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Generation of Warfighter Avatars from Weapon Training Scene Images for Blast Exposure Simulations

Military personnel involved in weapon training are subjected to repeated low-level blasts. The prevailing method of estimating blast loads involves ...

CFD RESEARCH CORPORATION

Subject-specific computer models (male and female) of the human head were used to investigate the possible axonal deformation resulting from the primary phase blast-induced skull flexures. The corresponding axonal tractography was explicitly incorporated into these finite element models using a recently developed technique based on the embedded finite element method. These models were subjected to extensive verification against experimental studies which examined their pressure and displacement response under a wide range of loading conditions. Once verified, a parametric study was developed to investigate the axonal deformation for a wide range of loading overpressures and directions as well as varying cerebrospinal fluid (CSF) material models. This study focuses on early times during a blast event, just as the shock transverses the skull (< 5 milliseconds). Corresponding boundary conditions were applied to eliminate the rotation effects and the resulting axonal deformation. A total of 138 simulations were developed- 128 simulations for studying the different loading scenarios and 10 simulations for studying the effects of CSF material model variance-leading to a total of 10,702 simulation core hours. Extreme strains and strain rates along each of the fiber tracts in each of these scenarios were documented and presented here. The results suggest that the blast-induced skull flexures result in strain rates as high as 150-378 s-1. These high-strain rates of the axonal fiber tracts, caused by flexural displacement of the skull, could lead to a rate dependent micro-structural axonal damage, as pointed by other researchers.

Do blast induced skull flexures result in axonal deformation?

The purpose of this paper is to propose and develop a large strain embedded finite element formulation that can be used to explicitly model axonal fiber bundle tractography from diffusion tensor imaging of the brain. Once incorporated, the fibers offer the capability to monitor tract-level strains that give insight into the biomechanics of brain injury. We show that one commercial software has a volume and mass redundancy issue when including embedded axonal fiber and that a newly developed algorithm is able to correct this discrepancy. We provide a validation analysis for stress and energy to demonstrate the method.

Embedded Finite Elements for Modeling Axonal Injury.

The delivery of therapeutic drugs through the skin is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (DSs) offer unique advantages, such as controlled drug release over sustained periods and a significant reduction in first-pass effects, thus reducing the required dosing frequency and the level of patient noncompliance. Furthermore, DSs find applications in multiple therapeutic areas, including drug repurposing. This article presents an integrated biophysical model of dermal absorption for simulating the permeation and absorption of compounds delivered transdermally. The biophysical model is physiologically/biologically inspired and combines a holistic model of healthy skin with whole-body physiology-based pharmacokinetics through the dermis microcirculation. The model also includes the effects of chemical penetration enhancers and hair follicles on transdermal transport. The model-predicted permeation and pharmacokinetics of select compounds were validated using in vivo data reported in the literature. We conjecture that the integrated model can be used to gather insights into the permeation and systemic absorption of transdermal formulations (including cosmetic products) released from novel depots and to optimize delivery systems. Furthermore, the model can be extended to diseased skin with parametrization and structural adjustments specific to skin diseases.

An integrated biophysical model for predicting the clinical pharmacokinetics of transdermally delivered compounds.

To investigate in vitro transdermal delivery of tofacitinib citrate across human skin using microporation by microneedles and iontophoresis alone and in combination.

Microneedle Mediated Iontophoretic Delivery of Tofacitinib Citrate.

Psoriasis is a condition of the skin which involves scales, dry patches, and inflammation. Methotrexate (logP: -1.8, MW:454.44 g/mol) is administered orally or intravenously to treat psoriasis. The first-pass metabolism and systemic toxicity can be avoided by administration via skin. Topical and transdermal delivery of methotrexate using iontophoresis and microneedles, alone and in combination was investigated using full-thickness healthy human skin. It is also equally relevant to evaluate the delivery into and across damaged/diseased skin. Hence, this study investigated the delivery of methotrexate using ex vivo healthy and psoriatic human skin to understand the effect of skin disease condition on delivery of methotrexate via skin. A lower resistance and a higher TEWL for psoriatic skin indicated damaged barrier function, while histology studies indicated epithelial hyperproliferation and elongated rete ridges. Using the optimized iontophoretic parameters, there was no significant difference in receptor delivery for psoriatic skin (39.51 ± 4.45 µg/sq.cm) as compared to healthy skin (43.15 ± 0.83 µg/sq.cm). However, methotrexate delivery into psoriatic skin (126.23 ± 24.65 µg/sq.cm) was significantly higher as compared to healthy skin (12.02 ± 4.89 µg/sq.cm). Thus, significantly higher total delivery was observed from psoriatic skin than healthy skin.

Microneedle and iontophoresis mediated delivery of methotrexate into and across healthy and psoriatic skin.

Application of drugs on skin with compromised barrier can significantly alter permeation of drugs with the possibility of increased adverse side effects or even toxicity. In this study, we tested in vitro delivery of diclofenac sodium from marketed brand and generic formulations across normal and compromised skin using microneedles and iontophoresis, alone and in combination. Ten tape strips on dermatomed human skin were used to create a compromised skin model, as demonstrated by changes in skin resistance and transepidermal water loss. Histology studies further confirmed creation of a compromised skin barrier. There was no significant difference between brand and generic formulations for delivery of diclofenac sodium into and across normal and compromised skin. Compromised skin showed higher total delivery (µg/sq.cm) of diclofenac sodium for all groups - microneedles (brand: 79.45 ± 8.81, generic: 92.15 ± 8.63), iontophoresis (brand: 233.13 ± 8.32, generic: 242.07 ± 11.17), combination (brand: 186.88 ± 6.76, generic: 193.8 ± 5.69) as compared to intact normal skin for same groups, microneedles (brand: 21.83 ± 1.96, generic: 20.38 ± 0.91), iontophoresis (brand: 149.78 ± 18.43, generic: 145.53 ± 12.61), and combination (brand: 80.97 ± 9.86, generic: 70.76 ± 6.56). These results indicate the effect of barrier integrity on delivery of diclofenac sodium which suggests increased absorption and systemic exposure of the drug across skin with compromised skin barrier.

Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis.

Blast induced Traumatic Brain Injury (bTBI) has become a signature casualty of military operations. Recently, military medics observed neurocognitive deficits in servicemen exposed to repeated low level blast (LLB) waves during military heavy weapons training. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics and mechanobiology of sensitive neuro-structures such as synapses may help in better understanding of injury mechanisms and in the development of improved diagnostics and neuroprotective strategies.

Mathematical model of mechanobiology of acute and repeated synaptic injury and systemic biomarker kinetics.

The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery methods, such as tablets and injections. In the context of drug development, it is crucial to identify the optimal doses and delivery routes that ensure successful outcomes. Physiologically based pharmacokinetic (PBPK) models have been proposed to simulate drug delivery and optimize drug formulations, but the calibration of these models is challenging due to the multitude of variables involved and limited experimental data. One significant research gap that this article addresses is the need for more efficient and accurate methods for calibrating PBPK models for dermal drug delivery. This manuscript presents a novel approach and an integrated dermal drug delivery model to address this gap that leverages virtual in vitro release (IVRT) and permeation (IVPT) testing data to optimize mechanistic models. The proposed approach was demonstrated through a study involving Desoximetasone cream and ointment formulations, where the release kinetics and permeation profiles of Desoximetasone were determined experimentally, and a computational model was created to simulate the results. The experimental studies showed that, even though the cumulative permeation of Desoximetasone at the end of the permeation study was comparable, there was a significant difference seen in the lag time in the permeation of Desoximetasone between the cream and ointment. Additionally, there was a significant difference seen in the amount of Desoximetasone permeated through human cadaver skin at early time points when the cream and ointment were compared. The computational model was optimized and validated, suggesting that this approach has the potential to bridge the existing research gap by improving the accuracy and efficiency of drug development processes. The model results show a good fit between the experimental data and model predictions. During the model optimization process, it became evident that there was variability in both the permeability and the partition coefficient within the stratum corneum. This variability had a significant and noteworthy influence on the overall performance of the model, especially when it came to its capacity to differentiate between cream and ointment formulations. Leveraging virtual models significantly aids the comprehension of drug release and permeation, mitigating the demanding data requirements. The use of virtual IVRT and IVPT data can accelerate the calibration of PBPK models, streamline the selection of the appropriate doses, and optimize drug delivery. Moreover, this novel approach could potentially reduce the time and resources involved in drug development, thus making it more cost-effective and efficient.

Article	Year
Do blast induced skull flexures result in axonal deformation? PloS one\| PubMed ID: 29547663	2018
Embedded Finite Elements for Modeling Axonal Injury. Annals of biomedical engineering\| PubMed ID: 30519759	2019
An integrated biophysical model for predicting the clinical pharmacokinetics of transdermally delivered compounds. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences\| PubMed ID: 34289340	2021
Microneedle Mediated Iontophoretic Delivery of Tofacitinib Citrate. Pharmaceutical research\| PubMed ID: 35174431	2023
Microneedle and iontophoresis mediated delivery of methotrexate into and across healthy and psoriatic skin. International journal of pharmaceutics\| PubMed ID: 35331833	2022
Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis. International journal of pharmaceutics\| PubMed ID: 36220591	2022
Mathematical model of mechanobiology of acute and repeated synaptic injury and systemic biomarker kinetics. Frontiers in cellular neuroscience\| PubMed ID: 36814869	2023
A Comparative Evaluation of Desoximetasone Cream and Ointment Formulations Using Experiments and In Silico Modeling. International journal of molecular sciences\| PubMed ID: 37894801	2023

Harsha T. Garimella

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