Table 2.

Methods of production of scaffolds and their advantages and disadvantages

Method of production	Description of the mechanism	Advantages (+)/Disadvantages (−)	References
Lyophilisation/freeze-drying	Polymers are solubilized in solvent, before being subjected to gelation sublimation of solid polymers (gel or foam) followed by freeze drying under vacuum	+ High porosity and pore interconnectivity – Small pore size − Irregular porosity − Time consuming process (days) − Residual solvent that may be harmful to cells − High energy-consuming	[142, 143]
SCPL	Insoluble salt particles are added to a solution of polymers solubilized in solvent. After solvent evaporation, a composite of polymers embedded with salt particles is obtained. Repeated washing of the composite with water allows the salt elimination and then the formation of a porous scaffold	+ Simple  + Reproducible  + No specific instrument required − Limited interconnectivity − Time consuming process (days) − Residual solvents that may induce cell damages	[144]
Gas foaming	Can be done chemically by: i) producing hydrophobic gas bubbles in liquid solution of polymers; ii) physically by subjecting a solid polymer to a high pressure gas that can dissolve into it and expands when the pressure is reduced, thus producing cavities when the bubbles collapse. It can be associated with SCPL	+ High porosity  + Controlled pore size  + Solvent-free − Limited interconnectivity	[145–147]
TIPS	Relies on the change in thermal energy to transform a homogeneous mixture of polymer and solvent into a multiple-phase system, composed of a polymer-rich phase (solvent-poor phase) and a polymer-poor phase (solvent rich phase). The solution is quenched below the freezing point of the solvent, and the solvent is removed by freeze-drying	+ Easily implementable  + High interconnectivity  + Easy modulation of pore size and structure − Time consuming process (days) − Residual solvents may induce cell damages − High energy-consuming	[148, 149]
Electrospinning	A charged liquid with a voltage high enough to counteract surface tension will stretch and erupt into a jet. It will solidify into a fibre when projected on a collector	+ High porosity  + High interconnectivity + Low cost  + Most soluble polymers can be used  + Mimic the fibrillar structure of ECM − Complex generation of 3D structure − Residual solvents that may induce cell damages − Small pores that lead to poor cell infiltration and distribution − Low mechanical strength	[150, 151]
Self-assembly	Spontaneous assembling of monomers into supramolecular nanostructures after exposure to pH or temperature modifications or enzymatic treatment	+ Different types of structure can be generated depending on the synthesis conditions  + Easy to functionalize with various molecules  + Less toxic because does not require cross-linker reagents + Low cost and rapid syntehesis − Difficult to control size of the self-assembled nanostructure − May be unstable under liquid conditions	[152, 153]
Rapid prototyping	Describes a group of manufacturing processes (e.g. stereolitography, 3D printing, selective laser sintering) that enables fabrication of scaffold layer by layer with precise spatial organization from a computer aided design (CAD)	+ High control on pore size, porosity, and interconnectivity + Good resolution  + Good reproducibility − Expensive − Time-consuming (creation of the design) − Potential wasting of polymers − Potential cytotoxicity of the polymers used	[154]

SCPL solvent-casting and particulate-leaching, TIPS thermally induced phase separation