Organs-on-chips at the frontiers of drug discovery

Abstract

Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs - known as organs-on-chips - that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology.

Figure 1. Lung-on-a-chip

a | A human breathing lung-on-a-chip was created by co-culturing human alveolar epithelial cells and pulmonary microvascular endothelial cells on opposite sides of a stretchable porous membrane to replicate the alveolar–capillary boundary of the breathing human lung. A vacuum was applied to mimic the tissue stretch that occurs during normal breathing. b | This system was used to reconstitute integrated organ-level functions such as inflammatory responses to intra-alveolar pathogenic bacteria such as Escherichia coli that are mediated by endothelial recruitment of circulating neutrophils, transmigration through the alveolar–capillary interface and subsequent bacterial phagocytosis. c | The lung-on-a-chip was used to model human lung diseases such as pulmonary oedema. Administration of interleukin-2 into the microvascular channel resulted in fluid leakage into the alveolar compartment, recapitulating the pulmonary oedema induced by acute toxicity of interleukin-2 that is observed in patients with cancer.

Figure 2. Organ-on-a-chip models for cancer research

a | A microvascular endothelium-on-a-chip created in a compartmentalized microfluidic device enabled basal stimulation and activation of endothelial cells grown on a porous membrane using chemokines to study the attachment of circulating breast tumour cells involved in cancer metastasis. The effect of chemokines, such as tumour necrosis factor, was investigated by adding these agents to the bottom channel. More cancer cells attached to the endothelium that was pre-treated with tumour necrosis factor than to untreated endothelium. b | The metastasis of breast cancer cells to bone was studied using human umbilical vein endothelial cells grown in a microfluidic channel adjacent to a 3D collagen gel containing bone cells differentiated from human bone marrow-derived mesenchymal stem cells (MSCs). Migration of the cancer cells into the bone was observed. c | To study epithelial–mesenchymal transition in cancer, lung cancer spheroids were embedded in micropatterned 3D matrices immediately contiguous to a microchannel lined with endothelial cells. Analysis of epithelial–mesenchymal transition is conducted using microfluorometry to detect dispersion of the cancer spheroids. PDMS, poly(dimethylsiloxane).

Figure 3. In vivo engineering of bone marrow

A bone marrow-on-a-chip model leveraged in vivo tissue engineering approaches to generate fully functional engineered bone marrow (eBM) for incorporation and perfusion culture in a microfluidic device. The eBM had a physiological structure and was used in an organ-on-a-chip system to study depletion and pharmacological protection of haematopoietic stem and progenitor cell populations exposed to γ-radiation. The red and green channels are medium perfusion channels used to maintain the eBM in the central chamber. PDMS, poly(dimethylsiloxane).

Figure 4. Brain tissue-on-a-chip

Higher-order functionality of the nervous system can be studied in a microdevice that enables culture of two brain tissue slices in separate media formulations. The two tissue slices are allowed to communicate by synaptic connections formed through microchannels between the culture chambers. Electrodes incorporated into this system enable measurement of synchronous electrophysiological activity between the two brain slices. This design allows for selective pharmacological treatment of only one tissue slice and measurement of its effects across the synaptic connections.

Figure 5. Body-on-chip systems

A | A microdevice containing interconnected cell culture microchambers was used to develop a multi-organ model that integrated microfluidic culture of intestinal epithelial cells, hepatocytes and breast cancer cells to simulate absorption, metabolism and activity of anticancer drugs. b | A micro cell culture analogue (μCCA) was created by linking together three interconnected microfluidic cell chambers representing a colon tumour, the bone marrow and liver with proportional physiological scaling to develop a more realistic physiological model of drug metabolism and anticancer activity. Culture media recirculates through the three inline chambers and an external reservoir, mimicking blood circulation and its residence times in the modelled organs. PBPK, physiologically based pharmacokinetic.