Bioethical implications of organ-on-a-chip on modernizing drug development

Abstract

Organ-on-chips are three-dimensional microdevices that emulate the structure, functionality, and behavior of specific tissues or organs using human cells. Combining organoids with microfabricated fluidic channels and microelectronics, these systems offer a promising platform for studying disease mechanisms, drug responses, and tissue performance. By replicating the in vivo microenvironment, these devices can recreate complex cell interactions in controlled conditions and facilitate research in various fields, including drug toxicity and efficacy studies, biochemical analysis, and disease pathogenesis. Integrating human induced pluripotent stem cells further enhances their applicability, thereby enabling patient-specific disease modeling for precision medicine. Although challenges like economy-of-scale, multichip integration, and regulatory compliance exist, advances in this modular technology show promise for lowering drug development costs, improving reproducibility, and reducing the reliance on animal testing. The ethical landscape surrounding organ-on-chip usage presents both benefits and concerns. While these chips offer an alternative to animal testing and potential cost savings, they raise ethical considerations related to community engagement, informed consent, and the need for standardized guidelines. Ensuring public acceptance and involvement in decision-making is vital to address misinformation and mistrust. Furthermore, personalized medicine models using patient-derived cells demand careful consideration of potential ethical dilemmas, such as modeling physiological functions of fetuses or brains and determining the extent of protection for these models. To achieve the full potential of organ-on-a-chip models, collaboration between scientists, ethicists, and regulators is essential to fulfil the promise of transforming drug development, advancing personalized medicine, and contributing to a more ethical and efficient biomedical research landscape.

Organ-on-chips are three-dimensional device that replicate the architecture, functionality, and behaviors of a particular tissue or organ system on a microchip. Also called, tissue chips, organs-on-chips are built from human cells and mimic the structure and function of our heart, kidneys, lungs, and other organ systems.¹ Two technologies combine to allow this physiological modeling to occur: organoids and microphysical systems (Figure 1). Organoids are three-dimensional structures that are grown from stem cells and other cell sources to more closely resemble an organ’s tissue and architecture. Scientists use organoids to study many aspects of disease, study organ performance, drug responses and development, and create transplantable material for treatments. When incorporated with microfabricated fluidic channels and microelectronics on silicon or glass, organoids create microphysical systems (MPS), which is another term for these organ-on-a-chip or tissue chips. These chips are indeed considered biochips as they house integrated three-dimensional cellular constructs (organoids), and contain nutrients and perfusion systems to help recreate the in vivo microenvironment.^2,3 Often, the chips are constructed using a variety of biomaterials including polymers, hydrogels, and other artificial materials that aid in the replication of the physical and biochemical microenvironment of real tissues. This mimicking of the microenvironment by the microfluidics allows for the chip to recreate and model human tissue function and disease.

FIGURE 1.

Organ-on-a-chip technology developed from the combined advances of many scientific and technical disciplines. This convergence of advances allows organ-on-a-chip technology to have wide impacts in many applications ranging from academic studies involving mechanistic biology and disease modeling through biotechnology and pharmaceutical companies’ development of drugs, diagnostics, and therapeutics.

1 |. ORGAN-ON-A-CHIP UTILITY

Organ-on-chips are an important tool for studying cell and tissue biology in controlled and reproducible conditions, outside of the body. Key needs for organs-on-chips include a platform for culturing the different cell types, a medium for optimal cell growth, sensors to measure cellular activity, perfusion systems to deliver and remove nutrients and other molecules, and precision movement systems to control the physical and chemical cues informing the cells. Additionally, multiplexed imaging systems and computational/artificial intelligence methods are frequently used as tools for data acquisition and analysis. By providing an environment that allows the examination of complex cell–cell and cell–matrix interactions, organs-on-chips are becoming increasingly valuable for both basic and applied research, including drug discovery, cell-based therapy evaluation, disease modeling, and risk assessment application. For example, organs-on-chips can be used to evaluate responses to a variety of stress factors, such as temperature, drugs, toxins, and inflammation. Currently, organs-on-a-chip technology provides a wealth of research opportunities including drug toxicity and efficacy studies, in-vitro analysis of biochemicals, pathogenetic study of diseases, and metabolic activities of human cells.

Another benefit of organs-on-a-chip technology is that it is a modular technology—these chip devices lend themselves to incorporating other technologies thereby increasing their potential utility and impact. For example, human physiology may be modeled by the use of human induced pluripotent stem cells (hiPSCs) that are integrated into the chip. hiPSCs are human cells that have been reprogrammed by inserting key genes into the cells so that the cells behave as though they were pluripotent and capable of yielding numerous terminal phenotypes. If one follows an appropriate differentiation protocol for deriving cardiac myocytes, then the hiPSCs would yield mature cardiac myocytes with the physiological features associated with the donor tissue, like ion channel composition of the heart.^4,5 To take this one step further, tissue samples from a patient can be used to generate patient-derived hiPSCs, which can directly emulate certain diseases with specific mutations. Additionally, if the correct patient source is not available, CRISPR editing of cells can be used as the basis for hiPSC to simulate these specific mutations. Dr. Joseph C. Wu and colleagues have demonstrated that this approach is particularly useful in modeling cardiac disorders, such as long QT syndrome,⁶ dilated cardiomyopathy,⁷ or coronary microvascular dysfunction.⁸ Incorporating hiPSCs into microfluidic chip-based studies has moved forward rapidly and made significant progress; however, issues such as separating out the desired cells, ensuring the maturity of the cells, and addressing whether differentiation should occur on or off the chip represent a current limitation of the approach.^9,10 These concerns are not fatal flaws for the implementation of the technology, but rather, they represent bottlenecks that must be addressed by science, engineering, and general technological development. As these obstacles are overcome, the potential for organs-on-chips-based drug screen will be enhanced as the screens will be able to uncover drugs that are safe in normal, undifferentiated hiPSCs but may cause dangerous problems in various patient-derived cells.¹¹ Patient-specific approaches may acknowledge and help detect certain genetic mutations or variants that predispose patients to a problem, like an arrhythmia, in response to a drug that would be safe in normal controls.^12,13 These developments provide the underlying basis for the expanded use in toxicology and its benefits for precision medicine.

2 |. ORGAN-ON-A-CHIP’S EVOLVING ROLE IN DRUG DEVELOPMENT

These organs-on-chip utilities are where the FDA Modernization Act 2.0 alters the regulatory landscape. The bill “allows for alternatives to animal testing for purposes of drug and biological product applications.” As detailed by Dr. Jason Han and Dr. Eli Adashi et al., the bill does not introduce an outright ban on animal testing, but it may significantly decrease the need for it.^14,15 The introduction of organ-on-chips as a viable alternative for animal studies in preclinical development offers an opportunity to lower costs, provide more accurate and relevant models, and help ameliorate many of the ethical issues surrounding the animal work in pharmaceutical development. Furthermore, the FDA Modernization Act 2.0, the Executive Order on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy and the CHIPS and Science Act of 2022 further create synergy and momentum propel this paradigm-shifting technology forward. In particular, the CHIPS and Science Act of 2022^16,17 calls for “advancing US global leadership in the technologies of the future. US leadership in new technologies—from artificial intelligence to biotechnology to computing—is critical to both our future economic competitiveness and our national security. Public investments in R&D lay the foundation for the future breakthroughs that over time yield new businesses, new jobs, and more exports,” which align with the push to embrace the development of organ-on-a-chip as a legitimate option for preclinical testing and IND-enabling studies. Currently, the FDA is actively facilitating discussions and collaborations to determine how best organ-on-chips and other types of “New Approach Methodologies (NAMs)” may be incorporated into the regulatory process and pharmaceutical development to assess drug safety and efficacy.¹⁸

How can organ-on-chips help lower drug development costs? The Congressional Budget Office (CBO) reported in 2019 that the pharmaceutical industry spent $83 billion in research and development costs, which is a tenfold increase in annual costs from what industry spent in the 1980s.¹⁹ Furthermore, the expected cost to develop a single new drug has been estimated to reach up to more than $2 billion.¹⁹ Attila Seyhan notes this rapid growth in spending by biopharmaceutical industry over time, and notes that costs to develop a single drug may exceed $16 billion by the year 2043.²⁰ Why does drug development cost so much? A great deal of the research and development utilizes animal work and much of this work fails. It is estimated that the average success rate for all therapeutic areas combined is 11%. Furthermore, approximately 37% of drugs that make it to human trials fail in Phase I human clinical trials, 55% fail in Phase II, and 12.6% fail in Phase III.²¹ Seen another way, approximately 30% of promising medications have failed in human clinical trials because they are determined to be toxic despite encouraging preclinical safety and toxicology studies in animal models.²² Furthermore, about 60% of new drugs fail to show effectiveness in treating human diseases due to poor prediction by current in vitro and in vivo models of adverse reactions to candidate compounds during clinical trials.²² For example Type 1 diabetes (T1D) research and therapeutic development has suffered from these drug development failures. In T1D, the field has advanced greatly on the usage of two animal models: the non-obese diabetic (NOD) mouse and the spontaneous diabetic Wistar rat (BB rat).²³ Researchers have generated fundamental insights regarding T1D’s pathophysiology; however, clinical translation has remained elusive.^23,24 Similarly, animal models of sepsis and neurodegeneration have also demonstrated similar failures in clinical translation.^25,26 Though these insights are useful, they cannot be directly applied toward devising human therapeutic options. These failures constitute a great expenditure of resources, including funds, time, reagents, and sacrificed animals.

3 |. CURRENT ETHICAL CONSIDERATIONS

It is not just about the money: there are a multitude of ethical issues involved in traditional drug development practices, particularly if there are alternatives! Cost itself raises ethical issues: although not a “zero sum” game, resources spent on drug development could, at least to some extent, be allocated to something else if drug development can be done more inexpensively. More importantly, though, the high cost of drug development contributes greatly to injustices such as “orphan diseases” in which therapies are not developed because there is not a large enough number of people with the problem to make it financially worthwhile, distributive injustice both domestically and globally, and the fact that drug development costs are ultimately passed on to the patient. It has been recognized for decades that high medical costs are one of the leading causes of bankruptcy in the USA.²⁷ Lost time translates most obviously into lost lives for the patients without appropriate therapy, but also into losses in professional development for the researchers involved. Finally, the basics of ethical use of animals in research are based on the “3 Rs” of replacement, reduction, and refinement; any time animal use can be eliminated, decreased, or made more productive, it should be! Thus, an emphasis on gaining valid human-relevant data generation during preclinical translation must be incorporated into such studies, and organ-on-a-chip development offers a potential solution.²⁴ The ultimate vision for organ-on-chips is to assemble and integrate multiple chips where each is representative of a particular organ and develop a body-on-a-chip model for use in drug development or even clinical trials-on-a-chip.^28,29

As rigor and the emphasis on reproducibility of data has increased, the potential increases for these animal studies to have success during translation. organ-on-chips offer the biopharmaceutical industry an opportunity to save almost 25% in research and development costs by generating more human-relevant data and increasing the efficiency of the research.³⁰ These cost savings come about from lowering costs during lead optimization and preclinical work where many experts felt organ-on-chips would have the largest impact on cost savings.³⁰ The increasing utility of transomics studies and systems biology support translational research and have benefited studies using zebrafish, mice, rats, and non-human primates (NHPs); however, timely application of these knowledge stores is a challenge.³¹

Organ-on-chips will potentially achieve this time and cost savings and have the potential to ease these concerns and to some extent mitigate the ethical concerns regarding animal models, especially NHPs. For example, organ-on-chips laden with cells for other species may help determine which model is most effective to test and generate data for benchmark comparisons to validate results from previous studies with these models.³² Before this vision is achieved, organ-on-chips must address a number of challenges.^28,29,32,33 (1) Economy of scale and the limitations of the chip size, materials available to create the three-dimensional microenvironment can reduce the efficiency of the system; (2) Multichip integration to simulate whole body not just one tissue/organ; (3) Standardization of manufacturing under GMP GLP (Good Manufacturing Practices, Good Laboratory Practices; GMP is a set of practices to ensure and create uniformity in manufacturing processes for medicinal products and GLP is a set of standards to ensure the quality and integrity of test data related to non-clinical safety studies); (4) Full understanding of regulatory and ethical implications, like cell sourcing and potentially coupling organ chips with artificial intelligence and machine learning (AI/ML).

4 |. THE SHIFTING ETHICAL LANDSCAPE

The use of organ-on-chips in drug development, while likely to solve some ethical issues, raises important new ones. Combining technological concepts or processes increase the complexity of the resulting platform. With each of these advances, questions arise regarding the implications or benefit to the community or society; as these technologies increase in complexity, the potential impact, good or bad, increases as well. This pattern is why inclusion of bioethics is critical, especially at this nascent stage. One place to start is with empirical research: what do people (the public) think about this type of research, and what “tradeoffs” are they willing to make? Community acceptance and engagement regarding novel technologies will proactively address misinformation and mistrust when science attempts to perform an old task in a new manner, as with organ-on-chips and drug development. This point is critical and most recently demonstrated by how COVID-19 guidance was received and implemented (or not) by the public at large.³⁴ Scientists, engineers, and healthcare providers have a duty to communicate how a particular aspect of science may benefit the community, and also what risks are entailed even when it is used correctly. Importantly, community engagement fundamentally includes two way communication: scientists and policy makers must both listen to what the public thinks about any new technology, and must recognize that the values and priorities of everyone should be respected.

Community engagement is always important, but arguably there are particular types and/or applications of new technology for which it is particularly crucial. For example, organ-on-chips lend themselves to personalized and precision medicine models. Utilizing a patient’s tissue and cells, a system could be developed to model a patient’s particular combination of genetics and environmental factors to be able to screen a particular drug or treatment. This modeling would permit more accurate simulated results of how a patient may be affected by a treatment, and in the case of vulnerable populations, like children or pregnant women, it may help anticipate potential benefits and dangers.³⁵ To extend this concept further, this modeling may also be applied to the fetus or the brain. Organoids may be used to determine short- and long-term fetal chemical exposure, which in turn permit the study of chemicals that could be detrimental to development, like endocrine disruptors.¹¹ Organoids could become the new standard for toxicology instead of fetal progenitors, which would help mitigate the ethical issues surrounding primary human tissue used to derive fetal progenitors.¹¹ Additionally, iPSC-derived cerebral organoids can be used to study more specific effects of chemical compounds or drugs to the brain, like alcohol or illegal substances.^11,36 Incorporation of organ-on-a-chip technology with these particular types of organoids opens a new line of inquiry and progresses science, and currently remains within the parameters of acceptable bioethics, but “currently” is key. The field is progressing rapidly, and major ethical dilemmas are imminent and should be considered and discussed right now. For example, when modeling physiological or cellular functions of a fetus, pregnant woman, recapitulating these in vivo processes, what do we consider the new model to actually be, and what protections does it deserve? What should a scientist consider if a brain organoid begins to develop consciousness or aspects of it, and how would the scientist know?³⁷ There are no regulatory standards for work with organoids, since they fall neither under those for laboratory animals nor under human subject protection. Scientists, ethicists and regulatory professionals should begin to work together now to formulate ethical and regulatory guidelines applicable to this space.

Scientists must also acknowledge the dangers inherent in new technology when used incorrectly or without the appropriate bioethical framework. A report³⁸ from the National Academies of Sciences, Engineering, and Medicine details these concerns and serves as an example of how to best communicate the potential benefits of a novel technology to the public. Community engagement is key!

Another important bioethical issue relates to the principle of autonomy (or respect for persons). Perhaps the most common and arguably most important way of preserving a patient’s autonomy is the requirement to obtain informed consent. This becomes problematic in the case of any new technology: how can consent truly be informed when the scientific community may not even know the true risks and benefits of a new or experimental treatment? How can complex pros, cons, and uncertainties be explained to a person without much scientific knowledge? Empirical bioethics research can help to determine what information is helpful for potential research participants to make informed decisions in situations like this, where there is so much uncertainty, and can also be used to provide information to institutional review boards to help them understand potential tradeoffs between risks and benefits.

The FDA’s recent decision to allow alternatives to animal testing for regulatory purposes has the potential to be a true game changer for research and development of new drugs and biologics. It could shorten the time to drug development, lower costs, improve access, and decrease (and improve efficacy of) the use of animals in research. Pairing “bench” research with data science and empirical bioethics research will be key as the field moves forward.