An update on microfluidic multi-organ-on-a-chip systems for reproducing drug pharmacokinetics: the current state-of-the-art

Figures & data

Table 1. Scopus.com database query terms.

Field of research		Query start	Field term	Year of publication term	SARS-CoV-2 term	Article or review term
Organ-on-a-chip		((TITLE-ABS-KEY(	organ-on-a-chip OR organ-on-chip OR	)AND PUBYEAR > 2009 AND PUBYEAR < 2024))		AND (LIMIT-TO (DOCTYPE,‘ar’))
	Body & MT		body-on-a-chip OR body-on-chip OR human-on-a-chip OR human-on-chip OR multi-tissue-on-a-chip OR multi-tissue-on-chip OR multi-organ-on-a-chip OR multi-organ-on-chip OR
	Liver		liver-on-a-chip OR liver-on-chip OR
	Brain		brain-on-a-chip OR brain-on-chip
	Gut		gut-on-a-chip OR gut-on-chip OR
	Kidney		kidney-on-a-chip OR kidney-on-chip OR		AND (sars-cov-2 OR covid-19)	AND (LIMIT-TO (DOCTYPE,‘re’))
	Lung		lung-on-a-chip OR lung-on-chip OR alveola-on-a-chip OR alveola-on-chip OR
	Barrier		barrier-on-a-chip OR barrier-on-chip OR
	Vascular		vasculature-on-a-chip OR vasculature-on-chip OR vascular-on-a-chip OR vascular-on-chip

Figure 1. Number of original articles and reviews published between 2010 and 2023 in the organ-on-a-chip field. (a) Publication rate of articles and reviews with the terms organ, or body and multi tissue -on-a-chip over the last decade and a half (b) and detailed view on articles and reviews for the terms body- and multi tissue-organ-on-a-chip (red area represents publications containing the keywords for SARS-CoV-2). (c) Publications of common organ-on-a-chip models over the last 24 years. (d) Term distribution of the publication number of various organ-on-a-chip models before and after the year 2020. Yellow, colored background shows the division between pre- and post-pandemic research. Information was gathered through SCOPUS query displayed in Table 1.

Table 2. Overview of the discussed papers.

Study	Cell types	Duration	Perfusion type	Perfusion rate	Integrated sensors	Tested drugs
F. Yin et al.	iPSC, Liver, Heart	20 Days	—	—	—	Clomipramine
R. Zandi Shafagh et al.	primary human hepatocytes (PHH), Primary human pancreatic islets	1–6 h 5–7 Days	Self-developed pressure pump	85 µL at 100 μL/min every 4 h	—	—
M. J. Rupar et al.	Primary human hepatocytes, Human umbilical vein endothelial cells (HUVEC), Primary human splenocytes, P. falciparum	8 Days	—	—	—	Chloroquine phosphate
S. A. P. Rajan et al.	See Article Table 1	14 and 21 Days	Peristaltic	4 μL/min	—	Capecitabine, Ifosfamide
K. Ronaldson-Bouchard et al.	See Article Section ‘METHOD − 3’	4 Weeks	Peristaltic	1.88 dynes/cm^2	—	—

Figure 2. Overview on three multi-tissue on-a-chip models. (ai) Design of a liver-heart chip with a polycarbonate membrane between cell types. (aii) Seeding assay to create liver and heart organoids in unique compartments inside the chip. (aiii) Effect of 1 µM Clomipramine on the beating velocity of the heart spheroids after liver metabolism. (aiv) Effect of 1 µM Clomipramine on the Ca²⁺ ion production of the heart spheroids in different culture conditions. (bi) Seeding procedure of pancreatic islets and liver spheroids into a pneumatic chip. (bii) Overlap of differentially expressed genes in liver spheroids and pancreatic islets after high glucose exposure in chip. (ci) 3 organ-on-a-chip system developed for malaria studies together with a flow profile simulation of the system. (cii) Over-time hepatocyte morphology and viability assay (via CYP3A4 activity) while inside.

The 3 organ system. (ciii) Response of malaria strain 3D7 to various doses of chloroquine inside the multi-tissue system. (civ) Response of resistant malaria strain W2 to various doses of chloroquine inside the multi-tissue system. [Adapted with permission from [40–42]]

Figure 3. Overview of a humanized multi-organ on-a-chip platform for drug metabolism and toxicity testing. (ai) Schematic designs for 3 and 6 integrated organoid systems. (aii) Pipetting assay schematics for a thiolated-hydrogel-based cell 3D culture. (aiii) Photography of a multi-organ system with external fluid flow control. (b) Viability study of the effects of ifosfamide on a 6-organoid system (bi) Counterstain of life (calcein AM) and death cells (ethidium homodimer 1) of all 6 organs in the system. condition 1 and 2 are treatment with 1 mM ifosfamide but in condition 2 the liver was removed before treatment. (bii) Quantification of life/dead staining, viability is shown as percentage. [Adapted with permission from [43]].

Figure 4. (a) Design of a multi-organ platform with shared fluid dynamics. (ai) final assembled platform. (aii) top and bottom views of the platform. (aiii) Schematic for modular connections of various multi-organ platforms. (aiv) alternative design for mono- and bi-organ cultures. (av) Computational simulation of shear stress on the system. (b) Cardiac tissues after maturation, (bi) α-actin alignment. (bii) Capture rate (biii) Excitation threshold. (biv) force response depending on calcium concentration. (c) Liver tissues after maturation (ci) Immunohistochemical staining images, (cii) Albumin secretion. (di) Immunohistochemical staining of engineered bone slices. (dii) Bone density over time. (ei) Immunohistochemical staining of engineered skin slices. (eii) Skin barrier function measured via TEER. [Adapted with permission from [38]].

Figure 5. Summary on the current challenges in body-on-a-chip systems.

Rajan SAP, Aleman J, Wan M, et al. Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform. Acta Biomaterialia. 2020;106:124–135. doi: 10.1016/j.actbio.2020.02.015

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Adam Kratz SR, Höll G, Schuller P, et al. Latest trends in biosensing for microphysiological organs-on-a-chip and body-on-a-chip systems. Biosensors (Basel) [Internet]. 2019 [cited 2023 Apr 3];9:110. Available from: https://www.mdpi.com/2079-6374/9/3/110/htm

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