02395nas a2200205   4500000000100000008004100001260001500042653001900057653002000076653002700096653002000123100002900143700002300172245011500195856007200310300001200382490000600394520177500400022001402175       2026                            d  c2026-01-0110a4D bioprinting10aChemoresistance10aDuct-mimetic scaffolds10aDynamic culture1 aSriram Bharath Gugulothu1 aKaushik Chatterjee00aDynamic 4D-bioprinted duct-like microenvironments for triple-negative breast cancer modeling and drug response  uhttps://www.sciencedirect.com/science/article/pii/S2666138126000113  a121-1340 v73 aFour-dimensional (4D) bioprinting offers a facile strategy for generating dynamic tissue constructs with physiologically relevant geometries for disease modeling. Here, we extend a previously established visible-light-crosslinkable hydrogel system to fabricate self-folding, duct-mimetic tubular constructs for triple-negative breast cancer (TNBC) modeling under dynamic culture conditions. Systematic optimization of photoinitiator concentration in bioink, scaffold thickness and length, cell density, and solvent conditions identified parameters that enabled robust self-folding of TNBC cell-laden constructs into closed thin-walled (≤ 0.8 mm) tubes with an internal diameter of ≈2.1 mm, comparable to those of mammary ducts. Nanoindentation confirmed a stable mechanical gradient in the tubular scaffolds over 14 days, with a softer outer surface (≈0.5 kPa) and a stiffer inner surface (≈20 kPa). Under rocker-based dynamic culture, MDA-MB-231-laden tubular constructs showed improved viability and a 1.4-fold increase in metabolic activity compared with their static culture counterparts at Day 14. Dynamic culture also promoted the appearance of mesenchymal-like spindle morphology by Day 7 and cellular aggregation by Day 14. Following doxorubicin treatment at Day 14, dynamically cultured tubes exhibited enhanced chemoresistance compared to static constructs, with lower cell death (65%vs. 75%) at approximately 10-fold higher half-maximal inhibitory concentration (IC50) (10 µM). Together, these findings establish a 4D-bioprinted TNBC model with a duct-like architecture and mechanical anisotropy to investigate the role of passive (stiffness gradients) and dynamic (interstitial flow) biophysical cues on tumor cell behavior and therapeutic response.  a2666-1381