Clinical strategies for the alleviation of contractures from a predictive mathematical model of dermal repair

Abstract

Hypertrophic scars arise when there is an overproduction of collagen during wound healing. These are often associated with poor regulation of the rate of programmed cell death (apoptosis) of the cells synthesizing the collagen or by an exuberant inflammatory response that prolongs collagen production and increases wound contraction. Severe contractures that occur, e.g., after a deep burn, can cause loss of function especially if the wound is over a joint such as the elbow or knee. Recently, we have developed a morphoelastic mathematical model for dermal repair that incorporates the chemical, cellular, and mechanical aspects of dermal wound healing. Using this model, we examine pathological scarring in dermal repair by first assuming a smaller than usual apoptotic rate for myofibroblasts, and then considering a prolonged inflammatory response, in an attempt to determine a possible optimal intervention strategy to promote normal repair, or terminate the fibrotic scarring response. Our model predicts that in both cases it is best to apply the intervention strategy early in the wound healing response. Further, the earlier an intervention is made, the less aggressive the intervention required. Finally, if intervention is conducted at a late time during healing, a significant intervention is required; however, there is a threshold concentration of the drug or therapy applied, above which minimal further improvement to wound repair is obtained.

Modelling the interaction of keratinocytes and fibroblasts during normal and abnormal wound healing processes

“…Furthermore, figure 6 shows that a treatment applied at days 2.5 and 5 can cause the wound to reepithelialize at a rate closer to the normal rate, while treatments applied after 12.5 days will not affect this process. These findings are in agreement with the results of Murphy et al [24], who noted that a healing strategy implemented after around two weeks is less effective in preventing hypertrophic scarring than an early treatment.…”

“…Such an assumption is justified by the observation that prolonged inflammation results in reduced levels of neutrophils, which in turn negatively affects the ability of chemoattractants to dissipate [84]. Thus, we follow the approach used by Murphy et al [24] and model this case by decreasing the value of the parameter that characterizes the decay of TGF-b, l 24 , by a factor of 10. We find that although keratinocytes quickly migrate across the domain to re-epithelialize the wound (figure 4a), the ECM levels in this case are significantly increased.…”

“…It is widely accepted that persistent, chronic hypoxia inhibits healing [30,31] and is one of the most common causes of chronic wounds [32] in which healing fails to produce anatomical and functional integrity [33]. In addition to chronic hypoxia, we consider the case of an excessively long inflammatory response, following Murphy et al [24]. We find that when treatment is initiated within an appropriate time frame, our model predicts that a normal healing outcome is achievable in each pathological case.…”

Common threads in cardiac fibrosis, infarct scar formation, and wound healing

“…Because fibroblasts are a heterogeneous population, the nature of these released substances varies by tissue type, and thus can have differential effects on inflammatory responses [19]. Inappropriate persistence of fibroblasts or myofibroblasts in the healing wound may thus not only exacerbate ECM production, but may also result in prolonged inflammation, which further contributes to hypertrophic scar formation [20]. …”

Treatment and Rehabilitation of Knee Joints Straight Stiffness After Burns

“…The main pathological changes of the burned joint stiffness are scar formation and articular soft tissue contracture caused by the patient's long-term immobility [9,10]. Some of the patients had their ectopic bone formatted [11,12].…”