Fabrication Strategies Towards Hydrogels for Biomedical Application: Chemical and Mechanical Insights

Abstract

This review aims at giving selected chemical and mechanical insights on design criteria that should be taken into account in hydrogel production for biomedical applications. Particular emphasis will be given to the chemical aspects involved in hydrogel design: macromer chemical composition, cross-linking strategies and chemistry towards "conventional" and smart/stimuli responsive hydrogels. Mechanical properties of hydrogels in view of regenerative medicine applications will also be considered.

Keywords: cross-linking; dynamic reactions; hydrogels; smart hydrogels; stimuli responsiveness.

Figure 1

Publication number returned by PubMed for “Hydrogels” in the last 50 years (1972–2021).

Figure 2

Hydrogel global market size forecast to 2030.

Figure 3

Chemical structure of most common polyacrylic‐based macromers.

Figure 4

Chemical structure of PEG, PVA and PVP.

Figure 5

Main polysaccharide structures used in hydrogels.

Figure 6

Main monosaccharide units composing pectins.

Figure 7

Physical or chemical cross‐linking strategies (only a selection of methods has been depicted).

Figure 8

Schematic view of zero‐length, homobifunctional and heterobifunctional cross‐linking.

Scheme 1

Schematic outline of zero‐length cross‐linking between proteins, mediated by EDC/NHS activation.

Scheme 2

Reaction mechanism for isopeptide bond formation between carboxyl group of aspartate and amino group of lysine in proteins, mediated by EDC and NHS (or NHSS).

Figure 9

Isomerisation of the O‐acylisourea to an N‐acylurea stable derivative (tetrahedral intermediate deriving from the nitrogen attack to the carbonyl of the O‐acylisourea is omitted).

Scheme 3

Reaction mechanism for the formation of genipin‐derived adducts a and b upon reaction with methylamine. Only one of the possible rearrangements of adduct a into adduct b is shown.

Figure 10

Possible dimerization products derived from genipin adducts obtained by reactions with primary amines (described in Scheme 3 for methyl amine).

Scheme 4

Schiff base cross‐links for hydrogel preparation.

Scheme 5

Glutaraldehyde cross‐linking products.

Scheme 6

Reaction steps between amino group (i. e. lysine in proteins) and carbonyl group of glutaraldehyde to form the Schiff's base; for crosslinking the reaction occurs on both carbonyls.

Scheme 7

Reaction steps between hydroxyl groups and carbonyl groups of glutaraldehyde to form the hemiacetal (exemplified for the group of hydroxyproline, abundant in collagen); for crosslinking the reaction occurs on both carbonyls.

Scheme 8

Base‐ or acid‐catalysed aldol condensation among glutaraldehyde molecules.

Scheme 9

Main thiol‐based click reactions for hydrogel preparation.

Scheme 10

Radical mechanism for the thiol‐ene reaction.

Scheme 11

Current proposed mechanism for the CuAAC reaction.

Scheme 12

General scheme for cross‐linking via SPAAC.

Scheme 13

Selected chemical reactions useful for dynamic cross‐linking.

Scheme 14

Dynamic cross linking through hydrazine/hydrazone equilibrium.

Figure 11

Schematic representation of external stimuli exploited in smart hydrogels.

Scheme 15

Glucose and pH‐responsive hydrogels based on boronic esters chemistry.

Scheme 16

Chemo‐orthogonal chemistry in redox‐responsive hydrogels.

Scheme 17

Schematic synthesis of a MMP‐sensitive PEG‐based hydrogel.

Scheme 18

Swelling/deswelling behaviour of smart hydrogel in response to different concentrations of antigen.

Figure 12

Hydrogel stiffness may influence stem cell differentiation to diverse cell lines.