TABLE 3.

Bioengineering approaches.

Technology	Materials	Domain	Application	Pros	Cons	References
3D hydrogel with a channel	Silk / Collagen IV / Laminin / fibronectin	in vitro	Interactions between hematopoietic cells and niche cells, extravasation into the circulating media	Presence of a barrier creating sites for intercompartment interactions	No presence of cellularized endothelial tubes	Di Buduo et al. (2015)
3D hydrogels	Alginate, Matrigel, Gelatin MA, StarPEG-heparin	in vitro	Heterotypic cell interactions, biochemical mechanisms	Very simple to implement, multiple interactions assays are possible	Vessels are not anastomosed to a feeding source	Bray et al. (2017), Braham et al. (2019)
Bioprinted / SLA bone matrix with self assembled vessels	Gelatin nanohydroxyapatite Gelatin MA/fibrin Polylactic Acid / Matrigel	in vitro	Fabrication of vascularized matrices within ossified material, can be used for grafts and cancer development	Possible generation of pseudo-organs with controlled geometry of the different compartments and guided vasculature	Perfusion system isn’t connected to the vasculature Direct printing hasn’t achieved the resolution necessary for the formation of a capillary vascular network.	Chiesa et al. (2020) Cui et al. (2016)
Bioprinting and sub-cutaneous/orthotopic implantation in mice/rabbit	Hyperelastic bone (Hydroxyapatite/PLGA or PCL) beta-TCP, BRT Bioceramic	in vivo/ in vitro	Bone environment reconstitution in vivo	Reconstruction of anastomosed organ for possible engraftment	The absence of perfusion system prevents in vitro investigations. Direct printing hasn’t achieved the resolution necessary for the formation of a capillary vascular network.	Jakus et al. (2016) Zhang et al. (2017)
Microfluidic chip with inverted vessels	Hyaluronic acid/gelatin, collagen I	in vitro	Cancer cells invasion / intravasation	Simple set up, possibility to compare different sources of endothelial cells	No tubular formation of endothelial cells, organisation investigations are impossible	Aleman et al. (2019), Khan et al. (2012)
Microfluidic chip with patterned vasculature	Collagen I	in vitro	Niche cells interaction, hematopoietic and leukemic cell extravasation	Controlled vascular organisation, assay standardization	Resolution limit in vessel size, non physiological organisation of endothelial cells	Kotha et al. (2018)
Microfluidic chip with self-assembled vasculature	Collagen I, fibrin, fibrin / hydroxyapatite, Matrigel, decellularized bone matrix	in vitro	Hematopoietic cells interaction with niche cells Vasculature dynamics, organisation, permeability… Cancer cell invasion, extravasation and response to drugs Niche response to radiotherapy	Highly versatile devices, moderately easy to establish in a laboratory. Possibility of fully perfused vascular system.	Few studies have included an endosteal compartment. Self-assembled vessels are not guided to follow native bone marrow organisation. Chip content cannot be retrieved easily and has not yet been used as a graft.	Bersini et al. (2014), Jeon et al. (2015), Jusoh et al. (2015), de la Puente et al. (2015), Ma et al. (2020), Marturano-Kruik et al. (2018), Palikuqi et al. (2020)
Bioprinted BM orthotopic implantation in mice	Star-PEG hydrogel, polycaprolactone	in vivo	Only example of full bone marrow graft	Possibility to control geometry and organisation of the graft. The use of various materials brings the appropriate mechanical properties.	Regressed human vasculature, overtaken by murine one. Difficult to implement, use of non-biological materials	Baldwin et al. (2017)
Sub-cutaneous scaffold implantation in immunodeficient mice	Matrigel embedded starch–poly (caprolactone) scaffold, fibronectin-collagen I scaffold, Matrigel, collagen sponge, gelatin sponge, laminin – entactin – collagen IV matrix	in vivo	Hematopoietic stem cell grafts and homing Vasculature organisation, and anastomosis with host vasculature Hematopoietic stem cell production	Highly versatile system. Possibility to include different growth factors to direct cell differentiation. Possibility to do long terms assays.	Heterotopic site of implantation. Little control on vascular formation. Long setting up time. Chimeric human-mouse vasculature	Koike et al. (2004), Au et al. (2008), Ghanaati et al. (2010), Chen et al. (2012), Reinisch et al. (2016, 2017), Abarrategi et al. (2017), Passaro et al. (2017a), Fritsch et al. (2018), Bourgine et al. (2019), Shah et al. (2019)
Sub-cutaneous implantation in mice / microfluidic chip	Demineralized bone powder, collagen I	in vivo/ in vitro	Only example of engineered BM alternatively grafted and studied in a microfluidic device	Having the graft in a microfluidic system allow follow-up experiments impossible in other devices.	The vascular system is not connected to the perfusion system.	Torisawa et al. (2014)