Unlocking the Future of Medicine: Recent Advances in Organ-on-a-Chip Technology

Listicle 1 Unlocking the Future of Medicine: Recent Advances in Organ-on-a-Chip Technology Stefaan Verbruggen, PhD In the realm of scientific inquiry, Organ-on-a-Chip (OOAC) technology has quietly emerged as a pioneering force, reshaping our methodologies in understanding the complexities of human organs. Originating at the intersection of tissue engineering, microfluidics and bioengineering, OOAC technology was conceived to transcend the many limitations of traditional cell cultures. The objective was to replicate the dynamic functions of human organs within a controlled microscale environment. The path toward precision in replicating complex microenvironments on miniature chips poses significant challenges. Creating a microscale representation of organs demands meticulous attention to detail. Researchers grapple with integrating diverse cell types, emulating physiological conditions and ensuring accurate biomimicry. It’s a methodological endeavor that requires both technological finesse and a profound understanding of the intricate interactions within organs. A particular recent boost has been in the area of standardization of OOAC platforms, which is crucial for ensuring reproducibility and comparability across different studies. Recently, the UK Organ-on-a-Chip Technologies Network surveyed a broad range of organ-chip developers and end-users.1 With a wide variety of stakeholders represented, it was generally agreed that there is a need for more detailed validation of individual and interconnected models in order to reach broader adoption and ease the transition of these new technologies through the start-up and scale-up phases.1 Establishing standardized protocols is being actively aided by regulatory agencies, with the European Medicines Agency having a commitment to reducing animal testing since 2010 (Directive 2010/63/EU),2 and in particular by the recent passing of the US FDA Modernization Act 2.0 (USS.5002)3 which is changing the regulatory landscape. Drug sponsors will now have the capacity to use alternative complex in vitro or in silico models in place of animal testing, where suitable. Despite the inherent challenges, the benefits afforded by OOAC technology are substantial. These miniature organ replicas have the potential to surpass traditional models, providing an unprecedented level of granularity. Scientists can now meticulously study the effects of drugs (e.g., on lung performance),4 simulate diseases (e.g., many cancer types),5 and unravel physiological mysteries (e.g., human-microbiome interactions)6 with exquisite precision. OOACs are not just microenvironments; they serve as tools for refined drug development processes, intricate disease modeling and the realization of personalized medicine. Here, we will discuss a number of recent landmark studies that demonstrate the recent strides being made at the frontier of this field of research. UNLOCKING THE FUTURE OF MEDICINE: RECENT ADVANCES IN ORGAN-ON-A-CHIP TECHNOLOGY 2 Listicle Pharmacology and toxicology Drug development, from target discovery to market approval, is a protracted process that takes a minimum of 10–15 years and is often unsuccessful, resulting in substantial financial losses for pharmaceutical and biotechnology companies. Historically, animal studies have been an integral part of this approvals process, despite the fact that drug toxicity for humans often does not show up in these preclinical models. This results in dangerous effects in humans only being discovered during clinical trials, or in the wider population upon release to the market. As these drugs will ultimately fail, this leads the pharmaceutical industry to waste much time and resources that could be spent on more promising drug candidates.7 If the investigated drug is not effective, incompatible with human metabolism, or has serious or fatal side effects, the resources invested have been wasted. This highlights the potential role that could be played by OOAC technology in both reducing the need for animal models and improving the screening of lead drug candidates for human clinical trials. This has been a goal for the field since its inception, with a landmark recent study demonstrating the efficacy of organ-chips to model drug toxicology for the first time. Using a well-established OOAC model, researchers used 870 liver-chips to test whether they could predict liver injury resulting from small molecule drugs used as benchmarks by the Innovation and Quality consortium, who publish guidelines for defined criteria to use when qualifying preclinical models.7 The liver-chips performed extremely well across a blinded set of 27 drugs either known to cause liver damage or known to be non-toxic, meeting or exceeding the qualification guidelines with a sensitivity of 87% and a specificity of 100%.7 By conducting an economic analysis, the researchers also calculated that if chips could be this effective broadly, they could either save or create value of more than $3 billion every year, allowing the pharmaceutical industry to focus on drugs more likely to succeed.7 As well as demonstrating the promise of the field for pharmacology, this study provides confidence that OOAC models can be deployed at scale to improve the drug discovery and development pipeline. Multi-organ systems: Emulating the body’s complex interactions The human body is a complex interplay of organs working in harmony, and recent advancements in OOAC technology are moving beyond single-organ models. Scientists are now developing multi-organ systems, where different organ chips are interconnected to simulate the intricate interactions between organs in the body. For instance, a cutting-edge development involves connecting heart and liver chips to study the effects of drug metabolism and toxicity on both organs simultaneously.8 Furthermore, it allowed the authors to explore the effect of liver metabolism on off-target cardiotoxicity, measuring the impact of drug activity in the liver on a distant organ like the heart.8 This holistic approach provides a more comprehensive understanding of how drugs impact various organs, allowing for safer and more effective drug development. Multi-organ systems represent a significant leap forward in capturing the complexity of human physiology, offering a more accurate platform for drug testing and disease research. Integration of sensors: Real-time monitoring for precise analysis To elevate the capabilities of OOAC technology, researchers are integrating sensors into the chips, enabling real-time monitoring of cellular activities. These sensors provide valuable data on parameters like pH, oxygen levels and drug concentrations within the microenvironment of the chip.9 In a recent breakthrough, a kidney-on-a-chip was equipped with sensors to monitor the response of renal cells to different drug concentrations. This real-time feedback allows researchers to observe subtle UNLOCKING THE FUTURE OF MEDICINE: RECENT ADVANCES IN ORGAN-ON-A-CHIP TECHNOLOGY 3 Listicle changes in cellular behavior and assess the effects of drugs more precisely. The integration of sensors not only enhances the accuracy of experiments but also provides a dynamic platform for studying the real-time effects of various stimuli on organ function.10 Disease modeling and personalized medicine: Targeting precision healthcare Organ-on-a-chip technology may yet prove to be a game-changer in disease modeling and the pursuit of personalized medicine. Recent advancements have focused on developing organ chips that replicate the pathological conditions of individual patients, allowing researchers to study disease progression and test potential treatments in a controlled environment that replicates in vivo microenvironment of an individual patient. For example, researchers have successfully created lung airway-on-a-chip models that mimic the inflammatory response seen in diseases like asthma and chronic obstructive pulmonary disease.11 These disease-specific models enable the testing of targeted therapies, bringing us closer to personalized treatment strategies tailored to an individual’s unique disease profile. By exposing the airway epithelial layer to agents that mimic bacterial or viral infections, the epithelium became highly inflamed and replicated the effects of an asthmatic response.11 This approach holds immense promise for the future of healthcare, where treatments can be tailored based on a patient’s specific genetic and physiological characteristics. 3D bioprinting: Building functional tissues on chips The advent of 3D bioprinting technology has significantly advanced the field of OOAC research. Scientists can now create intricate three-dimensional structures of tissues directly on the chip, providing a more physiologically relevant environment for cells to thrive. In a groundbreaking development, researchers have utilized 3D bioprinting to construct a heart-on-achip with aligned cardiac tissues that mimic the architecture of the human heart.9 This allows for more accurate studies of cardiac function, drug responses and disease mechanisms. 3D bioprinting not only enhances the structural fidelity of organ chips but also opens new possibilities for creating custom-designed tissues for personalized medicine applications.12 Conclusion Organ-on-a-chip technology has transcended the realm of experimental curiosity, emerging as a potential transformative new force in life sciences and drug discovery. These recent advances mark significant milestones in our journey toward understanding human physiology, disease and drug responses with unprecedented precision. As the field continues to evolve, OOAC technology holds the promise of revolutionizing drug development, disease modeling and personalized medicine, paving the way for a healthier and more tailored future in healthcare. References: 1. Allwardt V, Ainscough AJ, Viswanathan P, et al. Translational roadmap for the organs-on-a-chip industry toward broad adoption. Bioeng. 2020;7(3):112. doi: 10.3390/bioengineering7030112 2. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes. European Parliament and European Council. http://data.europa.eu/eli/dir/2010/63/2019-06- 26. Accessed January 18, 2023. 3. S.5002 – FDA Modernization Act 2.0. United States Senate – 117th Congress; 2022. https://www.congress.gov/ UNLOCKING THE FUTURE OF MEDICINE: RECENT ADVANCES IN ORGAN-ON-A-CHIP TECHNOLOGY 4 Listicle bill/117th-congress/senate-bill/5002/text. Accessed January 18, 2023. 4. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting organ-level lung functions on a chip. Science. 2010;328(5986):1662-1668. doi: 10.1126/science.1188302 5. Nolan J, Pearce OMT, Screen HRC, Knight MM, Verbruggen SW. Organ-on-a-chip and microfluidic platforms for oncology in the UK. Cancers. 2023;15(3):635. doi: 10.3390/cancers15030635 6. Shin YC, Than N, Min S, Shin W, Kim HJ. Modelling host–microbiome interactions in organ-on-a-chip platforms. Nat Rev Bioeng. Published online 2023. doi: 10.1038/s44222-023-00130-9 7. Ewart L, Apostolou A, Briggs SA, et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med. 2022;2(1):154. doi: 10.1038/s43856-022-00209-1 8. Oleaga C, Riu A, Rothemund S, et al. Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system. Biomater. 2018;182:176-190. doi: 10.1016/j.biomaterials.2018.07.062 9. Zhang YS, Arneri A, Bersini S, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomater. 2016;110:45-59. doi: 10.1016/j.biomaterials.2016.09.003 10. Asif A, Kim KH, Jabbar F, Kim S, Choi KH. Real-time sensors for live monitoring of disease and drug analysis in microfluidic model of proximal tubule. Microfluid Nanofluid. 2020;24(6):43. doi: 10.1007/s10404-020-02347-1 11. Benam KH, Villenave R, Lucchesi C, et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods. 2016;13(2):151-157. doi: 10.1038/nmeth.3697 12. Park JY, Jang J, Kang H-W. 3D Bioprinting and its application to organ-on-a-chip. Microelectron Eng. 2018;200:1-11. doi: 10.1016/j.mee.2018.08.004 About the author: Stefaan Verbruggen runs a lab in the Centre for Predictive in vitro Models, at Queen Mary University of London. As a biomedical engineer, his work focuses on building physiologically relevant organ-on-a-chip models to study bone diseases and for drug discovery in cancers.