Beyond 2D: polymeric derivatives in 3D cell culture revolutionizing cancer research – a systematic review

The emergence of three-dimensional (3D) cell culture techniques has transformed cancer research by providing more physiologically relevant tumor microenvironments (TME). Polymeric scaffolds create a dynamic environment that mimics physiological conditions, enabling cell-cell and cell-matrix interactions that are difficult to reproduce in traditional 2D cultures. This review examines the role of natural and synthetic polymeric derivatives in fabricating scaffolds for 3D cancer cell culture applications. Natural polymeric scaffolds from collagen, gelatin, cellulose, agarose, chitosan, alginate, and hyaluronic acid are reported to offer biocompatibility and bioactivity, promoting cell adhesion and differentiation, making them ideal for recreating native extracellular matrix (ECM) conditions. However, they often face limitations in mechanical strength and long-term stability. Conversely, synthetic polymeric scaffolds from polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(ethylene glycol) (PEG), and polyvinyl alcohol (PVA) provide enhanced control over mechanical properties and reproducibility for 3D culture but may lack inherent bioactivity. The limitations of natural and synthetic polymeric scaffolds can be overcome by combining them to form hybrid scaffolds that improve structural integrity while maintaining biocompatibility, presenting a promising approach. This review highlights recent advances in 3D scaffold-based cancer cell culture, demonstrating applications in drug testing, TME studies, and personalized medicine.