03762nas a2200229   4500000000100000000000100001008004100002260001500043653002100058653001800079653002600097653003100123653002600154100001900180700001800199245005600217856005600273300001200329490000700341520317000348022001403518       2025                            d  c2025-04-1510aDrug development10aorgan-on-chip10aregulatory acceptance10astandardization challenges10avalidation frameworks1 aThomas Hartung1 aLena Smirnova00aA path forward advancing microphysiological systems  uhttps://altex.org/index.php/altex/article/view/2965  a183-2030 v423 aMicrophysiological systems (MPS), including organ-on-chip platforms and complex organoid models, represent a transformative approach to human-relevant in vitro modeling. These technol­ogies bioengineer aspects of organ architecture and functionality, revolutionizing drug development, reducing animal testing, and enabling personalized medicine approaches. Despite significant advances, several critical challenges remain before their full potential can be realized. This article examines key obstacles facing MPS adoption and implementation while proposing actionable solu­tions to accelerate their development and acceptance. Major challenges include standardization issues across terminology and protocols, validation complexities requiring robust reference com­pounds and benchmarking standards, regulatory uncertainties regarding data requirements and qualification processes, and barriers to effective data sharing among stakeholders. The paper traces the field’s evolution through various international initiatives, particularly highlighting the Center for Alternatives to Animal Testing’s (CAAT) contributions, including the establishment of the International MPS Society and World Summits. Proposed solutions emphasize establishing global standards through international consortia, enhancing validation frameworks through specialized validation centers, fostering collaboration through pre-competitive consortia and standardized data formats, and advancing regulatory integration through detailed case studies and clear guidance documents. Future priorities focus on overcoming technical challenges in biological complexity, addressing engineering hurdles, standardizing technologies, improving data management, increasing eco­nomic accessibility, and integrating with other emerging technologies. The path forward requires coordinated, collaborative efforts across academia, industry, regulatory agencies, and technology suppliers to systematically address these interrelated challenges.
Plain language summary Microphysiological systems (MPS) are advanced laboratory models that mimic human organs using engineered tissues and microfluidic technology. These “organs-on-chips” and 3D orga­noids allow scientists to study disease and test drugs without using animals. Despite their promise, MPS face several challenges that slow their widespread adoption. These include inconsistent standards, difficulties proving they work reliably, regulatory uncertainties, and limited data sharing between organizations. This paper identifies these obstacles and proposes practical solu­tions: creating international standards, establishing dedicated centers to validate MPS models, encouraging organizations to share data, and developing clear regulatory pathways. The authors highlight ongoing collaborative efforts, including international conferences and societies dedicated to advancing MPS technologies. With coordinated effort from scientists, companies, and regulators, MPS could transform drug development, reduce animal testing, and enable more personalized treatment approaches, ultimately improving human health while reducing research costs.  a1868-8551