Hybrid living bioengineered hierarchical constructs with self-oxygenating capability


Tissue engineering (TE) has emerged as an alternative solution aiming to provide a surplus of temporary structural supports at the defect site until native tissue is endogenously regenerated and normal function is restored. Although progresses have been made in the last 20 years, it is not yet possible to address all the complexity and (multi)functional properties so that hybrid devices combining cells and biomaterials could lead to functional human tissues, in particular for highly vascularised tissues and organs.An integrative strategy that gathers the main requirements of the regenerative process by (i) proving oxygen supply and establish vascular networks, and (ii) permitting cells to self-organised in adequate microenvironments, is still required to bring bioengineered devices into the realm of standard clinical care.O2CELLS intends to be the cutting-edge of a new generation of advanced devices by: (i) exploring natural-based biomaterials for this bottom-up bioengineering process that will combine self-oxygenating microalgae and tissue progenitor cells in original multiscale structural arrangements tuned to stimulate the regeneration of high-quality vascularised microtissue in a symbiotic system; (ii) combine these ingredients in well designed multi-scale devices with precisely tune macro-architectures where cells could freely assemble under the effect of adequate mechanical and biochemical signals.O2CELLS will explore these principles to develop a versatile modular platform able to engineer hierarchically organised hybrid living constructs employing a fundamentally new combination of innovative “ingredients” and designs: (i) photosynthetic microalgae with the ability to supply oxygen to cells on demand upon exposure to light; (ii) polysaccharides to design carriers to accommodate such living cargo and act as supportive substrates where mesenchymal stem cells (MSCs) could adhere and proliferate; (iii) MSCs and endothelial cells (HUVECs) from the umbilical cord, since perinatal tissues are a promising source of stem cells, proteins and growth factors for therapeutic applications; (iv) technologies to encapsulate the living cell carriers and MSCs in liquified “Pockets” permitting the free organisation of the cells to generate the desired tissues, including under dynamic conditions triggered by an external magnetic field; and (v) proteins derived from the amniotic membrane (AM) functionalised with dynamic covalent groups to biofabricate the three-dimensional (3D) constructs. At the core of O2CELLS, living oxygenating cell carriers (LOCCs) will be produced by encapsulating microalgae within microbeads coated with an oppositely charged polymer gra????ed with cell-adhesive sites, which promote the anchorage and proliferation of MSCs, ensuring the capture and release of CO2 and O2, respectively. LOCCs will be combined with MSCs in liquified “Pockets” that will confine all necessary ingredients for internal microtissue development in fully freedom and self-regulated modes, being a paradigm example of LIVING MATERIALS. The degradation kinetics of the Pockets' shell will be enzymatically controlled. At a higher scale-level, jammed liquified “Pockets” will be assembled into a final desirable implantable device, bound by the developed dynamic hydrogels using non-conventional bioprinting processing methodologies. By including magnetic nanoparticles it will be also possible to stimulated the internal motion of these microcarriers inside the Pockets, permitting a dynamic culture of the biological cargo using external magnetic fields, even a????er implanting the devices, anticipating a completely new concept of in vivo bioreactor.O2CELLS will combine a multiplicity of individually pioneering concepts that could be virtually used in the bioengineering of distinct human tissues, both for therapies or to develop disease models. However, the proof-of-concept will be focusing on the in vitro bone generation, where endothelial cells (HUVECs) isolated from the umbilical cord will be included in the dynamic hydrogel binding the jammed liquified pockets. A complete package of advanced techniques will be employed to optimise the multiscale-organisation of the device (including its biological ecosystem) and the biological and structural characterisation of the formed tissue.Therefore, by combining these proposed elements and technologies, O2CELLS proposes unique toolboxes for the engineering of a self-sustainable system with scales and geometry compatible with virtually any tissue defect (Fig. 1). With this ground-breaking concept, it is expected to pave the way to solve one of the major challenges faced by in vitro bioengineered constructs and devise a disruptive broad platform for tissue engineering or other biotechnology challenges. Once we successfully overcome the challenges of O2CELLS, our technology has the potential to be exceptionally rewarding to the scientific and medical communities.


João Mano


Universidade de Aveiro (UA)


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