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

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

Magnetic resonance elastography of skeletal muscle deep tissue injury

The current state-of-the-art diagnosis method for deep tissue injury in muscle, a subcategory of pressure ulcers, is palpation. It is recognized that deep tissue injury is frequently preceded by altered biomechanical properties. A quantitative understanding of the changes in biomechanical properties preceding and during deep tissue injury development is therefore highly desired. In this paper we quantified the spatial–temporal changes in mechanical properties upon damage development and recovery in a rat model of deep tissue injury. Deep tissue injury was induced in nine rats by two hours of sustained deformation of the tibialis anterior muscle. Magnetic resonance elastography (MRE), T 2 -weighted, and T 2 -mapping measurements were performed before, directly after indentation, and at several timepoints during a 14-day follow-up. The results revealed a local hotspot of elevated shear modulus (from 3.30 ± 0.14 kPa before to 4.22 ± 0.90 kPa after) near the center of deformation at Day 0, whereas the T 2 was elevated in a larger area. During recovery there was a clear difference in the time course of the shear modulus and T 2 . Whereas T 2 showed a gradual normalization towards baseline, the shear modulus dropped below baseline from Day 3 up to Day 10 (from 3.29 ± 0.07 kPa before to 2.68 ± 0.23 kPa at Day 10, P < 0.001), followed by a normalization at Day 14. In conclusion, we found an initial increase in shear modulus directly after two hours of damage-inducing deformation, which was followed by decreased shear modulus from Day 3 up to Day 10, and subsequent normalization. The lower shear modulus originates from the moderate to severe degeneration of the muscle. MRE stiffness values were affected in a smaller area as compared with T 2 . Since T 2 elevation is related to edema, distributing along the muscle fibers proximally and distally from the injury, we suggest that MRE is more specific than T 2 for localization of the actual damaged area

A physically motivated constitutive model for cell-mediated compaction and collagen remodeling in soft tissues

Collagen is the main load-bearing component of many soft tissues and has a large influence on the mechanical behavior of tissues when exposed to mechanical loading. Therefore, it is important to increase our understanding of collagen remodeling in soft tissues to understand the mechanisms behind pathologies and to control the development of the collagen network in engineered tissues. In the present study, a constitutive model was developed by coupling a recently developed model describing the orientation and contractile stresses exerted by cells in response to mechanical stimuli to physically motivated collagen remodeling laws. In addition, cell-mediated contraction of the collagen fibers was included as a mechanism for tissue compaction. The model appeared to be successful in predicting a range of experimental observations, which are (1) the change in transition stretch of periosteum after remodeling at different applied stretches, (2) the compaction and alignment of collagen fibers in tissue-engineered strips, (3) the fiber alignment in cruciform gels with different arm widths, and (4) the alignment of collagen fibers in engineered vascular grafts. Moreover, by changing the boundary conditions, the model was able to predict a helical architecture in the vascular graft without assuming the presence of two helical fiber families a priori. Ultimately, this model may help to increase our understanding of collagen remodeling in physiological and pathological conditions, and it may provide a tool for determining the optimal experimental conditions for obtaining native-like collagen architectures in engineered tissue

Computational modeling for cardiovascular tissue engineering:the importance of including cell behavior in growth and remodeling algorithms

\u3cp\u3eUnderstanding cardiovascular growth and remodeling (G&amp;R) is fundamental for designing robust cardiovascular tissue engineering strategies, which enable synthetic or biological scaffolds to transform into healthy living tissues after implantation. Computational modeling, particularly when integrated with experimental research, is key for advancing our understanding, predicting the in vivo evolution of engineered tissues, and efficiently optimizing scaffold designs. As cells are ultimately the drivers of G&amp;R and known to change their behavior in response to mechanical cues, increasing efforts are currently undertaken to capture (mechano-mediated) cell behavior in computational models. In this selective review, we highlight some recent examples that are relevant in the context of cardiovascular tissue engineering and discuss the current and future biological and computational challenges for modeling cell-mediated G&amp;R.\u3c/p\u3