Design and Fabrication of Organ-on-Chips: Promises and Challenges
Abstract
:1. Introduction
2. Conceptual Design of OOC
2.1. Geometry and Dimensions
2.2. Flow Control in OOCs
2.3. Clog Avoidance in OOCs
2.4. Monitoring and Detection
3. Fabrication Materials
3.1. Materials Used in Chip Production
3.1.1. Polydimethylsiloxane (PDMS)
3.1.2. Glass
3.1.3. Thermoplastics
3.2. Other Materials Used in OOC Technology
3.2.1. Hydrogels
3.2.2. Silicon
3.2.3. Metals
3.2.4. Membranes
4. Fabrication Methods
4.1. Soft Lithography
4.2. Hot Embossing
4.3. Injection Molding
4.4. 3D Printing
5. Creative Methods
6. Applications of OOCs
6.1. OOC Technologies
6.1.1. Single Organ Models
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- BBB-on-Chip: Drugs are not effective in the CNS unless they pass through the highly selective brain microvascular endothelial cells [234]. The blood-brain barrier (BBB) is a combination of Brain Microvascular Endothelial Cells (BMECs) in the capillaries and the surrounding cells in the CNS, which consists of pericytes and astrocytes [235]. Although the BBB blocks numerous drug compounds from entering the brain, it protects the CNS and brain from pathogens [236]. It is expected that BBB-on-chip models based on human cells will be increasingly used in drug-discovery and drug-delivery research on the brain [237,238,239] as the in vivo expression of many solute carriers and efflux transporters varies widely between human and animal systems due to differences between species [59,240]. In the development of BBB-on-chip models for drug screening, the following aspects are crucial: (i) two compartments recapitulating blood and brain parts separated by a porous membrane provide the possibility to sample both brain and blood channels for permeability assays and to directly control and manipulate both the brain and the blood compartments simultaneously [49,50]; (ii) brain endothelial cells mimicking physiological functions, forming a high barrier integrity and expressing efflux pumps, which requires precise control of shear walls (viscosity and flow) to maintain polarity [241]. The literature provides some good examples of BBB-on-chip models that meet both of these criteria [49,50,242]. For example, Park et al. used a sandwiched double channel separated with a porous microfluidic chip to model the BBB within [49]. They used a unique, developmentally inspired iPS differentiation protocol to obtain brain endothelial cells seeded into the bottom channel of the chip to mimic the brain vasculature. Primary astrocytes and pericytes were seeded in the upper channel to mimic brain parenchyma. They demonstrated effective levels of barrier function for up to two weeks and the validation of delivery systems that transport drugs and therapeutic antibodies through the human BBB. Recently, Liang and Yoon used a well-based design of the BBB-on-chip with integrated sensors for sensing TEER, which was shown to be more effective compared to previous designs [242].
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- Lung-on-Chip: The interaction between the flow of air during inhalation and exhalation and the blood capillaries of the lungs is an important phenomenon to observe. One tangible reason for its importance is pandemic diseases, such as COVID-19 and influenza, as this is where viral or bacterial infections begin; therefore, physiologically relevant lung models can be used to develop effective drugs and treatments to protect the entire body [243,244]. Transparent, flexible, and low-cost OOCs are one of the best options to perform this type of research and investigate lung issues such as disease etiology and drug screening [40]. In most lung-on-chip designs, there are two channels separated by a porous membrane to recapitulate the microphysiological environment of the lung [76]. 1. Air channel: Lung epithelial cells are cultured in air without flowing media; they are nourished via the adjacent channel. 2. Blood channel: Lung endothelial cells are cultured here under flow conditions to recapitulate blood capillaries. Cyclic respiratory motion is another factor that must be considered when developing a physiologically relevant lung-on-a-chip model to recapitulate breathing motions at an exact rhythm, rate, and magnitude, which has been shown to have drastic effects on tissue function [34]. Vacuum chambers are the solution presented to exert a cyclic suction when combined with an elastic material to mimic this biomechanical motion [36]. Huang et al. presented a new design of a lung-on-chip, integrating gelatin hydrogel into a PDMS structure that can be subjected to cyclic stress to recapitulate the breathing motions [245]. This improves the similarity to the real organ as the mechanical properties as well as the stiffness are close to that of the human lung, and the results also better match the in vivo environment. In addition, Si et al. recently investigated the use of the lung-on-chip to model viral infections and rapidly screen therapeutic candidates [83]. They proposed a human lung bronchial airway modeled on-chip with lung epithelial cells and pulmonary endothelium. The chips were tested with a virus (coronavirus 2 (SARS-CoV-2)), and the best therapeutic was introduced accordingly.
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- Liver-on-Chip: Drug-induced toxicity is a critical factor in drug development models, and the liver is the organ most vulnerable to potential hazards. Regardless of the research conducted to treat liver disease, studying this organ reduces the number of drug failures. OOCs are considered the best approach for studying the liver because animal studies are expensive, time-consuming, and in some cases inaccurate [246]. Cellular components and biomechanical factors are some of the critical parameters for proper functioning of liver chips. There are several cell types in the liver that maintain the physiological functions, including Kupffer, stellate, and endothelial cells; thus, co-culturing approaches are recommended. Geometry and flow are the most important biomechanical aspects in developing a liver-on-chip. Moreover, liver microvessels are sinusoidal and have mainly rectangular cross-sections [247]. Therefore, when designing vascular sinusoids, aspect ratios and velocities must be accurately calculated to maintain a laminar flow regime (Re <1), which directly affects the compensation of the concentration gradients [43,248]. In this regard, Deng et al. performed a study on liver-on-chips to evaluate hepatoprotective activity [249]. They used a sinusoidal, single microchannel (PDMS-glass) chip seeded with four different hepatic cell lines and perfused with laminar flow. Their observations were promising as they recorded different mechanisms of hepatoprotectants. Kim et al. also used a PDMS-glass chip with straight microchannels and a porous membrane to study liver-on-chips in order to study the metastasis of breast-cancer-derived extracellular vesicles to the liver [246].
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- Kidney-on-Chip: The kidney is an organ that balances the body’s fluid and filters the blood. The process of waste removal is an important feature that is closely related to drug composition and toxicity and needs to be monitored accurately [250]. Apart from drugs, there are other conditions that affect the filtration process such as urinary stone disease leading to inflammation, which needs to be thoroughly investigated [251]. Nephrons are small functional units in the kidney that are responsible for purifying the blood [252]. The kidney is composed of various parts, including the glomerulus [253], the proximal [254], and the distal tubule [255], which have been studied individually on a chip. A typical kidney-on-chip has two channels where the urinary lumens are in contact with the interstitial flow. Ultra-filtering is a key consideration in the design of the chip and is tightly controlled by the shear stresses exerted on the cells, which are low (~0.2 dyn/cm2) compared to other organs [256].
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- Gut-on-Chip: The gut is a multifunctional organ where orally ingested drugs and nutrients are digested, transported, and absorbed. Therefore, it is an important factor in drug efficacy which must be in concert with the barrier function that blocks certain compounds to protect the body [257]. However, the gut is quite a complex physiological environment as other microbial symbionts also work to promote intestinal health [258]. Studying the gut is a step forward in improving the body’s immune function, and OOCs are providing a superior alternative to other approaches such as in vivo animal studies, which have often failed in the transition of the data to the clinic [259]. The relevant literature distinguishes between two types of gut-on-chips: intestine-on-chip [43,260,261] and colon-on-chip [262,263]. The most commonly used gut-on-chip models have typically two channels connected with a porous media; one is intestinal epithelial and the other is vascular endothelial. Accurate barrier function should be achieved for better results in the stage of designing and fabrication. Further cyclic strains and anaerobic environments are sometimes applied in the corresponding research [264].
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- Heart-on-Chip: Heart disease ranks first among potentially fatal diseases worldwide [265]. For this reason, effective and inexpensive drugs for its treatment are especially important to save the lives of many people. Three-dimensional, bioengineered OOCs of the heart are used effectively for drug testing because they can recapitulate the physiological mechanisms and cell interactions associated with the biomechanical factors [266]. “Cardiac motion” (Cardiac motion: the heart’s cyclic motion with a 0.6–2 Hz frequency as a result of the heart beating (40–120 beats per minute) [267]) is due to highly polarized and contractile cells called cardiomyocytes, and their function is directly related to flow rate, calcium ion concentration, and electrical stimuli [268]. Thus, providing cardiac physiology on a chip requires precise design to perform the mechanical, electrical, and chemical functions [269]. In addition, the design of cardiac chip models must take into account the ability of the chip to perform contractility techniques such as muscular thin films and to acquire electrophysiological and morphological data [270]. For example, Liu et al. used a double-channel microfluidic device made of PDMS to model a human heart-on-chip [86]. Their heart-on-chip was lined with vein endothelial cells, induced pluripotent stem cells, and fibroblasts (gingival fibroblasts). The model is expected to be a functional tool for pharmacological studies and personalized medicine.
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- Bone-on-Chip: Bones are living tissues that both serve as the structure of the body and produce the major blood cells [271]. It has three main tissues (compact, cancellous, and subchondral), in which different types of bone cells (osteoblasts, osteoclasts, osteocytes, and hematopoietic cells) maintain bone metabolism and blood cell production [272]. Cancellous bone tissue consists of a spongy substance called marrow, which is responsible for blood production in the middle of the bone. Chou et al. have introduced an in vitro model of “bone marrow” (Bone marrow: a sponge-like tissue inside the bone which produces diverse materials, including stem and blood cells [273]) using microfluidics to study toxicities and dysfunction caused by factors such as drugs and radiation. Their chip consists of two channels representing the vasculature and hematopoietic system separated by a porous membrane. They obtained promising results for studying responses to drugs and also to radiation [274]. In another study, Bahmaee et al. presented a new study consisting of a microfluidic device (bioreactor) and a scaffold chamber with a hexagonal pillar pattern to study osteogenesis-on-chip [275]. They claimed that their device is a new and effective platform for testing bone drugs compared to the usual approaches in this field. Additionally, there are related research trends using bone-on-chips to study bone metastasis and metastasis colonization for the purpose of cancer treatment and prevention [276].
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- Other Organs: The developing OOC models include different parts and bring revolutionary breakthroughs compared to the previous trend. The skin is the first external organ that protects the body and is very likely to be affected by chemical substances, pollutants, and Ultraviolet Light (UV); thus, conducting research to protect, prevent, or cure corresponding diseases is very important. Previously, optically visible skin layers were studied on chips to mimic the interactions between layers and to investigate the biology behind them [277]. Wufuer et al. designed a three-layer chip representing epidermal, dermal, and endothelial cells to recapitulate the dense skin barrier [278]. They were able to study the drugs and concluded that the chips were suitable for modeling inflammatory skin diseases. In recent studies, skin-on-chip modelers have been looking for new approaches to add hair follicles, sweat glands, and pigmentation for more advanced research [279].
6.1.2. Multi Organ Models
7. Discussion
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Studied Organ | Flow Rate | Refs. |
---|---|---|
Blood-Brain Barrier | 100 µL/h | [49] |
10 µL/min | [78] | |
16 µL/min | [79] | |
2.5 mL/h | [80] | |
Lung | 30 µL/h | [81] |
60 µL/h | [82,83] | |
Gut | 30 µL/h | [84,85] |
60 µL/h | [44] | |
Heart | 40 µL/h | [86] |
Ref. | Type | Available Flow Rate Range (mL/min) |
---|---|---|
[89] | Peristaltic micropump | 1.66 × 10−4–3600 |
[90] | Syringe pumps | 1 × 10−6–0.127 |
[91] | Electrokinetic pump | 1.8 × 10−3–0.01 |
[92] | Capillary pump | 5.05 × 10−4–210 |
Method | Cost | Facility requirement | Precision | Capability for surface treatment | |
---|---|---|---|---|---|
3D printing | Additive, Removal, and Patterning | ||||
Soft lithography | One step patterning and removal and molding | ||||
Hot Embossing | One step patterning and removal and molding | ||||
Injection molding | One step patterning and removal and molding | ||||
Miscellaneous | --- |
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Tajeddin, A.; Mustafaoglu, N. Design and Fabrication of Organ-on-Chips: Promises and Challenges. Micromachines 2021, 12, 1443. https://doi.org/10.3390/mi12121443
Tajeddin A, Mustafaoglu N. Design and Fabrication of Organ-on-Chips: Promises and Challenges. Micromachines. 2021; 12(12):1443. https://doi.org/10.3390/mi12121443
Chicago/Turabian StyleTajeddin, Alireza, and Nur Mustafaoglu. 2021. "Design and Fabrication of Organ-on-Chips: Promises and Challenges" Micromachines 12, no. 12: 1443. https://doi.org/10.3390/mi12121443
APA StyleTajeddin, A., & Mustafaoglu, N. (2021). Design and Fabrication of Organ-on-Chips: Promises and Challenges. Micromachines, 12(12), 1443. https://doi.org/10.3390/mi12121443