A combined experimental and computational approach to evaluate microclimate control at the support surface interface.

Temperature and humidity conditions at the interface between a support surface and the skin, termed microclimate, has been implicated in the development of pressure ulcers. Support surface technologies have been developed to control microclimate conditions, although only a few standard test methods exist to evaluate their performance. This study describes a combined experimental-computational approach to analyzing microclimate control systems. The study used a modified physical model protocol to evaluate two specific support surface systems involving a spacer fabric cover with i) no air flow and ii) an active fan. The physical model deposited moisture at a controlled rate for 25 min, and the microclimate conditions under the model and the surrounding area were monitored for 24 h. Using the experimental data as boundary conditions, a finite element model was developed using mass transport principles, which was calibrated using experimental results. Model inputs included mass density and mass diffusivity, resulting in an estimated absolute humidity change over time. The physical model tests revealed distinct differences between the support surfaces with and without active airflow, with the former having little effect on local humidity levels (RH>75% for 24hr). By contrast, there was a spatial and temporal change in microclimate with the active fan, with sensors positioned towards the source of airflow reaching ambient conditions within 24hr. The computational model was refined to produce comparable results with respect to both the spatial distribution of microclimate and the change in values over time. The combined experimental and computation approach was able to distinguish distinct difference in microclimate change between two support surface designs. The approach could enable the efficient evaluation of different mattress design principles to aid decision making for personalized support surface solutions, for the prevention of pressure ulcers.

Risk factors for developing heel ulcers for bedridden patients: A finite element study.

BACKGROUND: The heel is one of the most common sites of pressure ulcers and the anatomical location with the highest prevalence of deep tissue injury. Several finite element modeling studies investigate heel ulcers for bedridden patients. In the current study we have added the implementation of the calf structure to the current heel models. We tested the effect of foot posture, mattress stiffness, and a lateral calcaneus displacement to the contact pressure and internal maximum shear strain occurring at the heel. METHODS: A new 3D finite element model is created which includes the heel and calf structure. Sensitivity analyses are performed for the foot orientation relative to the mattress, the Young's modulus of the mattress, and a lateral displacement of the calcaneus relative to the other soft tissues in the heel. FINDINGS: The models predict that a stiffer mattress results in higher contact pressures and internal maximum shear strains at the heel as well as the calf. An abducted foot posture reduces the internal strains in the heel and a lateral calcaneus displacement increases the internal maximum shear strains. A parameter study with different mattress-skin friction coefficients showed that a coefficient below 0.4 decreases the maximum internal shear strains in all of the used loading conditions. INTERPRETATION: In clinical practice, it is advised to avoid internal shearing of the calcaneus of patients, and it could be taken into consideration by medical experts and nurses that a more abducted foot position may reduce the strains in the heel.

The expression of anaerobic metabolites in sweat and sebum from human skin subjected to intermittent and continuous mechanical loading.

Pressure ulcers (PUs) represent a substantial burden to both patients and healthcare providers. Accordingly, effective prevention strategies should follow early detection of PUs. Anaerobic metabolites, such as lactate and pyruvate, are promising noninvasive biomarkers indicative of tissue ischaemia, one of the major mechanisms leading to PU development. The aim of this study was to investigate if the temporal release profile of these metabolites in sweat and sebum is sensitive to detect local tissue changes resulting from prolonged mechanical loads. The sacrum of 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. Biomarker samples were collected every 20 min, with a total experimental time of 140 min. Sweat was collected at 37 ∘C and 80% relative humidity, and sebum at ambient conditions, from 11 to 13 volunteers, respectively. Both samples were analysed for lactate and pyruvate concentrations using ultra-high performance supercritical fluid chromatography mass spectrometry. Prior to analysis metabolite concentrations were normalized to individual baseline levels and, in the case of sweat, additional normalization was performed to an unloaded control site to account for fatigue of sweat glands. Although substantial variability was present, the temporal release profiles of both sweat and sebum metabolites reflected the applied loading regimen with increased levels upon load application, and recovery to baseline levels following load removal. Highest relative increases were 20% and 30% for sweat lactate and pyruvate, respectively, and 41% for sebum lactate. Sebum pyruvate was not present in quantifiable amounts. There was a linear correlation between the individual responses to intermittent and continuous loading. The present study revealed that metabolite biomarkers in both sweat and sebum were sensitive to the application of mechanical loads, indicative of local ischaemia within skin and soft tissues. Similar trends in metabolic biomarkers were observed in response to intermittent and continuous loading regimens in both sweat and sebum. Metabolites represent a potential means to monitor the health of loaded skin and soft tissues informing timely interventions of PU prevention.

Myoglobin and troponin concentrations are increased in early stage deep tissue injury.

Pressure-induced deep tissue injury is a form of pressure ulcer which is difficult to detect and diagnose at an early stage, before the wound has severely progressed and becomes visible at the skin surface. At the present time, no such detection technique is available. To test the hypothesis that muscle damage biomarkers can be indicative of the development of deep tissue injury after sustained mechanical loading, an indentation test was performed for 2 h on the tibialis anterior muscle of rats. Myoglobin and troponin were analysed in blood plasma and urine over a period of 5 days. The damage as detected by the biomarkers was compared to damage as observed with T2 MRI to validate the response. We found that myoglobin and troponin levels in blood increased due to the damage. Myoglobin was also increased in urine. The amount of damage observed with MRI immediately after loading had a strong correlation with the maximal biomarker levels: troponin in blood rs = 0.94; myoglobin in blood rs = 0.75; and myoglobin in urine rs = 0.57. This study suggests that muscle damage markers measured in blood and urine could serve as early diagnosis for pressure induced deep tissue injury.

Investigating the influence of intermittent and continuous mechanical loading on skin through non-invasive sampling of IL-1α.

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.

Ultrasonography Detects Deep Tissue Injuries in the Subcutaneous Layers of the Buttocks Following Spinal Cord Injury.

Background: Ultrasonography may have potential as an effective diagnostic tool for deep tissue injury (DTI) in tissues overlying bony prominences that are vulnerable when under sustained loading in sitting. Methods: Three cases of DTI in the fat and muscle layers overlying the ischial tuberosity of the pelvis in 3 persons with spinal cord injury (SCI) with different medical histories and abnormal tissue signs are described. Conclusion: There is a need for prospective studies using a reliable standardized ultrasonography protocol to diagnose DTI and to follow its natural history to determine its association with the development of pressure injuries.

A model of human skin under large amplitude oscillatory shear.

Skin mechanics is of importance in various fields of research when accurate predictions of the mechanical response of skin is essential. This study aims to develop a new constitutive model for human skin that is capable of describing the heterogeneous, nonlinear viscoelastic mechanical response of human skin under shear deformation. This complex mechanical response was determined by performing large amplitude oscillatory shear (LAOS) experiments on ex vivo human skin samples. It was combined with digital image correlation (DIC) on the cross-sectional area to assess heterogeneity. The skin is modeled as a one-dimensional layered structure, with every sublayer behaving as a nonlinear viscoelastic material. Heterogeneity is implemented by varying the stiffness with skin depth. Using an iterative parameter estimation method all model parameters were optimized simultaneously. The model accurately captures strain stiffening, shear thinning, softening effect and nonlinear viscous dissipation, as experimentally observed in the mechanical response to LAOS. The heterogeneous properties described by the model were in good agreement with the experimental DIC results. The presented mathematical description forms the basis for a future constitutive model definition that, by implementation in a finite element method, has the capability of describing the full 3D mechanical behavior of human skin.

Lmna knockout mouse embryonic fibroblasts are less contractile than their wild-type counterparts.

In order to maintain tissue homeostasis and functionality, adherent cells need to sense and respond to environmental mechanical stimuli. An important ability that adherent cells need in order to properly sense and respond to mechanical stimuli is the ability to exert contractile stress onto the environment via actin stress fibers. The actin stress fibers form a structural chain between the cells' environment via focal adhesions and the nucleus via the nuclear lamina. In case one of the links in this chain is missing or aberrant, contractile stress generation will be affected. This is especially the case in laminopathic cells, which have a missing or mutated form of the LMNA gene encoding for part of the nuclear lamina. Using the thin film method combined with sample specific finite element modeling, we quantitatively showed a fivefold lower contractile stress generation of Lmna knockout mouse embryonic fibroblasts (MEFs) as compared to wild-type MEFs. Via fluorescence microscopy it was demonstrated that the lower contractile stress generation was associated with an impaired actin stress fiber organization with thinner actin fibers and smaller focal adhesions. Similar experiments with wild-type MEFs with chemically disrupted actin stress fibers verified these findings. These data illustrate the importance of an organized actin stress fiber network for contractile stress generation and demonstrate the devastating effect of an impaired stress fiber organization in laminopathic fibroblasts. Next to this, the thin film method is expected to be a promising tool in unraveling contractility differences between fibroblasts with different types of laminopathic mutations.

Nondestructive mechanical characterization of developing biological tissues using inflation testing.

One of the hallmarks of biological soft tissues is their capacity to grow and remodel in response to changes in their environment. Although it is well-accepted that these processes occur at least partly to maintain a mechanical homeostasis, it remains unclear which mechanical constituent(s) determine(s) mechanical homeostasis. In the current study a nondestructive mechanical test and a two-step inverse analysis method were developed and validated to nondestructively estimate the mechanical properties of biological tissue during tissue culture. Nondestructive mechanical testing was achieved by performing an inflation test on tissues that were cultured inside a bioreactor, while the tissue displacement and thickness were nondestructively measured using ultrasound. The material parameters were estimated by an inverse finite element scheme, which was preceded by an analytical estimation step to rapidly obtain an initial estimate that already approximated the final solution. The efficiency and accuracy of the two-step inverse method was demonstrated on virtual experiments of several material types with known parameters. PDMS samples were used to demonstrate the method's feasibility, where it was shown that the proposed method yielded similar results to tensile testing. Finally, the method was applied to estimate the material properties of tissue-engineered constructs. Via this method, the evolution of mechanical properties during tissue growth and remodeling can now be monitored in a well-controlled system. The outcomes can be used to determine various mechanical constituents and to assess their contribution to mechanical homeostasis.

How does lateral tilting affect the internal strains in the sacral region of bed ridden patients? - A contribution to pressure ulcer prevention.

BACKGROUND: Repositioning of individuals with reduced mobility and at risk of pressure ulcers is an essential preventive step. Manual or automatic lateral tilting is a way of doing this and the international guidelines propose a 30° to 40° side lying position. The goal of the present study was to determine the internal strains in individuals lying in a supine position and during tilting. METHODS: Based on magnetic resonance imaging (MRI) of the sacral area of human volunteers, subject specific finite element models were developed. By comparing calculated contours of the skin, fat and muscle with MRI measurements on a flat surface the models were validated. A parameter study was performed to assess the sensitivity of the model for changes in material properties. Simulations were performed at tilting angles of volunteers between 0° and 45°. FINDINGS: Subjects in a supine position or tilted have the highest strains in the muscle and fat. Tilting does affect the strain distribution, taking away the highest peak strains. There seems to exist an optimal tilting angle between 20° and 30°, which may vary depending on factors such as BMI of the subject and is in the current paper investigated only for the sacrum. INTERPRETATION: The study shows that tilting indeed has a significant, positive influence on internal strains, which is important for the prevention of deep tissue injury. Additional studies are needed to draw conclusions about the greater trochanter area and the tissues around the shoulder.

Efficient computational simulation of actin stress fiber remodeling.

Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster.

Modeling the impact of scaffold architecture and mechanical loading on collagen turnover in engineered cardiovascular tissues.

The anisotropic collagen architecture of an engineered cardiovascular tissue has a major impact on its in vivo mechanical performance. This evolving collagen architecture is determined by initial scaffold microstructure and mechanical loading. Here, we developed and validated a theoretical and computational microscale model to quantitatively understand the interplay between scaffold architecture and mechanical loading on collagen synthesis and degradation. Using input from experimental studies, we hypothesize that both the microstructure of the scaffold and the loading conditions influence collagen turnover. The evaluation of the mechanical and topological properties of in vitro engineered constructs reveals that the formation of extracellular matrix layers on top of the scaffold surface influences the mechanical anisotropy on the construct. Results show that the microscale model can successfully capture the collagen arrangement between the fibers of an electrospun scaffold under static and cyclic loading conditions. Contact guidance by the scaffold, and not applied load, dominates the collagen architecture. Therefore, when the collagen grows inside the pores of the scaffold, pronounced scaffold anisotropy guarantees the development of a construct that mimics the mechanical anisotropy of the native cardiovascular tissue.

Monitoring the penetration process of single microneedles with varying tip diameters.

Microneedles represent promising tools for delivery of drugs to the skin. However, before these microneedles can be used in clinical practice, it is essential to understand the process of skin penetration by these microneedles. The present study was designed to monitor both penetration depth and force of single solid microneedles with various tip diameters ranging from 5 to 37µm to provide insight into the penetration process into the skin of these sharp microneedles. To determine the microneedle penetration depth, single microneedles were inserted in human ex vivo skin while monitoring the surface of the skin. Simultaneously, the force on the microneedles was measured. The average penetration depth at 1.5mm displacement was similar for all tip diameters. However, the process of penetration depth was significantly different for the various microneedles. Microneedles with a tip diameter of 5µm were smoothly inserted into the skin, while the penetration depth of microneedles with a larger tip diameter suddenly increased after initial superficial penetration. In addition, the force at insertion (defined as the force at a sudden decrease in measured force) linearly increased with tip diameter ranging from 20 to 167mN. The force drop at insertion was associated with a measured penetration depth of approximately 160µm for all tip diameters, suggesting that the drop in force was due to the penetration of a deeper skin layer. This study showed that sharp microneedles are essential to insert microneedles in a well-controlled way to a desired depth.

Mechanics of the pulmonary valve in the aortic position.

Mathematical models can provide valuable information to assess and evaluate the mechanical behavior and remodeling of native tissue. A relevant example when studying collagen remodeling is the Ross procedure because it involves placing the pulmonary autograft in the more demanding aortic valve mechanical environment. The objective of this study was therefore to assess and evaluate the mechanical differences between the aortic valve and pulmonary valve and the remodeling that may occur in the pulmonary valve when placed in the aortic position. The results from biaxial tensile tests of pairs of human aortic and pulmonary valves were compared and used to determine the parameters of a structurally based constitutive model. Finite element analyzes were then performed to simulate the mechanical response of both valves to the aortic diastolic load. Additionally, remodeling laws were applied to assess the remodeling of the pulmonary valve leaflet to the new environment. The pulmonary valve showed to be more extensible and less anisotropic than the aortic valve. When exposed to aortic pressure, the pulmonary leaflet appeared to remodel by increasing its thickness and reorganizing its collagen fibers, rotating them toward the circumferential direction.

A computational model to describe the collagen orientation in statically cultured engineered tissues.

Collagen provides cardiovascular tissues with the ability to withstand haemodynamic loads. A similar network is essential to obtain in tissue-engineered (TE) samples of the same nature. Yet, the mechanism of collagen orientation is not fully understood. Typically collagen remodelling is linked to mechanical loading. However, TE constructs also show an oriented collagen network when developed under static culture. Experiments under these conditions also indicate that the tissue gradually compacts due to contractile stresses developed in the α-actin fibres of the cells. Therefore, it is hypothesised that cellular contractile stresses are responsible for collagen orientation. A model describing the cellular α-actin turnover and the stresses developed by them is integrated in a structural constitutive model describing the mechanical behaviour of collagen fibres. Results show that the model can successfully capture the sample compaction, tissue stress generation and its heterogeneous collagen arrangement.

A numerical study to analyse the risk for pressure ulcer development on a spine board.

BACKGROUND: Spine boards are used to immobilise accident victims suspected of having spinal injury. Guidelines about the maximum time patients remain on the board are often exceeded and on occasions may lead to pressure ulcers. Etiological research has shown that two processes ultimately lead to pressure ulcers:"Ischemic damage" which takes several hours to initiate and "deformation damage" at high strains. The latter process is very quick and the first signs of cell damage are already evident within minutes. Thus in order to minimise the risk of pressure ulcer development during prolonged loading, a new soft-layered long spine board has been designed. METHODS: A subject specific numerical approach has been adopted to evaluate the prototype spine board in comparison to a conventional spine board, with reference to the estimated strains in the soft tissues adjacent to the sacrum in the supine position. The model geometry is derived from magnetic resonance images of three human volunteers in an unloaded situation. The loaded images are used to "tune" the material parameters of skin, fat and muscle. The prediction of the deformed contours on the soft-layered board is used to validate the model. FINDINGS: Comparison of the internal strains in muscle tissue near the spine showed that internal strains on the soft-layered board are reduced and maximum strains are considerably less than the threshold at which deformation damage is possible. By contrast, on the rigid spine board this threshold is exceeded in all cases. INTERPRETATION: The prototype comfort board is able to reduce the risk for deformation damage and thus reduces the risk of developing pressure ulcers.

Mechanical analysis of ovine and pediatric pulmonary artery for heart valve stent design.

Transcatheter heart valve replacement is an attractive and promising technique for congenital as well as acquired heart valve disease. In this procedure, the replacement valve is mounted in a stent that is expanded at the aimed valve position and fixated by clamping. However, for this technique to be appropriate for pediatric patients, the material properties of the host tissue need to be determined to design stents that can be optimized for this particular application. In this study we performed equibiaxial tensile tests on four adult ovine pulmonary artery walls and compared the outcomes with one pediatric pulmonary artery. Results show that the pediatric pulmonary artery was significantly thinner (1.06 ± 0.36 mm (mean ± SD)) than ovine tissue (2.85 ± 0.40 mm), considerably stiffer for strain values that exceed the physiological conditions (beyond 50% strain in the circumferential and 60% in the longitudinal direction), more anisotropic (with a significant difference in stiffness between the longitudinal and circumferential directions beyond 60% strain) and presented stronger non-linear stress-strain behavior at equivalent strains (beyond 26% strain) compared to ovine tissue. These discrepancies suggest that stents validated and optimized using the ovine pre-clinical model might not perform satisfactorily in pediatric patients. The material parameters derived from this study may be used to develop stent designs for both applications using computational models.

Effects of valve geometry and tissue anisotropy on the radial stretch and coaptation area of tissue-engineered heart valves.

Tissue engineering represents a promising technique to overcome the limitations of the current valve replacements, since it allows for creating living autologous heart valves that have the potential to grow and remodel. However, also this approach still faces a number of challenges. One particular problem is regurgitation, caused by cell-mediated tissue retraction or the mismatch in geometrical and material properties between tissue-engineered heart valves (TEHVs) and their native counterparts. The goal of the present study was to assess the influence of valve geometry and tissue anisotropy on the deformation profile and closed configuration of TEHVs. To achieve this aim, a range of finite element models incorporating different valve shapes was developed, and the constitutive behavior of the tissue was modeled using an established computational framework, where the degree of anisotropy was varied between values representative of TEHVs and native valves. The results of this study suggest that valve geometry and tissue anisotropy are both important to maximize the radial strains and thereby the coaptation area. Additionally, the minimum degree of anisotropy that is required to obtain positive radial strains was shown to depend on the valve shape and the pressure to which the valves are exposed. Exposure to pulmonary diastolic pressure only yielded positive radial strains if the anisotropy was comparable to the native situation, whereas considerably less anisotropy was required if the valves were exposed to aortic diastolic pressure.

Which factors influence the ability of a computational model to predict the in vivo deformation behaviour of skeletal muscle?

Deep tissue injury (DTI) is a severe form of pressure ulcer where tissue damage starts in deep tissues underneath intact skin. Tissue deformation may play an important role in the aetiology, which can be investigated using an experimental-numerical approach. Recently, an animal-specific finite element model has been developed to simulate experiments in which muscle tissue was compressed with an indenter. In this study, the material behaviour and boundary conditions were adapted to improve the agreement between model and experiment and to investigate the influence of these adaptations on the predicted strain distribution. The use of a highly nonlinear material law and including friction between the indenter and the muscle both improved the quality of the model and considerably influenced the estimated strain distribution. With the improved model, the required sample size to detect significant differences between loading conditions can be diminished, which is clearly relevant in experiments involving animals.

How does muscle stiffness affect the internal deformations within the soft tissue layers of the buttocks under constant loading?

Mechanical loading of soft tissues covering bony prominences can cause skeletal muscle damage, ultimately resulting in a severe pressure ulcer termed deep tissue injury (DTI). Deformation plays an important role in the aetiology of DTI. Therefore, it is essential to minimise internal muscle deformations in subjects at risk of DTI. As an example, spinal cord-injured (SCI) individuals exhibit structural changes leading to a decrease in muscle thickness and stiffness, which subsequently increase the tissue deformations. In the present study, an animal-specific finite element model, where the geometry and boundary conditions were derived from magnetic resonance images, was developed. It was used to investigate the internal deformations in the muscle, fat and skin layers of the porcine buttocks during loading. The model indicated the presence of large deformations in both the muscle and the fat layers, with maximum shear strains up to 0.65 in muscle tissue and 0.63 in fat. Furthermore, a sensitivity analysis showed that the tissue deformations depend considerably on the relative stiffness values of the different tissues. For example, a change in muscle stiffness had a large effect on the muscle deformations. A 50% decrease in stiffness caused an increase in maximum shear strain from 0.65 to 0.99, whereas a 50% increase in stiffness resulted in a decrease in maximum shear strain from 0.65 to 0.49. These results indicate the importance of restoring tissue properties after SCI, with the use of, for example, electrical stimulation, to prevent the development of DTI.