Collaboration Over Competition: Advancing the Use of Microphysiological Systems
By Dr. Anicca Harriot | February 20th, 2025
Microphysiological systems (MPS) or “organ-on-a-chip” platforms are sophisticated tools used to model human organ function. MPS harness techniques from cell biology, tissue engineering, and microengineering to recapitulate three-dimensional (3-D) tissue structures, organ function, and even intra-organ interactions. The biomimetic properties of MPS make them tantalizing tools to replace animal models in disease modeling, preclinical trials, and toxicity screening. However, the promise of MPS has yet to result in widespread adoption of these tools in academia, industry, or—critically—in regulatory decision making.
Challenges & Opportunities for MPS Applications
1. Qualification & Validation
To replace or reduce the use of animal models, academic institutions and industry stakeholders must collaborate with regulatory agencies to define requisite endpoint measurements that meet the regulations promulgated by the agency. Scientists have made an effort to introduce clinically relevant outcome measures such as force production in skeletal muscle MPS or dermal penetration in skin-on-a-chip systems. Despite the success of these platforms in achieving functional outcomes, it is unclear to what degree measures of organ function from MPS are scalable and transferable to humans. For example, the Environmental Protection Agency (EPA) states in their New Approach Methodologies (NAMs) Work Plan that significant gaps in the science “limit a complete reliance on NAMs for Agency decisions related to the assessment of a chemical’s potential risk to human health and the environment”.
A collaborative effort between regulatory agencies and research scientists is essential to the mission of reducing animal studies through the adoption of MPS. The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was launched to facilitate development, validation, and regulatory acceptance of new and revised regulatory test methods that reduce, refine, or replace the use of animals in testing. This committee has highlighted the need for federal agencies and scientific stakeholders to collaborate to identify and communicate about anticipated testing requirements for approval NAMs in regulatory decision making. Failure to consider the precise context of use is the most commonly cited reason for lack of NAMs implementation. There is an apparent disconnect between biomedical engineers developing MPS and other NAMs and the federal agencies that regulate toxicology policy and drug development. Research scientists will continue to advance MPS platforms to incorporate novel, high-content data driven outcomes – a process that has been ongoing for decades. Federal agencies hold the responsibility of evaluating these NAMs to define the testing requirements, necessary data, and specific applications of this information to explicate the potential contexts of use.
2. Development
While MPSs have gained traction for their potential to replace animal models, many of these tools are still in their infancy and require further optimization prior to being deployed. The success of these platforms in recapitulating functional outcomes is an achievement in tissue engineering, however biologists and clinicians challenge the translational potential of MPS due to persistent deficits in tissue maturation. That is, when MPS incorporate stem cell technology, these cells resemble their embryonic stage and fail to mimic adult features. Here, advancements in regenerative medicine to improve stem cell maturation can help to drive tissue engineering endeavors forward through collaborative efforts between biomedical scientists.
Applications of MPS in preclinical testing and toxicity screening are also limited by the inability of MPS to mimic the complex crosstalk between tissues and the immune system. Human physiology is regulated by constant, complex signaling between organ systems; while animal models may not always provide a direct comparison to human responses, they remain the gold standard to elucidate what biological mechanisms contribute to drug response, chemical exposure, and disease. Though a single screening in a high-volume animal model can be interpreted for a variety of outcomes, MPS results cannot be generalized in the same way. The push toward an integrated “human-on-a-chip” platform is one effort to incorporate immune responses, hormonal regulation, and intra-organ communication. Collaborative efforts between engineers who can refine the technology, scientists with expertise in cell physiology and molecular biology, and physicians with experience in clinical outcomes are needed to push toward more physiologically relevant MPS platforms. This cooperative work also holds the potential to clarify the appropriate context-of-use for individual MPS platforms, facilitating a more direct pathway to regulatory qualification and validation.
3. Accessibility
Another major hurdle to achieving cross-disciplinary application of MPS is the specialized knowledge required to deploy these tools. Many of these platforms require expertise in microfluidics and/or tissue engineering limiting the adoption of these tools in laboratories where 2-D culture and animal models are well-established. Collaborations between biomedical engineers developing MPS and biologists working at the bench can help distribute talent to train scientists on both sides of this new technology. Moreover, incorporation of MPS and other New Approach Methodologies (NAMs) into the educational pipeline for graduate students through curricula and/or funding of training grants is an unmet opportunity to begin to establish a robust workforce that is well-equipped to take on the challenge of replacing animal models.
Looking Forward
As we look toward the FDA Modernization Act 3.0 to support MPS as an alternative to animal testing in drug and biological product development, the fact remains that these methods are still evolving, and the scientific community is far from ubiquitous use of these systems in place of animal models. Though MPS and other organ-on-a-chip platforms have been around for decades, there are very few regulatory pathways that incentivize the use of MPS over traditional models. Traditional models such as animal testing and 2-D cell culture are tried and true approaches that have produced the majority of effective drugs on the market today. Furthermore, biomedical scientists outside of engineering fields lack the skills to deploy many of the existing MPS in service of their endeavors. While some commercially available platforms exist to bridge the gap in expertise, many MPS remain cost prohibitive.
There are also many reasons to be optimistic about the future of MPS. The National Institutes of Health (NIH) has recently announced a request for applications for the Complement Animal Research in Experimentation (Complement-ARIE) grant mechanism which aims to identify opportunities and use-trends for NAMs, including MPS, in biomedical research. The EPA has invested in complex tissue modeling through MPS to test organ-specific toxicity. As part of promoting this work the EPA has developed a three-part strategy that: 1) characterizes the scientific quality and relevance of existing animal tests, 2) develops recommended reporting requirements, and 3) demonstrates application of the NAMs to regulatory decisions through case studies. Key to this mission is a collaborative effort between the regulatory agency and academic scientists to ensure a high quality of scientific approaches and outcomes when compared to animal testing. Similarly, the FDA’s Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program includes a pathway to qualify proposed MPS as drug development tools. Since its inception in 2020, this program has accepted five letters of intent, one of which is an MPS platform. Only one of the ISTAND projects has moved into the qualification process, underscoring the need for a more robust effort to push NAMs adoption forward. As government agencies continue to endorse the use of MPS, the technology will continue to be popularized, but validation will remain a hurdle in its widespread adoption without federal guidance. Federal agencies have the power to define a clear path that drives MPS forward in reducing the use of animal testing. As with any emerging technology, cross-institutional collaborations will be an integral part of seeing the promise of MPS fulfilled.
The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.
