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Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient‐specific treatment strategies. Herein, novel 3D vascularized HCC on chips (HCCoCs), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness, are created. HCC inflammation is controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450‐3A4 (CYP3A4) is investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allows for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). It is shown that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increases vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, it is shown that further modulation of CYP3A4 activity of HCC cells by TACE delivery of doxorubicin provides an additional improvement to treatment response and reduces chemotherapy‐associated endothelial porosity increase. The HCCoCs are shown to have utility in uncovering the impact of the tumor microenvironment during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.

Variations in tumor biology from patient to patient combined with the low overall survival rate of hepatocellular carcinoma (HCC) present significant clinical challenges. During the progression of chronic liver diseases from inflammation to the development of HCC, microenvironmental properties, including tissue stiffness and oxygen concentration, change over time. This can potentially impact drug metabolism and subsequent therapy response to commonly utilized therapeutics, such as doxorubicin, multi-kinase inhibitors (e.g., sorafenib), and other drugs, including immunotherapies. In this study, we utilized four common HCC cell lines embedded in 3D collagen type-I gels of varying stiffnesses to mimic normal and cirrhotic livers with environmental oxygen regulation to quantify the impact of these microenvironmental factors on HCC chemoresistance. In general, we found that HCC cells with higher baseline levels of cytochrome p450-3A4 (CYP3A4) enzyme expression, HepG2 and C3Asub28, exhibited a cirrhosis-dependent increase in doxorubicin chemoresistance. Under the same conditions, HCC cell lines with lower CYP3A4 expression, HuH-7 and Hep3B2, showed a decrease in doxorubicin chemoresistance in response to an increase in microenvironmental stiffness. This differential therapeutic response was correlated with the regulation of CYP3A4 expression levels under the influence of stiffness and oxygen variation. In all tested HCC cell lines, the addition of sorafenib lowered the required doxorubicin dose to induce significant levels of cell death, demonstrating its potential to help reduce systemic doxorubicin toxicity when used in combination. These results suggest that patient-specific tumor microenvironmental factors, including tissue stiffness, hypoxia, and CYP3A4 activity levels, may need to be considered for more effective use of chemotherapeutics in HCC patients.

Abstract Background Tumor numerical models have been used to quantify solute transport with a single capillary embedded in an infinite tumor expanse, but measurements from different mammalian tumors suggest that a tissue containing a single capillary with an infinite intercapillary distance assumption is not physiological. The present study aims to investigate the limits of the intercapillary distance within which nanoparticle transport resembles solute extravasation in a breast tumor model as a function of the solute size, the intercapillary separation, and the flow direction in microvessels. Methods Solute transport is modeled in a breast tumor for different vascular configurations using mixture theory. A comparison of a single capillary configuration (SBC) with two parallel cylindrical blood vessels (2 BC) and a lymph vessel parallel to a blood vessel (BC_LC) embedded in the tissue cylinder is performed for five solute molecular weights between 0.1 kDa and 70 kDa. The effects of counter flow (CN) versus co-current flow (CO) on the solute accumulation were also investigated and the scaling of solute accumulation-decay time and concentration was explored. Results We found that the presence of a second capillary reduces the extravascular concentration compared to a single capillary and this reduction is enhanced by the presence of a lymph vessel. Varying the intercapillary distance with respect to vessel diameter shows a deviation of 10–30% concentration for 2 BC and 45–60% concentration for BC_LC configuration compared to the reference SBC configuration. Finally, we introduce a non-dimensional time scale that captures the concentration as a function of the transport and geometric parameters. We find that the peak solute concentration in the tissue space occurs at a non-dimensional time, Tpeak∗ $$ {T}_{peak}^{\ast } $$ = 0.027 ± 0.018, irrespective of the solute size, tissue architecture, and microvessel flow direction. Conclusions This work suggests that the knowledge of such a unique non-dimensional time would allow estimation of the time window at which solute concentration in tissue peaks. Hence this can aid in the design of future therapeutic efficacy studies as an example for triggering drug release or laser excitation in the case of photothermal therapies.

Primary liver cancer, or hepatocellular carcinoma (HCC), is a major worldwide cause of death from carcinoma. Most patients are not candidates for surgery and medical therapies, including new immunotherapies, have not shown major improvements since the modest benefit seen with the introduction of sorafenib over a decade ago. Locoregional therapies for intermediate stage disease are not curative but provide some benefit. However, upon close scrutiny, there is still residual disease in most cases. We review the current status for treatment of intermediate stage disease, summarize the literature on correlative histopathology, and discuss emerging methods at micro-, nano-, and pico-scales to improve therapy. These include transarterial hyperthermia methods and thermoembolization, along with microfluidics model systems and new applications of mass spectrometry imaging for label-free analysis of pharmacokinetics and pharmacodynamics.

Survival of living tumor cells underlies many influences such as nutrient saturation, oxygen level, drug concentrations or mechanical forces. Data-supported mathematical modeling can be a powerful tool to get a better understanding of cell behavior in different settings. However, under consideration of numerous environmental factors mathematical modeling can get challenging. We present an approach to model the separate influences of each environmental quantity on the cells in a collective manner by introducing the "environmental stress level". It is an immeasurable auxiliary variable, which quantifies to what extent viable cells would get in a stressed state, if exposed to certain conditions. A high stress level can inhibit cell growth, promote cell death and influence cell movement. As a proof of concept, we compare two systems of ordinary differential equations, which model tumor cell dynamics under various nutrient saturations respectively with and without considering an environmental stress level. Particle-based Bayesian inversion methods are used to quantify uncertainties and calibrate unknown model parameters with time resolved measurements of in vitro populations of liver cancer cells. The calibration results of both models are compared and the quality of fit is quantified. While predictions of both models show good agreement with the data, there is indication that the model considering the stress level yields a better fitting. The proposed modeling approach offers a flexible and extendable framework for considering systems with additional environmental factors affecting the cell dynamics.

In chronic liver diseases and hepatocellular carcinoma, the cells and extracellular matrix of the liver undergo significant alteration in response to chronic injury. Recent literature has highlighted the critical, but less studied, role of the liver vasculature in the progression of chronic liver diseases. Recent advancements in liver-on-a-chip systems has allowed in depth investigation of the role that the hepatic vasculature plays both in response to, and progression of, chronic liver disease. In this review, we first introduce the structure, gradients, mechanical properties, and cellular composition of the liver and describe how these factors influence the vasculature. We summarize state-of-the-art vascularized liver-on-a-chip platforms for investigating biological models of chronic liver disease and their influence on the liver sinusoidal endothelial cells of the hepatic vasculature. We conclude with a discussion of how future developments in the field may affect the study of chronic liver diseases, and drug development and testing.