Ayelet Levy

An air-cell-based cushion for pressure ulcer protection remarkably reduces tissue stresses in the seated buttocks with respect to foams: Finite element studies

A sitting-acquired pressure ulcer (PU) is a common injury in wheelchair-bound patients. Preventative measures for the post spinal cord injury (SCI) population include prescription of a supportive thick cushion on the wheelchair, in order to better distribute loads between the buttocks and support surface (which are quantifiable using interface pressure measurements), and potentially, to minimize internal soft tissue loads (which are typically unknown). Information about the biomechanical efficacy of commercially-available structured cushion designs such as air-cell-based (ACB) cushions, gel, and honeycomb-like cushions is sparse. Considering the importance of such evaluations to patient safety and quality of life, we studied the biomechanical performances of an ACB cushion in comparison to standard, flat foam cushions with different stiffness properties. Using a set of finite element (FE) model variants, we determined the mechanical stresses in muscle, fat, and skin tissues under the ischial tuberosities during sitting. Tissue stress analyses were conducted in a reference SCI anatomy, incorporating pathoanatomical and pathophysiological changes associated with chronic SCI, including bone shape adaptation, muscle atrophy, and spasms. We found up to 57% greater immersion and 4 orders-of-magnitude lower muscle, fat, and skin tissue stresses for the ACB cushion. We also found the ACB cushion provides better protection against the aforementioned bone shape adaptation, muscle atrophy, and spasms. Hence, theoretically, the use of a suitable ACB cushion should provide longer safe sitting times for SCI patients with respect to standard foam cushions.

CD38 Facilitates Recovery from Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunctions. TBI is accompanied by neuroinflammation, a process mediated largely by microglia. CD38 is an ectoenzyme that promotes transmembrane signaling via the synthesis of potent calcium mobilizing agents or via its receptor activity. CD38 is expressed in the brain in various cell types including microglia. In previous studies, we showed that CD38 regulates microglial activation and response to chemokines. In view of the important role of neuroinflammation in TBI and the effects of CD38 on microglial responses, the present study examines the role of CD38 in the recovery of mice from closed head injury (CHI), a model of focal TBI. For this purpose, CD38-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurobehavioral and cognitive functions was assessed by the Neurological Severity Score (NSS) and the Object Recognition Test, at various time points post-injury. The results show that recovery after CHI (as indicated by the NSS) was significantly lower in CD38-deficient mice than in WT mice and that the object recognition performance after injury was significantly impaired in injured CD38-deficient mice than in WT mice. In addition, we also observed that the amount of activated microglia/macrophages at the injury site was significantly lower in CD38-deficient mice compared with WT mice. Taken together, our findings indicate that CD38 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of CD38 on microglia responses.

The biomechanical efficacy of dressings in preventing heel ulcers

The heels are the most common site for facility-acquired pressure ulcers (PUs), and are also the most susceptible location for deep tissue injuries. The use of multilayer prophylactic dressings to prevent heel PUs is a relatively new prevention concept, generally aimed at minimizing the risk for heel ulcers (HUs) through mechanical cushioning and reduction of friction at the dressing-support interface. We used 9 finite element model variants of the posterior heel in order to evaluate the biomechanical performance of a multilayer dressing in prevention of HUs during supine lying. We compared volumetric exposures of the loaded soft tissues to effective and maximal shear strains, as well as peak stresses in the Achilles tendon, without any dressing and with a single-layer or a multilayer dressing (Mepilex(®) Border Heel-type), on supports with different stiffnesses. The use of the multilayer dressing consistently and considerably reduced soft tissue exposures to elevated strains at the posterior heel, on all of the tested support surfaces and when loaded with either pure compression or combined compression and shear. The aforementioned multilayer design showed (i) clear benefit over a single-layer dressing in terms of dissipating tissue strains, by promoting internal shear in the dressing which diverts loads from tissues; (ii) a protective effect that was consistent on supports with different stiffnesses. Recent randomized controlled trials confirmed the efficacy of the simulated multilayer dressing, and so, taken together with this modeling work, the use of a prophylactic multilayer dressing indicates a great promise in taking this route for prevention.

Inhibition of glioma progression by a newly discovered CD38 inhibitor.

Glioma, the most common cancer of the central nervous system, has very poor prognosis and no effective treatment. It has been shown that activated microglia/macrophages in the glioma tumor microenvironment support progression. Hence, inhibition of the supporting effect of these cells may constitute a useful therapeutic approach. Recently, using a syngeneic mouse glioma progression model, we showed that the ectoenzyme CD38 regulated microglia activation and, in addition, that the loss of CD38 from the tumor microenvironment attenuated glioma progression and prolonged the life span of the tumor‐bearing mice. These studies, which employed wild‐type (WT) and Cd38−/− C57BL/6J mice, suggest that inhibition of CD38 in glioma microenvironment may be used as a new therapeutic approach to treat glioma. Our study tested this hypothesis. Initially, we found that the natural anthranoid, 4,5‐dihydroxyanthraquinone‐2‐carboxylic acid (rhein), and its highly water‐soluble tri‐potassium salt form (K‐rhein) are inhibitors of CD38 enzymatic (nicotinamide adenine dinucleotide glycohydrolase) activity (IC50 = 1.24 and 0.84 μM, respectively, for recombinant mouse CD38). Treatment of WT, but not Cd38−/− microglia with rhein and K‐rhein inhibited microglia activation features known to be regulated by CD38 (lipopolysaccharide/IFN‐γ‐induced activation, induced cell death and NO production). Furthermore, nasal administration of K‐rhein into WT, but not Cd38−/− C57BL/6J, mice intracranially injected with GL261 cells substantially and significantly inhibited glioma progression. Hence, these results serve as a proof of concept, demonstrating that targeting CD38 at the tumor microenvironment by small‐molecule inhibitors of CD38, for example, K‐rhein, may serve as a useful therapeutic approach to treat glioma.

Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model.

Alzheimers disease (AD)‐associated dementia is due to tissue damage caused by amyloid β (Aβ) deposition within the brain and by accompanying neuroinflammation. The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD‐consuming enzymes and by producing NAD‐derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology.

Effects of foot posture and heel padding devices on soft tissue deformations under the heel in supine position in males: MRI studies

Heel ulcers (HUs) are the second most common pressure ulcers (PUs). Despite the significant morbidity and economic cost associated with HUs, there remains a lack of understanding of the basic pathophysiology of PUs because of limited basic research. There are only sparse data regarding the efficacy of prevention aids such as heel padding devices, and these data are based mainly on epidemiological research rather than biomechanical models and deformation measurements. This study was designed to explore the effects of foot posture and support stiffness properties on soft tissue deformations using magnetic resonance imaging (MRI). Subjects were scanned with and without weight bearing, in neutral external rotation position and in 90 degrees to supporting surface and with different heel padding devices. Tissue strains were calculated for skin, subcutaneous tissue, and effective (total) soft tissue. We found skin strains with the foot in external rotation to be significantly greater than when the foot was upright. Heel padding devices have a statistically significant effect on reducing the extent of deformations in both skin and subcutaneous tissues. Furthermore, the design features of heel padding devices have substantial influence on tissue deformations. This study demonstrates how MRI provides convenient, accurate, and quantitative comparison of biomechanical performances of heel padding devices.

Device-related pressure ulcers from a biomechanical perspective

Pressure ulcers (PUs) in the pediatric population are inherently different from those in adults, in their risk factors and etiology, with more than 50% of the cases related to contact with medical equipment at the care setting. The aims of this study were to: (i) Determine the mechanical loads in the scalp of a newborn lying supine, near a wedged encephalogram electrode or wire, which is deforming the scalp at the occiput. (ii) Evaluate the effect of a doughnut-shaped headrest on the mechanical state of tissues at the same site. We used finite element computational modeling to simulate a realistic three-dimensional head of a newborn interacting with the above devices. We examined effective (von Mises) stresses, shear stresses and strain energy density (SED) in the fat and skin tissues at the occipital region. The interfering wire resulted in the worse mechanical conditions in the soft tissues, compared to the lodged electrode and use of a doughnut-shaped headrest, with 345% and 50% increase in effective stresses in skin and fat tissues, respectively. Considering that elevated and localized tissue deformations, stresses and SED indicate a risk for PUs, our simulations suggest that misplaced medical devices, and using a doughnut-shaped headrest, impose an actual risk for developing device-related PUs. We conclude that guidelines for pediatric clinical care should recommend routine inspection of the medical device placement to prevent harmful contact conditions with the patient. Furthermore, improved design of medical equipment for pediatric settings is needed in order to protect these fragile young patients from PUs.

Bid regulates the immunological profile of murine microglia and macrophages

Apoptosis is a controlled cell‐death process mediated inter alia by proteins of the Bcl‐2 family. Some proteins previously shown to promote the apoptotic process were found to have nonapoptotic functions as well. Microglia, the resident immune cells of the central nervous system, respond to brain derangements by becoming activated to contend with the brain damage. Activated microglia can also undergo activation‐induced cell death. Previous studies have addressed the role of core apoptotic proteins in the death process, but whether these proteins also play a role or not in the activation process is not been reported. Here we explore the effect of the BH3‐only protein Bid on the immunological features of microglia and macrophages. Our results showed that Bid regulates both the phagocytotic activities and the inflammatory profiles of these cells. Deficiency of Bid attenuated the phagocytotic activity of primary microglia and peritoneal macrophages. It also changed the expression profile of distinct inflammation‐related genes in lipopolysaccharide‐activated microglia and peritoneal macrophages in vitro and in an in vivo sepsis‐like paradigm. Notably, similar changes followed downregulation of Bid in the N9 microglial cell line. Cell death could not be detected in any of the systems examined. Our findings demonstrate that Bid can regulate the immunological profiles of activated microglial and macrophages, via a novel nonapoptotic activity. In view of the critical role of these cells in various pathologies, including acute and chronic brain insults, our finings suggest that impairments in Bid expression may contribute to these pathologies also via a nonapoptotic activity.

Contoured Foam Cushions Cannot Provide Long-term Protection Against Pressure-Ulcers for Individuals with a Spinal Cord Injury: Modeling Studies.

OBJECTIVE: To determine changes in internal soft-tissue loads in the buttocks of individuals with a spinal cord injury (SCI), who undergo pathoanatomical changes during the first months and years following the occurrence of the SCI, while sitting on a contoured foam cushion (CFC) that has been fitted close to the time of the injury but has not been replaced in subsequent years. DESIGN: Internal tissue loads in variant buttocks anatomies on a CFC were analyzed by means of finite element computer simulations. The pathoanatomical changes that are characteristic to SCI and were simulated here are: increase in fat tissue mass, intramuscular fat infiltration, muscle atrophy, and combinations of these conditions. SETTING: Computational biomechanical modeling. MAIN RESULTS: Simulating the aforementioned pathoanatomical changes consistently resulted in greater mechanical strain and stress magnitudes and more inhomogeneity in the loading state of muscle and fat tissues, with a more profound effect in fat. The simulations further indicated a clear trend of exacerbation in tissue exposure to loads as the pathoanatomical changes progress chronologically and the CFC is not replaced. CONCLUSIONS: A CFC that has been fitted at a time close to the SCI, but has not been replaced in subsequent years, substantially loses its efficacy in protecting patients from developing pressure ulcers and deep tissue injury in particular.

Computer simulations of efficacy of air-cell-based cushions in protecting against reoccurrence of pressure ulcers

For individuals with a spinal cord injury (SCI) who depend on a wheelchair for mobility, sitting-acquired pressure ulcers (PUs) are a common and life-endangering complication. In the short time following an SCI, pathoanatomical and pathophysiological changes that affect the weight-bearing tissues of the buttocks may increase the risk for PUs, exposing this already-at-risk population to the additional potential risk caused by soft tissue scarring. In this work, we evaluated the biomechanical efficacies of an air-cell-based (ACB) cushion for individuals with SCI who have previously experienced PUs that healed but left scars in their soft tissues. We used 11 finite element model variants of the buttocks describing various scar shapes and severities to study the effects of the scars on soft tissue stresses during sitting on an ACB cushion and the resulting theoretical risk for the reoccurrence of PUs. Interestingly, the ACB cushion induced, in general, lower peak stress values in the soft tissues of the buttocks when scarring was present with respect to the stress levels in the (nonscarred) reference case. Our simulations therefore suggest that the ACB cushion is generally better protecting patients with a history of severe PUs manifested by large, possibly deep tissue scarring in their buttocks.