Modeling the transport of biochemical markers in skin : towards pressure ulcer risk assessment

Prolonged mechanical loading often results in degeneration of soft tissues, involving both skin and/or muscle tissues, resulting in a medical condition termed decubitus or pressure ulcers. Current risk assessment is primarily based on scales, all of which are based on patient characteristics that can easily be recorded by nursing staff in clinical settings. None of these scales incorporate a measure to indicate the tissue response to applied mechanical loading. However, the use of these scales often results in inappropriate risk assessment of the individuals. Hence, a more reliable measure, e.g. involving physical and/or biochemical measures, is required to reflect the individual risk of loaded tissues. In the current thesis, the transport of biochemical markers for assessing the skin response after mechanical damage is evaluated. For pressure ulcer risk assessment, it is preferred to measure the tissue response non-invasively. Therefore, biochemical markers that are released by the upper layer of the skin, the epidermis are of interest. Upon disruption of this upper layer, two main repair pathways are initiated, involving either a difference in the ion concentration or the release of cytokines from the cells. These two pathways were examined in more detail to determine whether the tissue response to mechanical loading could be assessed by measuring the ion or cytokine concentration. A computational model was developed to elaborate on the transport processes that were responsible for the differences in the calcium concentration. It was found that calcium transport was most influenced by a change in the electrical potential across the nucleated layers of the epidermis. This potential was only affected when the stratum corneum was completely damaged and therefore, it was concluded that calcium was not an appropriate marker to assess the tissue response after mechanical loading. The pathway involving release of cytokines was examined using both numerical and experimental model systems. To model the transport of cytokines in the epidermis, the diffusivity of these cytokines was determined using fluorescent recovery after photobleaching. It was observed that the diffusion coefficient in porcine and human epidermis was comparable, whereas it was significantly lower in tissue engineered epidermal equivalents. Other in vitro experiments were performed in which the concentration of cytokines (IL-1a, IL-1RA, IL-8, and TNF-a) was determined inside tissue engineered constructs and in its surrounding medium after prolonged mechanical loading. The results indicated that for all cytokines the concentration in the medium increased with time as response to mechanical loading and that the total amount of cytokines remained the same during the 24 hour loading period. A numerical model was developed in which the transport of cytokines was described and the release of the cytokines from the cells was estimated. It was observed that mechanical loading increased the release of cytokines from the cells. However, this increase did not endure the 24 hours loading period. From these in vitro results, it was concluded that measuring cytokines was promising for determination of the tissue response, since they were released after sustained mechanical loading. To determine whether these cytokines could also be measured in an in vivo situation, the release of cytokines was assessed in a non-invasive way after controlled mechanical loading of the forearm of human volunteers. In this study, the release of IL-1a was found to be increased in the compromised skin. Directly next to the loading spot, the IL-1a release was comparable to the control release, meaning that the release was local in nature. Furthermore, a temporal profile was found; the IL- 1a release remained significantly elevated for approximately 20 minutes. Release of the cytokines IL-1RA and IL-8 was below the detection limit of the assay and could, therefore, not be determined. With these non-invasive measurements, the cytokine values at the top surface of the epidermis were determined as a measure for the tissue response in the viable epidermis. Numerical simulations were performed in which it was established that the cytokine values measured at the top surface of the stratum corneum reflected those values in the viable epidermis. In conclusion, the current thesis evaluates transport of biochemical markers in the human epidermis to determine the tissue response after prolonged mechanical loading. It proved useful to combine experimental models with numerical simulations for a comprehensive interpretation of the experimental results. This research was aimed at developing a reliable method to assess the susceptibility of individuals to the development of pressure ulcers. Future work should be focused on determination of cytokine release in combination with other markers and on determination of differences in the values of these markers between susceptible and non-susceptible subjects.