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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.

The connective hard tissues bone and teeth are highly porous on a micrometer scale, but show high values of compression strength at a relatively low weight. The fabrication of porous materials has been actively researched and different processes have been developed that vary in preparation complexity and also in the type of porous material that they produce. Methodologies are available for determination of pore properties. The purpose of the paper is to give an overview of these methods, the role of porosity in natural porous materials and the effect of pore properties on the living tissues. The minimum pore size required to allow the ingrowth of mineralized tissue seems to be in the order of 50 µm: larger pore sizes seem to improve speed and depth of penetration of mineralized tissues into the biomaterial, but on the other hand impair the mechanical properties. The optimal pore size is therefore dependent on the application and the used material.

Here we describe of an 'Interrogator' instrument that uses liquid-handling robotics, a custom software package, and an integrated mobile microscope to enable automated culture, perfusion, medium addition, fluidic linking, sample collection, and in situ microscopic imaging of up to 10 Organ Chips inside a standard tissue culture incubator. The automated Interrogator platform maintained the viability and organ-specific functions of 8 different vascularized, 2-channel, Organ Chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier (BBB), and brain) for 3 weeks in culture when fluidically coupled through their endothelium-lined vascular channels using a common blood substitute medium. When an inulin tracer was perfused through the multi-organ Human Body-on-Chips (HuBoC) fluidic network, quantitative distributions of this tracer could be accurately predicted using a physiologically-based multi-compartmental reduced order (MCRO) in silico model of the experimental system derived from first principles. This automated culture platform enables non-invasive imaging of cells within human Organ Chips and repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling, which should facilitate future HuBoc studies and pharmacokinetics (PK) analysis in vitro.Vascularized human Organ Chips are microfluidic cell culture devices containing separate vascular and parenchymal compartments lined by living human organ-specific cells that recapitulate the multicellular architecture, tissue-tissue interfaces, and relevant physical microenvironments of key functional units of living organs, while providing vascular perfusion in vitro 1,2 . The growing recognition that animal models do not effectively predict drug responses in humans 3-5 and the related increase in demand for in vitro human toxicity and efficacy testing, has led to pursuit of time-course analyses of human Organ Chip models and fluidically linked,