A Tumor‐on‐a‐Chip System with Bioprinted Blood and Lymphatic Vessel Pair

Abstract

Current in vitro anti-tumor drug screening strategies are insufficiently portrayed lacking true perfusion and draining microcirculation systems, which may post significant limitation in reproducing the transport kinetics of cancer therapeutics explicitly. Herein, we report the fabrication of an improved tumor model consisting of bioprinted hollow blood vessel and lymphatic vessel pair, hosted in a threedimensional (3D) tumor microenvironment-mimetic hydrogel matrix, termed as the tumor-on-a-chip with bioprinted blood and lymphatic vessel pair (TOC-BBL). The bioprinted blood vessel was perfusable channel with opening on both ends while the bioprinted lymphatic vessel was blinded on one end, both of which were embedded in a hydrogel tumor mass, with vessel permeability individually tunable through optimization of the composition of the bioinks. We demonstrated that systems with different combinations of these bioprinted blood/lymphatic vessels exhibited varying levels of diffusion profiles for biomolecules and anti-cancer drugs. Our TOC-BBL platform mimicking the natural pathway of drug-tumor interactions would have the drug introduced through the perfusable blood vessel, cross the vascular wall into the tumor tissue via diffusion, and eventually drained into the lymphatic vessel along with the carrier flow. Our results suggested that this unique in vitro tumor model containing the bioprinted blood/lymphatic vessel pair may have the capacity of simulating the complex transport mechanisms of certain pharmaceutical compounds inside the tumor microenvironment, potentially providing improved accuracy in future cancer drug screening.

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

“…One variation of extrusion‐based printing, coaxial printing, is particularly useful for fabrication of vascular tube‐like structures. [ 219–222 ] Coaxial printing is based on the simultaneous extrusion of two or more bioinks using core and shell assemblies, the core material being dissolved to result in hollow filaments and perfusable, freestanding and functional microvessels. [ 220,221 ] Owing to the need for rapid crosslinking of the extruded shell material that forms the filament walls, CaCl 2 ‐induced crosslinking of sodium alginate remains the most popular choice, although MeHA, GelMA, and PEG‐based bioinks have also been employed.…”

“…Lymph vessel structure and dynamics and its role in lymphatic pathologies have been modeled in several in vitro and on‐chip platforms ( Figure ). [ 219,254,305,460–462 ] These include the role of shear stress on T cell‐dendritic cell trafficking, tumor‐dendritic cell communication, diffusional and perfusional transport dynamics between blood and lymphatic vasculature through the interstitial matrix, IF‐guided tumor cell migration, lymphatic morphogenesis and immune organoid development. [ 219,305,460,462–464 ] These studies aim to shed light on the various interstitial forces and associated biochemical signaling mechanisms that drive various pathologies including lymphedema, inflammation, and tumor cell dissemination.…”

“…Owing to the significant attention toward modeling of cancer in biomaterials‐based microfluidic platforms, several mechanistic insights have been elucidated (Figure 17). [ 219,460,493–496 ] This knowledge has in turn enabled the screening and development of anticancer drugs and therapeutic agents to target tumor cell proliferation, migration, invasion, and other events occurring during the metastatic cascade. Some important areas in in vitro tumor modeling that merit future consideration include the role of biophysical and hemodynamic forces in regulating tumor dormancy, metastatic recurrence, tumor–immune cell interactions, tumor lymphatic clearance, CSC‐phenotype maintenance, the role of obesity in tumor progression and gut microbiota‐mediated tumor control among others.…”

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

“…By adjusting the bioink flow rates, this bioprinting method enables independent control of the wall thicknesses of the tubes. More interestingly, the authors also recapitulated the one end-blinded characteristic of lymphatic capillaries using this method [56]. In addition to the luminal flow through the channels, Kim et al utilized a microfluidic platform to generate the interstitial flow across a channel.…”

“…Lymphatics-on-a-chip: (a) A single lymphatic vessel in a microfluidic system[55], (b) bioprinted perfusable blood vessel and one-end-blinded lymphatic vessel on a microfluidic chip[56], (c) Generation of interstitial flow using pressure gradient created by the volume difference between the two fluidic channels around the central channel[57].Figure republishedwith permission from each indicated reference as follows:[55] for part (a),[56] for part (b), and[57] for part (c).…”