Andrzej Przekwas

Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips

Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches are beginning to be integrated into drug development and approval processes because they enable key pharmacokinetic (PK) parameters to be predicted from in vitro data. However, these approaches are hampered by many limitations, including an inability to incorporate organ-specific differentials in drug clearance, distribution, and absorption that result from differences in cell uptake, transport, and metabolism. Moreover, such approaches are generally unable to provide insight into pharmacodynamic (PD) parameters. Recent development of microfluidic Organ-on-a-Chip (Organ Chip) cell culture devices that recapitulate tissue-tissue interfaces, vascular perfusion, and organ-level functionality offer the ability to overcome these limitations when multiple Organ Chips are linked via their endothelium-lined vascular channels. Here, we discuss successes and challenges in the use of existing culture models and vascularized Organ Chips for PBPK and PD modeling of human drug responses, as well as in vitro to in vivo extrapolation (IVIVE) of these results, and how these approaches might advance drug development and regulatory review processes in the future.

Synaptic Mechanisms of Blast-Induced Brain Injury.

Blast wave-induced traumatic brain injury (TBI) is one of the most common injuries to military personnel. Brain tissue compression/tension due to blast-induced cranial deformations and shear waves due to head rotation may generate diffuse micro-damage to neuro-axonal structures and trigger a cascade of neurobiological events culminating in cognitive and neurodegenerative disorders. Although diffuse axonal injury is regarded as a signature wound of mild TBI (mTBI), blast loads may also cause synaptic injury wherein neuronal synapses are stretched and sheared. This synaptic injury may result in temporary disconnect of the neural circuitry and transient loss in neuronal communication. We hypothesize that mTBI symptoms such as loss of consciousness or dizziness, which start immediately after the insult, could be attributed to synaptic injury. Although empirical evidence is beginning to emerge; the detailed mechanisms underlying synaptic injury are still elusive. Coordinated in vitro–in vivo experiments and mathematical modeling studies can shed light into the synaptic injury mechanisms and their role in the potentiation of mTBI symptoms.

Macro-Micro Biomechanics Finite Element Modeling of Brain Injury Under Concussive Loadings

Traumatic brain injury (TBI) occurs in many blunt, ballistic and blast impact events. During trauma axons in the white matter are especially vulnerable to injury due to the rapid mechanical loading of brain. The axonal pathology leads to cytoskeletal failure and disconnection. The microtubules are one of major structural components of the cytoskeleton filamentous network. By bridging the macroscopic forces acting on the whole brain with the cellular and subcellular failure, the macro-micro computational models in both time and space can help us better understand the complex biophysics and elucidate the injury mechanism of both severe and mild TBI (concussion). At the macroscopic scale we developed the high-fidelity anatomical human body finite element model (FEM) to predict intracranial pressures and strain and strain rate fields of brain in the blast event. The macro-scale models and the coupled blast and biomechanics approach were validated against test data of shock wave interacting with a surrogate head in the shock tube. The mechanical deformation of brain tissue was mapped to the white matter tracts to obtain local axonal strain and strain rate for the micromechanical models. We developed the micromechanical FEM of myelinated axons interconnected with the oligodendrocyte by the processes, utilizing a novel beam element free of rotational degrees of freedom (DOFs). The numerical results reveal the possible mechanism of impact-induced axon injury including demyelination, breakup of processes, and axonal varicosity. We also investigate the dynamic response of microtubules bundles under traumatic loading. Different from the commonly discrete bead-spring models, a network of microtubules cross-linked with microtubule-associated-protein (MAP) tau proteins was modeled by the nonlinear beam model. Tau protein is modeled by the rate-dependent bar element for its complicated material behavior. The model considers the rupture of microtubule and the failure of tau-tau interface and tau-microtubule interface. The simulation result of the combined effects of the failure of the cross-linked architecture and elongation and bending of the bundle are possibly correlated to the axonal undulations following traumatic loading observed in the experiments. The developed macro-micro biomechanics models can be used as a starting point for modeling the neurobiology effects and guide the design of novel injury protection strategies.Copyright

A New Level A Type IVIVC for the Rational Design of Clinical Trials Toward Regulatory Approval of Generic Polymeric Long-Acting Injectables.

Chronic neuropsychiatric disorders and diabetes mellitus affect millions of patients and require long-term supervision and expensive medical care. Although repeated drug administration can help manage these diseases, relapses and re-hospitalization owing to patient non-adherence and reduced therapeutic efficacy remain challenging. In response, long-acting injectables, which provide sustained drug release over longer periods at concentrations close to therapeutic ranges, have been proposed. Recent advancements include polymeric long-acting injectables (pLAIs), in which the active pharmaceutical ingredient (API) is encapsulated within U.S. Food and Drug Administration (FDA)-approved biocompatible polymers, such as poly(lactic-co-glycolic acid), or PLGA. Despite significant progress and development in the global pLAI market, FDA guidance for the approval of complex drug products, such as generic pLAIs, is not clearly defined. Although in vitro to in vivo correlation (IVIVC) can facilitate the identification of critical quality attributes (CQAs), drug formulations, and in vitro test platforms for evaluating drug performance in vivo, the application of IVIVC in order to shortlist time- and resource-intensive clinical trials for generic pLAIs has not been reported. Here, we propose a new Level A Type IVIVC that directly correlates the in vitro outcomes, such as drug dissolution, of candidate generic formulations with the clinical characteristics, such as drug absorption, of a reference listed drug (RLD), to help identify the specific generic pLAI formulations with clinical absorptions that are likely to be similar to that of the RLD, thereby reducing the number of clinical trials required for evaluation of clinical bioequivalence (BE). Therefore, the scope of the proposed method is intended only for the rational design of clinical trials, i.e., to shortlist the specific pLAI generic formulations for clinical BE evaluation, and not necessarily to analyze drug performances (i.e., drug safety and effectiveness) in the shortlisted clinical trials or post-approval. Once validated, this method will be of great value to developers of generic pLAIs and regulatory bodies to accelerate their approval of these generic pLAIs.

Computational Modeling of Blast Induced Human Injury Biomechanics and Traumatic Brain Injury

The work aims to understand the blast induced injury mechanism and facilitate the development of protection and treatment. Novel multi-scale and multi-physics computational models of coupled blast physics, whole body biodynamics and injury biomechanics are presented. Modeling components include blast wave threat characterization, anatomy-based high-fidelity human model, human body blast loading, biodynamics and body/brain biomechanics leading to primary injury, as well as the multi-physics solver suitable for high-performance computing. The coupled gas dynamics and biomechanics solutions were validated against shock tube test data. The parametric simulations of human body exposed to blasts were conducted to find biomechanical responses and brain injury mechanism.

A Fast Running Model for Skeletal Impact Biomechanics Analysis

Skeletal trauma occurs in many blunt, ballistic and blast impact events. Even though the personal body armors and protective equipment were effective in stopping the penetration of bullets or fragments, the resulting impact loading could lead to the significant injuries and fractures to the thoracic skeleton and extremities. The finite element (FEM) method, with its capability to handle complex geometries and nonlinear materials, are commonly used to analyze the tissue biomechanical responses and correlate the simulation results with the injury outcomes. However, it is very difficult to construct the three-dimensional (3D) FEM model for the skeletal biomechanics analysis because of the complex geometry and different materials involved. Moreover the simulation of 3D FEM model is computationally expensive because both small element size and high speed of sound in materials lead to very small time step in an explicit transient analysis. The simulation process is often not robust enough when the model experiences the large deformation. To shorten modeling and simulation times, we have developed a fast running model based on a novel nonlinear beam element for the skeletal impact biomechanics analysis. In contrast to the conventional beam elements, the kinematics of the developed beam element is free of rotational degrees of freedom (DOFs). The current beam element offers the desired constant lumped mass matrix for the large deformable explicit transient analysis. The realistic treatment of junctions and surface intersections among beams becomes straightforward. Furthermore the model can account for the irregular shape and different materials at beam cross sections by using the numerical integration. The sophisticated material models such as elastoplasticity can also be incorporated directly in the integration points. Thus the fast running model is suitable for the analysis of complex nonlinear composite structures such as the loading-carrying thoracic skeleton and extremities. The stereolithograph (STL)-based anatomical geometry of skeletal structure is used to extract the one-dimensional (1D) curved beam model and the associated beam cross sections. The anatomical surface of skeleton is also utilized for the calculation of transferred loads to the underlined beams. The 3D responses such as displacements and stresses from the fast running model are subsequently reconstructed on the anatomical surface for the visualization and skeletal trauma analysis. We demonstrate the efficiency of such modeling technique by simulating the rib cage and the lower extremity under the impact loadings. As compared to the 3D FEM model, the developed model runs fast and robust, and achieves good results without the need of laborious 3D meshing process.Copyright