Membrane-Stretch-Induced Cell Death in Deep Tissue Injury: Computer Model Studies

Abstract

Deep tissue injury (DTI) is a serious pressure ulcer, involving a mass of necrotic soft tissue under bony prominences as a consequence of sustained tissue deformations. Though several processes are thought to participate in the onset and development of DTI (e.g., cellular deformation, ischemia, and ischemia-reperfusion), the specific mechanisms responsible for it are currently unknown. Recent work indicated that pathological processes at the cell level, which relate to cell deformation, are involved in the etiology. We hypothesized that sustained tissue deformations can lead to elevated intracellular concentration of cell metabolites, e.g., calcium ion (Ca 2+ ), due to a stretch-induced increase in the local permeability of plasma membranes. This may ultimately lead to cell death due to intracellular cytotoxic concentrations of metabolites. In order to investigate this hypothesis, computational models were developed, for determining compression-induced membrane stretches and trends of times for reaching intracellular cytotoxic Ca 2+ levels due to uncontrolled Ca 2+ influx through stretched membranes. The simulations indicated that elevated compressive cell deformations exceeding 25% induce large tensional strains (>5%, and up to 11.5%) in membranes. These are likely to increase Ca 2+ influx from the extracellular space into the cytosol through the stretched sites. Consistent with this assumption, the Ca 2+ transport model showed high sensitivity of times for cell death to changes in membrane resistance. These results may open a new path in pressure ulcer research, by indicating how global tissue deformations are transformed to plasma membrane deformations, which in turn, affect transport properties and eventually, cell viability.

Use of weight-bearing MRI for evaluating wheelchair cushions based on internal soft-tissue deformations under ischial tuberosities

“…To demonstrate a theoretical implication of the present findings on muscle cell viability in prolonged sitting with or without a cushion, we used the cell-death tolerance of Gefen et al [22]. The rationale for analysis is that hierarchical computer modeling previously showed that high deformations at the tissue continuum scale are associated with high cell deformations [23]. Based on this result, we expect that the localized elevated muscle and fat deformations presently observed in this MRI study also substantially distort cells in soft tissues under the IT.…”

Relationship Between Strain Levels and Permeability of the Plasma Membrane in Statically Stretched Myoblasts

“…Poisson's ratios were taken as 0.45 for all the aforementioned cellular components. 38,40,41 All cell models were meshed automatically in ABAQUS using the element type M3D6 for the PM and type C3D10M for the cytoplasm and nucleus. The substrate was meshed using the element type C3D15.…”

“…This deformation-diffusion mechanism of loss of homeostasis eventually causes cell death, which may later on involve apoptotic reactions as well. 41 Some supporting evidence for the potential influence of mechanical loads on PM permeability exists in the neurotrauma literature, where several authors reported altered transport through the PM of cultured neurons after subjecting the cells to loading profiles such as instantaneous stretch, 19,20,42 fluid shear stress, 24,25,36 or impact compression. 29 Additional studies consistently provided evidence for mechanically induced PM permeability disruptions in cells subjected to mechanical stress levels exceeding critical thresholds, such as in aortic endothelial cells 17,50 and cardiomyocytes, 23 as well as in alveolar epithelial cells subjected to cyclic stretches.…”

“…14,18,41 However, experimental evidence for specific cell-scale mechanisms that could cause DTIs is still missing in the literature. In a previous paper, we proposed how macroscopic sustained soft tissue deformations might compromise cell viability, through excessive stretching of the plasma membrane (PM) of the deformed cells which increases PM permeability beyond physiological limits and hence, disrupts normal transport through the PM.…”

“…In a previous paper, we proposed how macroscopic sustained soft tissue deformations might compromise cell viability, through excessive stretching of the plasma membrane (PM) of the deformed cells which increases PM permeability beyond physiological limits and hence, disrupts normal transport through the PM. 41 If soft tissue loads are relieved intermittently, as in a healthy person who frequently moves while sitting or lying, such temporary PM permeability changes do not produce any clinical symptoms, since the time constants for substantial, detrimental diffusion of biomolecules from the extracellular matrix into the cells or from the cells outwards are longer than the intervals between postural changes. If a person statically maintains his posture for hours, however, as in the case of bedridden or chairfast patients, there is sufficient time for biomolecules that diffuse in a noncontrolled manner to build up cytotoxic concentrations intracellularly, or, critical substances may escape the cytosol.…”