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.

Enhanced capture of magnetic microbeads using combination of reduced magnetic field strength and sequentially switched electroosmotic flow--a numerical study.

Magnetophoretic immunoassay is a widely used technique in lab-on-chip systems for detection and isolation of target cells, pathogens, and biomolecules. In this method, target pathogens (antigens) bind to specific antibodies coated on magnetic microbeads (mMBs) which are then separated using an external magnetic field for further analysis. Better capture of mMB is important for improving the sensitivity and performance of magnetophoretic assay. The objective of this study was to develop a numerical model of magnetophoretic separation in electroosmotic flow (EOF) using magnetic field generated by a miniaturized magnet and to evaluate the capture efficiency (CE) of the mMBs. A finite-volume solver was used to compute the trajectory of mMBs under the coupled effects of EOF and external magnetic field. The effect of steady and time varying (switching) electric fields (150-450 V/cm) on the CE was studied under reduced magnetic field strength. During switching, the electric potential at the inlet and outlet of the microchannel was reversed or switched, causing reversal in flow direction. The CE was a function of the momentum of the mMB in EOF and the applied magnetic field strength. By switching the electric field, CE increased from 75% (for steady electric field) to 95% for lower electric fields (150-200 V/cm) and from 35% to 47.5% for higher electric fields (400-450 V/cm). The CE was lower at higher EOF electric fields because the momentum of the mMB overcame the external magnetic force. Switching allowed improved CE due to the reversal and decrease in EOF velocity and increase in mMB residence time under the reduced magnetic field strength. These improvements in CE, particularly at higher electric fields, made sequential switching of EOF an efficient separation technique of mMBs for use in high throughput magnetophoretic immunoassay devices. The reduced size of the magnet, along with the efficient mMB separation technique of switching can lead to the development of portable device for detection of target cells, pathogens, and biomolecules.

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

The delivery of therapeutic drugs through the skin is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (D3Ss) 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, D3Ss 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.

Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips.

Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.

Robotic fluidic coupling and interrogation of multiple vascularized organ chips.

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an 'interrogator' that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.

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.

Bioresorption and degradation of biomaterials.

The human body is a composite structure, completely constructed of biodegradable materials. This allows the cells of the body to remove and replace old or defective tissue with new material. Consequently, artificial resorbable biomaterials have been developed for application in regenerative medicine. We discuss here advantages and disadvantages of these bioresorbable materials for medical applications and give an overview of typically used metals, ceramics and polymers. Methods for the quantification of bioresorption in vitro and in vivo are described. The next challenge will be to better understand the interface between cell and material and to use this knowledge for the design of "intelligent" materials that can instruct the cells to build specific tissue geometries and degrade in the process.

A mathematical model of effects on specific joints during practice of the Sun Salutation--a sequence of yoga postures.

The 'Sun Salutation' consists of a sequence of ten yoga postures, each posture counteracting the preceding one producing a balance between flexion and extension, performed with synchronized breathing and aerobic activity. As this sequence is often performed and recommended by many yoga practitioners, there is a need for the development of a biomechanical model to support its reported clinical benefits. This requires a detailed knowledge of the nature of the forces and moments at the various joints involved. A simple mathematical model based on rigid body mechanics is developed for each of the Sun Salutation postures. Dynamic moments with high magnitudes and rates, applied with unusual distribution patterns, optimal for osteogenesis, are found to occur. Also, the joints are subjected to submaximal loadings thus ensuring that none of the joints are overstressed.

Motion analysis of sun salutation using magnetometer and accelerometer.

BACKGROUND: Sun salutation is a part of yoga. It consists of a sequence of postures done with synchronized breathing. The practice of few cycles of sun salutation is known to help in maintaining good health and vigor. The practice of sun salutation does not need any extra gadgets. Also it is very much aerobic and invigorates the body and the mind. sun salutation, which comprises 10 postures, involves most of the joints of the body. Understanding the transition phase during motion is a challenging task, and thus, new convenient methods need to be employed. AIMS: The purpose of this study was to get an insight into the motion analysis of sun salutation during the transition from each of the 10 postures. MATERIALS AND METHODS: A device MicroStrain sensor 3DM-GX1, which is a combination of magnetometers, accelerometers, and gyroscopes was used to measure the inclination and the acceleration of the body along the three axes. The acceleration obtained was then separated into gravitational and kinematic components. RESULTS AND CONCLUSIONS: The value of the gravitational component helps us to understand the position of the body and the kinematic component helps us to analyze the grace of the motion.