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Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

ABSTRACT: Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

SUBMITTER: Maschmeyer I

PROVIDER: S-EPMC6574126 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

Maschmeyer Ilka I Hasenberg Tobias T Jaenicke Annika A Lindner Marcus M Lorenz Alexandra Katharina AK Zech Julie J Garbe Leif-Alexander LA Sonntag Frank F Hayden Patrick P Ayehunie Seyoum S Lauster Roland R Marx Uwe U Materne Eva-Maria EM

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 20150406 Pt A

Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized ...[more]

PMID: 25857839

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Project description:Background and aimsThe integration of 12-Step philosophy and practices is common in adolescent substance use disorder (SUD) treatment programs, particularly in North America. However, although numerous experimental studies have tested 12-Step facilitation (TSF) treatments among adults, no studies have tested TSF-specific treatments for adolescents. We tested the efficacy of a novel integrated TSF.DesignExplanatory, parallel-group, randomized clinical trial comparing 10 sessions of either motivational enhancement therapy/cognitive-behavioral therapy (MET/CBT; n = 30) or a novel integrated TSF (iTSF; n = 29), with follow-up assessments at 3, 6 and 9 months following treatment entry.SettingOut-patient addiction clinic in the United States.ParticipantsAdolescents [n = 59; mean age = 16.8 (1.7) years; range = 14-21; 27% female; 78% white].Intervention and comparatorThe iTSF integrated 12-Step with motivational and cognitive-behavioral strategies, and was compared with state-of-the-art MET/CBT for SUD.MeasurementsPrimary outcome: percentage days abstinent (PDA); secondary outcomes: 12-Step attendance, substance-related consequences, longest period of abstinence, proportion abstinent/mostly abstinent, psychiatric symptoms.FindingsPrimary outcome: PDA was not significantly different across treatments [b = 0.08, 95% confidence interval (CI) = -0.08 to 0.24, P = 0.33; Bayes' factor = 0.28).Secondary outcomesduring treatment, iTSF patients had substantially greater 12-Step attendance, but this advantage declined thereafter (b = -0.87; 95% CI = -1.67 to 0.07, P = 0.03). iTSF did show a significant advantage at all follow-up points for substance-related consequences (b = -0.42; 95% CI = -0.80 to -0.04, P < 0.05; effect size range d = 0.26-0.71). Other secondary outcomes did not differ significantly between treatments, but effect sizes tended to favor iTSF. Throughout the entire sample, greater 12-Step meeting attendance was associated significantly with longer abstinence during (r = 0.39, P = 0.008), and early following (r = 0.30, P = 0.049), treatment.ConclusionCompared with motivational enhancement therapy/cognitive-behavioral therapy (MET/CBT), in terms of abstinence, a novel integrated 12-Step facilitation treatment for adolescent substance use disorder (iTSF) showed no greater benefits, but showed benefits in terms of 12-Step attendance and consequences. Given widespread use of combinations of 12-Step, MET and CBT in adolescent community out-patient settings in North America, iTSF may provide an integrated evidence-based option that is compatible with existing practices.

Dataset Information

Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

Publications

Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

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