Visualization and Evaluation of Chemoembolization on a 3D Decellularized Organ Scaffold

Abstract

Transarterial chemoembolization (TACE) has emerged as the mainstay treatment for patients suffering from unresectable intermediate hepatocellular carcinoma and also holds the potential to treat other types of hypervascular cancers such as renal cell carcinoma. However, an in vitro model for evaluating both embolic performance and drug-release kinetics of the TACE embolic agents is still lacking since the current models greatly simplified the in vivo vascular systems as well as the extracellular matrices (ECM) in the organs. Here, we developed a decellularized organ model with preserved ECM and vasculatures as well as a translucent appearance to investigate chemoembolization performances of a clinically widely used embolic agent, i.e., a doxorubicin-loaded ethiodised oil (EO)-based emulsion. We, for the first time, utilized an ex vivo model to evaluate the liquid-based embolic agent in two organs, i.e., liver and kidneys. We found that the EO-based emulsion with enhanced stability by incorporating an emulsifier, i.e., hydrogenated castor oil-40 (HCO), showed an enhanced occlusion level and presented sustained drug release in the ex vivo liver model, suggesting an advantageous therapeutic effect for TACE treatment of hepatocellular carcinoma. In contrast, we observed that drug-release burst happened when applying the same therapy in the kidney model even with the HCO emulsifier, which may be explained by the presence of the specific renal vasculature and calyceal systems, indicating an unfavorable effect in the renal tumor treatment. Such an ex vivo model presents a promising template for chemoembolization evaluation before in vivo experiments for the development of novel embolic agents.

A 3D Tumor‐Mimicking In Vitro Drug Release Model of Locoregional Chemoembolization Using Deep Learning‐Based Quantitative Analyses

“…Our previous work has shown that the acellular model could provide an optical translucent scaffold for direct chemoembolization examinations. [28,[56][57][58] Here the engineered drug release model successfully circumvented the limitations of current in vitro models through employing decellularized liver organ with the following three key features for locoregional drug release characterizations. Specifically, the intact vasculature systems obtained from native organ provide mature vessel branches with dimensions close to those in human HCC, which allows the direct characterization of clinical-relevant embolic agents.…”

Engineering orthotopic tumor spheroids with organ-specific vasculatures for local chemoembolization evaluation

“…A decellularized liver matrix (DLM) was first prepared through perfusion-based decellularization of healthy rat liver organ through the HV system using an optimized protocol as previously reported. 28,29 To grow tumor spheroids within the organ-based hepatic ECM, recellularized liver matrix (RLM) was obtained by seeding HepG2 cells in the DLM through the BD system. A carefully controlled injection pressure was applied to allow the cells to perfuse through the BD wall into the surrounding ECM adjacent to the BD system instead of being distributed throughout the whole organ.…”

“…[22][23][24][25][26][27] Compared to a fresh organ with opaque appearance, the decellularization process is advantageous to not only preserve intact vasculature systems but also greatly enhance the transparency by completely eliminating the inhabiting cellular components from the organ. [28][29][30][31][32] Here we hypothesize that by carefully seeding tumor spheroids into the acellular organ, we can utilize the organ-structured native vasculatures to evaluate therapeutic performances of endovascular interventional therapies.…”

Recent advances in multicellular human liver models

“…There is no perfect in vivo model of the liver; however, several in vitro multi-lineage liver models have been extensively developed (Fig. 3 and Table 1) [5,10,11,[30][31][32][35][36][37][38][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. Spheroids, which are 3D cultures of hepatic parenchymal and non-parenchymal cells, are among the most commonly used liver models [56] (Fig.…”

“…An important element of 3D modeling is the types and concentrations of ECM molecules, which are essential for cell attachment, proliferation, and differentiation, and are mainly proteins, including collagens, elastin, and fibronectin, polysaccharides, and proteoglycans [57,58]. Decellularization of tissues or organs is a good method to prepare ECM that potentially maintains the natural microenvironment and architecture of the tissue [44,47] (Fig. 3B).…”