Organoids are envisioned as unique human micro-tissue surrogates to understand and target human development and disease but this model systems lack important organ features, including maturity and life span. In this review the authors discuss how bioengineering design offers unique approaches to mirror biophysical properties of the native tissue to further generate bona fide organoids. Importantly, the experts collectively discuss how ethicists, engineers and stem cell biologists will need to collaborate on engineering-ethics and how this joint effort will benefit the success of the entire hPSC-derived organoid field.
Organoids are micrometre to centimetre tissue cultures which capture the architectural and functional features of human organs. Researchers have been refining the growth of pluripotent stem cells over the last two decades. Such progresses have led to the development of procedures to generate micro- and miniorgan-like structures on demand based on human pluripotent stem cells (hPSCs). To date, scientists have produced hPSCs-derived organoids including, brain, kidney, intestine, lung, retina, inner ear, liver, among others. Such cell culture platforms have allowed for the study of early morphogenetic programs driving tissue specification and differentiation as well as giving rise to a new class of safe and affordable three dimensional cultures for applications in biomedical research. Nevertheless, there are still several important limitations which preclude the immediate applications of these model systems in regenerative medicine including their limited maturity and life span.
Now, IBEC researchers Nuria Montserrat and Elena Garreta have explored the past and present of stem cells culture systems and the impact of such advances in organoid research in an effort to highlight affordable bioengineering strategies to overcome current organoid limitations. In a review paper published in Nature Materials, and written in collaboration with other international experts including Xavier Trepat from IBEC, Roger D. Kamm and Ron Weiss from MIT in USA, Susana M Chuva de Sousa Lopes from LUMC in the Netherlands, Madeline A. Lancaster von MRC in UK, and Insoo Hyun from Case West Research University in USA, the experts underline the crucial role that bioengineering and ethics will play in driving the successful future development of these models systems.
The convergence of organoids and bioengineering offers the potential to revolutionise biomedicine, since it will allow researchers to study pathologies with unprecedented precision.
The challenges since a century
Before the 1900’s, developmental biologists started to isolate and culture tissues and cells from various organisms, including sponges, chicks or mice. Later on the isolation of human embryonic stem cells and the reprogramming of somatic cells into induced pluripotent stem cells has resulted in the application of fundamental knowledge from the field of developmental biology to derive cells with similar properties as those found during development. During the last decade the possibility to generate micrometre size versions of human organs has allowed for the derivation of organoid model systems which recapitulate important features of the native counterpart, including how cells are spatially organized and even functional responses in front of challenges that include the use of compounds or after in vivo transplantation. Up to now, hPSCs derived organoids have relayed in the inherent properties of these unique cell sources, including their ability to self-organize or differentiate into any cell type of our body in front of external signals. At the same time, the little control over the supplied external stimuli results in unwanted responses as the lack of maturity or short life span. In this regard the experts outline several approaches to provide a vascular component to developing hPSCs-organoids as well as how to engineer vascular networks to create larger and more viable organoids, using solutions such as microfluidic systems, co-culture systems, or 3D bioprinting.
Creating the right environment
Another limitation of organoids is the random and uncontrolled nature of their growth. Even within the same stem cell lines, little homogeneity is observed, which means that they are not currently the truest reflection of the natural systems that they are modelled on. Engineered micro-environments could provide organoids with the instructions they need to grow in a more organised and consistent way—dynamic light-triggered hydrogel systems being just one promising solution.
It is equally important to recreate the tissue-tissue interactions and physiological conditions that natural organs experience. In this sense, micro-engineered devices have been used to create various types of “organ-on-a-chip”, which closely mimic key aspects of organ physiology. Researchers have already used this technology to develop organoid models of certain diseases, including type 2 diabetes and amyotrophic lateral sclerosis (ALS).
Although, there is still a lot of work to be done to construct ideal micro-environments for organoid production, growth and functionality, organoid technology is already revolutionizing developmental biology, drug screening, disease modelling and personalised medicine. Bioengineering strategies can contribute to bring this reality one step closer. However, according to the authors, such a revolution will require close collaboration between stem cell biologists, bioengineers and ethicists. It is the role of universities, institutes and administrations to allocate resources to ensuring that this is the case.
Elena Garreta, Roger D. Kamm, Susana M Chuva de Sousa Lopes, Madeline A. Lancaster, Ron Weiss, Xavier Trepat, Insoo Hyun and Nuria Montserrat (2020) “Rethinking organoid technology through bioengineering.” Nature Materials, 2020.