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• W4385609384 abstract "THE MEETING A major microphysiological systems (MPSs) meeting was recently organized in New Orleans,1 hosted by Suzie Fitzpatrick, Food and Drug Administration, Thomas Hartung, Johns Hopkins, and Donald E. Ingber, Harvard. It was attended by over 600 researchers, students, and representatives from industry, regulatory bodies, and funding agencies from all over the world (450 in person and 215 online from 26 countries). Fifty-two organizations led by the “Johns Hopkins Center for Alternatives to Animal Testing” joined by the Steering Group to develop this conference supported by 34 individual members of the Scientific Advisory Board. One hundred forty-two speakers and 189 poster presenters shared their work. Over four days (May 30–June 3, 2022) (https://mpsworldsummit.com), it covered different topics and research areas highlighting advancing frontiers in the MPS field, such as multiorgan-on-a-chip (MoC), integration of immune cells/system to organ-on-a-chip (OoC) MPSs, new organ and disease models, such as those focused on the nervous system,1 reproductive system, and use of induced pluripotent stem cells for the development of personalized medicine. In addition to the usual presentations, industry exhibitions, and posters, it also included a hands-on workshop, round-table discussions, and panels. The second MPS World Summit is currently prepared for to take place from June 26, 2023 to June 30, 2023 in Berlin, Germany. In the following sections, the authors summarize a few personal takeaways from the first summit. LESSONS LEARNT The importance of the use of MPS is increasingly being recognized in many ways. Experiments to study disease or test drugs and chemicals have been conventionally performed using two-dimensional (2D) cell cultures. In these cultures, there is not much cell-cell contact as it naturally occurs in the body (Fig. 1). There is more contact with the plastic of the culture dish and media, which is not natural.3 There is no real three-dimensional (3D) structure normally found in the body. Therefore, results obtained from these experiments cannot represent real in vivo events. Experimental animals were, therefore, required to demonstrate the safety and efficacy of drugs before a drug or an implant could be allowed to move to clinical trials. However, animals are different species, and their physiology is different than human physiology. Drugs that prove safe in animals may not necessarily behave well in humans, and therefore, serious or even fatal complications were seen after these were introduced to clinical trials and even the clinic.4,5 About 50% of cancer animal studies fail high-profile replication tests.6 Traditional cell culture also does not come without problems: There are ~25% of cell lines, which are misidentified (not what they are supposed to be), and 15% to 25% are mycoplasma infected. There is also the problem of genetic instability and the use of prophylactic antibiotics in cell culture.7FIGURE 1: Future of drug testing. Evolution of 3D physiologically relevant microfluidic models for nephrotoxicity screening. Reproduced from,2 with permission form Elsevier. 3D indicates three-dimensional; ECM, extracellular matrix.Search for alternatives to reduce animal testing and finding better options continued. The development of tissue engineering in the late 1980s and 1990s led to advancement toward this objective. Although the focus of tissue engineering at first was to develop replacement and augmentation therapies for lost or diseased tissues, the potential of using engineered tissue constructs for developing disease models and test modalities was recognized and explored. With advances made in bioreactors, microfabrication, 3D bioprinting (3DBP), and organoid technologies, it was possible to produce more sophisticated and controlled engineered multicellular systems, which can be composed of one or multiple cell types, with one or more of different types of biomaterials, in a microfluidic system or as organoids or in printed form. The term MPS, that is, models replicating aspects of organ architecture and functionality, was coined by the Food and Drug Administration to describe these models in a collective form.8 The MPS field, therefore, encompasses research into organoids, OoC, 3DBP, and their possible combinations. When MPSs were compared with results of in vivo experiments in animals and clinical data, it became more evident that cells polarize and function in a way mimicking more in vivo and superior to 2D cultures. The use of human-derived cells and induced pluripotent stem cells presents an unprecedented opportunity to develop individualized, personalized medicine.9 Research into MPS has increased exponentially in the last five to 10 years. Although single MPSs can be excellent representatives of in vivo, the development of MPS that integrates different organ representative units, such as the MoC system, is required to pick up secondary and systemic toxicity that may result from drug metabolism and circulation in the body. There have been reports on connecting 10 and 15-organ OoCs in MoC systems8,10 (Fig. 2). These systems, however, bring with them their own challenges that include problems related to connections, the need for different media and flow rates for different organ units, automation, and large data retrieval and analysis. The development of pumpless systems addresses some of the problems, such as those associated with connections and pumps; however, much is still needed.FIGURE 2: Concept map for an MoC or body-on-a-chip/human-on-a-chip device, which can integrate multiple biomimetic microengineered organs interconnected with a physiologically relevant dynamic microfluidic circulatory system (UFP, drug) (A) Examples of multi-organ-on-a-chip (MoC) or body-on-a-chip. (B) A 10-organ MoC. (C) A 6-organ MoC. (D) A 10-organ MoC. (E) A 14-organ MoC. “A” was reproduced from,11 with permission from Wiley. “B, C, and D” were reproduced from,8 with permission from Springer Spektrum, and “E” was reproduced from,10 with permission from Wiley. MoC indicates multiorgan-on-a-chip; UFP, ultrafine particle.ADVANCES Sensors have been integrated with MPSs, and some industrial products already integrate sensors, for example, pH, oxygen, impedance, trans-epithelial electrical resistance, and temperature sensors in the chips. High throughput is another challenge that can largely be helped with the integration of artificial intelligence. The use of mathematical models will advance the development of these aspects further in the future.12 The use of OoC oxygen gradients and flow rates will allow the development of specific models that suit the requirements of different cell types. This can be achieved by developing advanced OoC systems.13 Efforts to move forward with MPS translation to the clinic have been actively pursued. For the success of clinical translation, validation, scale-up production, and automation,14 approval and acceptance by clinicians are needed. To demonstrate MPS biomimicry, validation using clinical data is required. Also, a relevant comparison with data obtained from animal experiments or human studies is required to demonstrate its closeness in the representation of in vivo events. One has to remember that the scaling factor can be 1:100,000, for example, in HepaRG-stellate cell spheroids, and therefore, the dilution of tested drugs needs to consider this factor.8 Applications of MPSs, as implantable systems, need to undergo a thorough investigation to demonstrate their safety. Issues related to uncontrolled growth or tumorigenesis that may occur with the use of stem cells or organoids need to be clarified, and this will help the translation of implantable MPSs. Heterogenicity and batch-to-batch variability also remain as challenges to be addressed, and the use of automation is one way to reduce the occurrence of this problem. INSIGHTS The right choice of biomaterials used in MPSs is very important. The matrix may have an effect on cell response to drugs tested. For example, hydrogels are used in 3DBP and with cells and organoids. Although Matrigel has been widely used, new polyethylene glycol-based synthetic gels that can be engineered to create certain functionalities can be used to develop MPSs more representative of in vivo than those using Matrigel. Similarly, materials commonly used in the fabrication of OoC chips, such as polydimethylsiloxane, may not be ideal when testing drugs and chemicals as polydimethylsiloxane tends to absorb hydrophobic molecules. Alternatives, such as polymethylmethacrylate and other polymers, can, therefore, be used. The recently developed microvascularized tumor device model represents an important tool to further study the tumor microenvironment niche.15 In this patient-derived MPS tumor microenvironment model, fibrin and fibroblasts were used, perfusable networks were produced, and tumor spheroids were added. The importance of MPSs in developing personalized medicine, reducing the occurrence of serious and fatal complications later will be achieved. Also, it will contribute to reducing health inequity by targeting individual communities and groups of patients more accurately and developing more precise therapeutics. Pre-clinical trial use of MPS will help in the selection of patients for clinical trials (preclinical trials-on-a-chip). MPSs can be used to identify patients who can potentially respond most to the test drug.8 This will lead to more accurately predicting possible safety profiles (as compared to existing clinical, histological, and genetic methods). Application examples include the prediction of possible immune reactions before administering immunotherapy. It can be a part of evidence-based decision-making for the treatment of cancer. It will help pharma to optimize patient cohorts for clinical trials, and clinicians identify and prescribe the right drug for individual patients and can have an impact on the cost of drug development (Fig. 3). It may also reduce the number of patients required to include in clinical trials for investigating safety and efficacy. By integrating preclinical MPS-based platforms and clinical data, it will be possible to construct digital twins that can constitute an essential part of future medicine.FIGURE 3: Potential application of MPS in the process of drug development. Single-organ MPSs are envisioned to have a significant impact on target selection toward lead optimization (red box). Multiorgan microphysiological systems (MPSs) are intended to enable predictive measurements in the late lead optimization phase and early preclinical evaluation (blue box). All categories of MPS may have an impact by adding relevant data to the postapproval extension or restriction of indication to specific genotypic subpopulations (red-blue box). On the Y axis, approximate numbers of tests performed (grey) and related spending (blue) are shown, and on the X axis, the development time is shown in years. Reproduced from,8 with permission from Springer Spektrum. MPS indicates microphysiological system.WAY FORWARD Acceptance of MPS by the pharma industry and physicians, as well as regulatory bodies, will require more extensive efforts that demonstrate the efficacy of the technology, its cost-effectiveness, and its impact on driving innovations and improving health outcomes. In the future, one can envision that certain OoC will be approved by regulatory agencies for testing certain drugs and so on, as we do see today with the approval of devices and drugs. Indications of the use of certain MPSs will be expanding according to the results of validation with clinical studies and data. It is expected to see a much reduction in the use of experimental animals in the next 15 to 20 years (Fig. 4).FIGURE 4: Next microphysiological system developments meeting industrial needs. Reproduced from,8 with permission from Springer Spektrum. MPS indicates microphysiological system. ADMET indicates Absorption, Distribution, Metabolism, and Excretion; PK/PD, Pharmacokinetic/Pharmacodynamic.Development of proper standards is needed, and this should contribute to innovation and not to restriction of research and development.16 Compatibility between developed MPSs and conventional laboratory equipment is needed. Also, hospital equipment to enable easier integration into the current system and enhancing applications are required. An MPS society was founded,17 and this will take us together to the next level of advancing this field to connect, exchange, and educate. Discussions on including Africa, which has been absent in this effort, were brought up in the round-table discussion. One way would be the emerging MPS society role and industrial support for founding funds that can be used, for example, for training fellowships directed to less developed regions and underprivileged communities. Diversity and inclusion will contribute to making more innovations in MPS research, and the impact will be wider. We are expecting to see more funds integrated, focused programs initiated, and international collaboration fostered. The combination of approaches, such as organoids, 3DBP, co-culture, and microfluidic systems, will enable tackling many challenges and ignite the development of new generations of MPS. There are areas, which are less funded today, such as reproductive system problems, e.g. endometriosis, which affects 1/10 of women of reproductive age, and they should get proportional funding and funding MPS research, will help reduce inequity and provide major opportunities to explore and understand the disease better and develop effective therapies. It is expected to see wider studies and applications that combine the immune system, neural components, and other matrix-based components. The MPS work, and MPS adoption as an alternative testing method to current 2D culture and animal-based studies, will take the whole world to a new era in which we can save many lives of humans and animals." @default.
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• W4385609384 title "Lessons and Insights From the First Microphysiological World Summit" @default.
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