Reply: Lung organoids: a new frontier in neonatology and paediatric respiratory medicine

Extract

We would like to thank P. Das and V. Bhandari for their interest in and comments on our recently published review on lung organoids [1]. We welcome the opportunity offered by their thoughtful correspondence to further elaborate on specific aspects of organoid-based research that could not be addressed in our original review, which primarily focused on the strengths and limitations of the model itself. Overall, the authors' comments highlight several challenges associated with research involving substances of human origin (SoHO), including ethical, logistical and biological concerns.

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Sustainable development of neonatal and paediatric lung organoid research requires effective regulatory and collaborative frameworks. Ethically compliant tissue sources should be prioritised; robust ethical governance on sensitive sources is essential. https://bit.ly/4b9qeLf

Reply to P. Das and V. Bhandari:

We would like to thank P. Das and V. Bhandari for their interest in and comments on our recently published review on lung organoids [1]. We welcome the opportunity offered by their thoughtful correspondence to further elaborate on specific aspects of organoid-based research that could not be addressed in our original review, which primarily focused on the strengths and limitations of the model itself. Overall, the authors' comments highlight several challenges associated with research involving substances of human origin (SoHO), including ethical, logistical and biological concerns.

We are grateful for the authors' reference to the neonatal field and to bronchopulmonary dysplasia (BPD), an area in which we believe that advanced human-relevant models may provide important mechanistic insights and inform innovative interventional strategies.

In recent years, human bodily materials have assumed an increasingly prominent role in preclinical research and therapy development. Despite rapid progress in organoid technologies and growing support from health research funding agencies (e.g. the US National Institutes of Health), ethical and regulatory constraints – particularly those related to sensitive tissue sources – remain a major bottleneck for advancing lung research [2–4]. These constraints affect scalability, reproducibility and translational potential for fetal and neonatal lung organoids [5]. In the European Union, new legislation on SoHO (Regulation 2024/1938) is expected to be implemented nationally by 2027 [6]. During this transition, regulatory heterogeneity persists, potentially hindering cross-border collaboration.

Overcoming these challenges will depend on the implementation of complementary and collaborative strategies.

First, prioritising ethically compliant sources of tissue remains essential. These include perinatal surgical specimens, medical terminations conducted under strict ethical and legal frameworks, and biobanked materials obtained with comprehensive informed consent. Furthermore, encouraging collaborative consortia at the European and international levels could facilitate protocol standardisation and the establishment of shared repositories, thereby reducing the need for repeated tissue procurement and maximising the value of scarce primary samples [7].

In parallel, robust ethical governance and long-term institutional infrastructures are required, ensuring that the biobanking of human bodily materials is grounded in respect for the donor, careful handling of materials and data, and clear societal justification [8]. As an example of an institutional regulatory model for other settings, a dedicated biobank board was established at UMC Utrecht, operating in a manner comparable to a medical ethical review board. This framework oversees broad-consent biobanks for sensitive applications, including long-lived stem cell cultures, ensures traceability and linkage to clinical data, and requires independent approval for specific research uses. Neonatal tissues may be included based on parental consent, with renewed consent obtained as biobank participants reach 12 and 16 years of age [9]. Maintaining such high ethical and organisational standards entails substantial logistical and financial demands, underscoring the need for health research funding agencies to prioritise support infrastructures, including ethical oversight bodies, data infrastructures and well-curated biobank collections. Within Europe, initiatives such as Ombion (https://site.ombion-cpbt.nl/), an animal-free biotechnology innovation centre, exemplify this approach, with substantial public–private investment in human cell-based technologies, standardisation and regulatory pathways. Promoting international harmonisation of ethical guidelines would ensure oversight and transparency across jurisdictions.

In addition, increased investment in stem-cell-based alternatives, such as induced pluripotent stem cell (iPSC)-derived lung organoids, offers a valuable approach [10]. These models can recapitulate key stages of lung development and may serve as viable substitutes when access to primary fetal tissue is limited or not feasible. Taken together, these actions could help accelerate the translation of organoid-based research into clinically meaningful advances for neonates and children with respiratory diseases.

We agree that leveraging the diversity of cell origins is valuable for tailoring lung organoids to specific disease contexts and enhancing physiological relevance. However, all experimental models only partially recapitulate in vivo conditions. Cell subtype selection, epigenetic remodelling and genetic drift can be expected under ex vivo and in vitro culture conditions, particularly when cells adjust to in vitro conditions and upon long term expansion, and may vary across different culture approaches [11]. While expansion supports reproducibility, its impact depends on disease context and intended application. Demonstrating model validity therefore relies on establishing meaningful relationships between in vitro or ex vivo and in vivo disease and non-disease states.

We recognise that modelling complex neonatal lung diseases requires careful consideration of disease heterogeneity, developmental stage and appropriate control conditions [12]. BPD encompasses a broad spectrum of phenotypes evolving across lung development, from early injury and inflammation to impaired alveolarisation and remodelling. This complexity poses inherent challenges for any experimental system. Indeed, access to non-diseased, age-matched control tissue can be particularly challenging. Complementary human-relevant models, including iPSC-derived lung organoids engineered to capture key pathogenic mechanisms, may provide valuable insights when primary neonatal tissue is unavailable. Comparisons between affected and non-affected tissue from the same donor, or between samples from individuals with clearly differing disease severity, may represent valuable alternative strategies. Importantly, translational organoid-based studies need not rely exclusively on direct comparisons between established BPD and non-diseased lungs at divergent developmental stages. Instead, developmentally matched experimental designs may better preserve biological relevance and allow the interrogation of distinct disease-relevant mechanisms. For instance, organoids derived from diseased lungs may be particularly suited to exploring regenerative or antifibrotic pathways, whereas organoids from non-diseased lungs may allow investigation of alveolarisation signalling. Mechanistic insights gained from such studies may extend beyond paediatrics, informing therapeutic strategies for more established forms of disease, including prematurity-associated lung disease across the lifespan.