The relative contributions of muscle deformation and ischaemia to pressure ulcer development

Pressure ulcers are localised areas of soft tissue breakdown that develop over bony prominences as a result of sustained mechanical loading. They are particularly common in bedridden and wheelchair-bound individuals, and represent one of the most common secondary complications in spinal cord injured subjects. A specific form of pressure ulcers is termed deep tissue injury (DTI), which is defined as pressure-related injury to subcutaneous tissues such as skeletal muscle, initially under intact skin. DTI represents a severe problem, because tissue damage at the skin surface only becomes apparent at an advanced stage, and is associated with a variable prognosis. Therefore, early identification and subsequent treatment of DTI are critical to reduce comorbidities and the financial and manpower burdens associated with treatment. This requires a better understanding of its underlying aetiology, in order to develop appropriate risk assessment tools and early detection methods. Therefore, the main goal of the present thesis was to study the aetiology of DTI. In addition, some explorative studies were performed to examine potential methods for the early detection of DTI. The aetiological factors were investigated using a combination of experiments and numerical models. This involved an established rat model for DTI that has previously been used to study the effects of deformation due to 2 h continuous loading. In the present thesis, different loading regimens were applied to further investigate the role of deformation. In addition, a previously developed finite element model to estimate muscle deformations during loading, was substantially improved to enable a local comparison of deformation with damage. Furthermore, the duration of the experiments was extended to 6 h to investigate the effects of ischaemia and reperfusion. It was found that deformation is the primary trigger for muscle damage for loading periods up to 2 h when a specific deformation threshold is exceeded. Ischaemia started to cause changes in muscle tissue between 2-4 h loading. Therefore, the damage development in skeletal muscle during prolonged loading is determined by deformation, ischaemia, and reperfusion, each mechanism exhibiting a unique time profile. The developed methods were also applied to a porcine model for DTI to investigate the deformations of the different soft tissues of the buttocks during loading. In this study, it was shown that the relative mechanical properties of the different tissue layers have a large influence on the distribution of the internal deformations. The release of biochemical damage markers from injured muscle tissue into the circulation was studied to investigate the possibility of using these proteins for the early detection of DTI. Baseline variations of creatine kinase, myoglobin, heart-type fatty acid binding protein, and C-reactive protein were assessed in able-bodied and spinal cord injured human volunteers. These variations were small compared to the predicted increase in biomarker concentrations during DTI development, indicating that this combination of markers may prove appropriate for the early detection of DTI. Moreover, a considerable increase in myoglobin concentrations in blood and urine was observed in a rat model for DTI after 6 h mechanical loading. The present findings have implications for clinical practice. In particular, it is important to minimise the internal tissue deformations in subjects at risk of DTI, such as present in subjects with spinal cord injury and those positioned on hard surfaces, such as stretchers or operating tables, for prolonged periods. Furthermore, the period of loading should be limited to prevent the accumulation of ischaemic damage. The observation of increased myoglobin levels in blood and urine after mechanical loading demonstrates the potential of using biochemical markers of muscle damage for the early detection of DTI. Moreover, the increase of myoglobin levels in urine suggests that a noninvasive approach for this screening method may be satisfactory

Deep tissue injury : how deep is our understanding?

No abstract

A multiscale computational model of arterial growth and remodeling including Notch signaling

Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis. Here, we present a multiscale framework coupling a constrained mixture model, capturing the mechanics and turnover of arterial constituents, to a cell-cell signaling model, describing Notch signaling dynamics among vascular smooth muscle cells (SMCs) as influenced by mechanical stimuli. Tissue turnover was regulated by both Notch activity, informed by in vitro data, and a phenomenological contribution, accounting for mechanisms other than Notch. This novel framework predicted changes in wall thickness and arterial composition in response to hypertension similar to previous in vivo data. The simulations suggested that Notch contributes to arterial growth in hypertension mainly by promoting SMC proliferation, while other mechanisms are needed to fully capture remodeling. The results also indicated that interventions to Notch, such as external Jagged ligands, can alter both the geometry and composition of hypertensive vessels, especially in the short term. Overall, our model enables a deeper analysis of the role of Notch and Notch interventions in arterial growth and remodeling and could be adopted to investigate therapeutic strategies and optimize vascular regeneration protocols.</p

Increased Cell Traction-Induced Prestress in Dynamically Cultured Microtissues

Prestress is a phenomenon present in many cardiovascular tissues and has profound implications on their in vivo functionality. For instance, the in vivo mechanical properties are altered by the presence of prestress, and prestress also influences tissue growth and remodeling processes. The development of tissue prestress typically originates from complex growth and remodeling phenomena which yet remain to be elucidated. One particularly interesting mechanism in which prestress develops is by active traction forces generated by cells embedded in the tissue by means of their actin stress fibers. In order to understand how these traction forces influence tissue prestress, many have used microfabricated, high-throughput, micrometer scale setups to culture microtissues which actively generate prestress to specially designed cantilevers. By measuring the displacement of these cantilevers, the prestress response to all kinds of perturbations can be monitored. In the present study, such a microfabricated tissue gauge platform was combined with the commercially available Flexcell system to facilitate dynamic cyclic stretching of microtissues. First, the setup was validated to quantify the dynamic microtissue stretch applied during the experiments. Next, the microtissues were subjected to a dynamic loading regime for 24 h. After this interval, the prestress increased to levels over twice as high compared to static controls. The prestress in these tissues was completely abated when a ROCK-inhibitor was added, showing that the development of this prestress can be completely attributed to the cell-generated traction forces. Finally, after switching the microtissues back to static loading conditions, or when removing the ROCK-inhibitor, prestress magnitudes were restored to original values. These findings show that intrinsic cell-generated prestress is a highly controlled parameter, where the actin stress fibers serve as a mechanostat to regulate this prestress. Since almost all cardiovascular tissues are exposed to a dynamic loading regime, these findings have important implications for the mechanical testing of these tissues, or when designing cardiovascular tissue engineering therapies

Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.</p

Mechanosensitivity of Jagged-Notch signaling can induce a switch-type behavior in vascular homeostasis

Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down-regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis