# Organoids, organs-on-chips, complex in vitro model: Definitions, applications, validation, ethics

Guillaume Mottet, Alexandre Grassart, Philippe Barthélemy, Corinne Antignac, Samuel Arrabal, Arnaud Bourdin, Stéphanie Descroix, John de Vos, Agathe Doutriaux, Quentin Fabrega, et al.

► To cite this version:

Guillaume Mottet, Alexandre Grassart, Philippe Barthélemy, Corinne Antignac, Samuel Arrabal, et al. Organoids, organs-on-chips, complex in vitro model: Definitions, applications, validation, ethics. Therapies, 2024, 80 (1), pp.17-31. 10.1016/j.therap.2024.12.002. hal-04824905

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# Organoids, organs-on-chips, complex in vitro model: Definitions, applications, validation, ethics

Guillaume Mottet¹, Alexandre Grassart², Philippe Barthélemy³, Corinne Antignac⁴, Samuel Arrabal⁵, Arnaud Bourdin⁶, Stéphanie Descroix⁷, John De Vos⁸, Agathe Doutriaux⁹, Quentin Fabrega¹⁰, Ariane Galaup¹¹, Stéphanie Graff-Dubois¹², Stéphane Illiano¹³, Cécile Legallais¹⁴, Benoît Maisonneuve¹⁵, David Piwnica¹⁶, Eric Quéméneur¹⁷, Valérie Salentey¹⁸, Julian Rozenberg⁹, Athanassia Sotiropoulos¹⁹, Raphael Tomasi²⁰, Nathalie Vergnolle²¹, Philippe Devillier²²

¹ Large Molecule Research Platform, Microfluidic Team, Sanofi R&D, 94400 Vitry-sur-Seine, France.

² CNRS, Inserm, institut Pasteur de Lille, U1019, UMR 9017, Center for Infection and Immunity of Lille (CIIL), CHU de Lille, université de Lille, 59000 Lille, France. Electronic address: alexandre.grassart@cnrs.fr.

³ Hôpital Antoine-Béclère, AP-HP, 92140 Clamart, France.

⁴ Laboratoire des maladies rénales héréditaires, Inserm UMR1153, institut Imagine, université Paris Cité, 75000 Paris, France.

⁵ Agence de la biomédecine, 93200 Saint-Denis, France.

⁶ Département de pneumologie et addictologie, PhyMedExp, Inserm U1046, CNRS UMR 9214, University of Montpellier, 34000 Montpellier, France; Hôpital Arnaud-de-Villeneuve, CHU de Montpellier, 34000 Montpellier, France.

⁷ Laboratoire physique des cellules et cancer, PCC, CNRS UMR168, institut Curie, Sorbonne University, PSL University, 75000 Paris, France.

⁸ Ingénierie cellulaire et tissulaire, unité de thérapie cellulaire, CHU de Montpellier, 34000 Montpellier, France.

⁹ Agence de l'innovation en santé (AIS), 75000 Paris, France.

¹⁰ Direction des filières industrielles, Bpifrance, 75000 Paris, France.

¹¹ LEEM, 75000 Paris, France.

¹² UMRS 959, laboratoire i3, groupe hospitalier Pitié-Salpêtrière, Sorbonne université, 75000 Paris, France.

¹³ Sanofi, 94400 Vitry-sur-Seine, France.

¹⁴ UMR CNRS 7338 biomécanique et bioingénierie, université de technologie de Compiègne, 60200 Compiègne, France.

¹⁵ NETRI, 69000 Lyon, France.
¹⁶ Institut de R&D Servier Paris-Saclay, 91190 Gif-sur-Yvette, France.

¹⁷ Transgene, 67400 Illkirch-Graffenstaden, France.

¹⁸ Regulatory Affairs and Quality Assurance, Sensorion, 34000 Montpellier, France.

¹⁹ Inserm, GIS FC3R, 94700 Maisons-Alfort, France.

²⁰ Okomera, 93100 Montreuil, France.

²¹ IRSD, Inserm, INRAE, ENVT, université Toulouse III - Paul-Sabatier, université de Toulouse, 31000 Toulouse, France.

²² VIM Suresnes, UMR_0892, hôpital Foch, université Paris-Saclay, 92150 Suresnes, France.

**Keywords:**

CIVM; Ethics; Organ on chip; Organoid; Stem cells.

\* Corresponding author.

Center for Infection & Immunity of Lille, CNRS UMR 9017, Inserm U 1019, institut Pasteur of Lille, 1, rue du Professeur-Calmette, 59000 Lille, France.

**E-mail address:**

alexandre.grassart@cnrs.fr

(A. Grassart).

1 Participants of Round Table “Pharmacology and translational research” of Giens Workshops 2024.

2 Co-first authors.

**Abbreviations**

3R replace, reduce, refine; AIS Agency for Health Innovation (Agence de l'innovation en santé) French ; ANR National Research Agency (Agence nationale de la recherche) ; ANSM French National Agency for Medicines and Health Products Safety (Agence nationale de sécurité du médicament et des produits de santé) APP projects appeals (appels à projets) BBTI biotherapy and bioproduction of innovative therapies (biothérapie et bioproduction de
thérapies innovantes) BPI France French Public Investment Bank (Banque publique d'investissement française); CEA French Alternative Energies and Atomic Energy Commission CIVM complex in vitro model CNIL French Data Protection Authority (Commission nationale de l'informatique et des libertés) CNRS French National Center for Scientific Research CSF Industry and Health Technology Strategic Commit tee (Comité stratégique de la filière) DMPK drug metabolism and pharmacokinetics ECVAM European Centre for the Validation of Alternative Methods EMA European Medicines Agency EUROoCS European Organ-on-Chip Society EURL European Union Reference Laboratories FC3R French Center for the 3Rs (Centre français pour les 3R) FDA Food and Drug Administration FSSCR French Society for Stem Cell Research GCCP Guidance on Good Cell Culture Practice hESCs human embryonic stem cells HSR human subject research IFPMA International Federation of Pharmaceutical Manufacturers & Associations iPSCs induced pluripotent stem cells INRAE France's National Research Institute for Agriculture, Food, and Environment INRIA French National Institute for Research in Digital Science and Technology Inserm French National Institute of Health and Medical Research (Institut national de la santé et de la recherche médicale) IRB institutional review board IRSD Digestive Health Research Institute (Institut de recherche en santé digestive) ISSCR International Society for Stem Cell Research ITS industrie et technologie de santé MASA French Ministry of Agriculture MESR French Ministry of Higher Education and Research MITI Mission for Transversal and Interdisciplinary Initiatives MPS microphysiological systems NAMS new approach methodologies OoC OTC Organ-on-a-Chip Open Translational Center PEPR MED-OOC Priority Exploratory Research Program and Equipment for Organs and Organoids on Chips RHU Hospital-University Health Research (recherche hospitalouniversitaire en santé) SBEA animal welfare structures (structures chargées du bien-être des animaux) SIG scientific interest group
Abstract

Over the past decade, new in vitro biological models have emerged which can reproduce
certain characteristics of human physiology and pathologies. From organoids to organs-on-
chips, these new technologies are currently revolutionizing the entire chain of research and
development in pharmacology. All stakeholders are thus involved, from academic laboratories
to pharmaceutical companies, start-ups, and assessment agencies. By providing better
predictability, these new human biomimetic models also help address societal and ethical
challenges regarding the place and use of animals in biomedical research. In this context,
participants at the Ateliers de Giens (Giens Workshops) roundtable wished to examine the
issues related to these new technologies with their various expertise and, given the stakes
involved in the medicine and pharmacology of the future, formulate several recommendations
aimed at strengthening the national structuring of the academic and industrial sector, therefore
accelerating the development and validation of these new models.
# Introduction

Organoids: a complex definition The roundtable participants first agreed to outline the use of the term organoid. It seems clear that a single word can only succinctly represent the complexity of all in vitro models [1,2] (experiment outside a living organism). In a process of popularization, organoids are often referred to as ‘‘mini organs,’’ implying miniature, functioning reproductions of organs. However, organoids are still far from attaining this reality and the use of this term is there- fore inappropriate. In fact, if we stick to the etymology of the word organoid, we find the suffixoid, which in Greek means ‘‘which looks like’’/‘‘which resembles.’’ The definition of Marsee et al. [3] proposing an organoid as ‘‘a three-dimensional structure derived from pluripotent or multipotent stem cells, progenitor cells which self-renew and self-organize through cell-cell and cell-matrix inter- actions which mimic, in vitro, certain architectural and functional aspects of native tissues’’ seems the most appropriate at this stage. However, only talking about organoids would greatly limit the scope of developments and applications of in vitro biological trials. Numerous technological advances have made it possible to complexify biological systems using 3D printers [4] and/or by adding, for example, microelectrodes [5] or microchannels. It is thus possible to reproduce vascularization via these microchannels [6,7], or to activate targeted nerve cells via these microelectrodes by applying an electrical field [8]. By generating a physiological flow in cells, the use of these microchannels results in a better reproduction of their observed in vivo phenotype [9]. As they are closer to the physiology of the organ, these systems are known in English as ‘‘microphysiological systems’’ (MPS). Usually, however, we find the more marketable French term ‘‘organe sur puce’’ and especially its English equivalent ‘‘Organ-on-a-Chip’’ (OoC). In order to cover all of these complementary technologies, ‘‘organoid’’ and ‘‘organ-on-a-chip,’’ we propose to use the usual and more generic term ‘‘complex in vitro model’’ (CIVM), as its French equivalent ‘‘modèle in vitro complexe’’ is very little used. The American and European medicines agencies (Food and Drug Administration [FDA], and European Medicines Agency [EMA]) have classified CIVMs as new approach methodologies (NAMS). These same institutions have opened the door to their use in the validation of future therapeutic agents, particularly in toxicology, with the aim of limiting the number of animals used for these studies, and also of limiting the potential risks of translating data obtained in animals as opposed to using data obtained from human cells.

## The various cellular components from which CIVMs are derived

Organoids can be generated from various types of cells (Fig. 1): (i) induced pluripotent stem cells (iPSCs) obtained in healthy or sick adults from skin or blood samples, (ii) human embryonic stem cells (hESCs) collected from embryos with or without genetic diseases, (iii) adult or primary stem cells from healthy or tumor tissue, in which last case they are known as tumoroids. Pluripotency is the ability of iPSCs and hESCs to differentiate into any type of cells in the body, with- out restriction. Depending on the origin of the constituent cells and the purpose of the CIVMs, the ethical, regulatory, legal, and societal aspects differ and their use is
more or less strictly governed. Embryos pose specific ethical issues and have an appropriate
legal framework.

<figure><img src="image_2.png" /><figcaption>Figure 1. Origin and generation of organoids.</figcaption></figure>

**Domains of application and objectives**

***Domains of application***

The field of application of CIVMs is very broad (Fig. 2) and may thus cover the entire
development chain of a drug, up to and including the drug itself. We have identified five main
domains of application:

* pre-clinical: CIVMs can be involved in all the key validation stages in the development of a drug: drug research (or therapeutic screening), efficacy testing, toxicology testing, and drug pharmacokinetics and metabolism testing. Due to their biological complexity and human origin, CIVMs may allow the development of advanced functional trials, allowing a better representation of the therapeutic target or therapeutic agent in its biological, physiological, or pathophysiological context. This gives better transposability and thus selection of drugs with a high therapeutic impact while having limited/controlled undesirable effects;

* in vitro clinical applications: developed from human cells, CIVMs might allow the development of in vitro clinical trials by providing great genetic diversity. This pre-screening could highlight at-risk populations (more significant undesirable effects) or subpopulations, which respond poorly or, conversely, very well to the drug. The assessment of the risk—benefit ratio and/or efficacy would thus be greatly improved. This application of
CIVMs is especially awaited, as patient selection criteria in clinical trials may limit the transposability of outcomes to the target population;

* diagnosis/prognosis tool: the goal is ultimately to develop CIVMs from a patient's cells which will have the potential to reproduce certain metabolic or pathological characteristics of their organs [10]. These CIVMs will then be a primary tool for personalized medicine, in particular for guiding therapeutic strategies: using tumoroids to optimize the choice of anti-cancer treatment, for example;

* drug: by enabling differentiation of highly functional human cells, CIVMs open the way to cell or tissue therapy, using allografts or autografts. By cultivating large amounts of pancreatic organoids, we can thus imagine reinjecting these organoids into a diabetic patient [11,12];

* basic and applied research: CIVMs were originally derived from academic research [13] and are still being driven by academic innovation. With the emergence of the first biotechs over the last ten years, significant research work, primarily in engineering, has also been undertaken. In addition to this specific research on CIVMs, a new field with robust processes has emerged based on their use for better understanding the biology and physiology of healthy or diseased organs.

Each of these CIVM applications will use the full range of complexity of this technology. Thus, for drug screening, a less biologically complex CIVM will be sought, but one which is easy to produce in large quantities in a standardized manner. Conversely, for a hepatic pharmacokinetic test, a complex CIVM will be needed to reproduce the metabolism of the liver as well as its vascularization. To reflect this wide variety of CIVM needs by application, we have provided a summary table (Fig. 3). Only the application for research is not documented as it encompasses all the possibilities: simple or complex CIVMs from a technological/biological perspective, low cost or high cost etc.

<figure><img src="image_3.png" /><figcaption>**Figure 2.** The main fields of application of complex in vitro models (CIVMs) and the major advances expected through their use.</figcaption></figure>
## Objectives

Due to their wide-ranging fields of action and their great potential, ambitious objectives are claimed for CIVMs:

* acceleration of basic knowledge in the domain of medical and biological research: by enabling a greater number of complex in vitro studies (outside of living organisms) under controlled conditions and based on healthy or dis-eased donor cells;

* acceleration and improvement of the industrial development of new drugs: by allowing better prediction of efficacy and undesirable effects (the failure rate of a drug at the clinical development stage is currently more than 70%) [14,15];

* significant reduction in the use of animal experiments: through a massive use of CIVMs in the domain of drug and basic research. This change in the drug research and validation paradigm, no longer on animals but on CIVMs, is a major development for ethics and animal welfare (see chapter State of the art of research in the domain of CIVMs);

* development of personalized medicine with a precision until now unrivaled, based on CIVMs from patient biopsies. These CIVMs would become guiding tools for therapeutic decisions with a high level of prediction of efficacy or toxicity at individual level (a drug for all → a drug for one);

* development of new cell/tissue therapy using CIVMs to produce highly differentiated cells or tissues (e.g., neurons, pancreatic islets, etc.). By offering ready-for-use or rapidly available autologous or allograft cells/tissues, regenerative medicine would be revolutionized; development of complex digital algorithms such as neuron networks thanks to the amplification of the amount of experimental data generated by CIVMs, enabling the advent of more qualitative digital medicine (e.g., digital twins, etc.).

<figure><img src="image_4.png" /><figcaption>Figure 3. The different properties expected from complex in vitro models (CIVMs) according to their applications.</figcaption></figure>

While these objectives may seem very ambitious or futuristic, there are already numerous proofs of concept in the scientific literature (see chapter State of the art of research in the domain of CIVMs), and many biotech companies already have ambitions to industrialize the applications of CIVMs. Some examples in the field of personalized medicine include: the screening of various chemotherapies on patient tumoroids to assess their efficacy [16,17], or
cell therapy with the transplantation of neurons from iPSCs in animal models using rats with neurological lesions [18]. However, as with any cutting-edge technology, the control of costs must remain an objective, so as to allow access to as many as possible and, especially in the case of organoids, controlled and reproducible industrial bioproduction.

## State of the art of research in the domain of CIVMs

Research and development on CIVMs is rapidly evolving but we wished to illustrate in a non-exhaustive way the state of progress and the prospects offered by the CIVMs of various organs.

### Liver CIVMs

Several hepatic CIVMs have been developed. These models can be classified as either hepatic or hepatobiliary epithelial organoids, with specific differentiation between hepatocytes and cholangiocytes, or hepatic multi-tissue organoids using the co-culture of co-differentiated cells (epithelial and stromal). Currently, other complementary strategies are aimed at improving the reconstruction of complex models through the use of hydrogel, cellular or acellular scaffolding, 3D printing, and organs-on-chips [19].

### Lung CIVMs

Bronchial or bronchiolar organoids, which reproduce the epithelium of the airways or even imitate the bronchial tree can be distinguished from alveolar organoids. These organoids can model genetic diseases (cystic fibrosis, Hermansky-Pudlak syndrome) and viral infections. Improving pulmonary organoids involves the introduction of blood vessels, nerves, and immune cells. Convergence with organs-on-chips is opening up new possibilities for studying the impact of respiratory biomechanics [20—22]. In addition to the new prospects in regards to pharmacological screening or our understanding of the pathophysiology, these organoids are opening the doors to pulmonary regenerative medicine [23].

### Kidney CIVMs

Renal organoids have been developed based on the stages of renal development, comprising the major segments of the nephron expressing terminal markers of differentiation. These models have been used to model some genetic diseases (especially cystic diseases) and to test potential therapies, but they are still very immature, are not vascularized, and do not allow
urine to be expelled if formed. The recent development of ureteric bud organoids, as well as organ-on-chip techniques, by promoting the development of vessels, are opening up interesting prospects for addressing the hurdles discussed above [24]. Numerous large international initiatives have taken place, such as the Consortium (Re) Building a Kidney [25] financed by the NIH, or the reNEW consortium [26], to accelerate the development of these technologies and ultimately implement regenerative medicine. This would allow us to overcome the lack of transplantable kidneys and the immunological problems during transplantation.

## Intestinal CIVMs

Current progress is making it possible to obtain CIVMs from various regions of the intestine, from the small intestine to the colon and rectum. In a similar way to in vivo conditions, organoids will self-organize in three dimensions in which stem cells, located at the bottom of the glands, will differentiate into a variety of cell types capable of reproducing their physiological functions (barrier, secretion, transport). The emergence of organs-on-chips is opening up new prospects for better control of three-dimensional organization, the creation of vascular, nerve, immune and/or microbial interfaces, or even the reproduction of mechanical stimuli such as peristaltic movements. Future developments include the development of multi-organ organoids on chips to reproduce gut-other organ axes, such as the brain, liver, and skin.

## Brain-cerebroid CIVMs

Cerebroids are miniature fragments of the brain, which can constitute models of cerebral development, of genetic, infectious, psychiatric and neurodegenerative diseases, and of cerebral senescence. They may also be useful in drug screening, the assessment of toxicological risks and the crossing of the blood-brain barrier [27].

## Tumor CIVMs

Tumoroids composed of cancer cells similar to the original tumor can be rapidly obtained from a biopsy. These tumoroids can be used to predict the anti-tumor efficacy of various drug options (personalized medicine) [28,29]. Tumoroids, or tumoroids on chips, from different patients may be useful in the development of new anti-cancer treatments.
Immune CIVMs

The development of immunocompetent organoids is necessary for a better understanding of organ pathophysiology. Although lymphoid organs are home to highly complex immunological processes, the majority of current models use immune cells derived from blood. Very recently, intestinal organoids including an immune compartment have provided a better understanding of the side effects of anti-tumor immunotherapies in colorectal cancer [30]. However, to limit the risk of organoid rejection by the immune compartment, the immune cells must come from the same individual or be histocompatible [31]. In addition, immune organoids based on the use of immune cells from the tonsils have been used to model the immune response induced by various types of vaccines [32]. In addition to organoids, the use of CIVMs, by allowing the dynamic perfusion of blood cells with antigens, has induced the differentiation of specific antibody-producing cells [33]. This last configuration may eventually enhance multiorgan CIVM models connected to the immune system for the study of autoimmunity, viral infections, and cancers.

Embryoid CIVMs

Embryoids mimic early embryonic development, and many applications can be considered: improved assisted fertilization techniques, a better understanding of developmental abnormalities and early miscarriages (particularly between day 14 and day 28 of development) with the possibility of considering preventive approaches, and the assessment of the risks associated with taking drugs early in pregnancy [34,35].

Animal CIVMs

CIVMs from cells of animal origin are used to generate the same types of CIVMs as those mentioned above. Beyond their clear benefit in animal (or veterinary) health and the reduction in live animal testing, the development of these models is useful in their validation by comparing them with the numerous data already obtained in animals, thus contributing to the continuum of knowledge between animal and human models. CIVMs of animals are thus useful in linking animal health, the health of the ecosystem, and human health (commonly referred to as the “One Health” concept).
# CIVMs and animal experiments

## Towards a reduction in the use of animal experiments

Each year, approximately 8 million animals are used for scientific purposes in the EU. Decreasing and optimizing the use of animals for scientific purposes (3R approach: replace, reduce, refine) [36] for basic and applied research, in pre-clinical drug development and for chemical prod- uct safety testing, has been a clearly demonstrated desire of both European (EMA, European Union Reference Lab- oratories [EURL], European Centre for the Validation of Alternative Methods [ECVAM]) [37] and North American (FDA) authorities for more than ten years. This desire is rein- forced by demonstrations of a form of animal awareness, which has to be taken into account in animal experiments [38].

Animal models have contributed significantly to the understanding of the pathophysiology of human diseases, but the use of animal models raises ethical questions. In addition, genetic diversity, the anatomical and physiological differences between animals and humans, as well as the methodological differences in animal and human studies, limit the likelihood of a favorable risk/benefit ratio for humans based on the outcomes of animal experimentation [14]. In particular, the brains of rodents, non-human primates differ from those of human beings in numerous structural, cellular, and molecular aspects which limits the possibilities for developing effective drugs against human brain diseases from animal models. Thus, the rate of the marketing of drugs whose pre-clinical outcomes (in vitro, in silico, and especially in vivo in animal models) justified moving to the clinical development stage is less than 10%. Efficacy was considered insufficient in humans in two-thirds of cases and tolerability was unacceptable in one-third of cases. The annual cost of these failures was estimated at 28 billion dollars [15].

In 2022, the FDA and the European Parliament (2021/2784[RSP]) implemented new measures and propos- als, one of the aims of which was to minimize tests performed on animals by encouraging the pharmaceutical industry to adopt alternative approaches. In silico trials (computer models), digital twins of organs, organoids and organ-on-a-chip systems are an integral part of alternative methods to studies using animals (EU reference laboratory for animal experimentation alternatives, EMA) [15]. In late 2022, the FDA Modernization Act 2.0 authorized the use of these alternatives to animal experiments [15]. While it is clear and desirable that these alternative methods may be substituted for some pre-clinical tests on laboratory animals, they will not be able to completely replace animal models as they cannot replicate the functioning of an organ- ism as a whole. However, the reduction in the use of animal experiments through the use of CIVMs should be accompanied by the constitution of maintained, characterized biobanks (animal or human).
Ethics, organoids, and animal experimentation

In science, a chimera is defined as an organism consisting of two or, less commonly, several varieties of cells of different genetic origin but without the mixing of genetic material.

Injection of human iPSCs to an immunodeficient animal results in the formation of teratomas, and is a test for the pluripotency of iPSCs or hESCs. This animal pluripotency test is no longer recommended and must be replaced by in vitro methods as part of the 3Rs (International Society for Stem Cell Research [ISSCR] 2023 recommendation) [39].

The development of secondary chimeras in animals as part of basic or preclinical research, by transferring iPSCs, differentiated precursors from iPSCs, or even human organoids, does not raise major ethical issues beyond compliance with the 3R rule. However, the transplantation of human cerebroids into animal brains raises specific eth- ical issues. Cerebroids from a human brain region may be implanted in order to replace excised portions of the ani- mal’s brain (mouse, rat, macaque). These transplanted brain cells can correct deficiencies in animals created by surgical removal [18] but can also establish connections with other parts of the brain, resulting in behavioral changes in the animal which are not specific to its species and thus damage the integrity of the animal as an individual. If the development of cerebroids leads to the onset of conscious- ness (which remains to be defined), the ethical limitations of transplantation of a conscious human entity into an animal itself endowed with consciousness, should be clearly defined.

Primary chimeras can be obtained by introducing human iPSCs or hESCs into non-human embryos with the possible development of human brain organoids and gonads in animals. In large animals, primary chimeras might provide organs, which can be transplanted into humans by blocking the development of one of the animal's organs and allowing the development of an organ of human origin. The most com- mon example suggested is that of the production of human pancreas in pigs. These primary chimeras go beyond the strict context of organoids. However, these primary and secondary chimeras raise some major ethical issues of removing species barriers between humans and animals [40].

In this context of the possible uses of iPSCs, hESCs and organoids in animals, a donor could completely object to the injection of his/her cells, or organoids from his/her cells, into the animal.
# A framework of reflection for the validation of CIVMs in France

Through their ability to revolutionize the entire healthcare industry, CIVMs are going to have a significant impact on our society. It is thus vital not to miss this scientific and technological revolution as with the quantum computer revolution. This is all the more so since France already has an industrial base and cutting-edge laboratories in this domain. We have identified five areas of reflection to ensure the development of CIVMs in France:

* structuring of the sector;

* validation and transposition of CIVMs;

* funding;

* regulatory, legal, and ethical framework

* communication to the general public and training.

# Reflections and recommendations

## Structuring

### Context

Several initiatives aiming to structure the research and development of CIVMs at both academic and industrial levels have emerged in recent years. At the European level, the H2020 ORCHID project facilitated exchanges between experts on the development of organ-on-chips from 2017 to 2019 and established a European Organ-on-Chip Society (EUROoCS), a community grouping together stakeholders from academic laboratories, industry, patient associations, and regulatory agencies.

In France, following multiple methodological approaches related to CIVMs, namely stem cells, organoids and organ-on-chip technologies, several initiatives aimed at structuring research have recently emerged. In particular, the list includes the French Society for Stem Cell Research (FSSCR), and the microfluidic and organoid research groups placed under the supervision of the French National Center for Scientific Research (CNRS) emerging from focus groups initially supported by the Instituts Thématiques (topic- specific institutes) of French National Institute of Health and Medical Research (Inserm — Institut national de la santé et de la recherche médicale). The French Center for the 3Rs FC3R — Centre français pour les 3R [41] is a scientific interest group (SIG) aiming to support alternative methods to animals including CVIMs. It was founded in 2021 and placed under the supervision of ten major actors in French research (CNRS, INSERM, INRIA [French National Institute for Research in Digital Science and Technology], CEA [French Alternative Energies and Atomic Energy Commission], INRAE [France's National Research Institute for Agriculture, Food,
and Environment], the Pasteur Institute, the France Universités association, Udice [French Research Universities], MESR [French Ministry of Higher Education and Research] and MASA [French Ministry of Agriculture]). Various initiatives have been conducted since the creation of these groups, notably the start-up funding of projects or the establishment of a skills mapping for CIVMs (AREA) [42]. These groups also aim to support the development of technology platforms in the area. To date, about fifteen “CIVM” platforms have been distributed around the country, four of which were IBISA-certified in 2022. Depending on the structure, the expertise may be specific: organoids, tumoroids, organs-on-chips, or even bioprinting. A network of bioproduction platforms was started-up in 2023 (RIBBON Project) and the Priority Exploratory Research Program and Equipment for Organs and Organoids on Chips (PEPR MED-OOC) and Biotherapy and Bioproduction of Innovative Therapies (BBTI — Biothérapie et bioproduction de thérapies innovantes) also supporting these capabilities as an objective. Finally, at the interface between industrial and academic stakeholders, Bio Valley-France (competitiveness unit) also joins this growing national ambition to structure and economically develop the organs-on-chips community. This work falls completely under the Industrie et Technologie de Santé (ITS) comité stratégique de la filière (CSF) [Indus-try and Health Technology Strategic Committee] agreement for the years 2023—2026 through project 14 (co-piloted by Bio Valley-France and France Biotech). Its purpose is to energize and structure the stakeholders of pre-clinical and clinical research in France. This agreement aims to strengthen France’s position in the healthcare sector by relying on the synergy between industrial, academic, and administrative stakeholders. Among the five planned areas, project 14, the area of “creation of a dynamic ecosystem of innovation,” aims to energize and structure the clinical and pre-clinical research stakeholders in France around three specific topics, one of which concerns new in vitro models (organoids, organs-on-chips microphysiological systems, stem cells, etc.). CSF-14 aims to provide a map of stakeholders and their area of expertise, implement pilot projects, create a national association, establish a regulatory process with authorities, motivate the community, arrange training, establish models from pilot projects, develop access to hiPSCs, and develop pharmaceutical-grade iPSCs.

Finally, it is also important to note that Inserm has created a national integrator in the domain of bioproduction of organoids and extracellular vesicles, the OBBI, situated in Occitania: Toulouse and Montpellier. The integrator’s objective is to make academic platforms, which resolve technological problems, available to industrial stakeholders for industrial projects. As regards organoids, the OBBI is largely focused on resolution of the issues of the reproducibility of organoid bioproduction, quality control, the integration of new materials, and the creation of new inter-faced models.

France thus has a rich and varied ecosystem of expertise and structures, reflecting the thoughts and ambitions of each of the players linked to this expanding field. It is now vital to continue to amplify this stimulation by strengthening the possibilities for dialogue between all parties while building a common roadmap.
## Recommendations

**Recommendation 1: support the development of technological platforms**

The network of technological infrastructure needs to be expanded in order to cover the entire country to ensure quick access as close as possible to the stakeholders. This proximity will promote synergies and fill the gap between academic and industrial stakeholders. The enhanced visibility of the platforms is also essential. Similar to the Renatech National Network of Technical Platforms for Micro and Nano Manufacturing, a consistent and shared organization of platforms for CIVMs would provide competitive infrastructure for research and R&D. The foundation of this organization could be based on platforms with identified, hierarchical technological channels (primary or secondary). The creation of these centers of technological excellence could have multiple advantages: ensuring a coordinated level of reference expertise, supplying specific/key resources, and supporting guidance of a national policy of investment in equipment and operation for CIVMs. The creation of the “Open Translational Center” (OTC) as part of PEPR MED-OOC (CHU-Research-Industry) could serve as the prototype for structuring into certified centers of technological excellence.

**Recommendation 2: improve the development of best practices and know-how**

In addition to work structuring a technological platform, it is also important to improve the means of interaction between stakeholders to facilitate the exchange of know-how. The harmonization of practices through improved data sharing is essential, an approach which is also supported by a resolution of the European Parliament (2021/2784[RSP]). The sharing of data between academic institutions, and also with industry stakeholders and validation agencies is essential for the acceleration of innovation, validation and acceptance of these new models. The importance of platform structuring would thus appear to be double. The connections of this network could also act as a bridge for the dissemination of technological solutions and knowledge, ensuring an adequate level of quality of protocols, procedures and good practice, such as the “Guidance on Good Cell Culture Practice (GCCP)” or the “ISSCR Guidelines for Stem Cell Research and Clinical Translation.” In coordination with universities, the network of technological platforms could also be responsible for teaching, training, and the exchange of knowledge.

**Recommendation 3: stimulate scientific and technical communities, both public and private**

The stimulation of CIVM communities is currently fragmented into several groups. The promotion of all of these technologies via a common digitalized platform could strengthen the referencing of stakeholders involved in research, R&D and teaching, and increase the
dissemination of knowledge for all academic, industrial, and societal stakeholders. This digital organization would increase visibility and the value chain among the parties involved while still preserving the richness of the existing ecosystem.

## Validation and transposition: from in vitro to human

### Context

The acceptance of the numerous promises of CIVMs in preclinical and clinical domains, in drug toxicity assessment, or in basic research areas, requires a qualification of these models. Depending on the domain of application, the required latitude of validation can be extremely variable and vary from scientific assessment by peers to in-depth qualification by regulatory agencies. In addition, this necessary step for ensuring the quality and reproducibility of the outcomes obtained from CIVMs is all the more difficult to achieve because, to date, no official, regulatory prerequisites, or recommendations validating the robustness and relevance of CIVMs have been published. Given the multitude of methodologies, CIVMs also suffer from the fragmentation of expert laboratories validating these models in France. It therefore seems essential for the success- ful development of these new models that their validation practices are harmonized, particularly for applications in toxicology, drug metabolism and pharmacokinetics (DMPK), clinical trials, drugs, and personalized medicine. Coordination between all stakeholders, academics, industry and regulatory agencies is now critical in order to validate the necessary methodologies and assess the outcomes in order to accelerate their use.

## Recommendations

**Recommendation 4: establish a best practice guide for the validation of CIVMs**

As with existing guides for cell culture (GCCP) or European Good Manufacturing Practice guidelines specific to innovative therapy drugs, establishing a best practice guide for the validation of CIVMs with all CIVM-related stakeholders would raise confidence in the use of these new models and also establish precise standards stimulating technological innovation. This guide should also provide methodological tools to deal with specific issues, prerequisites for different levels of final scientific or regulatory use. Finally, this guide may also include some recent recommendations proposed by the Hybrida project [43] to facilitate the implementation of CIVM models in drug development pipelines and to educate stakeholders on the selection and control of raw materials and reagents, as well as their receipt, handling, sampling and storage, and on the management of equipment, including computerized systems.
**Recommendation 5: create an LNE-type of control and validation laboratory for CIVMs**

As with the national reference centers responsible for epidemiological monitoring or the national metrology and testing laboratory, the creation of an expert CIVM validation and control laboratory would ensure a high level of expertise, harmonize methodologies, and maintain characterization techniques. This laboratory could also ensure the management of the biological samples collected and maintain a database relating to the qualification of the model, thus ensuring national sovereignty. As methodological approaches are constantly and rapidly evolving, the national laboratory would also be responsible for optimizing, validating, and disseminating recommendations to the technological platform network. Finally, the laboratory might also act in an advisory role with national regulatory and government agencies.

**Recommendation 6: facilitate and encourage the sharing of toxicology, DMPK, and clinical trial data to accelerate the development and validation of CIVMs**

Since 2010, a large number of pharmaceutical companies have already committed to making their clinical trials public (International Federation of Pharmaceutical Manufacturers & Associations, IFPMA [44]). Data on the undesirable effects of products in development or drugs are currently made public [45,46]. Nevertheless, details of possible toxicities are not necessarily shared, especially the link between outcomes in humans and the species used for preclinical validation. Since these data are primarily generated by pharmaceutical companies, it may be important for biotechnology companies or academic laboratories which are developing CIVMs to be able to share these limited-access data. This would greatly facilitate the demonstration of the efficacy of CIVMs in light of the outcomes in animal models and clinical trials.

There are already initiatives, in Europe and in the United States, such as the eTransafe consortium [47] completed in 2023, which had the initial objective of developing a data sharing infrastructure as well as improving the translational aspect of the trials used for drug safety during clinical development. The ToxHub platform, released by this consortium, integrated the creation of standardized data registry with the development of clinical and preclinical data visualization tools. The Critical Path Institute, launched in 2023 [48], may also be cited. This is a collaborative FDA-funded project, which includes researchers from academia, the pharmaceutical industry, and biotechnology companies so as to develop a network on methods contributing to the qualification and implementation of CIVMs in the regulatory decision process. The sharing of data is an accelerator for laboratories and companies having access to them and is therefore a strategic advantage. It is thus important that Europe continue to fund these projects, while integrating the future data generated via
CIVMs, to facilitate their dissemination, validation, and integration by regulatory institutions (FDA, EMA).

**Recommendation 7: create a national biobank for the creation of CIVMs**

The CIVMs discussed are based on the use of organoids, which can be biobanked. An initiative common to all stakeholders holding or proposing to implement an organoid biobank (human or animal) for the purposes of using CIVMs should be proposed in order to:

* establish the conditions for implementation, storage, and distribution of biobanked organoids;

* establish the characterizations and data deemed necessary for biobanked samples;

* establish a mapping of biobanks available for CIVMs;

* propose a ‘‘Biobank for the creation of CIVMs’’ label;

These approaches will require significant structuring support, but could be based on the early work of the RIBBON network of organoid platforms. Initiatives to promote the donation of samples for the creation of CIVMs among the public and participatory science should be considered to drive the constitution of cohorts and biobanks.

**Recommendation 8: create an independent association for CIVMs**

Building on the success of the ‘‘The European Micro- biome Innovation for Health’’ association [49] which brought together academics and industry to promote their projects on the topic of the microbiota, we propose the creation of an independent association for CIVMs (in agreement with CSF-14), which would be led by a tripartite committee representing the worlds of academia, industry, and government agencies. The purpose of the tripartite committee will be to: collect feedback from all those involved, discuss, advise, and make recommendations. The association could be a one-stop shop allowing end users (industrial, academic, regulatory, investor, and media) and public and private funders to ask for advice and request project funding.

In the longer term, the association could be:

* a participant in the certification for young biotech companies and academic laboratories, and in the promotion of trainings;

* a referral center for the coordination of assessments of new systems related to the use of CIVMs;
* a coordinator of experimental databases related to CIVMs;

* a site coordinating existing toxicity, DMPK, and clinical trials databases.

# Funding

## Context

France already has a significant impact in the field of CIVM thanks to its research organizations, healthcare facilities, and biotech companies. The French ecosystem is also significant and has the advantage of holding several leading positions in some technologies associated with CIVMs including microfluidics, instrumentation, or even AI. These include several start-ups including Fluigent, Netri, Okomera, ElveFlow, CherryBiotech, and TreeFrog Therapeutics. It should be noted that all of these biotech companies were or are supported by funding from the Banque publique d'investissement française (Bpifrance) [French Public Investment Bank]. A key player in the funding of startups in France, Bpifrance thus provided funds of more than D 14M in 2023 (reimbursable advances and grants) for CIVMs, a figure which has been growing sharply over the past few years.

A cornerstone of the entire healthcare pipeline of the future, several European countries included CIVMs in their priority roadmap for health innovation at a very early stage. Examples include the Netherlands, with the creation of several major initiatives, such as D 18.8 million for the NOCI (Netherlands Organ-on-Chip Initiative project), initiated in 2016, D 17 million for NecstGen (Netherlands Center for Clinical advancement of Stem Cell & Gene therapies), funded in 2021, and the creation of hDMT INFRA (human organ disease model technologies), thanks to the support of D 13.5 million in 2023, in order to strengthen the structuring of technological platforms linked to CIVMs.

thrown into an inevitably globalized innovation race, it is essential to increase funding, in a dynamic recently initiated by the Priority Exploratory Research Program and Equipment (PEPR) including PEPR MED-OOC (D 48.4 million), so as to keep French research sufficiently competitive.
## Recommendations

**Recommendation 9: plan public funding for basic research and establish a national technological infrastructure**

As with the PEPR MED-OOC, major investment efforts in academic and industrial research must be pursued in order to maintain our current leading position in the global market and to sustain national and European sovereignty. Massive investment is also desirable, not only in physical infrastructures for collecting biological samples, but also in "virtual" infrastructures, essential links in the collecting and usability of quality data for computational modelling based on IA.

**Recommendation 10: strengthen the consistency of public funding and investments for CIVMs**

In order to mobilize all parts of the network, support a consistent acceleration strategy according to the roadmap of the Agence de l'innovation en santé (AIS) [Agency for Health Innovation]. This encourages the transition from animal models to the implementation of CIVMs for more predictive medicine (PEPR Med-OOC, RHU [recherche hospital universitaire en santé — Hospital- University Health Research], Organomics).

Stimulate innovation by developing "high risk/high gain" programs.

Strengthen Bpifrance's targeted funding for biotechnology companies in relation to CIVMs.

Develop suitable programs of an interdisciplinary nature. Generic Agence nationale de la recherche (ANR [French National Research Agency]), APP (appels à projets [project appeals]) funding is no longer suitable for the needs and in the face of international competition.

Follow the example of European funding to support the basic research of RCTs and for the innovation of the EIC. This funding must follow two complementary formats: open (to create new fields) and targeted (to boost areas identified as a priority).
**Recommendation 11: develop public/private partnerships through incentivized funding**

Stimulate innovation through equally innovative funding mechanisms and allowing private partners to engage more freely and/or increase fundraising. This complimentary funding or “Matching funds” seems ideal for associating academic and industrial stakeholders with the aim of addressing common challenges related to clearly identified technological barriers. As an example, these new-type initiatives were launched a few years ago in the United Kingdom by the NC3Rs and the organization of Crack-It Challenges, competitions focused on the creation of collaborations between industrial stakeholders, SMBs and academics to solve business and scientific challenges favoring research related to NAMs and 3R.

**Ethics and donor consent**

*Context*

Organoids can be obtained from human embryonic stem cells (hESCs) from human induced pluripotent stem cells (iPSCs) or adult stem cells. In contrast, tumoroids are obtained from tumor cells taken directly from a person during a biopsy or surgical removal.

**hESCs**

hESCs are obtained from embryos which are frozen as part of assisted fertilization and are no longer the subject of family planning, with the prior written consent of the couple from whom the embryos originate, or the surviving member of that couple. The Agence de la biomédecine (French Agency of Biomedicine) provides a template consent form for the donation of cryopreserved embryos for research (March 28, 2024). Research programs have to be authorized or announced, then governed and monitored by the Agence de la biomédicine, which ensures their compliance with ethical rules and the current legal framework. Couples are informed that they have a three-month period of reflection in which to revoke their consent in writing, that consent can continue to be revoked without cause as long as there has been no intervention on the embryo as part of the research, that hESCs can be stored for many years, made available to researchers in France or possibly abroad, may be differentiated into specialized tissue cells, can serve a variety of research purposes and may one day lead to therapeutic developments.

**iPSCs**

In contrast to research on HESCs, no specific framework has to date been planned for research on iPSCs. They are considered to be any type of cell grown in vitro, for example, fibroblasts. Regulatory supervision depends on the origin of the cells:
* the samples collected specifically from volunteers (healthy or patients) for scientific research purposes fall under the regulations on type 2 human subject research (HSR). They require an information sheet and a written consent form for participants, the favorable opinion of an institutional review board (IRB), or the signing of a biobank/collection consent form in order to be able to store these samples for future research;

* the collection of blood, or biological samples other than blood, for research purposes during procedures performed for treatment, comes under type 3 HSR. They require a participant information sheet and the favorable opinion of an IRB, but do not require written consent, unless genetic testing is planned;

* residues from samples taken during a treatment procedure, for example, tissue taken as part of a surgical excision for curative purposes, or residual blood after laboratory analysis, come under the “non-opposition” of the donor procedure and are not subject to explicit consent, unless genetic testing is planned. In this context, individual written information for participants explaining the possibility of objecting to the use of their data and samples is sufficient. For these sample residues, healthcare facilities usually rely on a very general information sheet, in which it is indicated that in the absence of opposition, all the samples may be used for research.

In these three situations, no prior administrative authorization is required from the Agence nationale de sécurité du médicament et des produits de santé (ANSM) [French National Agency for Medicines and Health Products Safety]. Sample collections, however, must be reported to the French Ministry of Research and, in some cases, to the Commission nationale de l'informatique et des libertés (French Data Protection Authority — CNIL), and submitted to an IRB if required. The simple “non-opposition” to the use of treatment samples for the purposes of obtaining iPSCs is not appropriated [50]. Indeed, the initial characterization of iPSCs goes through genetic profiling, in particular by microsatellite analysis (STR: genetic fingerprinting — see 2023 ISSCR recommendations). Genotyping may show susceptibility to some potentially serious diseases, which are likely to be susceptible to preventive or curative measures, and communication of this information must be offered to donors who can choose to refuse to be informed of these outcomes.

Specific information and written consent therefore appear to be required for any sampling from which iPSC derivation is planned or contemplated. In addition, the information and consent documents must have obtained the prior favorable opinion of an IRB (or local ethics committee) for imported cell lines, which is responsible for assessing the adequacy, completeness and intelligibility of the written information to be supplied in order to obtain the prior informed consent of the donor. The question of the intelligibility of donor information is a particularly acute one given the complexity of the concepts related to iPSCs/hESCs, organoids/embryoids and the multitude of applications, some of which are not yet known today.
Special case of embryoids and cerebroids

These two types of organoids give rise to specific eth- ical issues [35]. Embryos are able to
model the early stages of human embryonic development, but at the cur- rent state of
development, they are unable to reconstruct the entire embryonic and fetal development.
Cerebroids are organoids, which model certain structures of the human brain in vitro but are
incapable of reproducing brain func- tions, even when combined in the form of
“assembloids.” Nevertheless, the risk that increasingly complex cerebroids may develop a
state of consciousness cannot be excluded, and it is therefore necessary to consider methods,
which would measure pain and consciousness in cerebroids in vitro or implanted into animals
[27,51,52]. Embryoids and cerebroids are the topic of discussions and debates within the
scientific community. Special case of adult stem cells Adult stem cells are collected from
biopsies (colon, lung, etc.). The consent form mentions acceptance of donation of a sample
for research purposes and explains the research. Recommendations Recommendation 12: an
appropriate regulatory framework is needed to ensure the ethics and integrity of research on
organoids developed from hESCs or iPSCs This recommendation is based on proposals drawn
up by the steering committee of the Agence de la biomédecine in its opinion on iPSCs, as well
as the European Hybrida project devoted to organoids [53]. It also answers one of the issues
tackled in one of the workshops of the Groupe- ment de recherche organoïdes (Organoid
Research Group) [54]. The introduction of a list setting out the possible uses of the donor’s
cells is proposed so that the donor can selec- tively grant consent. When pluripotent
embryonic stem cells (hESCs) or repro- grammed stem cells (iPSCs) are used, points of
vigilance call for the following recommendations: • organoids from embryonic stem cells:
signed writ- ten consent (template proposed by the Agence de la biomédecine); organoids
from induced pluripotent stem cells (iPSCs): ◦ signed, written informed consent including the
• “genetic” characterization of iPSCs, allowing the donor to choose not to be informed of the
outcomes, even in the event of incidental discovery of abnormal- ities associated with the risk
of serious illness, ◦ consent adapted to the objectives/purposes with spe- cific information if: -
personalized medicine, - uses in animals: primary/secondary chimera, - possible/planned
commercial use (drug develop- ment by the pharmaceutical industry/regenerative medicine)
with mention of no payment for the dona- tion and no benefit for the donor in the event of
patents or the commercial use of cells or their deriva- tives, - development of cerebroids or
embryoids, - transplantation in patients, - sharing cell lines with other researchers in France or
abroad. Recommendation 13: a template appears to be needed for the information sheet and
written con- sent form for donations from which the acquisition of stem cells is planned or
envisaged, and for their use to generate organoids A specific form and information have
already been proposed by the Agence de la biomédecine for embryos derived from hESCs.
The information sheet should mention the possibility of storing stem cells for many years
before they are made available to researchers and the possibility of recontacting the donor
regarding their state of health. Recommendation 14: it is recommended that spe- cific
information is provided on research aimed at developing embryos or cerebroids with
reference to current recommendations With regard to embryos, this research is governed by
the Agence de la biomédecine. The Agency’s steering committee has issued an opinion on
these models recommending their development in vitro to a stage not exceeding the
equivalent of 28 days of natural embryo development. With regards to cerebroids, the
International Society for Stem Cell Research (ISSCR), currently exempts cerebroids from
specific ethical control (International Society for Stem Cell Research 2024), but this position
could change depend- ing on the developments. Training and communication Education and
training Context: a resolution of the European Parliament (2021/2784[RSP]) aimed at
accelerating the move to an innovation not requiring the use of animals in research, prioritizes
actions aimed at educating, training and retraining scientists, researchers and technicians for using advanced models which do not require the use of animals and for sharing best practices. In addition, it emphasizes the need for sustained efforts in regard to training and education so that laboratories and competent authorities are as familiar as possible with the alternative methods and processes. It should be mentioned that academic or private researchers, engineers, and technicians can be trained in organoid development within organoid platforms, as is the case in Toulouse, on the Organoids Platform of the Institut de recherche en santé digestive (IRSD) [Digestive Health Research Institute].

Recommendation 15 Strengthen interdisciplinary funding (MITI [Mission for Transversal and Interdisciplinary Initiatives])/targeted the- sis grants. Open and recognize training on technological infrastruc- tures (platforms). As with the Chairs of Excellence program, create a position of Engineer of Excellence incorporating time for technical training in the form of university and/or private workshops (source of funding and stimulator of pub- lic/private partnerships). Communication to the general public Context: it is essential that accurate information is commu- nicated about the capabilities, benefits and limitations of CIVMs, including cerebroids and embryos, as well as the supervision of research by health authorities, not only to maintain public confidence in these scientific advances but also to limit the dissemination of ‘‘fake news.’’ [55] GIRCOR [56] is an association grouping together public and private stakeholders in research and higher education, which use animals for scientific purposes. The objective of this association is to transparently inform and respond to public inquiries about the necessity for animal experi- ments and the methods used as well as about alternative methods. Animal experiments remain required by the reg- ulations and are essential, particularly for ensuring the development and safety of drugs for humans and animals. However, they are governed by strict regulations demanding a high level of animal protection and based on the 3Rs rule (replace, reduce, refine). Structures chargées du bien-être des animaux (SBEA) [animal welfare structures] have been established in facilities using and/or raising laboratory ani- mals. Infographics presenting the 3R principle in a concise and effective manner were published by the Centre Franc, ais pour les 3R (FC3R) [41] and the French Animal Welfare Chair as well as by the GIRCOR. Communication with associations, which help and protect animals (Société protectrice des ani- maux [French Society for the Protection of Animals], Brigitte Bardot Foundation, Fondation 30 million d’amis [30 Million Friends Foundation], etc.) could help to break down oppo- sition, which is prejudicial to the development of CIVMs. Articles published in newspapers, such as Le Monde [57,58], or journals popularizing science, such as Epsilon in French or MIT Technology Review in English, have already initiated the dissemination of information on organoids and organs-on- chips as well as biomedicine letters published by the Agence de Biomédecine. Communication about CIVMs should probably be developed with medical, veterinary or biological and human science societies, with patient associa- tions, and with potential donors of cells, tissues, or embryos and should go beyond the information sheets and consent forms provided at the time of donation. They should, for example, make use of brochures such as the assisted fertil- ization guide, which gives information about the donation of embryos for research. Recommendation 16 Communication about CIVMs must prohibit the use of mis- leading terms which are far from reflecting the scientific reality and the limitations of these models and may wrongly raise fears or even opposition from the general public; for example, ‘‘mini-organs’’ for organoids, ‘‘mini-brains’’ or ‘‘cultured brains’’ for cerebroids, and ‘‘mini- embryos’’ or ‘‘artificial embryos’’ for embryos. It is particularly important to highlight the benefit of CIVMs in advancing our knowledge and understanding of dis- eases, in developing
new treatments, in personalized and regenerative medicine, and in a reduction in the need to
use animal experiments, which may result from the research and industrial development of
organoids. However, it is also important not to convey false hopes. Conclusion As with the
digital revolution, organoids and organs-on-chips have become a technological sovereignty
challenge in since the past ten years. Aiming to model human physiology in vitro with
unparalleled precision, models generating bio-logical data are opening up new prospects in
the domains of research, health, and drugs. Currently, France's position remains inferior to
those of other major countries in the world and in Europe. At the end of this roundtable
discussion, 16 recommendations have been provided to accelerate the structuring,
development, and validation of organoids in French research. Disclosure of interest The
authors declare that they have no competing interest. Acknowledgements For review and
informed comments: Etienne Guillot. We thank the ANSM teams, Valérie Salomon, Gaelle
Louin, and Paul Houeto, for their fruitful discussions. AG is supported by Atip-Avenir
funding, Métropole européenne de Lille (MEL [European Metropolis of Lille]) "Accueil de
talents [wel-coming talent]" funding. The French government under the France-2030
programme, the University of Lille and the Lille European Metropolis are thanked for their
funding and support for the project R-CDP-24-007-MOSAIC granted to AG. References [1]
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