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. 2019 May 3;364(6439):458-464.
doi: 10.1126/science.aav9750.

Multivascular networks and functional intravascular topologies within biocompatible hydrogels

Bagrat Grigoryan #  1 , Samantha J Paulsen #  1 , Daniel C Corbett #  2   3 , Daniel W Sazer  1 , Chelsea L Fortin  3   4 , Alexander J Zaita  1 , Paul T Greenfield  1 , Nicholas J Calafat  1 , John P Gounley  5 , Anderson H Ta  1 , Fredrik Johansson  2   3 , Amanda Randles  5 , Jessica E Rosenkrantz  6 , Jesse D Louis-Rosenberg  6 , Peter A Galie  7 , Kelly R Stevens  8   3   4 , Jordan S Miller  9
Affiliations

Multivascular networks and functional intravascular topologies within biocompatible hydrogels

Bagrat Grigoryan et al. Science. .

Abstract

Solid organs transport fluids through distinct vascular networks that are biophysically and biochemically entangled, creating complex three-dimensional (3D) transport regimes that have remained difficult to produce and study. We establish intravascular and multivascular design freedoms with photopolymerizable hydrogels by using food dye additives as biocompatible yet potent photoabsorbers for projection stereolithography. We demonstrate monolithic transparent hydrogels, produced in minutes, comprising efficient intravascular 3D fluid mixers and functional bicuspid valves. We further elaborate entangled vascular networks from space-filling mathematical topologies and explore the oxygenation and flow of human red blood cells during tidal ventilation and distension of a proximate airway. In addition, we deploy structured biodegradable hydrogel carriers in a rodent model of chronic liver injury to highlight the potential translational utility of this materials innovation.

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Conflict of interest statement

Competing interests: J.S.M. and B.G. are cofounders of and hold an equity stake in the startup company Volumetric, Inc. J.E.R. and J.D.L-R. are cofounders and hold an equity stake in Nervous System, Inc., a design studio that works at the intersection of science, art, and technology. B.G., A.H.T., and J.S.M. are listed as co-inventors on pending U.S. patent application 15/709,392. D.C.C., K.R.S., B.G., and J.S.M. are listed as co-inventors on pending U.S. patent application 62/746,106. The remaining coauthors declare no competing interests.

Figures

Fig. 1.
Fig. 1.. Monolithic hydrogels with functional intravascular topologies.
(A) Monolithic hydrogels with a perfusable channel containing integrated fin elements of alternating chirality. These static elements rapidly promote fluid dividing and mixing (as shown by fluorescence imaging), consistent with a computational model of flow (scale bars, 1 mm). (B) Hydrogels with a functional 3D bicuspid valve integrated into the vessel wall under anterograde and retrograde flows (scale bars, 500 μm). Particle image velocimetry demonstrates stable mirror image vortices in the sinus region behind open valve leaflets.
Fig. 2.
Fig. 2.. Entangled vascular networks. (A to D)
Adaptations of mathematical space-filling curves to entangled vessel topologies within hydrogels (20 wt % PEGDA, 6 kDa): (A) axial vessel and helix, (B) interpenetrating Hilbert curves, (C) bicontinuous cubic lattice, and (D) torus and (3,10) torus knot (scale bars, 3 mm). (E) Tessellation of the axial vessel and its encompassing helix along a serpentine pathway. The photograph is a top-down view of a fabricated hydrogel with oxygen and RBC delivery to respective vessels. During perfusion, RBCs change color from dark red (at the RBC inlet) to bright red (at the RBC outlet) (scale bar, 3 mm). Boxed regions are magnified in (F) (scale bar, 1 mm). (G) Perfused RBCs were collected at the outlet and quantified for SO2 and PO2. Oxygen flow increased SO2 and PO2 of perfused RBCs compared with deoxygenated RBCs perfused at the inlet (dashed line) and a nitrogen flow negative control (N ≥ 3 replicates, data are mean ± SD, *P < 2 × 10−7 by Student’s t test).
Fig. 3.
Fig. 3.. Tidal ventilation and oxygenation in hydrogels with vascularized alveolar model topologies.
(A) (Top) Architectural design of an alveolar model topology based on a Weaire-Phelan 3D tessellation and topologic offset to derive an ensheathing vasculature. (Bottom) Cutaway view illustrates the model alveoli (alv.) with a shared airway atrium. Convex (blue) and concave (green) regions of the airway are highlighted. (B) Photograph of a printed hydrogel during RBC perfusion while the air sac was ventilated with O2 (scale bar, 1 mm). (C) Upon airway inflation with oxygen, concave regions of the airway (dashed black circles) squeeze adjacent blood vessels and cause RBC clearance (scale bar, 500 μm). (D) A computational model of airway inflation demonstrates increased displacement at concave regions (dashed yellow circles). (E) Oxygen saturation of RBCs increased with decreasing RBC flow rate (N = 3, data are mean ± SD, *P < 9 × 10−4 by Student’s t test).The dashed line indicates SO2 of deoxygenated RBCs perfused at the inlet. (F) Elaboration of a lung-mimetic design through generative growth of the airway, offset growth of opposing inlet and outlet vascular networks, and population of branch tips with a distal lung subunit. (G) The distal lung subunit is composed of a concave and convex airway ensheathed in vasculature by 3D offset and anisotropicVoronoi tessellation. (H) Photograph of a printed hydrogel containing the distal lung subunit during RBC perfusion while the air sac was ventilated with O2 (scale bar, 1 mm). (I) Threshold view of the area enclosed by the dashed box in (H) demonstrates bidirectional RBC flow during ventilation. (J) Distal lung subunit can stably withstand ventilation for more than 10,000 cycles (24 kPa, 0.5 Hz) and demonstrates RBC sensitivity to ventilation gas (N2 or O2).
Fig. 4.
Fig. 4.. Engraftment of functional hepatic hydrogel carriers.
(A to C) Albumin promoter activity was enhanced in hydrogel carriers containing hepatic aggregates after implantation in nude mice. Data from all time points for each condition are shown in (B) [N = 4, *P < 0.05 by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test]. Cumulative bioluminescence for each condition is shown in (C) (N = 4, *P < 0.05 by one-way ANOVA followed by Tukey’s post-hoc test). Error bars indicate SEM. GelMA, gelatin methacrylate. (D) Gross images of hydrogels upon resection (scale bars, 5 mm). (E) (Left) Prevascularized hepatic hydrogel carriers are created by seeding endothelial cells (HUVECs) in the vascular network after printing. (Right) Confocal microscopy observations show that hydrogel anchors physically entrap fibrin gel containing the hepatocyte aggregates (Hep) (scale bar, 1 mm). (F) Hepatocytes in prevascularized hepatic hydrogel carriers exhibit albumin promoter activity after implantation in mice with chronic liver injury. Graft sections stained with H&E show positioning of hepatic aggregates (black arrows) relative to printed (case, anchor) and nonprinted (fibrin) components of the carrier system (scale bar, 50 μm). (G) Hydrogel carriers are infiltrated with host blood (gross, H&E). Carriers contain aggregates that express the marker cytokeratin-18 (Ck-18) and are in close proximity to Ter-119–positive RBCs (scale bars, 40 μm).
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    1. Supplementary figures, as well as materials and methods, are available as supplementary materials.

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