Abstract
Tissue vasculature efficiently distributes nutrients, removes metabolites, and possesses selective cellular permeability for tissue growth and function. Engineered tissue models have been limited by small volumes, low cell densities, and invasive cell extraction due to ineffective nutrient diffusion and cell-biomaterial attachment. Herein, we describe the fabrication and testing of ceramic hollow fibre membranes (HFs) able to separate red blood cells (RBCs) and mononuclear cells (MNCs) and be incorporated into 3D tissue models to improve nutrient and metabolite exchange. These HFs filtered RBCs from human umbilical cord blood (CB) suspensions of 20% RBCs to produce 90% RBC filtrate suspensions. When incorporated within 5 mL of 3D collagen-coated polyurethane porous scaffold, medium-perfused HFs maintained nontoxic glucose, lactate, pH levels, and higher cell densities over 21 days of culture in comparison to nonperfused 0.125 mL scaffolds. This hollow fibre bioreactor (HFBR) required a smaller per-cell medium requirement and operated at cell densities > 10-fold higher than current 2D methods whilst allowing for continuous cell harvest through HFs. Herein, we propose HFs to improve 3D cell culture nutrient and metabolite diffusion, increase culture volume and cell density, and continuously harvest products for translational cell therapy biomanufacturing protocols.
Highlights
Cell biomanufacturing platforms for cellular therapy, disease modelling, and tissue regeneration have been limited by nonphysiological cell growth, culture architecture, and ineffective nutrient diffusion to small biomaterial volumes, sparse cell densities, and impure cell product harvests [1]
Fibres were first screened for structural integrity and shape and sintered at high temperatures to form the final products before assessing porosity by mercury intrusion porosimetry (MIP), capillary flow porometry (CFP), and scanning electron microscopy (SEM)
Eight different types of ceramic hollow fibres (HFs) were fabricated through steps of dope preparation, fibre extrusion, phase inversion, and sintering by adjusting dope alumina particle size and PES binder composition, bore fluid, dope and bore fluid flow rate, and sintering temperatures
Summary
Cell biomanufacturing platforms for cellular therapy, disease modelling, and tissue regeneration have been limited by nonphysiological cell growth, culture architecture, and ineffective nutrient diffusion to small biomaterial volumes, sparse cell densities, and impure cell product harvests [1]. Culture of human cells in static liquid suspension and 2D systems has been restricted to densities below 5 × cells/mL [2] which improve under enhanced nutrient transfer provided by stirred tank or rocking bioreactors to cells/mL [3]. Despite providing a biomimetic structure and cell density, 3D cultures require termination for cell harvest and are usually mixed with cells of other lineages or maturational stage other than that desired for cell therapy or study [8, 9]. CB-derived RBC production has demonstrated clinical utility for human transfusion [12] but remains limited by unnaturally low production densities and exorbitant medium
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