Rapid 3D bioprinting of decellularized extracellular matrix with regionally varied mechanical properties and biomimetic microarchitecture

Abstract

Hepatocellular carcinoma (HCC), as the fifth most common malignant cancer, develops and progresses mostly in a cirrhotic liver where stiff nodules are separated by fibrous bands. Scaffolds that can provide a 3D cirrhotic mechanical environment with complex native composition and biomimetic architecture are necessary for the development of better predictive tissue models. Here, we developed photocrosslinkable liver decellularized extracellular matrix (dECM) and a rapid light-based 3D bioprinting process to pattern liver dECM with tailorable mechanical properties to serve as a platform for HCC progression study. 3D bioprinted liver dECM scaffolds were able to stably recapitulate the clinically relevant mechanical properties of cirrhotic liver tissue. When encapsulated in dECM scaffolds with cirrhotic stiffness, HepG2 cells demonstrated reduced growth along with an upregulation of invasion markers compared to healthy controls. Moreover, an engineered cancer tissue platform possessing tissue-scale organization and distinct regional stiffness enabled the visualization of HepG2 stromal invasion from the nodule with cirrhotic stiffness. This work demonstrates a significant advancement in rapid 3D patterning of complex ECM biomaterials with biomimetic architecture and tunable mechanical properties for in vitro disease modeling.

Processed Tissue–Derived Extracellular Matrices: Tailored Platforms Empowering Diverse Therapeutic Applications

“…While the physical properties of synthetic polymers are easily controllable, they generally exhibit poor biocompatibility, toxic degradation products, and lack of bioactivity . The utilization of dECM as a bioink for 3D printing of tissue engineered constructs is, therefore, increasingly being employed by numerous research groups . For its printing, the dECM must first be solubilized or “fluidized” to enable its extrusion through the printing apparatus.…”

“…Processed dECM‐based models are extensively being developed for the investigation of tumor biology . A glioblastoma multiforme (GBM) brain tumor model was developed combining decellularized patient‐specific GBM‐derived hydrogel and patient‐derived GBM cells ( Figure a) .…”

“…dECM 3D‐printing was also shown to be a useful tool for the establishment of tumor models. A hepatocellular carcinoma, which is known to progress predominantly in a stiff cirrhotic microenvironment, could be modeled by a light‐based bioprinting process of liver dECM blended with the photo‐crosslinkable gelatin methacrylate (Figure c) . Construct stiffness was controlled through variance of printing exposure time, as these parameters were shown to linearly correlate.…”

“…d) A quantitative analysis demonstrating the enhanced invasive behavior of HepG2 cells within a stiff carcinoma‐like microenvironment. Reproduced with permission . Copyright 2018, Elsevier.…”

Clinical Perspectives on 3D Bioprinting Paradigms for Regenerative Medicine

“…Figure 7 details the 3D bioprinting scheme for this tri-culture liver model, which has significant potential for pathophysiological studies with a patient-specific platform and early drug screening. In a different report, 3D bioprinted liver decellularized ECM scaffolds were created with tailorable mechanical properties to mimic regional stiffness in the cirrhotic liver [142]. Using this model, the authors showed that HepG2, a human liver cancer cell line, displayed stromal invasion from the nodule with cirrhotic stiffness.…”