Microphysiological Systems: Next Generation Systems for Assessing Toxicity and Therapeutic Effects of Nanomaterials

Abstract

Microphysiological systems, also known as organ-on-a-chip platforms, show promise for the development of new testing methods that can be more accurate than both conventional two-dimensional cultures and costly animal studies. The development of more intricate microphysiological systems can help to better mimic the human physiology and highlight the systemic effects of different drugs and materials. Nanomaterials are among a technologically important class of materials used for diagnostic, therapeutic, and monitoring purposes; all of which and can be tested using new organ-on-a-chip systems. In addition, the toxicity of nanomaterials which have entered the body from ambient air or diet can have deleterious effects on various body systems. This in turn can be studied in newly developed microphysiological systems. While organ-on-a-chip models can be useful, they cannot pick up secondary and systemic toxicity. Thus, the utilization of multi-organ-on-a-chip systems for advancing nanotechnology will largely be reflected in the future of drug development, toxicology studies and precision medicine. Various aspects of related studies, current challenges, and future perspectives are discussed in this paper.

Keywords: multi-organ-on-a-chips; nanomaterials; organ-on-a-chips; personalized medicine; toxicity.

Figure 1:

Nanomaterial points of entry and drainage into the body. Nanomaterials can enter the body through the lungs, skin, and GI tract. Once inside, the circulatory system readily transports them throughout the body. Their small size enables facile translocation into a variety of tissue structures found in the kidney, spleen, liver, and lungs.

Figure 2.

Concept map for a human-on-a-chip device which can integrate multiple biomimetic microengineered organs interconnected with a physiologically relevant dynamic microfluidic circulatory system. The human-on-a-chip can be used to study the complex processes of drug distribution, absorption, excretion, and metabolism for a comprehensive evaluation of the drug efficiency, toxicity, and optimized dosage. As shown in this schematic, drug/ultrafine particle (UFP) absorption can be studied as they enter a microengineered lung model and pass into the circulation. From here, cardiotoxicity in a heart-mimetic microsystem, transport and clearance in the kidney-mimetic system, metabolic functions in the liver, and immune system of cells can all be studied. If the UFPs pass through relevant physiological barriers such as the BBB and intestinal metabolic pathways, organs such as the brain and gut can be included to study more systemic effects. Oral administration of drugs absorbed into the gut compartment can be modelled to study the interaction between drug and molecular transporters and metabolizing enzymes expressed in the various organs.

Figure 3.

Skin and hair on-a-chip: (A) A two-circuit skin and hair MoC device used to study the culture response under dynamic perfusion and static conditions simultaneously. (B) Breakdown of the fluidic circuit elements including integrated micropump (red), injection port (yellow), and Transwell® compatible tissue inserts (blue). (C) Schematic of two submerged tissue inserts culturing in vitro skin equivalents and ex vivo skin biopsies under dynamic perfusion. (D) Example of skin equivalent in a Transwell® insert before being placed into the MoC. (E) Image of the follicular unit extracts inside the MoC. Reproduced from ^[70] with permission from the Royal Society of Chemistry.

Figure 4.

(A) Four organ MoC device used to study the distribution, absorption, metabolism, and excretion profiles of drug candidates with repeated doses to assess systemic toxicity. The numbers correspond to the culture organs including (1) intestine, (2) liver, (3) skin, and (4) kidney. B) Schematic of locations in which microparticle image velocimetry was employed for flow analysis, where A, B and C are sample points for the surrogate blood circuit and D and E are for the excretory circuit. (C) The average volumetric flow rates versus pumping frequency for both the surrogate blood and excretory circuit. Pumping was driven by two on-chip peristaltic micropumps capable of circulating the media for weeks. Reproduced from ^[36a] with permission from the Royal Society of Chemistry.

Figure 5.

Small intestine-liver on-a-chip: (A) Schematic displaying design of PDMS-based chip consisted of upper and lower layers. (B) Schematic representation of the device consisting of multiorgan in separated chambers (small intestine, liver, and lung) and stir-based micropumps linked to microchannels to mimic arteries and veins. (C) Photograph showing the microfluidic device. Black color represents microchannels on the upper layer and grey color displays microchannels on the lower layer of the device. Reproduced from ^[87] with permission from SAGE.

Figure 6.

(A) MoC device which could sustain the co-culture of skin biopsies and liver microtissues. The chip contained two fluidic circuits to simultaneously study the culture’s response to direct fluid flow and shielded flow ^[103]. (B) throughput MoC device that evaluated the effect of anti-cancer drugs on two organs (colon and liver) and four organs system (cancer, liver, intestine, and connective tissue). Reproduced from ^[105] with permission from the Royal Society of Chemistry.

Figure 7.

(A) Schematic and MoC microfluidic device layout with external device controls and monitors. (B) Liver-and-heart MoC and liver-cancer-heart MoC devices with integrated sensors (pH, O₂, temperature, and electrochemical immunobiosensors) and a miniature microscope to study drug effects. Continual measurements of (C) Temperature, (D) pH and (E) oxygen with on-chip sensors. F) Live/dead staining of the liver organoids after drug administration and (G) normalized cell viability in response to acetaminophen. Continual electrochemical detection of (H) albumin, (I) GST-α, and (J) CK-MB with on-chip immunobiosensors. (K) Beating rate over time of cardiac tissue. (F-K) data monitored the cellular responses over 5 days, where the red arrows indicate the addition time of acetaminophen (72hr). Reproduced from ^[56] with permission from the National Academy of Sciences.