Tissue development, wound healing, pathogenesis, regeneration, and homeostasis rely upon coordinated and dynamic spatial and temporal remodeling of extracellular matrix (ECM) molecules. ECM reorganization and normal physiological tissue function, require...
Malignant tumor tissues exhibit inter- and intratumoral heterogeneities, aberrant development, dynamic stromal composition, diverse tissue phenotypes, and cell populations growing within localized mechanical stresses in hypoxic conditions. Experimental tumor models employing engineered systems that isolate and study these complex variables using in vitro techniques are under development as complementary methods to preclinical in vivo models. Here, advances in extrusion bioprinting as an enabling technology to recreate the three-dimensional tumor milieu and its complex heterogeneous characteristics are reviewed. Extrusion bioprinting allows for the deposition of multiple materials, or selected cell types and concentrations, into models based upon physiological features of the tumor. This affords the creation of complex samples with representative extracellular or stromal compositions that replicate the biology of patient tissue. Biomaterial engineering of printable materials that replicate specific features of the tumor microenvironment offer experimental reproducibility, throughput, and physiological relevance compared to animal models. In this review, we describe the potential of extrusion-based bioprinting to recreate the tumor microenvironment within in vitro models.
Continuous extracellular matrix (ECM) remodeling and cellular heterogeneity are key contributors to cancer development and can both profoundly affect treatment efficacy. Developing in-vitro models that recapitulate matrix and cellular heterogeneity of the tumor microenvironment (TME) can aid in observations that are currently challenging to acquire with conventional 2D cultures and preclinical animal models. Here we report an extrusion bioprinted co-culture model of head and neck cancer and stromal fibroblasts using a composite bioink containing a reinforced decellularized extracellular matrix hydrogel. Fibroblasts have a significant role in remodeling and matrix deposition. When cultured in the bioactive extracellular matrix ink, they provide the cellular elements typically found in the tumor stroma. Head and neck squamous carcinoma cells (UM-SCC-38) were integrated into the bioink, and in the presence of fibroblasts (HVFFs), they began to proliferate into cell-cell interactive spheroids. As the co-culture model is capable of remodeling, we evaluated the ultrastructure of the bioink. We observed a fibrous collagenous network retained from the ECM of the source tissue containing nanometer-scale pores. Following the deposition of the co-culture model, we observed UM-SCC-38 spheroid formation that began during the first week in culture and continued over a three-week period in which the fibroblasts migrated to regions directly surrounding each spheroid. Using a Luminex assay to quantify matrix metalloproteases in co-cultures compared to monocultures, we observed significant differences in the presence of MMP-9 and MMP-10 expression corresponding to periods of the culture in which collagen underwent remodeling. Time-dependent characterization of collagen synthesis, protease activity, and spheroid growth rates are developed to characterize the system as an advanced co-culture model to evaluate tumor-stromal interactions and remodeling.
: Dengue virus (DENV) disease has become one of the major challenges in public health. Currently, there is no antiviral treatment for this infection. Since human transmission occurs via mosquitoes of the Aedes genus, most efforts have been focused on controlling this vector. However, these control strategies have not been totally successful, as reflected in the increasing number of DENV infections per year, becoming an endemic disease in more than 100 countries worldwide. Consequently, the development of a safe antiviral agent is urgently needed. In this sense, rational design approaches have been applied in the development of antiviral compounds that inhibit one or more steps in the viral replication cycle. The entry of viruses into host cells is an early and specific stage of infection. Targeting either viral components or cellular protein targets is an affordable and effective strategy for therapeutic intervention of viral infections. This review provides an extensive overview of the small organic molecules, peptides, and inorganic moieties that have been tested so far as DENV entry direct-acting antiviral agents. The latest advances based on computer-aided drug design (CADD) strategies and traditional medicinal chemistry approaches in the design and evaluation of DENV virus entry inhibitors will be discussed. Furthermore, physicochemical drug properties such as solubility, lipophilicity, stability, and current results of pre-clinical and clinical studies will also be discussed in detail.
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