Engineering Bone Marrow Bioreactors for the Infinite Production of Blood Products

Objective

Life-saving blood replacement therapies depend entirely on voluntary donations, but demand surpasses supply. In the EU, 25 million blood donations are collected annually, yet shortages persist with about 20% yearly increase in demand. A promising solution is preservation of hematopoietic stem cells (HSC) in the laboratory to provide a limitless, off-the-shelf source of blood cells. In vivo, these HSC, primarily residing in the bone marrow (BM), continuously regenerate blood. Yet, in vitro attempts to recreate this lead to rapid loss of HSC self-renewal and differentiation capabilities. I hypothesize that this is related to the lack of necessary cues of the BM niche created by its highly vascularized extracellular matrix (ECM) where HSC are maintained during adulthood. In InfiniBlood, I will advance Xolography, a new two-colour volumetric manufacturing technology, into a unique continuous bioprinting process to engineer the first BM-like material bioreactor capable of sustaining HSC self-renewal and differentiation for extended periods (months) in vitro. To achieve this, I will 1)develop BM mini-tissues (organoids) within novel two-colour photoinitiators and viscoelastic hydrogels with functional proteins, thus recapitulating BM ECM properties allowing for guidance of HSC maintenance; 2) engineer perfusion of BM organoids for nutrient and oxygen supply, ensuring long-term HSC maintenance in culture and mature blood cell collection; 3) advance Xolography to continuous bioprinting on a moving belt (roll-to-roll), thus enabling indefinite extension of build volumes, ultimately producing clinically relevant blood cell amounts; and as proof-of-concept, 4) investigate the ability of bioreactor-cultured HSC, to self-renew and differentiate into erythrocytes and thrombocytes. Overall, this ambitious project will engineer novel material bioreactors via the first continuous bioprinting method to unlock infinite blood cell production in vitro to address patient needs worldwide.