Organ-on-a-Chip and Microfluidic Platforms for Oncology in the UK

Abstract

Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build complex models of the tumour microenvironment. Interest in applying organ chips to investigate mechanisms such as metastatsis and to test therapeutics has grown rapidly, and this review draws together the published research using these microfluidic platforms to study cancer. We focus on both in-house systems and commercial platforms being used in the UK for fundamental discovery science and therapeutics testing. We cover the wide variety of cancers being investigated, ranging from common carcinomas to rare sarcomas, as well as secondary cancers. We also cover the broad sweep of different matrix microenvironments, physiological mechanical stimuli and immunological effects being replicated in these models. We examine microfluidic models specifically, rather than organoids or complex tissue or cell co-cultures, which have been reviewed elsewhere. However, there is increasing interest in incorporating organoids, spheroids and other tissue cultures into microfluidic organ chips and this overlap is included. Our review includes a commentary on cancer organ-chip models being developed and used in the UK, including work conducted by members of the UK Organ-on-a-Chip Technologies Network. We conclude with a reflection on the likely future of this rapidly expanding field of oncological research.

Keywords: cancer; mechanobiology; microfluidic; microphysiological system; oncology; organ-on-chip; pre-clinical model; spheroid; tumour cell.

Figure 1

UK cancer research centres building organ-chip models, and worldwide UK collaborations in the field. Global collaborators include institutions in China (Beijing, Dalian, Guangzhou, Hong Kong, Zhejiang), Europe (Finland, France, Germany, Italy, the Netherlands, Spain) and the United States (California, Massachusetts, Washington, Wisconsin).

Figure 2

Organ-chip models of tumour growth and cancer cell proliferation. (A) Proliferation of cancer cells over 5 days in a chip model of human colon carcinoma (red = dead cells; green = live cells; scale bar = 400 µm) [31]; (B) A chip co-culture used to investigate the growth of (1) lung tumours and (2) skin microtissues over 5 days (scale bar = 500 µm) [32]; (C) A chip model exploring the proliferation of cervical cancer cells over 5 days, with staining delivered via tumour targetting nanoparticles [33]. Figures reproducued with permission.

Figure 3

Organ-chip models investigating the metastatic cascade. (A) A chip model investigating the effect of fluid flow and barrier formation on the transendothelial migration (TEM) of breast cancer cells [36]. (B) A mechanobiological model showing increased invasion of breast and prostate cancer cells when co-cultured in a chip with mechanically-stimulated osteocytes (scale bar = 20 µm; * indicates instance of invasion) [38]. (C) Live/dead staining of breast cancer spheroids, showing more growth under flow conditions when compared to static conditions (scale bar = 200 µm) [39]. (D) Live-cell tracking of migration trajectories of glioblastoma cells over 12 h in a chip with microvessels, crossing an epithelial barrier and entering the extracellular matrix (ECM) (scale bar = 100 µm) [41]. (E) Increased invasion of breast cancer cells in a chip when over-expressing the p62 gene (p62-OE) (scale bar = 100 µm; * indicates p < 0.05, two-tailed Student’s t-test) [42]. (F) The rate of breast cancer cell (red) extravasation from microvessels (green) over seven days (D-0 to D-7) was affected by the presence of monocytes (white) (scale bar = 10 µm) [43]. Figures reproduced with permission.

Figure 4

Organ-chip models of cancer-associated behaviours. (A) The spreading speed of liver microtumour spheroids depended on the epithelial layer on which they are placed (scale bar = 100 µm) [44]. (B) Angiogenic sprouting, modelled and analysed in a microfluidic chip under a range of different anti-angiogenic drug treatments (thalidomide, C#1, C#2) (scale bar = 100 µm) [45]. (C) Chips placed in series allowed the monitoring of the uptake of procoagulant microvesicles secreted by glioblastoma and ovarian carcinoma cells (MV, green) by human endothelial cells (scale bar = 200 µm) [46]. Figures reproduced with permission.

Figure 5

Organ-chip models applied for therapeutic testing in oncological research. (A) A chip model to test the delivery of TRAIL treatment to breast tumour cells [50]. (B) Organ-chip models of liver cacinoma can be applied to build metablomics profiles under a range of drug treatments [51]. (C) Testing of enhanced drug delivery via nanoparticles to kidney cancer cells (scale bar = 100 µm; * indicates p < 0.05, one-way ANOVA) [53]. (D) A tumouroid chip model of breast cancer cells, demonstrating increased resistance to doxirubicin treatment under mechanical stimulation (scale bar = 100 µm; * indicates p < 0.05, paired Student’s t-test) [54]. (E) A chip model demonstrating similar response profiles of colorectal cancer spheroids to drug treatments to those observed in implanted tumours in immunocompromised mice (scale bar = 100 µm; **** indicates p < 0.0001, one-way ANOVA with Tukey’s post-hoc test) [55]. (F) A custom-desgined chip investigating the effect of radiation and cisplatin treatment on tissue samples of head and neck squamous cell carcinomas (scale bar = 200 µm) [56]. Figures reproduced with permission.