomly received both 10 cm H2O of CPAP with and without humidification through an oronasal mask. Skin integrity was evaluated by measuring transepidermal water loss, skin hydration, and skin pH at the bridge of the nose. Device-skin interface conditions (pressure and microclimate) were recorded at the bridge of the nose and both cheeks. The pro-inflammatory cytokine interleukin-1α was collected from the nose bridge before and after CPAP application by using a skin analysis tape. Nasal symptoms were collected by using a validated 6-point score.
RESULTS: Humidified CPAP significantly increased transepidermal water loss (P < .001) and skin humidity (P = .02) compared with non-humidified CPAP. There were no significant differences in skin hydration, skin pH, skin temperature, and cytokine expression between both conditions. However, there was a trend of increased median ratios of interleukin-1α concentrations in the humidified CPAP. There was a significant increase in the interface pressure at the bridge of the nose after CPAP application (P = .02), with higher interface pressure values at the nose bridge compared with both left (P = .002) and right (P = .003) cheeks. The participants reported elevated nasal discomfort during non-humidified CPAP.
CONCLUSIONS: These findings indicated that noninvasive ventilation with humidification had a potential disrupting effect on the barrier function of facial skin, associated with changes in skin microclimate and function. Further research is required to establish the cause of mask-related skin damage and to evaluate the effects of mask design, application techniques, and air flow and humidity settings.
... Detection of the proinflammatory cytokine IL-1α from skin sebum has previously been identified as a key indicator in loaded skin. 18,23 However, this is the first study to investigate the physiological response of the skin to C-collar application. The results indicated an increase in IL-1α concentration in response to collar application, with median ratios of post-:pre-collar application between 2.4 and 5.8. ...
Background
Research has shown that up to 33% of pressure ulcers (PUs) acquired in hospitals result from the application of a medical device. Cervical collars (C-collars) have been implicated in causing PUs, due to the mechanical force they apply to the skin. In order to improve our understanding of collar-related PUs, the present study aimed to assess the biomechanical, biochemical, and microclimate effects of C-collar design and fitting tension.
Methods
A cohort of 15 healthy volunteers was fit with two different C-collars according to the manufacturer guidelines. Two further collar tensions were also defined as loose and tight for each device. Each collar condition was applied for 15 minutes, with a 10 minute refractory period. Measurements at the device–skin interface included interface pressures, inflammatory biomarkers, microclimate, range of cervical motion, and comfort scores.
Results
The interface pressures at each tissue site increased monotonically with greater collar tension (p<0.01), irrespective of collar design. Biomarker analysis revealed that inflammatory cytokines (IL-1a) were elevated during collar application, with the highest increase during the tight fit condition, representing over a fourfold increase from unloaded conditions. Regardless of collar tension or type, there was an increase in temperature 1.5°C ±0.8°C compared to baseline values. Range of motion significantly decreased with greater strap tension (p<0.05), with an associated increase in discomfort.
Conclusion
The present findings revealed that increasing C-collar tensions caused elevated contact pressures at the device–skin interface, with a corresponding inflammatory response at the skin. These peak contact pressures were highest at the occiput, corresponding with reported PU locations. Devices should be designed to uniformly distribute pressures, and appropriate guidance is needed for their application.
... Regardless of humidity, CPAP resulted in an increased physiologic response in the form of cytokine release, which may be an early indication of skin damage. 33 To the best of our knowledge, ours was the first study that investigated the in vivo impact of humidified CPAP on the potential for developing facial pressure ulcers. The use of humidification with CPAP disrupted the skin barrier function as evidenced by the rise in transepidermal water loss. ...
b>Background
The use of noninvasive ventilation (NIV) masks is known to cause damage to facial skin tissues, affecting both the efficacy of the intervention and patients’ quality of life. The use of humidification with NIV is a common practice, but its relative role in the development of facial pressure ulcers has not been fully studied.
Methods
A crossover cohort design was used in this study with 15 healthy volunteers. Each volunteer was randomly receiving both 10 cmH2O of continuous positive airway pressure (CPAP) with and without humidification through an oronasal mask. Skin integrity was evaluated by measuring transepidermal water loss (TEWL), skin hydration and skin pH at the nose bridge. Device-skin interface conditions (pressure and microclimate) were recorded at the bridge of the nose and both cheeks. The pro-inflammatory cytokine IL-1α was collected from the nose bridge before and after CPAP application using Sebutape®. Nasal symptoms were collected using a validated six-point score.
Results
Humidified CPAP significantly increased TEWL (P<0.001) and skin humidity (P<0.02) compared to non-humidified CPAP. There were no significant differences in skin hydration, skin pH, skin temperature and cytokine expression between both conditions. However, there was a trend of increased median ratios of IL-1a concentrations in the humidified CPAP. There was a significant increase in the interface pressure at the nose bridge after CPAP application (P< 0.02), with higher interface pressure values at the nose bridge comparing with both left (P<0.002) and right (P<0.003) cheeks. The participants reported elevated nasal discomfort during non-humidified CPAP.
Conclusion
These findings indicate that NIV with humidification has a potential disrupting effect on the barrier function of facial skin, associated with changes in skin microclimate and function. Further research is required to establish the cause of mask related skin damage, evaluating the effects of mask design, application techniques and airflow/humidity settings.<br/
... Regardless of humidity, CPAP resulted in an increased physiologic response in the form of cytokine release, which may be an early indication of skin damage. 33 To the best of our knowledge, ours was the first study that investigated the in vivo impact of humidified CPAP on the potential for developing facial pressure ulcers. The use of humidification with CPAP disrupted the skin barrier function as evidenced by the rise in transepidermal water loss. ...
Rationale The use of noninvasive ventilation (NIV) masks have been implicated in damaging facial skin tissue, consequently having a considerable effect on patients’ quality of life and wound care. The use of humidification with NIV is common practice, but its role in the development of facial pressure ulceration, has not been studied. Methods A crossover cohort design was used in this study, with 15 healthy volunteers serving as their own controls, randomly receiving both 10 cmH2O of continuous positive airway pressure (CPAP) with humidification, and without through an oronasal mask. Skin integrity was evaluated by measuring transepidermal water loss (TEWL), skin hydration and skin pH at the nose bridge. Device-skin interface conditions (pressure and microclimate) were recorded at the bridge of the nose and both cheeks. The pro-inflammatory cytokine Interleukin 1α (IL-1α) was collected from the nose bridge before and after CPAP application using Sebutape. Nasal symptom scoring was collected using a six-point nasal score. Results Humidified CPAP significantly increases TEWL (P<0.001) and skin humidity (P<0.02) compared to non-humidified CPAP (table 1). There were no significant differences in skin hydration, skin pH, skin temperature and cytokine expression between both conditions. However, higher mean ratios of Interleukin-1α concentrations were recorded following humidified CPAP application. There was a significant increase in the interface pressure at the nose bridge following CPAP application (P<0.04), with higher baseline interface pressure at the nose bridge comparing with left (P<0.003) and right (P<0.006) cheeks. Non-humidified CPAP elevated nasal discomfort, as reported by the participants. Conclusion These findings indicate that humidification with NIV has a significant disrupting effect on the barrier function of facial skin, associated with significant changes in skin microclimate and function. Prophylactic strategies to maintain dry skin and manage the microclimate between the skin and the mask are required to safeguard skin integrity.
... Previous studies have used sebum sampled with Sebutape to measure the inflammatory response during mechanical loading of the forearm using indenters. 24 One such study revealed that a pressure of 100 mmHg applied for 2 hours at the volar aspect of the forearm revealed a 2.5-fold increase in IL-1α concentrations compared to the value at an adjacent unloaded control site. In a separate study, a combined biaxial load was applied at the forearm, incorporating an applied pressure of 30 mmHg and a shear force equivalent to 18 mmHg. ...
... A previous study has proposed a refractory period of ~20 minutes for upregulated cytokines to return to basal levels. 24 Indeed, this was evident in some cases with some "carry over effect" of upregulated cytokines between loaded and unloaded conditions ( Figure 4C). However, in clinical practice, if NIV interventions are removed for prolonged periods, patients may be at risk of oxygen desaturation. ...
Non-invasive ventilation is commonly used for respiratory support. However, in some cases, mask application can cause pressure ulcers to specific features of the face, resulting in pain and reduced quality of life for the individual. This study investigated the effects of mask strap tension on the biomechanical and biomarker responses at the skin interface. Healthy participants (n = 13) were recruited and assigned two different masks in a random order, which were fitted with three strap conditions representing increments of 5 mm to increase tension. Masks were worn for 10 minutes at each tension followed by a 10-minute refractory period. Assessment at the device–skin interface included measurements of pressures at the nose and cheeks, temperature and humidity, a selection of inflammatory cytokine concentrations collected from sebum and scores of comfort. The results indicated significantly higher interface pressures at the bridge of the nose compared to the cheeks for both masks (p < 0.05), with nasal interface pressures significantly increasing with elevated strap tension (p < 0.05). One inflammatory cytokine, IL-1α, increased following mask application at the highest tension, with median increases from baselines ranging from 21 to 33%. The other cytokines revealed a less consistent trend with strap tension. The participants reported statistically greater discomfort during elevated strap tension. Temperature and humidity values under the mask were elevated from ambient conditions, although no differences were observed between mask type or strap tension. The bony prominence on the bridge of the nose represented a vulnerable area of skin during respiratory mask application. This study has shown that mask strap tension has a significant effect on the pressure exerted on the nose. This can result in discomfort and an inflammatory response at the skin surface. Further studies are required to investigate respiratory mask application for appropriate individuals with comorbidities.
... In this porcine skin model, the TNFa secretion but not IL-8 secretion by epidermal keratinocytes observed in EpiDerm in response to pressure was recapitulated. 8,18 It remains unclear whether IL-8 secretion is also elevated in pressure ulcers in vivo. ...
Pressure ulcers are complex wounds caused by pressure- and shear-induced trauma to skin and underlying tissues. Pressure-reducing devices, such as dressings, have been shown to successfully reduce pressure ulcer incidence, when used in adjunct to pressure ulcer preventative care. While pressure-reducing devices are available in a range of materials, with differing mechanical properties, understanding of how a material's mechanical properties will influence clinical efficacy remains limited. The aim of this study was to establish a standardised ex vivo model to allow comparison of the cell protection potential of two gel-like pressure-reducing devices with differing mechanical properties (elastic moduli of 77 kPa v 35 kPa). The devices also displayed differing energy dissipation under compressive loading, and resisted strain differently under constant load in compressive creep tests. To evaluate biological efficacy we employed a new ex vivo porcine skin model, with a confirmed elastic moduli closely matching that of human skin (113 kPa vs 119 kPa, respectively). Static loads up to 20 kPa were applied to porcine skin ex vivo with subsequent evaluation of pressure-induced cell death and cytokine release. Pressure application alone increased the percentage of epidermal apoptotic cells from <2% to over 40%, and increased cellular secretion of the pro-inflammatory cytokine TNF-alpha. Co-application of a pressure-reducing device significantly reduced both cellular apoptosis and cytokine production, protecting against cellular damage. These data reveal new insight into the relationship between mechanical properties of pressure-reducing devices and their biological effects. After appropriate validation of these results in clinical pressure ulcer prevention with all tissue layers present between the bony prominence and external surface, this ex vivo porcine skin model could be widely employed to optimise design and evaluation of devices aimed at reducing pressure-induced skin damage. This article is protected by copyright. All rights reserved.
