Keywords: Drug discovery, High-throughput system, In vitro model, Microphysiological systems

Introduction

The biopharmaceutical industry utilizes its scientific and industrial expertise to advance basic science research and develop safe, effective treatments that can be made accessible to patients. This industry is uniquely equipped to shoulder the risks associated with furthering research into these treatments. The 2021 report of the Pharmaceutical Research and Manufacturers of America indicates that, on average, developing a single new medicine takes between 10 to 15 years and costs US dollar (USD) 2.6 billion, factoring in the costs of numerous failures. However, only 12% of new molecular entities that enter clinical trials ultimately receive approval from the U.S. Food and Drug Administration (FDA). Today, approximately 7,000 rare diseases are documented, yet treatments are available for only about 5% of them. The biopharmaceutical pipeline currently includes nearly 260 vaccines aimed at treating and preventing diseases, including dozens targeting coronavirus disease 2019 (COVID-19).

The substantial investments made by biopharmaceutical companies over the past several decades regarding new technologies, research, and prior vaccine development prepared the industry to respond to the COVID-19 pandemic swiftly, without compromising safety or efficacy. However, recent studies indicate that pharmaceutical companies face escalating costs to bring new drugs to market, as high as USD 2.6 billion per drug. These rising expenses have contributed to a relatively low annual average of 32 new molecular entities and biologic license application approvals by the FDA over the past two decades, with further decreases in recent years [1-4].

New drug discovery involves the screening of numerous candidate chemicals. Thousands of initial hits on high-throughput screening (HTS) are subsequently tested and refined through a series of assays, yielding a few hundred qualified leads. To manage resources and costs, alternative drug development paradigms that emphasize a “quick win, fast fail” approach have been proposed. This strategy is intended to resolve technical uncertainties early in the development process [5]. Its adoption requires the development and implementation of new assays and testing systems, such as HTS, that offer significantly improved drug predictivity and physiological relevance.

In recent years, organ-on-chip (OoC) systems have progressed from a theoretical concept to a powerful alternative to conventional in vitro and animal models [6]. These systems incorporate human tissues that exhibit physiological structure and function within a microphysiological environment that is precisely controlled and features vasculature-like perfusion [7]. Researchers have created a range of OoC systems, from single-organ platforms (such as those for vascular, heart, or lung tissue) to highly intricate multi-organ systems that integrate multiple tissues within a single circulatory flow [8-10]. Several academic studies have demonstrated the considerable potential of OoC systems as in vitro disease models that offer high physiological relevance [11].

Recently, OoC technologies have transitioned from primarily academic uses to tangible industrial applications [12]. Several start-up companies are now entering the biotechnology market with these innovations. To apply OoC technologies in early drug discovery and development, it is essential to automate the systems to increase throughput. Thus, the industrialization of OoC systems necessitates the establishment of high-throughput, physiologically relevant systems.

High throughput organ-on-chip systems

Cells in vivo are exposed to a complex, three-dimensional (3D) environment that includes circulating molecules, neighboring cells, and the extracellular matrix (ECM). Organ-on-chip (OoC) is a powerful technology that provides superior human relevance through microfluidic techniques. Since most platform technologies rely on one or a few chips within dedicated environments, OoCs are primarily envisioned for use in preclinical testing. In contrast, high throughput organ-on-chip (HT-OoC) platforms combine physiological relevance with the scalability of a single chip. This combination enables automation, facilitating the scaling and streamlining of research processes. Recent OoC systems combine individual devices, which contain only one or a few tissues per chip, into modules that integrate multiple chips. To apply OoC technology to HT system, a limited number of OoCs have been adapted for high throughput experimentation by using parallelization to increase the number of replicates per chip.

Currently, most commercially available OoC products are in use as a limited number of parallelized OoC setups that function as HT-OoC systems. In practice, the development of HT-OoC systems has focused on batch processing for perfusion, sampling, and cell injection; scaling up using standard well plates (384-, 96-, 64-, and 40-well); sensor integration; and online analysis. A handful of companies are at the global forefront of HT-OoC platforms. For hydrogel patterning-based HT-OoC, these include AIM Biotech, MIMETAS, and Qureator Inc. For membrane-based HT-OoC, Emulate, Dynamic42 GmbH, PREDICT96-ALI (Draper Laboratory), Bi/ond, and AlveoliX AG predominate. Leaders in non-sacrificial or sacrificial material-based HT-OoC include Nortis Bio and Dr. Jennifer Lewis’ platforms (Wyss Institute). The area of multi-chamber–based HT-OoC (compatible with transwells) is led by TissUse GmbH, CN Bio, and Kirkstall Ltd., while companies engaging in microwell-/milliwell-based HT-OoC include Curi Bio, Hesperos Inc., and MISO Chip.

1. Multi-well plate HT-OoC

1. Multi-well plate HT-OoC

Recent advances in phenotypic tissue and disease modeling are central to the development of therapies in the 21st century. The OrganoPlate technology is available in various formats to accommodate different culture setups, facilitating the development of complex 3D tissue, organ, and disease models. This technology has been demonstrated to be robust and amenable to screening assays, making it one of the most versatile platforms available [13-15]. As shown in Table 1, the OrganoPlate HT-OoC system offers a comprehensive solution for in vitro tissue culture applications [16]. The platform supports the creation of unique tissue cultures and applications through several microfluidic designs and dedicated instruments. Each plate features a single in-gel culture channel and two perfusion channels. This configuration enables the cultivation of one or multiple tissues within an ECM and up to two perfused tubules adjacent to an ECM of choice, without the need for artificial membranes. Compounds and stimuli can be directly applied to both the apical and basolateral sides of the culture. With this level of direct access, the platform enables perfusion and supports a variety of barrier integrity, transport, and migration assays.

2. OrganoPlate with organoid models

2. OrganoPlate with organoid models

In Table 2, the term “organoid” indicates ready-to-use 3D tissue models that are utilized for drug exposure, transport, and permeability studies [17]. Due to their superior physiological resemblance to tissues compared to cell lines, primary tissue, or induced pluripotent stem cell-derived cells, these tubules represent an ideal model for examining the mechanistic toxicity of both small and large molecules, as well as for assessing their absorption, metabolism, and secretion.

3. Multi-chip plate HT-OoC systems

3. Multi-chip plate HT-OoC systems

As shown in Table 3, multi-chip plates enable the recreation of complex human biology and the accurate prediction of human drug responses. They are purpose-designed to more accurately recapitulate the physiology and function of human organs and tissues in vitro [18]. The familiar plate-based format contains multiple chips to facilitate rapid adoption, increase throughput, and decrease costs [19,20].

4. Multi-array HT-OoC

4. Multi-array HT-OoC

Multi-array HT-OoC is advancing the development of next-generation human medicines by integrating human cells, systems, and data. Table 4 showcases tissue-specific multi-array plates featuring human induced pluripotent stem cells, supporting all actors within the drug discovery pipeline—from pharmaceutical companies engaged in drug discovery to the individuals depending on new therapies to be both safe and effective [21-23]. Specifically, the optical-array 96-well plate is rapidly advancing, aiming to fulfill the demand for more accurate, effective, and scalable preclinical screening tools that can predict a drug’s potential toxic effects in humans.

5. Tissue-specific design of HT-OoC

5. Tissue-specific design of HT-OoC

The development of tissue-specific microphysiological systems, commonly known as organ chips [24-30], is revolutionizing the study of biology and the advancement of drug development, therapies, and cures for those in greatest need (Table 5). These tissue-specific designs of OoC technologies provide human-relevant models for complex biological processes. Multiple validated organ chip models now exist, allowing researchers to more accurately replicate human biology. This is achieved by integrating human cell sources, an organ-specific microenvironment, and tissue-relevant mechanical forces. These models can simulate the functions of various organs, such as the liver, intestine, brain, kidney, and lung. Each model also facilitates robust data collection throughout the course of a study, including imaging, effluent analysis, biomarker analysis, etc.

Challenges addressed by HT-OoC

The uniqueness and power of OoC technology lie in its capacity to support the reverse-engineering of all living human tissues using microengineered devices. OoC technologies replicate the intricate biological interactions and physiological functions of these tissues in a manner that has not been achievable using traditional cell culture techniques. This marks a major progression in our capacity to model and comprehend the complex processes of human physiological systems.

Generally, OoC devices are constructed from clear silicone rubber, with variable size and design. These devices contain microfabricated 3D chambers lined with human cells of various types. These cells are arranged and cultivated to form structures sufficiently complex to emulate the essential functions of a living organ. OoC technologies are increasingly being applied across different fields. Most chip models that incorporate two or more types of tissue or organs can effectively provide a supply of patient-specific cells, blood, or diseased cells. This creates an environment conducive to clinical research based on HT-OoC or high-throughput organ-on-a-plate methodologies. Additionally, these technologies are being developed as new drug development platforms and fostering research on reproductive OoC models relevant to both human and animal reproductive medicine.

The primary fields of industrial HT-OoC systems are attempting to address the following challenges, as outlined in Table 6.

1. Cancer research

1. Cancer research

Although animal models can effectively model certain behaviors of human cancers, they fall short in allowing researchers to examine the effects of specific tissue components and investigate the role of the tumor microenvironment [31]. Consequently, we continue to face a shortage of effective and safe treatments for many types of cancer, due in part to the lack of models that accurately reflect cancer progression in humans. OoC technologies enable researchers to replicate the human tumor microenvironment in vitro, facilitating mechanistic studies of tumor cell behavior as well as drug efficacy and safety. Co-culturing endothelial cells within OoC systems produces key cell-cell interactions, while the application of media flow and tissue-relevant stretching simulates the mechanical forces encountered by cancer cells within the body. These highly tunable OoC systems allow for the precise modulation of various cellular, molecular, chemical, and biophysical properties to explore their effects on cancer progression and behavior. For instance, cancer progression is a complex process that remains incompletely understood, partially due to the limitations of animal and in vitro models in replicating the human tumor microenvironment. OoC technology can be employed to model the early stages of cancer metastasis, including the intravasation of tumor cells into the vasculature. By accurately modeling and adjusting the tumor microenvironment, researchers can gain a deeper understanding of, and ultimately influence, various facets of cancer progression.

2. Gene therapy research

2. Gene therapy research

Developing safe and effective viral vectors for gene therapy is both time-consuming and challenging. Gene therapy holds promise for treating both inherited and acquired diseases; however, predicting responses is difficult due to the complex mechanisms involved and the scarcity of clinical data or predictive non-clinical models. A key challenge in gene therapy is the development of gene delivery vehicles. Conventional in vitro models are limited in complexity, often producing non-physiological responses. OoC technology that models the intravenous infusion of gene therapy vectors can be utilized to evaluate the transport of these vectors from the vasculature into the target tissue [32,33]. The application of adeno-associated virus (AAV) transduction for human tissue-based OoC systems allows for rapid testing and iteration of AAV designs within a human-relevant model of the liver sinusoid, thereby accelerating vector optimization.

3. Immunology research

3. Immunology research

Human inflammation mechanisms remain poorly understood, largely due to the challenge of modeling complex immune responses in vitro and the fundamental differences between animal and human immune systems [34]. More human-relevant models of inflammation and the immune response are required to advance our understanding and facilitate the development of treatments for inflammatory diseases. OoC technology offers a promising avenue for constructing more human-relevant models of inflammation. This technology enables the incorporation of the cellular diversity observed in vivo into a tissue-specific microenvironment that more closely emulates the complex cell-cell interactions involved in inflammation. Additionally, it enables the control and examination of the individual contributions of various factors to the inflammatory process. These factors include resident and circulating immune cells, inflammatory cytokines, cell-cell interactions, and organ-relevant mechanical forces. In particular, the complex mechanisms of the human immune response in inflammatory bowel disease require further elucidation. This disease is characterized by dysregulation of colon immune cell recruitment, cytokine-mediated disruption of the colonic barrier, and neuroinflammation, the last of which involves both the neuronal compartment and brain microvascular endothelial-like cells.

4. Infectious disease research

4. Infectious disease research

The COVID-19 pandemic has demonstrated that infectious diseases can have profound global implications due to their rapid spread and unpredictable nature [35]. OoC technology, with its intricate 3D architecture and the mechanical forces induced by flow and stretch, offers a more physiologically relevant model for studying infectious diseases. This technology enables the examination of host-pathogen interactions, the investigation of bacterial and viral infection progression, and the evaluation of treatment efficacy for these infections.

5. Neuroscience research

5. Neuroscience research

The human brain and nervous system are notoriously complex [36,37]. To accelerate the development of safe and increasingly effective treatments for neurodegenerative diseases, a more physiologically relevant model of the human brain is needed. OoC technology can provide a more representative model of the human brain’s neurovascular unit, enabling a more accurate understanding of neurodegenerative disease mechanisms. This includes elucidating the inner workings of the blood-brain barrier and increasing the likelihood that preclinical drug studies will translate to human responses. Although animal models have provided many insights into human neurophysiology, differences between species have often limited the successful translation of neurodegenerative therapies to clinical settings. Conventional in vitro models typically lack the necessary cellular complexity, leading to discrepancies in permeability and transporter expression that hinder clinical translation. Even advanced in vitro models, such as brain organoids, usually do not include microglia, media flow, or vasculature, which are critical for studying a disease’s impact on the blood-brain barrier. Recent brain OoC studies have made strides by incorporating microglia, which are essential for modeling neuroinflammation. These studies also include both the neuronal compartment and brain microvascular endothelial-like cells, featuring models such as blood-brain barrier-penetrating OoC and neuroinflammation OoC.

6. Toxicology assessment research

6. Toxicology assessment research

Biopharmaceutical companies face numerous challenges when developing human drugs, with the assessment of potential toxicity during the clinical stage being particularly daunting [38,39]. Despite passing preclinical safety evaluations in animal models, approximately half of all drugs fail during human trials due to toxicity. Traditional models lack the predictive value necessary to confidently advance drug candidates to clinical testing. The use of HT-OoC systems for earlier prediction of human responses can lead to safer drug candidates and diminish the reliance on animal testing, in contexts such as assessing hepatotoxicity for drug-induced liver injury.

7. Microbiome research

7. Microbiome research

Understanding the biology and function of the gut microbiome is crucial [40,41]. The human gut microbiome plays a pivotal role in immune system regulation, inflammatory bowel disease, and cancer, while impacting drug absorption and metabolism. OoC systems enable the culture of human intestinal cells in direct contact with human gut microbiota. These systems could serve as a platform for clarifying the role of the microbiome in both healthy and disease physiology, and they may accelerate the development of microbiome-related therapies, probiotics, and nutraceuticals. The colon intestine-chip allows for the co-culture of a complex human microbiome with primary intestinal epithelium over several days. This technology provides a means to investigate the microbiome’s role in maintaining barrier function, explore the effects of shear forces and peristaltic-like cyclic stretch, and study the impact of drugs on the intestinal microenvironment.

8. Research in human and animal reproductive medicine

8. Research in human and animal reproductive medicine

Over the past decade, numerous studies have demonstrated the feasibility of developing OoC models of intractable reproductive diseases. These models improve our understanding of disease pathophysiology and support the advancement of clinical and pharmaceutical interventions. Specifically, OoC technology has been instrumental in studying the female reproductive system [42].

A newer OoC model for reproductive medicine has recently been developed, one that replicates the interface between maternal tissue and placental cells during the critical moments of early pregnancy when the embryo implants in the uterus [43,44]. Reproductive OoC technology is still in its infancy. A defining characteristic of the reproductive system is its highly complex and dynamically regulated secretome, which is crucial for maintaining physiological homeostasis and is implicated in various disease processes. To create realistic reproductive OoC models, it will be necessary to capture this complexity and to quantitatively measure, characterize, and validate the complex soluble environment of the engineered constructs. As such, the potential for using these models in medium- or even HTS has not yet been established. Nonetheless, the potential for advancing and applying reproductive OoC technology holds great promise.

Outlook

Globally, North America and the European Union are expected to remain the largest-growing markets for OoC in the coming years. This growth is primarily due to the increasing number of manufacturing companies and the rising demand for HT-OoC systems. Additionally, factors such as increased research and development (R&D) spending and the growing trend of outsourcing R&D activities are likely to contribute to the expansion of the OoC market in these regions. In particular, the increasing number of clinical trials conducted in these areas is a key driver of market growth. North America leads the world in the number of clinical trials performed, with various studies currently underway. The growing adoption and preference for personalized medicine in the European region are key factors driving the European OoC market forward. Many developments in personalized medicine utilize OoC technology to achieve optimal results. OoC technology, which combines biology and engineering, allows pharmaceutical and biotechnology companies to simulate human tissue and organ functions without the use of animals. Consequently, many OoC system product companies are focusing on the implementation and scaling of OoC technologies, particularly HT-OoC systems, across various sectors of pharmaceuticals and healthcare. Advancements in 3D bioprinting and 3D microfabrication are aiding in tissue modeling and the creation of organ-like structures. These developments are crucial for the advancement of HT-OoC technologies and have a broad range of applications, including micro-robotics, drug delivery, and therapeutics. Such innovations are instrumental in driving market growth.

In the coming years, the OoC market is anticipated to experience global growth, driven by a surge in market activities including product launches, collaborations, mergers, and acquisitions.

Notes

Conflict of interest

There is no conflict of interest with Ginkgo Bioworks Inc.

Author contributions

Conceptualization: SHS. Data curation: SHS. Investigation: SJ. Writing-original draft: SHS. Writing-review & editing: SHS, SJ. Approval of final manuscript: SHS, SJ.

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