A multiscale hybrid mathematical model of epidermal-dermal interactions during skin wound healing.

Following injury, skin activates a complex wound healing programme. While cellular and signalling mechanisms of wound repair have been extensively studied, the principles of epidermal-dermal interactions and their effects on wound healing outcomes are only partially understood. To gain new insight into the effects of epidermal-dermal interactions, we developed a multiscale, hybrid mathematical model of skin wound healing. The model takes into consideration interactions between epidermis and dermis across the basement membrane via diffusible signals, defined as activator and inhibitor. Simulations revealed that epidermal-dermal interactions are critical for proper extracellular matrix deposition in the dermis, suggesting these signals may influence how wound scars form. Our model makes several theoretical predictions. First, basal levels of epidermal activator and inhibitor help to maintain dermis in a steady state, whereas their absence results in a raised, scar-like dermal phenotype. Second, wound-triggered increase in activator and inhibitor production by basal epidermal cells, coupled with fast re-epithelialization kinetics, reduces dermal scar size. Third, high-density fibrin clot leads to a raised, hypertrophic scar phenotype, whereas low-density fibrin clot leads to a hypotrophic phenotype. Fourth, shallow wounds, compared to deep wounds, result in overall reduced scarring. Taken together, our model predicts the important role of signalling across dermal-epidermal interface and the effect of fibrin clot density and wound geometry on scar formation. This hybrid modelling approach may be also applicable to other complex tissue systems, enabling the simulation of dynamic processes, otherwise computationally prohibitive with fully discrete models due to a large number of variables

Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch

How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non-intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation

Extramuscular myofascial force transmission alters substantially the acute effects of surgical aponeurotomy: assessment by finite element modeling

Effects of extramuscular myofascial force transmission on the acute effects of aponeurotomy were studied using finite element modeling and implications of such effects on surgery were discussed. Aponeurotomized EDL muscle of the rat was modeled in two conditions: (1) fully isolated (2) with intact extramuscular connections. The specific goal was to assess the alterations in muscle length-force characteristics in relation to sarcomere length distributions and to investigate how the mechanical mechanism of the intervention is affected if the muscle is not isolated. Major effects of extramuscular myofascial force transmission were shown on muscle length-force characteristics. In contrast to the identical proximal and distal forces of the aponeurotomized isolated muscle, substantial proximo-distal force differences were shown for aponeurotomized muscle with extramuscular connections (for all muscle lengths F dist > F prox after distal muscle lengthening). Proximal optimal length did not change whereas distal optimal length was lower (by 0.5 mm). The optimal forces of the aponeurotomized muscle with extramuscular connections exerted at both proximal and distal tendons were lower than that of isolated muscle (by 15 and 7%, respectively). The length of the gap separating the two cut ends of the intervened aponeurosis decreases substantially due to extramuscular myofascial force transmission. The amplitude of the difference in gap length was muscle length dependent (maximally 11.6% of the gap length of the extramuscularly connected muscle). Extramuscular myofascial force transmission has substantial effects on distributions of lengths of sarcomeres within the muscle fiber populations distal and proximal to the location of intervention: (a) Within the distal population, the substantial sarcomere shortening at the proximal ends of muscle fibers due to the intervention remained unaffected however, extramuscular myofascial force transmission caused a more pronounced serial distribution towards the distal ends of muscle fibers. (b) In contrast, extramuscular myofascial force transmission limits the serial distribution of sarcomere lengths shown for the aponeurotomized isolated muscle in the proximal population. Fiber stress distributions showed that extramuscular myofascial force transmission causes most sarcomeres within the aponeurotomized muscle to attain lengths favorable for higher force exertion. It is concluded that acute effects of aponeurotomy on muscular mechanics are affected greatly by extramuscular myofascial force transmission. Such effects have important implications for the outcome of surgery performed to improve impeded function since muscle in vivo is not isolated both anatomically and mechanically

Calculating Tumor Volume Using Three-Dimensional Models in Preoperative Soft-Tissue Sarcoma Surgical Planning:Does Size Matter?

This feasibility study aims to explore the use of three-dimensional virtual surgical planning to preoperatively determine the need for reconstructive surgery following resection of an extremity soft-tissue sarcoma. As flap reconstruction is performed more often in advanced disease, we hypothesized that tumor volume would be larger in the group of patients that had undergone flap reconstruction. All patients that were treated by surgical resection for an extremity soft-tissue sarcoma between 1 January 2016 and 1 October 2019 in the University Medical Center Groningen were included retrospectively. Three-dimensional models were created using the diagnostic magnetic resonance scan. Tumor volume was calculated for all patients. Three-dimensional tumor volume was 107.8 (349.1) mL in the group of patients that had undergone primary closure and 29.4 (47.4) mL in the group of patients in which a flap reconstruction was performed, p = 0.004. Three-dimensional tumor volume was 76.1 (295.3) mL in the group of patients with a complication following ESTS treatment, versus 57.0 (132.4) mL in patients with an uncomplicated course following ESTS treatment, p = 0.311. Patients who had undergone flap reconstruction had smaller tumor volumes compared to those in the group of patients treated by primary closure. Furthermore, a larger tumor volume did not result in complications for patients undergoing ESTS treatment. Therefore, tumor volume does not seem to influence the need for reconstruction. Despite the capability of three-dimensional virtual surgical planning to measure tumor volume, we do not recommend its utilization in the multidisciplinary extremity soft-tissue sarcoma treatment, considering the findings of the study. </p

Calculating Tumor Volume Using Three-Dimensional Models in Preoperative Soft-Tissue Sarcoma Surgical Planning:Does Size Matter?

This feasibility study aims to explore the use of three-dimensional virtual surgical planning to preoperatively determine the need for reconstructive surgery following resection of an extremity soft-tissue sarcoma. As flap reconstruction is performed more often in advanced disease, we hypothesized that tumor volume would be larger in the group of patients that had undergone flap reconstruction. All patients that were treated by surgical resection for an extremity soft-tissue sarcoma between 1 January 2016 and 1 October 2019 in the University Medical Center Groningen were included retrospectively. Three-dimensional models were created using the diagnostic magnetic resonance scan. Tumor volume was calculated for all patients. Three-dimensional tumor volume was 107.8 (349.1) mL in the group of patients that had undergone primary closure and 29.4 (47.4) mL in the group of patients in which a flap reconstruction was performed, p = 0.004. Three-dimensional tumor volume was 76.1 (295.3) mL in the group of patients with a complication following ESTS treatment, versus 57.0 (132.4) mL in patients with an uncomplicated course following ESTS treatment, p = 0.311. Patients who had undergone flap reconstruction had smaller tumor volumes compared to those in the group of patients treated by primary closure. Furthermore, a larger tumor volume did not result in complications for patients undergoing ESTS treatment. Therefore, tumor volume does not seem to influence the need for reconstruction. Despite the capability of three-dimensional virtual surgical planning to measure tumor volume, we do not recommend its utilization in the multidisciplinary extremity soft-tissue sarcoma treatment, considering the findings of the study. </p