Human-Derived Organ-on-a-Chip for Personalized Drug Development

Abstract

To reduce the required capital and time investment in the development of new pharmaceutical agents, there is an urgent need for preclinical drug testing models that are predictive of drug response in human tissues or organs. Despite tremendous advancements and rigorous multistage screening of drug candidates involving computational models, traditional cell culture platforms, animal models and most recently humanized animals, there is still a large deficit in our ability to predict drug response in patient groups and overall attrition rates from phase 1 through phase 4 of clinical studies remain well above 90%. Organ-on-a-chip (OOC) platforms have proven potential in providing tremendous flexibility and robustness in drug screening and development by employing engineering techniques and materials. More importantly, in recent years, there is a clear upward trend in studies that utilize human-induced pluripotent stem cell (hiPSC) to develop personalized tissue or organ models. Additionally, integrated multiple organs on the single chip with increasingly more sophisticated representation of absorption, distribution, metabolism, excretion and toxicity (ADMET) process are being utilized to better understand drug interaction mechanisms in the human body and thus showing great potential to better predict drug efficacy and safety. In this review, we summarize these advances, highlighting studies that took the next step to clinical trials and research areas with the utmost potential and discuss the role of the OOCs in the overall drug discovery process at a preclinical and clinical stage, as well as outline remaining challenges.

Keywords: Organ-on-a-chip; drug development; human-derived induced pluripotent stem cells; microfluidic technology; personalized medicine; tissue engineering..

Figure 1.

Schematic of the cycle used in OOCs for personalized medicine. The cells are derived from patient and cultured and reprogrammed to different cell types. The device is fabricated using various microfabrication and 3D printing techniques. Next, the printed cells are seeded and cultured on the device. The target drug candidates are tested and analyzed using the OOC model followed by in vivo test. Next, the drug dosage and type are decided based on the responses received from the in vivo and OOC device and are later scaled to achieve the personalized drug for the patient.

Figure 2.

Schematic showing microwell array PDMS plate based liver-on-a-chip device. (B) Generated 3D spheroids (mono-culture and co-cultured) on day 3 and 8. Reproduced from Lee et al (58) with permission from The Royal Society of Chemistry. (C) Hydrogel-based 3D bioprinted hepatic construct. hiPSC-HPCs and the support cells were patterned using two-step 3D bioprinting technique. (D) Fluorescent image is showing patterns of hiPSC-HPCs (green) and supporting cells (red). (E) Fluorescent images of albumin, E-cadherin, and nucleus staining of hiPSC-HPCs without supporting cells and in 3D triculture constructs. Reproduced from Ma et al. (63) with permission from Proceedings of the National Academy of Sciences of the United States of America.

Figure 3.

(A) Side view of designed BBB-on-a-chip showing the fluid pathway, electrode wiring and BBB co-culture orientation. (B) Image is showing the actual assembled device with or without the lid. (C) Verification of BBB characteristic barrier integrity after co-cultures of hiPSC-derived BMECs and astrocytes for 10 days. Reproduced from Wang et al. (78) with permission from Wiley. (D) Schematic and image of a insert of a 3D printed holder and PLGA mesh developed for a BBB model (Top). Schematic showing the co-culture of hiPSC-ECs and hiPSC-Astro on the PLGA mesh. (E) Verification of astrocyte marker (GFAP) and EC junction marker (CD31), and glycoprotein (vWF) along with the tight junction protein after 7 days of culture. Reproduced from Qi et al. (79) with permission from ACS Publications.

Figure 4.

Fabrication of biomimetic muscle-on-a-chip to study the effect and toxicity of drugs in muscles. (A) and (B) Gelatin hydrogel based muscular thin films (MTFs) were developed and cardiac tissues were cultured on gelatin hydrogel cantilevers. (C) Human iPS-derived cardiac myocytes were cultured on microfabricated MTFs and images were taken at diastole and systole. Reproduced from McCain et al. (87) with permission from Elsevier. (D) and (E) Schematic of vessel wall on a chip capable of creating physiological arterial strain and shear stress from the blood flow. (F) and (G) VSMCs were aligned and were more elongated compared to the cells cultured in the static condition. Reproduced from van England et al. (89) with permission from The Royal Society of Chemistry.

Figure 5.

Research on OOCs within Companies. A) Main topics of the publications acknowledged by companies on OOC technologies from 2015 to 2018. B) Most studied single organs for OOC technologies. Co-cultured organs (multi-organ systems) are listed in table 2.