A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.

Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood-brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.

An Individual Patient's "Body" on Chips-How Organismoid Theory Can Translate Into Your Personal Precision Therapy Approach.

The first concepts for reproducing human systemic organismal biology in vitro were developed over 12 years ago. Such concepts, then called human- or body-on-a-chip, claimed that microphysiological systems would become the relevant technology platform emulating the physiology and morphology of human organisms at the smallest biologically acceptable scale in vitro and, therefore, would enable the selection of personalized therapies for any patient at unprecedented precision. Meanwhile, the first human organoids-stem cell-derived complex three-dimensional organ models that expand and self-organize in vitro-have proven that in vitro self-assembly of minute premature human organ-like structures is feasible, once the respective stimuli of ontogenesis are provided to human stem cells. Such premature organoids can precisely reflect a number of distinct physiological and pathophysiological features of their respective counterparts in the human body. We now develop the human-on-a-chip concepts of the past into an organismoid theory. We describe the current concept and principles to create a series of organismoids-minute, mindless and emotion-free physiological in vitro equivalents of an individual's mature human body-by an artificially short process of morphogenetic self-assembly mimicking an individual's ontogenesis from egg cell to sexually mature organism. Subsequently, we provide the concept and principles to maintain such an individual's set of organismoids at a self-sustained functional healthy homeostasis over very long time frames in vitro. Principles how to perturb a subset of healthy organismoids by means of the natural or artificial induction of diseases are enrolled to emulate an individual's disease process. Finally, we discuss using such series of healthy and perturbed organismoids in predictively selecting, scheduling and dosing an individual patient's personalized therapy or medicine precisely. The potential impact of the organismoid theory on our healthcare system generally and the rapid adoption of disruptive personalized T-cell therapies particularly is highlighted.

Supporting dataset of two integration-free induced pluripotent stem cell lines from related human donors.

Integration-free induced pluripotent stem cells from related human donors' exhibit great potential to the ongoing development of organ models. Blood cells from two different human donors were isolated, purified and reprogrammed into induced pluripotent stem cells. These induced pluripotent stem cell lines were characterized precisely for pluripotency markers (with the PluriTest and flow cytometry analysis) and their differentiation capacities into meso-, ecto- and endoderm. The induced pluripotent stem cell lines are available for commercial use and are therefore of high interest for many groups working in stem cell research. A normal karyotype of the induced pluripotent stem cells was proven with the KaryoStat assay. In total 6 human donors that belong to one family donated blood for induced pluripotent stem cell reprogramming. In this "Data in Brief" publication, we show the dataset for the two male iPSC lines HUMIMIC TISSUi006-A (StemUse106) and TISSUi007-A (StemUse107). The main characterisation was recently published by Ramme et al. in Stem Cell Research [1]. All iPSC lines were also examined negative for any mycoplasma or bacteria contamination.

Generation of two additional integration-free iPSC lines from related human donors.

The integration-free iPSC lines TISSUi006-A and TISSUi007-A were generated by reprogramming blood cells with episomal vectors. The male human donors belong to a Caucasian family in which four additional family members donated and iPSC lines were generated. All iPSC lines within this family are approved for commercial use by donor consent. Those iPSC lines offer the opportunity to study the influence of affiliation within one family. In future, more iPSCs lines of many more family members can be created to understand the effects of relatives with different ages on the reprogramming into iPSCs and differentiation into specific cell types.

Generation of four integration-free iPSC lines from related human donors.

Four integration-free iPSC lines were generated by reprogramming peripheral blood mononuclear cells with episomal vectors. All four human donors (two male and two female donors) belong to one Caucasian family within three different generations with the age between 19-82 years. Additionally, all iPSC lines are approved for commercial use by donor consent. Those iPSC lines offer the opportunity to study the influence of affiliation within one family. In future, more iPSCs lines of many more family members can be created to understand the effects of relatives with different ages on the reprogramming into iPSCs and differentiation into specific cell types.

Autologous induced pluripotent stem cell-derived four-organ-chip.

Microphysiological systems play a pivotal role in progressing toward a global paradigm shift in drug development. Here, we designed a four-organ-chip interconnecting miniaturized human intestine, liver, brain and kidney equivalents. All four organ models were predifferentiated from induced pluripotent stem cells from the same healthy donor and integrated into the microphysiological system. The coculture of the four autologous tissue models in one common medium deprived of tissue specific growth factors was successful over 14-days. Although there were no added growth factors present in the coculture medium, the intestine, liver and neuronal model maintained defined marker expression. Only the renal model was overgrown by coexisting cells and did not further differentiate. This model platform will pave the way for autologous coculture cross-talk assays, disease induction and subsequent drug testing.