Thermally induced phase separation as a heat exchange-driven technique to produce poly-(L-lactic acid) scaffolds with controlled-gradient pore size morphology

Continuous Gradient Pore Scaffolds (CGPS) represent a promising strategy in tissue engineering to mimic the hierarchical structures of human tissues. CGPS provide a suitable microenvironment for cell growth while ensuring mechanical support during tissue regeneration due to a gradual transition in geometry, density, and porosity. In this study, poly-L-lactic acid (PLLA) scaffolds were produced via Thermally Induced Phase Separation (TIPS), an exchange-driven technique that enables customized morphologies in terms of pore size and distribution by tuning the thermal path. Heat transfer phenomena were analyzed using MATLAB to predict the temperature-time profiles and evaluate the thermal driving force as a key factor in pore gradient generation. To validate the model, scaffolds were produced in four configurations by changing the presence of a polytetrafluoroethylene (PTFE) thermal resistance during two cooling steps (thermostatic baths), starting from a ternary solution of PLLA (4 wt%), 1,4-dioxane/deionized water (87/13 wt%). Morphological, quantitative, and calorimetric analyses confirmed that both cooling steps influence pore size. In particular, the first bath affects pore dimensions, whereas the quench influences pore gradient generation. Samples quenched without thermal insulation showed a gradient from border (126 ± 51 μm) to center (184 ± 60 μm). Those with PTFE insulator exhibited a more homogeneous morphology (225 ± 90 μm at the border and 244 ± 112 μm at the center). These results suggest that heat-transfer tuning is an effective strategy to produce customized CGPS. This strategy overcomes the difficulty of controlling scaffold morphology and producing porous and well-interconnected networks, essential features for tissue regeneration.