Towards a Physiological Scale of Vocal Fold Agent-Based Models of Surgical Injury and Repair: Sensitivity Analysis, Calibration and Verification

Abstract

Agent based models (ABM) were developed to numerically simulate the biological response to surgical vocal fold injury and repair at the physiological level. This study aimed to improve the representation of existing ABM through a combination of empirical and computational experiments. Empirical data of vocal fold cell populations including neutrophils, macrophages and fibroblasts were obtained using flow cytometry up to four weeks following surgical injury. Random Forests were used as a sensitivity analysis method to identify model parameters that were most influential to ABM outputs. Statistical Parameter Optimization Tool for Python was used to calibrate those parameter values to match the ABM-simulation data with the corresponding empirical data from Day 1 to Day 5 following surgery. Model performance was evaluated by verifying if the empirical data fell within the 95% confidence intervals of ABM outputs of cell quantities at Day 7, Week 2 and Week 4. For Day 7, all empirical data were within the ABM output ranges. The trends of ABM-simulated cell populations were also qualitatively comparable to those of the empirical data beyond Day 7. Exact values, however, fell outside of the 95% statistical confidence intervals. Parameters related to fibroblast proliferation were indicative to the ABM-simulation of fibroblast dynamics in final stages of wound healing.

Progress in Vocal Fold Regenerative Biomaterials: An Immunological Perspective

“…However, to effectively resolve inflammation and promote healing, M2 polarization would be required to succeed M1 as the dominant local population of macrophages. Such speculations of vocal fold macrophage polarizations were observed in the animal study [44] and later confirmed by Kishimoto's research team. [40] Also, fibroblastÀmyofibroblast transdifferentiation was observed in the same animal study, emulating in vitro studies, subjecting vocal fold fibroblasts to growth factor stimulations from Thibeault's and Kishimoto's research teams, respectively.…”

“…Fibroblasts were abundantly populated across all layers of the lamina propria, with the highest number found in the deep lamina propria (DLP). [38] Upon injury to the lamina propria, rapid neutrophil and monocyte recruitment from peripheral capillaries occurs, as demonstrated across experimental models of mice, [40] rats, [41][42][43][44] rabbits, [45] and pigs. [46,47] Li-Jessen's team applied multicolor flow cytometry to characterize temporal trajectories of neutrophils…”

“…in surgically injured rat vocal folds. [44] In particular, nonpolarized, basal macrophages were expected to dominate the local macrophage population of the vocal folds. Following injury, M1 polarization would be significantly upregulated during the initial, proinflammatory response.…”

An in vitro assessment of the response of THP‐1 macrophages to varying stiffness of a glycol‐chitosan hydrogel for vocal fold tissue engineering applications

“…Specifically, VFFs represent the most abundant cell type found within the lamina propria where they serve to maintain and repair the vocal fold mucosa 22‐24 . VFFs have been recognized for their mechanosensitive and immunomodulatory properties including their ability to suppress pro‐inflammatory cytokine production 25‐28 . Fibroblast‐like cells have been suggested to have some behavioral capacities similar to innate immune cells and also play a role in inflammatory resolution 29 .…”

Prolactin may serve as a regulator to promote vocal fold wound healing

“…GSEA results showed that the inhibitors of PRL influenced by wounding were mainly involved in interferon-gamma signaling, epithelial cell and endothelial cell proliferation, wound healing and growth factor responds, which were suggested to associate with VF wound healing [19][20][21][22]. These results indicated that VF wound might up-regulate these pathways that influence the secretion of prolactin.…”