What are the alternatives to animal testing? Applying Bionic Chips in Drug Development

Animal experiments are currently a necessary part of the pre-clinical verification process in the development of new drugs. It is, unfortunately, a necessary evil for the continued development of human medicine and the advancement of life sciences. Recent studies estimate that approximately 1 hundred million vertebrates are experimented with around the world each year. In the European Union alone, roughly 11 million vertebrates are used in medical experiments every year. Of these animals, the number used in basic research is the largest, followed by the number used in biomedical research and toxicity testing for household products and other consumer products, etc. At the same time, there are many companies that raise and sell tens of millions of these animals every year in order to obtain huge profits.

There have always been fierce debates around the cruelty of animal experiments. Everyone has to admit that the qualities that make certain animals more suitable test subjects also tend to make experimenting on them morally indefensible. Fortunately, with the advancement of biotechnology, alternatives have been found for specific animal experiments. These have already aided in confirming the safety of many drugs. This, combined with growing awareness of the concept of animal protection, has prompted many countries to begin amending their laws regarding animal experiments in recent years. The world has reached a general consensus on the “3R Principles” for the humane treatment of animals used in experiments. The 3Rs refer to Replacement, Reduction, and Refinement. However, the best way to prevent future animal sacrifices is to develop a fully functional alternative.

The bionic cell chip is a “compassionate” technology that mankind urgently needs. In essence, it is an applied technology evolved from the microfluidic chip. Its development combines the expertise of many different disciplines, including physics, chemistry, biology, medicine, materials science, engineering and Micro-electromechanical systems (MEMS). It is considered one of the “Top Ten Emerging Technologies”. The typical biomimetic chip is small in size and requires the use of only small amounts of reagents and samples to meet detection requirements. Also, unlike the traditional 2D culture, bionic chips controlled via microfluidic environments can simulate a 3D environment similar to that of a human body to effectively replace or assist the existing cell and animal experiment models used to test the response of human organs to drugs. It can also be used to perform high throughput drug screening and more. Because it can more accurately analyze the actions of biological mechanisms and improve the accuracy of drug testing, it will provide a great opportunity to accelerate the development of new drugs in the future. At the same time, it can greatly reduce both the number of animal experiments and the risk to human lives in clinical trials.       

Director of R&D Center & Marketing Division, Chris Chen, 2022/09/15

What are the alternatives to animal testing? Applying Bionic Chips in Drug Development

Yi-Chiung Hsu, Associate Professor, Department of Medical Science and Engineering, Central University

Traditional 2D cell culture technology is a planar culturing method. Because it differs greatly from the actual three-dimensional environment of the body, the morphology, differentiation, cell matrix interaction, cell to cell interactions and many other aspects of the resulting cell growth can easily be significantly different from real in vivo cell behavior. Therefore, in order to further confirm the correctness of the cell culture results, relevant animal experiments are usually still required for verification. However, the cost of establishing animal models is extremely high [1]. It is time-consuming and expensive, and it must overcome issues such as potential mouse genome contamination. This also greatly limits the possible applications of the 2D cell culture method. In view of this, in order to accelerate the development of research in the field of biomedicine, scholars have begun to seek out better potential alternatives in recent years.

The traditional planar cell culture method is mostly carried out using polystyrene as the material of the culture dish. Although this method can cultivate a large number of cells, it has difficulty simulating the real growth behavior of in vivo cells. Most cells require cues from the 3D environment in order to grow in a manner more similar to that of relevant in vivo tissues and organs. Collagen and Matrigel, for example, are common materials used to coat cultured cells. However, previous studies on the influence of matrix stiffness on cell behavior and function in 2D and quasi-3D environments all confirm that the results cannot accurately represent the real situation in the body. In recent years, the continued evolution of biotechnology and the development of cell culture technology has gradually moved from 2D to 3D. In particular, the research on the applications of bionic cell chips as a drug development tool has been the focus of much attention.

Bionic cell chips mainly adopt a 3D dynamic culturing method to simulate the behavior of tissue cells in vivo conditions. Cells cultured in 3D can emulate true cell-to-cell contact and be applied via different cell types and cellular matrices to engineer complex tissue structures that match in vivo cell behaviors and gene expression trends, simulating in vivo phenomena such as gradient changes in oxygen and nutrient delivery. With the assistance of 3D cell culturing methods, drug screening data can be made more accurate. We will also be able to more accurately predict the benefits and toxicity of different drug concentrations. This technology has unlimited potential for future development [2].

Establishing bionic culture models with bionic chips has become a hot topic of research in the field of biotechnology. The very popular research topic, the “Organ-on-a-chip, OOC”, has been of particular interest in recent years. It is a chip that can simulate the internal environment to the greatest extent, bringing about new possibilities for medical and drug research and development. Bionic chips can be used not only as a drug screening platform that can correctly screen for useful drug candidates in a simulated environment but also as a test platform for drug treatment evaluation and drug effect mechanism confirmation, as well as to establish various biomarkers through gene sequencing analysis and functional exploration of target message transmission pathways under the influence of drugs.

The “Organ-on-a-Chip” refers to a microsystem that simulates the operation of internal organs in the human body. This concept was first proposed by Donald E. Ingber and Dan Dongeun Huh of Harvard University in the United States [3,4]. They succeeded first in simulating the operation of the lungs on a microchip (Figure 1). The chip structure consisted mainly of a Polydimethylsiloxane (PDMS) film, which divided the microfluidic channels in the central area into upper and lower layers. PDMS is a highly biocompatible, highly elastic material well suited to having cells cultured on it. There are many small holes on the surface of the PDMS film. The flow channels at the upper and lower ends pass air and blood respectively and can be used to simulate trachea and blood vessels. The flow channels on the left and right sides provide the proper vacuum to give the film the necessary tension. When a high tension is applied to the PDMS film, it can simulate the expansion and contraction of the alveolar membrane.

Figure 1.　Bionic Lung Chip

Figure 1 (A, B) illustrates how the microfluidic chip mimics the lung environment. It induces mechanical respiration by applying a vacuum to both chambers to stretch the PDMS film in a manner similar to that of physiological respiration. (C) is where the upper and lower parts of the chip are bonded with the PDMS film. After bonding, as shown in (D), use an appropriate etching solution to selectively etch and remove the PDMS film layer in the channels on both sides. (E) is the outer appearance of the actual lung microfluidic chip that was fabricated [3]. Using this biomimetic chip, it is possible to truly simulate the closely fitted structure of human lung epithelial and endothelial cell layers. It can also mimic the normal respiratory movements of lung tissue through the introduction of air and fluid flows and periodic mechanical straining of the membrane.Current pre-clinical drug development research based on traditionally 2D cell culturing models still relies on expensive and time-consuming animal testing. Using the above chip’s channel and membrane design to create a disease test model that mimics human lungs can provide the opportunity to eliminate the need for validation in subsequent animal models, enabling quick and convenient alveolar-capillary interface interaction research.

At this point, micro biomimetic cell culture chips with similar principles have been successfully applied to the simulation of various human organ functions, such as the multilayer interface between the epithelial and endothelial layer undergoing respiration-induced cyclic mechanical stretching [5] and more. Biomimetic chip technology has numerous advantages over common in vitro research models, such as in vitro cancer cell cultures, whether it is in terms of experimental operation, time required, or high throughput screening, etc. In fact, in recent years, ion channel inhibitors (GSK2193874) for treating lung toxicity caused by IL-2 [6] were successfully screened using bionic chip research. It is hoped that more organ chips with integrated functions that can replace early live animal testing on a large scale will soon be developed in the field of biomedicine, allowing quick and convenient observation of the physiological changes of cells or tissues. Researchers also expect to create a certain level of disease-producing cells in the cells of the chip in the future to observe whether diseases are alleviated by the input of drugs.

In terms of applied research on the mechanism of disease formation, bionic chips can already use bioengineering methods to control tension and flow and accurately assess cellular changes and the outcomes of clinical treatments [7]. Figure 2 sorts various related microfluidic devices that can simulate different stages of lung cancer metastasis [8]. For example, a hydrogel-induced microfluidic chip device and a collagen-mixed matrigel composition can be used to simulate the microenvironment of lung cells in different stages of cancer invasion. Its approach is to adjust the state conditions of the hydrogel chip through morphological changes and mechanical forces. Quantitative image analysis is then used to measure the migration of H1299 lung adenocarcinoma cancer cells under different experimental conditions.

Figure 2.　Various Bio-Inspired Microfluidic Chip Designs for Studying Lung Cancer Metastasis [8]

Research of these bionic chips revealed that lung tumor cells can migrate from the mesenchyme in a collagen matrix towards the collagen matrix membrane. This can be applied to high throughput drug screening studies and therapeutic drug evaluations [9]. In addition, such chips also have the ability to simulate physiological parameters. As such, they have the potential to replace animal experiments for predicting the efficacy and toxicity of anticancer drugs (Figure 3) [10].

Figure 3.　Sensitivity of Chemotherapy Drugs (including Cisplatin and Etoposide) (a)：Images of the morphological changes in the LCO cultured on a microfluidic chip on day 1 (T-24h) and day 3 (T-72h) of Cisplatin treatment (b)：Images of lung cancer cells cultured on the microfluidic chip on day 1 (T-24h) and day 3 (T-72h) of Etoposide treatment (c)：Morphological changes in lung cancer cells cultured in plastic-adhered Matrigel droplets on day 1 (T-24h) and day 3 (T-72h) of Cisplatin treatment (d)：Representative images of LCO cultured in plastic-adhered Matrigel droplets after treatment with Etoposide on day 1 (T-24h) and day 3 (T-72h) (e)：Florescent measurement of cell vitality after 72 hours of drug treatment using a microfluidic chip device (f)：Fluorescent measurement of cell vitality 72 hours after drug treatment [10]

Rapid screening of antiviral drugs is absolutely essential during viral epidemics. Bionic bronchi on a chip can be used to simulate viral infections, strain-dependant virulence, cytokine production, activation of circulating immune cells and more. It is also an extremely convenient tool for antiviral drug effect evaluation and dosage testing. It has the potential to accelerate the screening of potential therapeutic drugs (Figure 4) [11-13].

Figure 4.　Illustration of a Virus Infection on a Lung Bionic Chip Model (A)：Used to Study the Drug Resistance of Influenza (B)：In Vivo 3D Human Alveolar-Capillary Barrier; Bionic Alveolar Chip Infected with SARS-CoV-2 (C)：Porous Membrane Human Alveolar Chip Design Combining Upper Alveolar Epithelial Channels and Lower Microvascular Endothelial Channels (D)：A Multi-Tissue Airway Chip Model for the Study of Human Host Pathogen Interactions; Includes Nasal, Bronchial and Acinar Airways (E)：Results of SARS-CoV-2 Infection in Human Lung Chip Model [12]

Compared to animal models, the organ-on-a-Chip can simulate human bodily systems more accurately. By controlling various parameters, it can precisely pinpoint drug targets, such as cancer cell migration and invasion, extracellular signaling, biophysical factors in the tumor microenvironment and tumor heterogeneity [14-16], etc. The main pre-clinical drug development stages are the early, pre-clinical discovery of potential drugs and activity testing. In the future, how to effectively apply bionic chip technology in the different clinical stages of drug development will also be a very important area of research (Figure 5).

Figure 5.　Bionic Chip Platform for Pre-Clinical Drug Development [17] (a)：PDAC-on-a-Chip (Left) with Biomimetic Vascular Network (Right) (HUVEC, Red) and Pancreatic Cancer Ducts (PD7591 Cells, Green) (b)：A bioengineered glioblastoma brain tumor model with biomimetic tumor-immune-vascular interactions demonstrates that blocking immune suppression by tumor-associated macrophages improves anti-PD-1 immunotherapy. (c)：Non-small cell lung cancer microenvironment model studies found that the mechanical forces generated in the lungs during respiration (vacuum actuation of bilateral channels) may increase drug resistance in NSCLC cells. (d)：Application of Multi-Organ System Chip in the Prediction of the Pharmacokinetic Parameters of Nicotine (e)：Liver Organ-on-a-Chip for Analysis of Adverse Drug Reactions Caused by Drug-Drug Interactions (f)：A Multi-Organ Platform with Multiple Integrated Biomarker Analysis Modules for the Monitoring of Hepatotoxicity and Metabolism-Mediated Inter-Organ Cardiotoxicity *Abbreviations: NSCLC-Non-Small Cell Lung Cancer; PDAC-Pancreatic Ductal Adenocarcinoma。

Different tissues have different mechanical properties. For example, there are soft tissues such as the brain (~1kPa), tough tissues such as skeletal muscles (~10kPa), and high-strength bone tissues [18,19], etc. According to research data, the mechanical properties of these tissues that constitute the microenvironment in the body, including the Stiffness of the extracellular matrix, the geometric structure, and more, also affect the physiological functions of cells. The rigidity of these microenvironments is largely determined by the composition of the specific extracellular matrix [20] and directly affects the operation of many important physiological mechanisms in the body, including stem cell differentiation, wound healing, and cell migration during Morphogenesis [21], etc..

Therefore, by changing the stiffness of the matrix, the force applied to the cells can be adjusted. An exogenous force can also be applied directly to stimulate cells. In this way, it is possible to control the direction of stem cell differentiation in order to achieve the goal of controlling the distribution and formation of the Cell Lineage of stem cells. In this regard, cell regulation technology is very important. However, if the traditional method of cell mechanics research is used to study the relevant physiological mechanisms, mechanical stimulation of cells would be limited to the 2D. In this case, whether the results obtained are consistent with actual in vivo conditions would be highly uncertain. Therefore, biomimetic chips suitable for 3D in vivo cell growth are expected to play a key role in future research of this type.

The author of this article, Professor Yi-Chiung Hsu, and her laboratory research team have long been committed to the research of dynamic bionic chip applications, and they have published many important, related research findings. At present, the most common methods used in effect studies and toxicity tests on cells in the pharmaceutical industry are still 2D. However, 3D culturing technology is already being widely used in academic research. The evolution of biotechnology has reduced the cost of 3D culturing. As such, the use of 3D cultures in regenerative medicine, basic research and drug development has become increasingly widespread and important, allowing cell culture technology to move first from 2D cultures to 3D cultures then to the tissue engineering of the 3D Dynamic Culture and the integration of systems biology big data analysis. The use of dynamic culturing differs from the previous static effects as it can not only simulate the in vivo environment to the greatest extent but also show the intuitiveness of cell cultures. The advantage of the controllability of conditions in particular is of great significance to the innovative research of biotechnology (Figure 6).

Figure 6.　Artificial Intelligence Dynamic Cultivation Gene Database; The Next Generation Dynamic Culture Technology Integrates Drug Screening and Regenerative Medicine Applications

Furthermore, once established, a bionic organ-on-a-chip gene expression database could be used as a cancer cell metastasis assessment and drug screening platform that can screen for suitable drug treatment targets, and, through genomic analysis and related functions, investigate the way drugs affect tumor cell growth, invasiveness and drug resistance signal transmission pathways as well as indicators of their toxicity to normal cells. It will help establish a variety of related biomarkers for biological risk assessment and drug development. It will also bring about great market opportunities for the future development of biotechnology.

Finally, it is worth noting that, in recent years, many different cell technologies have been derived from 3D culturing, such as the preparation of organoids [22]. However, since organoids cannot grow beyond a few millimeters in size, they lack the structural features of natural organs. Therefore, they are unable to exhibit the characteristics of higher-level functions. This is the bottleneck of and challenge for existing technologies [23]. In terms of drug development, many drugs that are effective in animal experiments are ineffective in humans [24-26]. Current pre-clinical research methods have very limited success in predicting outcomes. Therefore, continuing to develop new biomimetic culture models to improve the predictive validity of drug therapy assessments is an essential focus of the development of biomedical technology [27,28].

Reference: 

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According to market research, approximately 4.5 trillion doses of medication were administered by 2020, and there were more than 200 types of new drugs released on the market. Generally speaking, every new drug goes through four stages of development and must typically go through at least 2 years of pre-clinical animal experiments before moving into human clinical trials to prove its efficacy and safety. However, even after passing animal testing, nearly 90% of newly developed drugs fail in the human clinical trial stage due to unexpected toxicity or side effects. Furthermore, animal and human trials alike require a lot of money and time in addition to facing issues of moral controversy. Therefore, actively seeking alternatives to animal experiments and human trials has long been a common goal of biomedical researchers around the world.

The industry’s attention and expectations are currently focused on the bionic chip, the emerging technology believed to have the best chance to fully replace existing cell and animal experiment models and become the ultimate solution. In 2010, the Ingber Laboratory at Harvard University published the first research results on the lung organ-on-a-chip, kicking off the development of bionic chips. In September of 2011, U.S. President Obama announced that the NIH, FDA and DARPA were jointly establishing the 140 million dollar “Microphysiological system (MPS system)” bionic chip research project to ensure the U.S.’s position as a global leader in the field of new drug development over the next 20 years. In 2018, the MIT research team also successfully developed a bionic chip that could simulate the simultaneous operation of up to 10 human organs and tissues and published this landmark research study in Science Advances. Decades of effort by the governments and research institutions of various countries have enabled many laboratories around the world to develop bionic chips for various organs, including the brain, heart, liver, lungs, muscles, skin, intestines, bones and even the placenta. Moreover, high complexity microsystem chips built by combining different organ tissues have also come out one after another—even becoming a commodity. This kind of system chip, which integrates multiple organs, is generally referred to as a body-on-a-chip.

In addition to replacing some of the current animal experiments, the human body-on-a-chip greatly reduces the cost and time needed for new drug development. It also opens up the possibility of creating individualized disease models based on individuals’ disease cells, which could help lower drug risks and enable more precise treatment. This would greatly increase the chance that cures will succeed and reduce the patient mortality rate. In terms of drug delivery, most drugs do not act directly on affected areas. Instead, they must pass through other transmission channels. For example, most oral drugs must be absorbed by the intestinal tract and metabolized by the liver before they can produce therapeutic activity. During the delivery of the drug through the human body, it may cause toxicity in or harm to organs outside the affected area. Using the body-on-a-chip, the functions and characteristics of different human tissues and organs can be simulated in vitro along with the physiological effects and interactions between and in those organs. As such, it can be used to predict the human body’s response to drugs and different external stimuli. In the future, bionic chips that combine multiple organs may also serve as models for testing pharmacokinetics, helping us to understand how drugs are absorbed, distributed, metabolized and eliminated, as well as their toxic effects in the human body.

The author of this article, Professor Yi-Chiung Hsu, is currently working in the Department of Medical Sciences at Central University and heads the school’s “Cancer Genome Laboratory”. Professor Hsu has long been committed to tumor genomics and medical system database analysis research and applications and has published more than 60 related journal articles so far. Professor Hsu also holds several important patents as the leader of many highly innovative research studies. Her work won her the gold medal and bronze medal of the Taiwan Innovation Technology Expo in 2019 and 2021 respectively. MA-tek is honored to be able to work with Professor Hsu this year in industry-university collaborations by providing all the analysis services required by the laboratory team in constructing biomimetic tissue studies for cancer drug therapy. MA-tek has the full range of biomedical and liquid nano sample detection technology needed to meet the various analysis needs of nanomedicine-related research.