The extracellular matrix (ECM) is a critical cue to direct tumorigenesis and metastasis. Although two-dimensional (2D) culture models have been widely employed to understand breast cancer microenvironments over the past several decades, the 2D models still exhibit limited success. Overwhelming evidence supports that three dimensional (3D), physiologically relevant culture models are required to better understand cancer progression and develop more effective treatment. Such platforms should include cancer-specific architectures, relevant physicochemical signals, stromal–cancer cell interactions, immune components, vascular components, and cell-ECM interactions found in patient tumors. This review briefly summarizes how cancer microenvironments (stromal component, cell-ECM interactions, and molecular modulators) are defined and what emerging technologies (perfusable scaffold, tumor stiffness, supporting cells within tumors and complex patterning) can be utilized to better mimic native-like breast cancer microenvironments. Furthermore, this review emphasizes biophysical properties that differ between primary tumor ECM and tissue sites of metastatic lesions with a focus on matrix modulation of cancer stem cells, providing a rationale for investigation of underexplored ECM proteins that could alter patient prognosis. To engineer breast cancer microenvironments, we categorized technologies into two groups: (1) biochemical factors modulating breast cancer cell-ECM interactions and (2) 3D bioprinting methods and its applications to model breast cancer microenvironments. Biochemical factors include matrix-associated proteins, soluble factors, ECMs, and synthetic biomaterials. For the application of 3D bioprinting, we discuss the transition of 2D patterning to 3D scaffolding with various bioprinting technologies to implement biophysical cues to model breast cancer microenvironments.

We report the use of phenolic functional groups of lignosulfonate to impart antioxidant properties and the cell binding domains of gelatin to enhance cell adhesion for poly(ethylene glycol) (PEG)-based scaffolds. Chemoselective thiol–ene chemistry was utilized to form composites with thiolated lignosulfonate (TLS) and methacrylated fish gelatin (fGelMA). Antioxidant properties of TLS were not altered after thiolation and the levels of antioxidation were comparable to those of L -ascorbic acid. PEG-fGelMA-TLS composites significantly reduced the difference in COL1A1 , ACTA2 , TGFB1 , and HIF1A genes between high-scarring and low-scarring hdFBs, providing the potential utility of TLS to attenuate fibrotic responses.

Three-dimensional matrices of collagen type I (Col I) are widely used in tissue engineering applications for its abundance in many tissues, bioactivity with many cell types, and excellent biocompatibility. Inspired by the structural role of lignin in a plant tissue, we found that sodium lignosulfonate (SLS) and an alkali-extracted lignin from switchgrass (SG) increased the stiffness of Col I gels. SLS and SG enhanced the stiffness of Col I gels from 52 to 670 Pa and 52 to 320 Pa, respectively, and attenuated shear-thinning properties, with the formulation of 1.8 mg/mL Col I and 5.0 mg/mL SLS or SG. In 2D cultures, the cytotoxicity of collagen–SLS to adipose-derived stromal cells was not observed and the cell viability was maintained over 7 days in 3D cultures. Collagen–SLS composites did not elicit immunogenicity when compared to SLS-only groups. Our collagen–SLS composites present a case that exploits lignins as an enhancer of mechanical properties of Col I without adverse cytotoxicity and immunogenicity for in vitro scaffolds or in vivo tissue repairs.

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Hydroxyapatite (HA)-coated metals are biocompatible composites, which have potential for various applications for bone replacement and regeneration in the human body. In this study, we proposed the design of biocompatible, flexible composite implants by using a metal mesh as substrate and HA coating as bone regenerative stimulant derived from a simple sol–gel method. Experiments were performed to understand the effect of coating method (dip-coating and drop casting), substrate material (titanium and stainless steel) and substrate mesh characteristics (mesh size, weave pattern) on implant’s performance. HA-coated samples were characterized by X-ray diffractometer, transmission electron microscope, field-emission scanning electron microscope, nanoindenter, polarization and electrochemical impedance spectroscopy, and biocompatibility test. Pure or biphasic nanorod HA coating was obtained on mesh substrates with thicknesses varying from 4.0 to 7.9 μm. Different coating procedures and number of layers did not affect crystal structure, shape, or most intense plane reflections of the HA coating. Moduli of elasticity below 18.5 GPa were reported for HA-coated samples, falling within the range of natural skull bone. Coated samples led to at least 90% cell viability and up to 99.5% extracellular matrix coverage into a 3-dimensional network (16.4% to 76.5% higher than bare substrates). Fluorescent imaging showed no antagonistic effect of the coatings on osteogenic differentiation. Finer mesh size enhanced coating coverage and adhesion, but a low number of HA layers was preferable to maintain open mesh areas promoting extracellular matrix formation. Finally, electrochemical behavior studies revealed that, although corrosion protection for HA-coated samples was generally higher than bare samples, galvanic corrosion occurred on some samples. Overall, the results indicated that while HA-coated titanium grade 1 showed the best performance as a potential implant, HA-coated stainless steel 316 with the finest mesh size constitutes an adequate, lower cost alternative.