We summarise a recent review article, published in Nature Materials, that has underlined the need to provide engineering solutions to gain control of organoid technology. High-grade organoid technology has important applications for drug screening and personalised medicine.
Organoid technology
In recent years, there has been great progress in the development of procedures for the differentiation of human pluripotent stem cells (hPSCs). Such progress has led to the development of micro- and miniorgan-like structures, so-called organoids. Simultaneously, the emergence of the bioengineering field is leading to technological advances that can generate proper instructive environments (physical and chemical).
Current organoid technology relies on traditional three-dimensional culture techniques that exploit cell-autonomous self-organisation responses of hPSCs. Nonetheless, hPSC-derived organoids still exhibit several shortcomings. These include the lack of reproducibility, lack of specificity with regard to cell-type composition, uncontrolled shape, shape heterogeneity, absence of proper vascular, immune and innervation components and lack of functionality. As a result, efforts are now focussed on improving organoid cellular and morphological complexity, providing perfusable vascular networks and enhancing organoid maturation.
The convergence of stem cell biology and bioengineering offers the possibility to provide stimuli in a controlled fashion. This could lead to the development of naturally inspired approaches that would help overcome some of the limitations of current technology. Bioengineering design may increase control of self-organisation and functionality of hPSC-derived organoids. This will help the scientific community to generate higher-grade organoids for developmental biology, drug screening, disease modelling and personalised medicine applications.
Bioengineering strategies
The derivation of hPSC organoids mainly relies on the self-organisation principle with limited control over the external inputs supplied to the system. The uncontrolled nature of these processes contributes to the high heterogeneity of these systems and thus their low reproducibility. Engineering-controlled microenvironments by the presentation of both chemical factors (e.g. growth factors) and physical instructions (e.g. applied forces) could enable better control of organoid self-organisation and differentiation.
Additionally, emerging transcriptomics and tissue mechanics techniques offer unprecedented opportunities to study human development and tissue morphogenesis as well as new prospects for precision medicine. The field is now moving towards a more in-depth knowledge of the cellular composition of organoids. Moreover, the increased availability of organ-specific datasets with the use of machine learning algorithms is making it possible to predict accurately the identity score of cell types present within organoids. Coupling transcriptional information and mechanical signatures of cells within the organoid in time and space will provide a more precise description of the organoid dynamics.
Moreover, current organoid methodologies have generated organoid structures with limited lifespan and functionality. Using approaches, such as patient specific iPSCs or CRISPR/Cas9-mediated gene editing, has started to show the utility of these systems for disease modelling applications. In addition, engineering approaches could also provide the necessary nutritional and gas exchange needs that would increase size, lifespan, complexity and maturation.
Future directions
The field of organoid engineering is rapidly progressing. However, the absence of experimental and conceptual access to organoid mechanisms is proving challenging. Several engineering solutions are being explored to control self-organisation, differentiation and tissue boundary conditions in order to improve organoid outcomes. The application of these engineering approaches coupled with emergent technologies from the fields of transcriptomics and mechanics are expected to provide a better control of hPSC organoid generation. In turn, this will guide the community to generate higher-grade hPSC-derived organoids for several applications, including drug screening. At the same time, experts must consider ethical concerns including patient consent, biobanking and animal use to develop a productive and responsible partnership between the disciplines of bioengineering and human organoid research.
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