Hydrogel Synthesis and Design

  • Michael J. Majcher
  • Todd HoareEmail author
Living reference work entry
Part of the Polymers and Polymeric Composites: A Reference Series book series (POPOC)


The capacity to exploit the many possible applications of hydrogels is strongly tied to our capacity to synthesize hydrogels with well-defined chemistries and structures. Herein, we review the major strategies used for the synthesis of hydrogels, focusing on the key choices to be made in terms of the chemical and structural properties of the backbone polymer, the nature of the crosslinking strategy used (in terms of both the mechanism and the permanence of network formation), and the length scale at which network formation is conducted. The impacts of these various choices on the ultimate properties of the hydrogels generated are emphasized in the context of the rational design of hydrogel compositions and structures for target applications.



Dimethyl 2,2′-azobis(2-methylpropionate)






Cellulose nanocrystals


Cetyltrimethylammonium bromide


Copper(I)-catalyzed alkyne-azide click reaction


Coefficient of variance


Dendrimer-based hydrogels


Generally recognized as safe (FDA)


Methacrylated gelatin


Hyaluronic acid, HA


Hydroxypropyl methylcellulose


Interpenetrating polymer network


International Union of Pure and Applied Chemistry


Poly(acrylic acid)




Poly(allylamine hydrochloride)




Poly(ɛ -caprolactone)


Poly(diallyldimethylammonium chloride)


Poly(d-lactic acid)


Poly(ethylene glycol)


Poly(ethylene oxide)


Poly(hydroxyethyl methacrylate)


Poly(lactic acid)




Poly(l-lactic acid)


Poly(methacrylic acid)




Poly(oligoethylene glycol methacrylate)


Poly(oligolactic acid methacrylate)


Poly(propylene fumarate)


Particle replication in non-wetting templates


Poly(styrene sulfonate)




Poly(vinyl alcohol)




Quantum dots


Strain-promoted alkyne-azide click reactions


Sodium trimetaphosphate


Sodium tripolyphosphate


Transmission electron microscopy



1 Definitions and Introduction

Hydrogels are networks of water-soluble polymers swollen in water. This affinity for water differentiates hydrogels from organogels (that swell in organic solvents) or gels (a more general term that encompasses any solvent-swellable network, including but not limited to hydrogels).

While there is no formal minimum water content associated with differentiating a hydrogel from other types of polymer networks, most functional hydrogels used in applications contain at least 50% by weight water, with some applications of hydrogels (e.g., superabsorbents) containing >99.9% by weight water. A clearer definition of what is or is not a hydrogel can be given based on an understanding of the nature of water binding to a hydrogel network. Figure 1 shows a schematic diagram of the various interactions of water with a hydrogel network.
Fig. 1

States of water inside a hydrogel. (Adapted with permission from [1])

While the nature or existence of “semi-bound” (or interfacial) water is still a matter of some debate [2], the inherent hydrophilicity of the polymers crosslinked to form a hydrogel results in a fraction of water being “bound” inside the network by hydrogen bonding/dipole interactions with hydrogen bond donors/acceptors or polar functional groups on the polymer backbone; this bound water is difficult to remove from the hydrogel even upon drying. The remaining water is “free” in that it is present inside the hydrogel phase due to the osmotic pressure gradient between the bulk (low polymer concentration) and gel (high polymer concentration) phases, leading to the uptake of water and thus hydrogel swelling. On this basis, instead of defining a hydrogel solely based on its overall water content, the following three criteria best define whether or not a material should be considered to be a hydrogel.
  1. 1.

    Although the polymer chains comprising a hydrogel have an affinity for water (and would themselves dissolve in water if they were not networked), hydrogels will not fully dissolve no matter how much water is added. This criterion distinguishes hydrogels from viscous water-soluble polymer solutions that may have similar bulk properties at higher polymer concentrations but simply dissolve upon dilution. Note that this criterion does not exclude that hydrogels can degrade; indeed degradation can be specifically designed into the building block or crosslinking chemistry of a hydrogel as desired. However, degradation of the hydrogel into soluble components must involve the breaking or dissociation of some kind of physical or chemical bond.

  2. 2.

    Water is fully contained inside the volume of a hydrogel. This criterion distinguishes hydrogels from many types of coacervates or aggregates which expel the majority of the solvent upon forming intermolecular interactions/crosslinks.

  3. 3.

    Hydrogels contain a mixture of bound water and free water. This criterion distinguishes hydrogels from other types of micro-/nanoporous scaffolds or sponges comprised of materials that do not themselves have a specific affinity to swell in water but can absorb large quantities of water due to their porous nature (e.g., cellulose sponges).


In this chapter, we will outline the options for fabricating hydrogels using various building blocks and crosslinking strategies on different length scales.

2 Hydrogel Classifications

Hydrogels are conventionally defined by the nature of the polymers comprising their chains (Sect. 2.1), the mechanism and resulting organization of network assembly (Sects. 2.2 and 2.3), and the length scale of the assembled network (Sect. 2.4). Note that the literature examples and research studies selected for inclusion in these sections are not meant to be exhaustive but are rather selected in order to give the reader insight with respect to the major engineering and design principles governing hydrogels designed for unique applications.

2.1 Types of Building Blocks

2.1.1 Natural

Hydrogels derived from natural or biological sources have inherent advantages such as low cost, non-toxicity, renewability, and (typically at least) degradability [3] relative to synthetic polymers. In addition, as naturally occurring polymers, their degradation products are typically considered to be safe since they are natively used by the body for subsequent cellular reactions [4]. For instance, when starch degrades, the resulting products are amylose (α 1 ➔ 4 glycosidic linkages) and amylopectin (α 1 ➔ 6 glycosidic linkages), both of which naturally occur in the human body [5, 6]. As such, starch and other natural polymers that have natural metabolic by-products have thus been deemed as GRAS (i.e., “generally regarded as safe”) by the Food and Drug Administration (FDA) [7]. Furthermore, in some biomedical applications in which a particular cell response to a hydrogel is targeted, the use of natural polymers that naturally induce such responses is directly beneficial; for example, hyaluronic acid (HA)-based hydrogels have been shown to promote cell spreading based on the native biological function of HA [8]. Despite these advantages, natural polymers do have limitations in hydrogel design. Batch-to-batch variation is a particularly challenging problem given the varying biological sources of such polymers and the fact they are typically extracted from complex mixtures of natural polymers, an expensive and often inefficient processing step that must be customized for each target natural polymer. For instance, the extraction of lignin and similar phenolic constituents from wood requires a two-step process involving pre-extraction of hemicellulose followed by lignin extraction using one of the many commonly implemented methods (i.e., deep eutectic solvent, organosolv, soda/AQ, hydrotrope) [9], while the conversion of chitosan from shellfish chitin requires acid treatment in order to dissolve the calcium carbonate in the shell followed by an alkaline extraction in order to solubilize the proteins present [8]. The often limited number of functional groups amenable to crosslinking reactions can also result in many natural polymer-based hydrogels exhibiting relatively weak mechanical properties, although this is not a universal problem with such hydrogels.

The most heavily studied natural polymers for hydrogel synthesis are carbohydrates such as hyaluronic acid [8, 10], chitin/chitosan [8], water-soluble cellulose derivatives (i.e., ethyl cellulose) and nanoscale cellulose (i.e., cellulose nanocrystals or CNCs) [11, 12], dextran [13], starch [14, 15], alginate [16, 17], fibrin [18], and agarose [19]. Each of these polymers has their own unique chemical compositions and resulting properties. Other biological macromolecules can also be used, with proteins such as gelatin [20], collagen [21], and fibrinogen [22] being most widely used. The diversity of proteins with respect to their number/types of amino acids and overall properties can also be used to control the physical and biological properties of the resulting hydrogels [23], with both natural and synthetic amino acids having been used to direct gel properties. The same advantages are accessible when peptides, short amino acid oligomers, are used as gel building blocks. By tuning the amino acid sequence of the peptide, the capacity of the peptide to form self-assembled fibers, tapes, sheets, wires, or ribbons that can subsequently assemble into fibrillar networks and ultimately hydrogel structures can be tuned [24]. The sequence of the amino acids determines the assembly into β-sheet, β-hairpin, α-helix, and/or coiled-coil structural motifs, with elastin-like polypeptides based on VPGXG pentapeptide repeats being particularly well-studied due to their capacity to spontaneously form fibers and, in some cases, hydrogels upon heating [25]. However, peptides as short as 1–2 repeat units (particularly those containing protecting groups from the solid-phase synthesis process) can also spontaneously form fibers and thus gels under the correct conditions [26]. Alternately, peptide amphiphiles containing both hydrophilic and hydrophobic domains can self-assemble with tunable physical properties depending on the length and relative hydrophobicity/hydrophilicity of the domains produced [27]. The reader is referred to the excellent review by Dasgupta et al. for a broader perspective on the types of peptides that can form gels [24]. Hydrogels have also been successfully fabricated from polynucleotides, with whole DNA sequences or molecularly imprinted sections of genomes successfully used to prepare gel structures [28].

2.1.2 Synthetic

Synthetic hydrogels are based on chemically derived building blocks prepared from small molecule monomeric units. Relative to natural polymers, synthetic polymers offer significantly more chemical flexibility in terms of introducing crosslinking or functional tags (as facilitated by copolymerization, blending, or other chemical strategies) [29], show more consistent batch-to-batch chemistry (and thus properties), and minimize the risk of introducing biological contaminants into the final hydrogel product [30]. The capacity to add any desired density of crosslinking groups as well as introduce any degree of chain conformational mobility also enables synthetic polymer-based hydrogels to exhibit generally enhanced mechanics relative to natural polymer-based hydrogels. However, the native degradability and bioactivity of natural polymers is sacrificed if synthetic polymers are instead used to fabricate hydrogels. As such, judicious selection of the hydrogel building block is essential to achieve the targeted physicochemical properties depending on the targeted hydrogel application.

While many synthetic polymers have been used to form hydrogels, the most commonly used materials for this purpose are poly(ethylene glycol) (PEG) [31], poly(vinyl alcohol) (PVA) [32, 33], poly((meth) acrylic acid) (PMAA/PAA) [34, 35], poly(vinylpyrrolidone) (PVP) [36, 37], and poly(hydroxyethyl methacrylate) (PHEMA) [38, 39]. Copolymerization is typically used to introduce functional groups that enable crosslinking of these polymers via the desired mechanism and at the desired density, a significant benefit relative to natural polymers which tend to have a limited capacity for polymer functionalization.

2.1.3 Hybrid

Hybrid hydrogels are fabricated using a combination of natural and synthetic polymer building blocks, typically aiming to take advantage of the key advantages of each type of material while suppressing the disadvantages. For example, Patenaude et al. [40] demonstrated the fabrication of mixed natural/synthetic hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) and a range of natural polymers that enabled enhanced enzymatic degradation (hyaluronic acid), reduced protein adsorption (dextran), or enhanced pH responsiveness (carboxymethyl cellulose) relative to PNIPAM hydrogels alone. Alternately, Widusha et al. developed hybrid hydrogels based on a mixture of short- and long-chain alginates and polyacrylamide that provided the required stiffness/toughness (modulus ~1 MPa and fracture energy 4–16 kJ/m2) as well as load-bearing capabilities required for mimicking native cartilage (Fig. 2) [41].
Fig. 2

Visualization of how hybrid hydrogels can offer specific mechanical properties which are not attainable by purely natural (alginate) or purely synthetic (PVA or PAAm). (Image reproduced with permission from [41])

2.2 Building Block Compositions

Hydrogel building blocks can be further classified based on their physical structures and chemical compositions. Homopolymers (one monomer type) or copolymers (made from more than one type of monomeric unit) can both be fabricated with different morphologies in which the monomers are arranged in different spatial orientations.

2.2.1 Linear Polymer Hydrogels

Linear homopolymers consist of a single main chain which propagates/grows only along a single spatial plane from a single monomer type. As representative examples across the range of polymers already discussed, cellulose is formed by connecting d-glucose repeating units via β (1 ➔4) glycosidic linkages, poly(ethylene glycol) (PEG) is formed by ring-opening polymerization of epoxide monomers, and poly(acrylic acid) (PAA) is formed by free radical polymerization through the C=C double bond.

2.2.2 Copolymer Hydrogels

Copolymerization methods, in which more than one monomer is used to prepare a single polymer chain (provided that any monomer selected for the copolymer can be polymerized using the same step-growth or chain-growth polymerization mechanism), offer significant potential to expand the scope of hydrogel properties achievable. In this manner, monomers with dissimilar properties (e.g., charged and neutral, hydrophobic and hydrophilic, or degradable and nondegradable) can be incorporated into a single polymeric building block. This diversity of potential compositions imparts a diversity of properties into the resulting hydrogel in a manner likely to result in a homogeneous gel structure than simple blending of different precursor polymers that is more prone to phase separation and domain formation.

Copolymer structures, and thus their role in governing hydrogel properties, are dependent on the relative reactivity (e.g., reactivity ratios or f values) of the comonomers. For instance, copolymerization can result in alternating (regularly repeating A- and B- units), periodic (repeating sequences of A- and B-) random/statistical (random distribution of A- and B- following the probabilities of the different monomers finding each other in solution), or block copolymers (two or more homopolymers referred to as A- and B- which are linked by covalent bonds or junction blocks) depending on the reactivity ratios of the monomers (Fig. 3).
Fig. 3

Visual representation of the most common copolymer arrangements. Note that the red A and the green B represent two unique monomer units for ease of visualization

Periodic or alternating structures tend to result in hydrogels with relatively uniform distributions of monomer compositions throughout the hydrogel volume, as the covalent bonds along the polymer backbone prevent any kind of phase separation [42]; in contrast, block structures are more prone to phase separation, although typically more on the nanoscale than the microscale (as possible with blend or hybrid hydrogels) given that the A and B phases are covalently connected and thus cannot fully phase separate [43]. Statistical copolymers will exhibit intermediate behavior between these extremes depending on the distribution of monomers most probable in the structure [44, 45].

Prediction of the composition of the copolymer, and thus the nature of the assemblies of such copolymers when networked to form a hydrogel, can be achieved for free radical copolymers based on the reactivity ratios of the comonomers involved in the polymerization. The molar comonomer concentration ratios fA (for component A) and fB (for monomer B) are given in Eq. 1:
$$ {f}_A=\frac{\left[A\right]}{\left[A\right]+\left[B\right]};\, \,{f}_B=\frac{\left[B\right]}{\left[A\right]+\left[B\right]} $$

However, the comonomer compositions defined above are general in the sense that they do not consider the change in comonomer concentrations (A and B) as the reaction proceeds. Therefore, it is much more accurate to calculate an instantaneous copolymer composition F, as defined in Eq. 2:

$$ {F}_A=\frac{\left(-\frac{d\left[A\right]}{dt}\right)}{\left[\left(-\frac{d\left[A\right]}{dt}\right)+\left(-\frac{d\left[B\right]}{dt}\right)\right]};{F}_B=\frac{\left(-\frac{d\left[B\right]}{dt}\right)}{\left[\left(-\frac{d\left[A\right]}{dt}\right)+\left(-\frac{d\left[B\right]}{dt}\right)\right]} $$
The rates included in Eq. 2 can be defined by considering the possible reactions of a radical of either type with a monomer of each type, each of which has an independent kinetic rate constant k (Eqs. 3, 4, 5, and 6):
$$ {P}_{m,n,1}^{\ast }+A\ \overset{k_{p1A}}{\to }{P}_{m+1,n,1}^{\ast } $$
$$ {P}_{m,n,1}^{\ast }+B\ \overset{k_{p1B}}{\to }{P}_{m+1,n,2}^{\ast } $$
$$ {P}_{m,n,2}^{\ast }+A\ \overset{k_{p2A}}{\to }{P}_{m+1,n,1}^{\ast } $$
$$ {P}_{m,n,2}^{\ast }+B\ \overset{k_{p2B}}{\to }{P}_{m+1,n,2}^{\ast } $$
The reactivity ratios r can thus be defined as the ratio between the rate constants associated with the propagation of monomers A and B from each type of radical, associated with the relative probabilities of reaction (and thus incorporation into the polymer) of each monomer as the reaction proceeds (Eqs. 7 and 8):
$$ {r}_1=\frac{k_{p1A}}{k_{p1B}} $$
$$ {r}_2=\frac{k_{p2B}}{k_{p2A}} $$

The resulting compositions of copolymers can be predicted based on these reactivity ratios, with r1 = 0 and r2 = 0 leading to an alternating copolymer, r1 = ∞ and r2 = ∞ yielding two homopolymers (a rare case), r1 = r2 = 1 resulting in a random copolymer, r1 < 1 and r2 < 1 resulting in a random alternating copolymer, r1 = r2 > 1 resulting in a block copolymer, r1 = r2 resulting in F1 = f1 throughout the polymerization, and r1 = r2, resulting in f1 = F1 = 0.5.

The rate of disappearance of each monomer A and B can also be written based on these possible reaction pathways (Eqs. 9 and 10):
$$ -\frac{d\left[A\right]}{dt}={k}_{p1A}\left[{P}_1^{\ast}\right]\left[A\right]+{k}_{p2A}\left[{P}_2^{\ast}\right]\left[A\right] $$
$$ -\frac{d\left[B\right]}{dt}={k}_{p1B}\left[{P}_1^{\ast}\right]\left[B\right]+{k}_{p2B}\left[{P}_2^{\ast}\right]\left[B\right] $$

By substituting Eqs. 3, 4, 5, 6, 7, 8, 9, and 10 back into Eq. 2, an experimentally accessible expression for predicting the instantaneous fraction of each monomer in a comonomer at any given conversion (i.e., fraction of monomer present) can be expressed as Eqs. 11 and 12:

$$ {F}_A=\frac{r_1{f}_A^2+{f}_A{f}_B}{r_1{f}_A^2+2{f}_A{f}_B+{r}_2{f}_B^2} $$
$$ {F}_B=\frac{r_2{f}_B^2+{f}_A{f}_B}{r_1{f}_A^2+2{f}_A{f}_B+{r}_2{f}_B^2} $$

More recently, gradient copolymers in which the monomer composition varies gradually from all A to all B over the length of the chain (rather than block copolymers, in which the two constituent monomers are present only in homopolymer blocks tethered together) have attracted interest. In this case, monomer B is typically fed into a controlled radical polymerization at a particular rate, enabling control of the comonomer distribution not only by alteration of the kinetic copolymerization ratios but also by dynamically changing the mixture of monomers available to react (i.e., f changes dynamically with time). Such materials can self-assemble similar to block copolymers but with finely tuned strength of self-association not achievable with conventional block copolymers.

Note that these same copolymerization ratio arguments can be used to predict the consumption of crosslinker during the preparation of a hydrogel but considering propagation of the polymerization through both reactive vinylic groups in the monomer. For example, we have previously shown that the reactivity ratios between the monomer(s) and the crosslinker(s) used to prepare nanogel particles via precipitation methods (Sect. 2.5.3) can be used to predict the radial crosslinker distributions within such nanogels, essential to engineer desired swelling responses in these materials [46].

2.2.3 Multipolymer or Terpolymer Hydrogels

Hydrogels based on multiple types of polymers mixed together and networked offer a hybrid/heterogeneous phenotype with respect to material properties and thus expand on the number of possibilities available via copolymerization techniques. Such hydrogels are particularly relevant when two types of functionality are required in a hydrogel that cannot be polymerized via the same mechanism, as is required to make a copolymer building block. Examples of such multipolymer hydrogels include poly(acrylamide) (PAAm)/gelatin and poly(acrylic acid-co-hydroxyethyl methacrylate) (P(AA-co-HEMA)/gelatin hydrogels [47, 48], in which the strength and the high water-binding capacity of PAAm and P(AA-co-HEMA) synthetic polymer component is combined with the degradability and the cell adhesive properties of the gelatin component to create a functional hydrogel material.

2.3 Building Block Chain Orientations

By combining different polymerization principles, more advanced polymer chain orientations may be attained, each having unique properties that again impart unique properties to their constituent hydrogels following crosslinking. Figure 4 shows the structures of some of these more advanced polymer morphologies, with the morphologies most commonly applied for forming hydrogels described below.
Fig. 4

Visual depiction of the various polymer chain compositions which may be attained through a combination of optimized reaction conditions and synthesis routes

2.3.1 Branched and Hyperbranched Polymer Hydrogels

Branched polymers are compact and globular structures with a large amount of available functionalities at their periphery but low viscosities; this combination of properties makes such polymers interesting building blocks for functional hydrogels with stronger mechanics or well-controlled distributions of internal functional groups [49]. Branched polymers can be prepared using the general scheme shown in Fig. 5.
Fig. 5

Visual representation of how branching and crosslinking occurs in accordance to Flory’s theory of gelation

The extent of chain branching can be described by applying statistical principles to Flory’s theory of gelation [50, 51]. Following the general scheme shown below, the instantaneous conversion of a particular monomer x can be expressed based on the initial concentration of that monomer (Ao) and the instantaneous concentration of that monomer A (Eq. 13).
$$ x=\frac{{\left[A\right]}_0-\left[A\right]}{{\left[A\right]}_0} $$
For each step of the branching process, a general equation can describe the relative probabilities of conversion. In these equations (Eqs. 14, 15, 16, 17, and 18), A3 is the growing polymer chain, while AA and BB (or aa and bb following polymerization) represent the two unique repeating units that branch off of the linear backbone, each time creating a unique structure with a specific probability of occurrence.
$$ {A}_3+ BB\to {A}_2 abB\qquad x $$
$$ {A}_2 abB+ AA\to {A}_2 abbaA\qquad x\left[\alpha x\left(1-\rho \right)\right] $$
$$ {A}_2 abbaA+ BB\to {A}_2 abbaabB\quad x\left[\alpha x\left(1-\rho \right)x\right] $$
$$ {A}_2 abbaA+ AA+ BB\to {A}_2a{(bbaa)}_n bB\quad x{\left[\alpha x\left(1-\rho \right)x\right]}^n $$
$$ {A}_2 abbaA+{A}_3\to {A}_2a{(bbaa)}_n{bbaA}_2\quad x{\left[\alpha x\left(1-\rho \right)x\right]}^n\alpha x\rho $$
Here, α represents the imbalance ratio between the reactive monomer species AA and BB (Eq. 19), while ρ describes the fraction of A on the polymer backbone (A3) (Eq. 20):
$$ \alpha =\frac{2{\left[ AA\right]}_0+3{\left[{A}_3\right]}_0}{2{\left[ BB\right]}_0} $$
$$ \rho =\frac{3{\left[{A}_3\right]}_0}{2{\left[ AA\right]}_0+3{\left[{A}_3\right]}_0} $$
The branching coefficient (δ) of a polymer can subsequently be calculated to predict the extent to which a polymer chain will branch and whether or not there is sufficient interaction of the chains in solution to promote gelation, which occurs when the branching coefficient equals 0.50 (Eq. 21).
$$ \delta =\sum \limits_{n=0}^{\infty}\alpha {x}^2\rho {\left[\alpha {x}^2\left(1-\rho \right)\right]}^n=\frac{\alpha {x}^2\rho }{1-\alpha {x}^2\left(1-\rho \right)} $$

The use of branched polymers for the development of hydrogels has been described extensively in the literature for a variety of different polymers such as poly(ethylene glycol), polysaccharides, and polyglycerols, with the latter particularly of interest in biomedical applications due to their derivatizable polyether polyol groups and generally low toxicity in biological applications [52, 53].

The term “hyperbranched” was coined with respect to polymers in the late 1980s by Kim and Webster [54], but the concept was first described in Flory’s work in the 1950s (ABm-random polycondensates). More recent designs have exploited the use of hyperbranched polymers prepared via one-step reactions that have large molecular weights (>1 million g/mol) but relatively broad polydispersities and random overall structures [55, 56, 57]. This typically broad polydispersity can be reduced using a slow addition semi-batch protocol for polymerizing vinylic monomers via controlled polymerization mechanisms [58], anionic ring-opening polymerization schemes for polyglycerols and other step-growth polymers [59], and optimized monomer to initiator ratios [60]. Several types of hyperbranched hydrogels based on poly(ethylene glycol) [61], poly(phosphoramidate) [62], poly(ether amines) [63], and poly(glycerols) [64] have been reported, with various advantages relative to linear polymer-based hydrogels including enhanced uptake of dyes and drugs, increased stiffness and toughness, lower degrees of swelling, and prolonged controlled release.

2.3.2 Dendrimer Hydrogels

Branching strategies can also be used to create dendrimers, polymeric structures containing a single focal point from which “dendrons” grow using sequential grafting/deprotection cycles to create a very highly ordered branched structure. Dendrimers differ from hyperbranched polymers in the sense that internal cyclization is not possible; as a result, well-defined, monodispersed structures can be attained. However, based on the sequential reactions and required protecting group chemistry used to prepare dendrimers, synthesis requires multiple steps and purification schemes that limit the practical use of dendrimers in hydrogel systems. Regardless, a variety of dendrimer hydrogels (DHs) designed by Yang and co-workers using G3.0 and G5.0 polyamidoamine (PAMAM) dendrimers tethered to PEG-acrylate chains of varying sizes [65, 66] have been reported, with the resulting gels exhibiting excellent drug delivery capabilities for ophthalmic applications relative to hydrogels prepared from linear polymer building blocks due to their greater loading capacities [67] and tunable macroscopic properties [68].

2.3.3 Star and Comb Polymer Hydrogels

Star polymers in which there is one single point from which all growing polymer chains originate have been particularly widely used for preparing hydrogels, with the most notable example being star polymers based on poly(ethylene glycol) (PEG). Star-PEG building blocks have been demonstrated to create stronger hydrogels than corresponding linear building blocks of the same molecular weight, including structurally homogeneous hydrogels [69, 70, 71]. Comb/brush polymers in which polymer chains are grown off a polymer backbone are also common, with hydrogels based on poly(oligoethylene glycol methacrylate) (POEGMA) [72, 73] and/or copolymers of POEGMA and poly(oligolactic acid methacrylate) (POLAMA) (the latter of which can exhibit some degree of internal domain formation due to nanoscale phase separation of the hydrophobic POLAMA side chains) being among the most widely studied [74].

2.3.4 Telechelic Polymer Hydrogels

A telechelic polymer is a polymer whose ends are both capped with a particular active moiety which offers some type of property different than the rest of the polymer chain. While most step-growth polymers are inherently telechelic (corresponding to the end group of the monomeric unit that is in excess in the reaction), telechelic chain-growth polymers have recently become of increasing interest, especially with respect to their role in living/controlled radical polymerizations [75]. The active end group may be chemically reactive (facilitating formation of a covalently crosslinked hydrogel [76]) or physically associative (facilitating the formation of an interconnected micelle-type hydrogel [77]). In some cases, the telechelic group can incorporate both a chemically reactive and physically associative component to facilitate dual physical-covalent gelation. For example, Hamley and Castelletto described the insertion of hydrophobic dipeptides (phenylalanine-phenylalanine or tyrosine-tyrosine) to the ends of 1500 Da PEG chains that can promote self-assembled hydrogelation near the body temperature without the need for further crosslinking while still presenting terminal functional groups for additional modification and/or crosslinking [78]. Other self-associative/reactive telechelic polymers such as diisocyanate-extended PEG conjugates end-capped with hydrophobic alcohols and alkyl groups, [79, 80, 81], aldehyde end-capped poly(vinyl alcohol) [82], and methacrylate end-capped poly(hydroxyl ethyl acrylamide)-b-poly-(N,N′-dimethyl acrylamide)-b-poly(dimethylsiloxane)-b-poly-(N,N′-dimethyl acrylamide)-b-poly(hydroxyl ethyl acrylamide) block copolymers [83] have also been described to facilitate multimodal gelation. Reversible telechelic polymer-based hydrogels have additionally been reported that can use the free functional group to induce dynamic changes in hydrogel properties with respect to the surrounding pH [84, 85], self-heal [86], and/or immobilize specific biomolecules [87].

2.4 Crosslinking Chemistry

For any given combination of building blocks discussed in Sects. 2.1, 2.2, and 2.3, the chemistry by which those building blocks are subsequently connected into a hydrogel network has significant impacts on the ultimate properties of the hydrogels formed. Crosslinking strategies can be broadly classified as either chemical or physical. Chemical crosslinks form as a result of hetero- or homo-covalent bond-forming reactions between chains, while physical crosslinks arise from typically more transient interactions arising physical interactions such as ionic/electrostatic, stereocomplexation, supramolecular interactions, hydrophobic interactions, and/or simple chain entanglement [30].

2.4.1 Physical Crosslinking Ionic/Electrostatic Interactions

In ionic crosslinking, two polymers with opposite charges or one polymer and one multivalent ion/small molecule with opposite charges self-associate due to electrostatic attraction. The extent to which ionic association occurs depends on the free energy of the polymer complexation relative to the free energy associated with the original counterion association with the free cationic or anionic polymer(s), a property related to the dielectric constant of the solvent system used. In hydrogels, such polymeric associations are typically highly favorable from an energetic standpoint, as the complexation of two polymer-bound charges releases two highly mobile small counterions to increase the net entropy of the system. Note that while polyelectrolyte hydrogels and charge coacervates are similar in terms of their mechanism of interaction, the capacity of polyelectrolyte hydrogels to retain water within their volume (as opposed to coacervates) is the key differentiating feature.

The most commonly reported ionic crosslinking mechanism involves the complexation of alginate with Ca+2 ions, an interaction that has been studied extensively for the controlled release of pharmaceuticals [88] and the entrapment of living cells [16, 89] given that the crosslinking mechanism is mild and can occur at physiological temperature. The use of higher charge density polycations (i.e., poly(allylamine hydrochloride) (PAH), poly(diallyldimethylammonium chloride) (PDADMAC), or poly-l-lysine (PLL)) and polyanions (i.e., hyaluronic acid (HA), poly(styrene sulfonate) (PSS), and chondroitin sulfate) [90, 91] has also led to the development of unique hydrogel structures using layer-by-layer assemblies of polymersomes [92], capsosomes [93], and polyelectrolyte DNA bridges [94]. Stereocomplexation

Polymers with stereoisomeric chiral centers can interact more strongly than two like stereoisomers due to the relative orientations of the two isomers. A notable example of this phenomenon for hydrogel formation involves the stereocomplexation between poly(d-lactic acid) (PDLA) and poly(l-lactic acid) (PLLA), first described in 1987 by Ikada et al. [95, 96]. When oligomers of d- and l-lactic acid are attached to water-soluble polymers such as dextran or PEG, hydrogels can be formed due to the enhanced van der Waals interactions between the two enantiomeric helices that cause the helices to pack into a dense crystalline stereocomplex [97, 98]. Hydrogen Bonding

Hydrogen bonding between an electron donor and an electron acceptor is widely used for preparing organogels. However, in water (which is also a strongly hydrogen bonding medium), hydrogen bonds used as crosslinks between polymers are highly labile and can be readily disrupted via changes in temperature, pH, or mechanical agitation (e.g., sonication), making hydrogen bonding less useful as a viable crosslinking strategy for hydrogel formation [99]. That being said, there are some examples of polymer solutions in which hydrogen bonding is sufficient to promote gelation, particularly when polymers exhibiting rheological synergism (i.e., polymers whose structures are inherently oriented to promote hydrogen bonding) are selected. As an example, Hoare et al. reported blends of hyaluronic acid (HA) and hydroxypropyl methylcellulose (HPMC) that exhibited highly shear thinning rheological properties but extended gel-like properties relative to either solution alone as a result of complementary hydrogen bonding interactions between the HA and HPMC chains [100]. Hydrogen bonding can also be used to promote hydrogel formation in the context of supramolecular complexation, for example, crosslinking via complementary base pair sequence interactions of single-stranded DNA [28] or peptide self-assembly (in the latter case often in concert with other physical interactions) [101, 102]. Strong hydrogen bond-forming groups can furthermore be grafted to other polymers to promote supramolecular hydrogel formation. For example, ureido-pyrimidinone (crosslinked by urea) [103], benzenetricarboxamides [104], and guanosines [105] can all be used to facilitate hydrogen bond formation in water that results in a much more stable interaction, although one that can still be disrupted by larger shear forces. Host-Guest Interactions

An increasingly popular method of hydrogel crosslinking is the use of inclusion complexes. Cyclodextrins (CD), cyclic oligosaccharides that contain R-1,4-coupled d-glucose units, are the most commonly applied, as the orientation of the cyclic structure results in the outside of the CD unit being hydrophilic and the inside being hydrophobic. As such, hydrophobic molecules [106] or poly(ethylene oxide) or PEO [107, 108] can complex with these hydrophobic internal cavities; if the complexing CD and hydrophobic units are grafted to water-soluble polymer backbones, this interaction results in the formation of crosslinks. The benefits of such supramolecular interactions are that, while the crosslink formed is relatively strong, it can also be disrupted by the addition of a competitive complexing agent (e.g., for CDs, something more hydrophobic or with a size that better matches the internal cavity size of the CD ring such as adamantane groups) [109]. As such, environmentally responsive degradation responses and/or self-healing responses following shearing can be engineered into CD-crosslinked hydrogels. While CDs are the most commonly used complexing agent for this purpose, a variety of other supramolecular complexing agents such as cucurbit[n]uril [110] (which can uniquely bind two separate guest molecules simultaneously and equally within its cavity, allowing for specific tuning of both the strength and directionality of the resulting bond) or silsesquioxane (which has an organic outer shell and a silicone internal core, allowing for assembly via silicone grafts) can also be used. Hydrophobic Interactions

Self-association of hydrophobic moieties in aqueous solution, driven by the maximization of the entropy of water when the contact area between a hydrophobic entity and water is minimized, is one of the most commonly applied strategies for physical hydrogel formation [111]. The hydrophobic group can be incorporated into the hydrogel precursor polymers in several ways, including hydrophobic-hydrophilic block copolymers [112], hydrophobically grafted copolymers [113, 114], or copolymers of hydrophilic and hydrophobic comonomers [115]. Such self-associative polymers are widely used as rheological modifiers for aqueous commercial products [116]. Commonly used hydrophobic grafts include cholesteryl (cholesterol) groups [117], long-chain hydrocarbon alkyl chains [118], or even whole lipids and sphingolipids [119]. Comb or graft copolymers containing hydrophobic blocks, including poly(propylene oxide), poly(lactide-co-glycolic acid), poly(N-isopropylacrylamide), poly(propylene fumarate) (PPF), poly(caprolactone) (PCL), poly(urethane) (PU), and poly(organophosphazene), can also be used as the gelators for hydrophobic self-association [120]; some of these (most notably poly(N-isopropylacrylamide) are hydrophobic only in a temperature-responsive manner to allow for temperature-triggered reversible gelation. Pluronics (poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) copolymers) are the most notable example of such thermogelling systems, with self-association of the poly(propylene oxide) block creating hydrogels that have been applied for a variety of drug delivery and tissue engineering applications [121, 122]; however, a variety of other ABA-type hydrogels in the A block which can be either hydrophilic [123] or hydrophobic [124] have been successfully used to fabricate self-associative polymers. The strength and duration of the self-associated gel can be controlled based on the physical and chemical properties of the hydrophobic segments (e.g., length, degree of hydrophobicity, the presence of any supporting interactions beyond simple hydrophobic interactions) as well as the polymer chains to which the hydrophobes are grafted (molecular weight, hygroscopicity). Crystalline Domain Formation and Freeze-Thawing

The promotion of crystalline domains through freeze-thaw cycles or other physical treatments creates strong intermolecular interactions that can be applied as hydrogel crosslinks. Freeze-thawing using a mixture of dry ice or liquid nitrogen with various organic solvents such as butyl acetate, isopropanol, and acetone is most commonly used, with subsequent lyophilization to sublime the microscale ice lattices resulting in the promotion of intermolecular interactions (most commonly via hydrogen bonding) that can persist upon rehydration due to the lack of solvent accessibility into the crystalline self-assembled domains. The most common example of freeze-thaw-induced gelation, or “cryogelation,” involves poly(vinyl alcohol) (PVA) [125], with the strong hydrogen bond donor/acceptor hydroxyl groups on the polymer side chain promoting crystallization over subsequent freeze-thaw cycles. Effective hydrogels based on other carbohydrates such as xanthan gum [126] have also been reported. Pi-pi Stacking

The interaction of aromatic double bond π orbitals, also known as pi-pi stacking, has been successfully used to create a variety of hydrogels. It should be noted that the terms “pi-stacking” and “pi-pi interactions” are controversial within the scientific community since they do not accurately describe the fundamental phenomena occurring among aromatic groups [127]; furthermore, most systems that promote pi-pi stacking also exhibit other physical interactions such as hydrogen bonding and/or hydrophobic interactions that can enhance the crosslinking achievable with pi-pi stacking alone [128, 129]. However, pi-pi interactions at least strengthen other types of physical interactions. Among the most common pi-pi stacking groups used for hydrogel assembly, N-(fluorenyl-9-methoxycarbonyl) or Fmoc, a typical protecting group used during solid-phase peptide synthesis, forms antiparallel β-sheets with alternating positions of the fluorenyl groups [130] and ultimately interlocks to form a cylindrical structure that forms a hydrogel from functionalized polymers [131, 132] or small molecule hydrogelators [133]. 3-hydroxyflavone (3-HF) fluorophores [134], porphyrins [135], and Fmoc compounds [136] are also effective via a similar mechanism. Metal-Ligand Coordination

Metal-ligand coordination chemistry between specific ligands and a metal ion with a bond order greater than one can also be used to form hydrogels crosslinked by coordinate covalent bonds/dipolar bonds [137, 138]. The most common coordination centers are transition metals such as ruthenium (Ru), zinc (Zn), nickel (Ni), manganese (Mn), platinum (Pt), palladium (Pd), iron (Fe), and cobalt (Co) [139], although any multivalent ion (particularly with an electron-deficient outer shell) can be used. The most common pi-donor ligands include oxide (O−2), nitride (N−3), imide (RN−2), alkoxide (RO), amide (R2N), and fluoride (F), while carbine (alkylidene), amido, alkoxide, imido, carbyne (alkylidyne), oxo, and nitride groups also have the capacity to form metal-ligand multiple bond complexes. One of the earliest examples of such hydrogels was the work of Chujo et al., in which poly(oxazoline) polymer chains functionalized with bipyridine groups underwent coordinate crosslinking with Co(II) [140] and Fe(II) [141]. Similar approaches were used to fabricate coordinative hydrogels with PEG [142], Pluronics [143], and PEG-PLA copolymers [144] containing end-functionalized ligands like terpyridine or bipyridine that can interact with transition metal ions like Mn(II) and Ni(II) to promote gelation. Newer technologies have described the synthesis and fabrication of metallohydrogels containing unique coordination centers such as cobalt [145], copper [146], platinum [147], nickel [148], silver [149], and lead [150]. Composite metallohydrogels using metallic nanoparticles as crosslinking sites have similarly been reported. For example, CdSe quantum dots (QDs) have been encapsulated into cetyltrimethylammonium bromide (CTAB) micelles without the need for any surface modification with ligands to create self-assembled photoluminescent composite metallohydrogels [151].

2.4.2 Chemical

Relative to physical crosslinking approaches that are all at least on some level inherently reversible, chemical crosslinking can offer unique properties in terms of degradability and stability, both in terms of permanence as well as the capacity for rational tuning of gel degradation times. Broadly, chemical crosslinking can be conducted during the synthesis stage (i.e., from monomers) or to link functionalized prepolymers together (i.e., from polymers), both of which are described in the following section. Assembly from Monomer Units

Crosslinking from monomer units requires the addition of a multifunctional monomer into the reaction that can react at two or more sites and thus form bridges between the growing polymer chains. For step-growth polymers, this requires introducing at least one monomer with at least three functional groups that can participate in the step-growth reaction (typically condensation), allowing for the typical growth of a chain via the first two reactive groups and the formation of a crosslink between chains with the third (or higher number) functional group. In such a scenario, gelation will occur at a conversion directly predictable by both the percentage and the degree of functional group content of the crosslinking monomer. Alternately, for chain-growth polymers prepared typically via free radical polymerization, including at minimum a difunctional monomer will induce crosslinking. The production of radicals via the thermal decomposition of peroxides or azo-containing compounds (i.e., azobisisobutyronitrile (AIBN) or dimethyl 2,2′-azobis(2-methylpropionate (AIBME)), radiation (short wave UV at 254 nm, long wave UV at 365 nm, gamma, or electron beam), and/or chemical treatments (i.e., oxidation) will induce polymerization through the vinyl, (meth)acrylate, and/or allylic C=C unsaturated sites in both the monomers and the crosslinkers to result in bulk gel formation. It should be emphasized that the prediction or measurement of crosslinking density as a result of chemical crosslinking from monomers is challenging, as both step-growth and (in particular) chain-growth crosslinking mechanisms can be relatively inefficient due to steric inhibition as a result of network formation. As such, relative to the desired crosslink density, it is common to add slightly more than the theoretically calculated amount of crosslinker to account for unreacted end groups (step-growth) or unpolymerized/terminated chain ends (chain-growth).

Additives can be used to control the properties of the chains produced between the crosslinks even when networking is done simultaneous to polymerization. In step-growth polymers, doping of monofunctional monomers will result in chain ends that can alter the swelling, degradation, mechanical, and chemical properties of the resulting hydrogels [152]. Alternately, in chain-growth polymers, chain transfer agents or controlled radical polymerization initiators/agents [153] can be added during the networking process to control the molecular weight of the polymer chains between crosslinks, yielding the same net effects in addition to (if degradable chemistries are integrated into the crosslinker) promoting the degradability of the resulting network [153]. Accelerators such as tetramethylethylenediamine (TEMED) are commonly also used in chain-growth systems to stabilize the free radicals and thus reduce termination/chain transfer events that compete with polymerization and crosslinking, typically resulting in faster generation of networked structures [154]. Assembly from Prepolymers

Rather than assembling hydrogels through the growth of monomeric units, an alternative approach is to chemically modify prepolymers with reactive functional groups in order to promote chain crosslinking and network reinforcement. While the most common chemistries will be briefly reviewed below, the interested reader is encouraged to consult critical reviews on covalent crosslinking mechanisms for hydrogel production for additional details [30, 155].

Bi- or Multifunctional Small Molecule Crosslinkers

Bifunctional or multifunctional small molecule crosslinkers have been widely explored for crosslinking polymers into hydrogels. While the exact nature of the crosslinker required depends on the chemistry of the chains to be crosslinked, as a representative example, linear starch chains and related polysaccharides have been successfully crosslinked with small molecules such as epichlorohydrin [156, 157], formaldehyde, glutaraldehyde [158, 159, 160], phosphoryl chloride (POCl3) [161, 162], sodium tripolyphosphate (STPP) [163], and sodium trimetaphosphate (STMP) [164, 165, 166], among others. While all of these crosslinkers use unique chemistries, the commonality is their capacity to react with hydroxyl groups on native starch to promote network formation without requiring additional modification of the building block polymers [167]. The interested reader is referred to Hermanson’s excellent Bioconjugate Techniques book for several more examples of commercially available multifunctional small molecule crosslinkers for crosslinking these and other types of hydrogel building blocks [168]. It should be noted that the use of small molecule crosslinkers typically results in residual unreacted crosslinker being entrapped within the hydrogel formed. If purification (e.g., by dialysis) is an option for the application, this is not problematic; however, in other applications (e.g., in vivo injectable hydrogels), such residual chemicals are not typically desirable.

Polymer-Polymer Crosslinking

As an alternative to small molecules, two polymers with complementary functionalities can be crosslinked via an appropriate mechanism.

Free Radical Crosslinking

The most common example of such crosslinking is the UV or thermally induced polymerization of polymers functionalized with methacrylate groups that can undergo free radical crosslinking to create a hydrogel [169]. Methacrylated gelatin (GelMA) has attracted particular interest in this regard in the biomedical literature in terms of its capacity to support cell adhesion and growth for tissue engineering applications, although a range of other methacrylated natural polymers such as hyaluronic acid [170], starch [171], and chitosan [172] has also been demonstrated in the context of both homopolymer gels and blends that can be stabilized by the covalent crosslinking between the chains (i.e., methacrylated chitosan + PNIPAM hydrogels [173]). Relative to the small molecule crosslinkers, this approach typically induces less cytotoxicity, making it more amenable to biological applications. However, such approaches still require UV light or heat as a stimulus to induce gelation.

Functional Group Crosslinking

As an alternative to the use of UV crosslinking, covalent bond-forming reactions between two complementary functional groups on polymers can be used to induce crosslinking. Any type of bond (most commonly esters, amides, urethanes, anhydrides, or ureas in the context of hydrogels) can be formed if the precursor polymers are functionalized with appropriate functional groups for making these bonds [174]. Chemistries that can proceed in water and at or near room temperature are of particular recent interest. For example, carbodiimide-mediated crosslinking between amine (or, with appropriate base activation, hydroxyl groups) [168, 175] and carboxylic acid groups [168, 176] has been extensively used to form hydrogels from polymeric starting materials. However, such reactions typically require either heating, anhydrous conditions, or the use of additives (such as carbodiimides) to lower the activation energies associated with bond formation, which may be problematic in a biological context.

In Situ Gelling Crosslinking

In response, more recently, a range of in situ gelling (or click) chemistries has been intensively investigated for preparing hydrogels under conditions that can be performed at room temperature in water without the need for an external stimulus or additional additives (Fig. 6).
Fig. 6

In situ gelling approach and chemistries

Depending on the chemistry used, both the rate at which gelation occurs and the stability of the resulting bond (and thus the degradation time of the hydrogel network) can be controlled. In addition, the rate of reaction of many of these chemistries makes them amenable to their use as injectable hydrogel formulations, in which low-viscosity precursor polymers can be easily injected and rapidly crosslink (ideally orthogonally to native body chemistry) to form a hydrogel following injection in vivo. Such properties eliminate the need for surgical implantation of hydrogels used in biomedical contexts.

Michael-Type Addition

A Michael-type addition describes the 1,4-addition of a nucleophile (Michael donor) to the β position of an α,β-unsaturated carbonyl group (Michael acceptor). Within the biomedical domain, the most commonly exploited carbonyl containing compounds or Michael acceptors are aldehydes, ketones, acrylates/acryloyls [177], and methacrylates [178, 179, 180], with (meth)acrylates the most commonly applied to produce injectable hydrogels for tissue engineering [181, 182] and drug delivery [183, 184]. Maleimides [185] or vinyl sulfones [186], both of which are better electrophiles and/or better in stabilizing the reactive intermediate than the functional groups listed above, have also been used in contexts where faster gelation is desired. Potential nucleophiles for Michael addition chemistry include halide ions, cyanide ions, thiols, alcohols, and amines, with thiols (-SH) and both primary (-NH2) and secondary (-NHR) amines [187, 188, 189] most commonly used (although halides and cyanides are also highly effective in applications where there is no concern about toxicity of residual reagents) [190]. Thiols are typically preferred over amines for injectable applications since they have a lower pKa (~8) and thus stronger nucleophilicity in mild fabrication conditions [191]. A Michael-type addition crosslinking mechanism can spontaneously occur under physiological conditions to create a nondegradable bond on the time frame of a few minutes to tens of minutes at physiological pH [192]. The addition of slightly basic solutions or the use of phosphine-based catalysts can accelerate the reaction, although at the cost of adding a small molecule [193]. Michael addition chemistry can optionally be combined with other physical gelation strategies in order to reduce the time required for a gel network to be formed. For example, Vermonden’s group demonstrated crosslinking of (meth)acrylate bearing triblock copolymers in which a poly(ethylene glycol) middle block was flanked by thermosensitive blocks of random N-isopropylacrylamide (PNIPAM)/N-(2-hydroxypropyl) methacrylamide dilactate that underwent rapid thermogelation at the body temperature; the Michael-type addition of thiolated hyaluronic acid was then performed to cure the hydrogels to form a structurally stable hydrogel [180].


Disulfide bridges (S-S bonds) are formed in oxidizing environments, including many areas of the body (e.g., endoplasmic reticulum and the extracellular space). Oxygen alone is typically sufficient to drive dithiol-crosslinking [194], although the reaction can be accelerated by adding additional oxidizing agents such as peroxides in order to accelerate the reaction. For instance, Vercruysse and co-workers made hydrogels based on hyaluronic acid (HA) and polyvalent hydrazide crosslinkers using atmospheric oxygen and 0.3% hydrogen peroxide which can gel in 15 min and degrade in the presence of 1,4- dithiothreitol (DTT) [195]. Residual thiol groups left after gelation typically have minimal impact on cytotoxicity and immunological response [196]; however, if such free thiols are problematic in a given application, disulfide exchange reactions can be used to end-cap residual thiols and/or use disulfides themselves as crosslinkers, essentially using disulfides as protecting groups for thiols [197, 198]. Disulfide chemistry generally has relatively long gelation times at physiological pH (tens of minutes to hours), although the combined use of thiol chemistry with a faster gelation chemistry to form a double-network hydrogel [199] can be used to maintain the advantages of disulfides (reversibility, biological compatibility) but maintain injectability.


Imines or Schiff bases (general structure R2C=NR′, where R′ is not H) can be generally described as either secondary ketimines or secondary aldimines, depending on if the connectivity of the molecule is in aldehyde or ketone form. Imines form rapidly between amines and aldehydes/ketones but are typically highly labile in water, allowing for rapid formation but also relatively rapid dilution of the hydrogel network formed. Manipulation of the hydrophobicity of the groups around the imine bond, and thus the accessibility of water to the imine bond for hydrolysis, can be used to at least influence the lifetime of the crosslink formed [200, 201]. Double-network approaches in which the imine chemistry is used as the fast-reacting chemistry can also be successfully applied (e.g., combining imines with disulfides) [199]. Imines can also be reduced via sodium cyanoborohydride addition to yield stable secondary amine linkages if a nondegradable crosslink is desired, although this does constitute an additional reaction step using a biologically incompatible small molecule reagent.


A more stable variety of a Schiff base is a hydrazone bond, formed by the nucleophilic addition of a nitrogen from a hydrazine group or a related derivative to a carbonyl group (typically an aldehyde or ketone). Due to the moderate to high toxicity of hydrazine to biological systems [202], structurally similar hydrazide groups are typically used as the nucleophile for hydrogel fabrication. In comparison to imines, hydrazone bonds form relatively faster (on the timescale of seconds) [40, 203, 204] and yield a more hydrolytically stable bond due to the increased nucleophilicity of the lone-pair-bearing amines through the alpha effect [205], with slow degradation (over weeks to months) observed at neutral pH and faster degradation in acidic conditions [206, 207]. Inductive effects as a result of incorporating aromatic groups on either side of the hydrazone bond can also tune bond degradation [208], in some cases creating functionally nondegradable bonds at neutral pH. While hydrazone-based hydrogels have been extensively and successfully demonstrated for biological applications in the literature [40, 204], the storage stability and potential cross-reactivity of aldehyde groups with native tissues can pose challenges. Replacing aldehydes with ketones slows down the gelation but can also form crosslinks with somewhat slower degradation rates and fully biologically orthogonal chemistry [209].


Oxime bonds can be rapidly formed between an aldehyde or a ketone and a hydroxylamine under physiological conditions. While the oxime bond is also hydrolytically labile, the rate of hydrolysis is significantly less than imines or even hydrazones under physiological conditions [210, 211]. A potential drawback of utilizing this chemistry is that an acid catalyst is typically required in order to yield realistic reaction rates of crosslinking since the adjacent oxygen has electron withdrawing capabilities which affect crosslinking kinetics [210]. Because of these properties, many researchers have applied oxime click chemistry for crosslinking in regions of interest with a lowered pH (<7.4), although titrating the area of injection with an acidic buffering agent either during or following injection can also be effective [212].

[2 + 4] (Diels-Alder) Cycloaddition

The Diels-Alder reaction, in which a conjugated diene reacts with an activated double bond (dienophile) in a single step, is one of the only pericyclic chemistries reported in the literature which has been described in relation to the crosslinking of hydrogels [213]. While the resulting crosslink is widely considered to be nondegradable, retro Diels-Alder reactions have been achieved at higher temperatures (>80 °C) or in alternate solvents to facilitate hydrogel degradation if desired [214]. Maleimide and furan groups are the most common Diels-Alder pair used for hydrogel crosslinking, copolymerization of these functionalities tethered to monomers also possible. Relative to other chemistries discussed, Diels-Alder chemistry is highly specific, and the functional groups involved are relatively unreactive in physiological conditions [215, 216, 217]. However, Diels-Alder chemistry typically offers relatively low gelation times on the timescale of tens of minutes to hours, although the combination of the Diels-Alder reaction with other physical crosslinking mechanisms can be achieved in order to reduce the gelation time if desired [218].

Alkyne-Azide “Click” Reaction

Cycloaddition between an azide and a terminal alkyne to yield a nondegradable triazole linkage (the first reported “click” chemistry) was first described by Huisgen et al. [219] but made more amenable to use for hydrogel crosslinking under physiological conditions following the development of the copper(I)-catalyzed alkyne-azide click (CuAAC) reaction developed by Sharpless’ group in 2003 [220]. Ossipov and co-workers first applied the chemistry for hydrogel crosslinking [221], with functional hydrogels having since been made based on this chemistry using synthetic polymers [222], biopolymers [223, 224, 225], and peptides/proteins [226]. The high selectivity, biorthogonality, and relatively fast gelation kinetics make this a very attractive candidate for in situ forming hydrogels. However, the potential toxicity of any unremoved copper(I) from CuAAC reactions can limit the use of this technique for biomedical applications [223]. Cyclic strained alkynes with lower activation energies (strain-promoted alkyne-azide click reactions or SPAAC) can be used to perform “copper free” cycloadditions, reactions that have been used to prepare hydrogels spontaneously upon mixing functionalized prepolymers without the need for additives [227].

2.5 Length Scale

The physical size of the hydrogel formed represents another key factor determining the properties and thus potential utility of hydrogels in applications.

2.5.1 Bulk Hydrogels

The majority of examples previously cited are bulk hydrogels with macroscopic dimensions (typically defined as >1 cm) and a shape defined either by (1) adding the hydrogel building blocks/crosslinker(s) into a mold with particular dimensions prior to gelation or (2) punching/cutting a sample of a defined size out of a preformed gel. Injectable bulk hydrogels on the bulk scale are typically formed using a double barrel syringe in which the reactive precursor polymers are loaded into separate barrels and then co-extruded into a mold through a mixing baffle to initiate the in situ gelation reaction.

2.5.2 Gel Microparticles

Gel microparticles or microbeads on the tens to hundreds of microns length scale are widely used for separations and cell encapsulation applications. The most commonly fabricated gel microbead is based on the ionic complexation of alginate and calcium (Ca+2), barium (Ba+2), and/or strontium (Sr+2) ions [228], although PEG-DA-based microbeads have also been commonly fabricated via UV photopolymerization [229].

Microbeads may be fabricated in many ways. First, extrusion dipping can be used in which an alginate solution is extruded through a nozzle, allowed to break into droplets under gravitational or mechanical force (e.g., air-induced shear), and dropped into the counterion solution to ionically crosslink [230]. While most commonly used among all methods due to its simplicity, the size of beads attained is commonly greater than 1000 μm without air jetting and >200 μm with air jetting, albeit with a relatively small coefficient of variance (CV) less than 15% [231]. This method is not amenable to use with slower crosslinking chemistries since the aqueous polymer droplet would dissolve in the aqueous receiving media unless crosslinking is very fast. However, methods such as adding an oil layer between the droplets and the bath [232] and/or using a fast crosslinking reaction (like alginate-calcium) to confine a secondary crosslinking reaction within a preformed microbead [233] have enabled the use of this method with slower chemistries. Second, an inverse emulsion in which the alginate (or another polymer or monomer) dissolved in water is the dispersed phase and an organic solvent is the continuous phase can be used to template the size of the microbeads [234]. Depending on the shear applied, particle sizes from the tens of microns scale down to the nanoscale (Sect. 2.5.3) can be achieved; furthermore, given that the resulting droplets are stabilized at least kinetically, slower crosslinking reactions (e.g., Diels-Alder) can be undertaken relative to the extrusion process without destabilizing the droplets. In addition, the confinement of the prepolymers in droplets allows for a variety of bulk polymerization techniques (e.g., photopolymerization or heat-induced free radical initiation) to be used to prepare the networks inside the droplets. However, this method requires organic solvent use and typically results in broad particle size distributions. The use of a microfluidic droplet generator can address the latter problem to significantly reduce the polydispersity of the resulting microbeads, albeit at the cost of fabrication speed [235]. Controlling the relative rates of microfluidic processing versus crosslinking can also lead to the production of non-spherical gels with defined microscale dimensions [236]. High-shear processing of bulk gels has also been used to create gel microparticles [237], a process whose simplicity is tempered by the extremely broad range of particulate shapes/sizes of the microparticle products. Photolithographic methods like particle replication in non-wetting templates (PRINT) [238] and other types of templating techniques can also be used, techniques that trade their high size resolution relative to other techniques for slow production rates.

2.5.3 Microgels and Nanogels

Microgels and nanogels are colloidal hydrogel particles (typically on the length scale <5 μm) consisting of a water-swollen, crosslinked polymer network. The literature is highly ambiguous on the distinction between microgels and nanogels. While the International Union of Pure and Applied Chemistry (IUPAC) defines a nanogel as a particle of gel, of any shape, with an equivalent diameter between 1 nm and 100 nm and a microgel as a gel particle with an equivalent diameter in the range of 100 nm–100 μm, the terms are largely used interchangeably in the broad literature for any colloidally stable gel particle.

A variety of fabrication techniques have been developed to fabricate microgels/nanogels. Inverse emulsion techniques described in Sect. 2.5.2 (but using higher shear to break up smaller droplets) are the most commonly used approach, with gelation inside the droplets stimulated by UV photopolymerization, heat, or the addition of an external crosslinker [239]. Membrane emulsification in which a preformed inverse emulsion is forced through a membrane containing pores of equal sizes can assist in reducing the polydispersity typically achieved with inverse emulsion approaches [240]. For thermoresponsive polymer microgels (e.g., based on poly(N-isopropylacrylamide), poly(oligoethylene glycol methacrylate), or poly(vinyl caprolactam)), a precipitation technique developed by Pelton and co-workers [241] can be used in which the growing polymers in solution aggregate on to growing particle seeds once a critical molecular weight (and thus transition temperature) is reached. This technique typically results in highly monodisperse microgels/nanogels on the hundreds of nanometer size scale. Coacervation techniques in which changes in solvent composition, changes in salt concentration, and/or changes in pH [242] can drive similar aggregative assembly from polymer solutions can also be applied to create micro-/nanogels, albeit typically with somewhat broader polydispersities than achievable with the thermal precipitation method. Ionic complexation of polyelectrolytes or a polyelectrolyte with a multivalent ion [243] or hydrophobically driven self-assembly (e.g., of cholesterol-grafted soluble polymers) [244] performed in dilute solutions under stirring can also in some cases result in micro-/nanogel formation, although again typically with relatively broad particle size distributions. The addition of surfactant to these solution complexation/coacervation preparation techniques can assist in stabilizing the resulting particles and minimizing the resulting particle size distribution [245].

Hydrogels can also be formed in other, non-spherical diameters at the micro- or nanoscales. Chief among those are micro-/nanofibrous hydrogels that can be formed via 3D printing [246, 247, 248] or electrospinning processes [249, 250]. Hydrogel fibers prepared via 3D printing or other additive manufacturing processes can be formed via templated or free-form methodologies. In templated systems, the gel is deposited around a preprinted sacrificial template [251] or printed as a liquid into a sacrificial gel template [252], with template removal resulting in the desired structure. Alternately, free-form printing directly prints a 3D gel structure in a single processing step using one of the four approaches: (a) extrusion of preformed hydrogel tubes [253], (b) printing and simultaneous rapid photocrosslinking of (meth)acrylated prepolymer solutions to convert the liquid-like prepolymer into a gel [248], (c) printing a polyelectrolyte into a counterion solution (e.g., sodium alginate into a calcium ion bath) [247] to facilitate near-instantaneous ionotropic gelation, or (d) extrusion of thermoresponsive gelling pairs (e.g., sodium alginate/gelatin [254]) on a cooled or heated support that induces gelation on contact. It should be noted however that existing printing technologies are limited to printing such features on the microscale, with nanoscale resolution not yet achievable. Electrospinning, in which a potential difference is applied to stretch a polymer solution at the outlet of a nozzle, can be used to access nanoscale fibers, typically by either rapidly (photo)polymerizing a functionalized polymer solution as it is electrospun [255] and/or mixing in situ gelling functionalized precursor polymer solutions just before the nozzle such that they can crosslink prior to contacting the collector (Fig. 7) [249].
Fig. 7

Reactive electrospinning of hydrogel nanofibers by rapid reaction of hydrazide and aldehyde-functionalized precursor polymers during the electrospinning process. (Reproduced with permission from [249])

3 Conclusions

The diversity of functional building blocks, crosslinking strategies, and length scales with which hydrogels can be prepared is key to enabling the diverse applications of hydrogels across multiple fields. In particular, judicious selection of the chemistry of the gel building blocks (i.e., is a natural or synthetic polymer backbone most appropriate, what residual functionality is required in the network) linked with a crosslinking strategy that is most beneficial for the application (i.e., is in situ gelation required, is dynamic crosslinking beneficial, and over what time period – if at all – should the network degrade) is essential to design a hydrogel that works appropriately in a targeted application. Emerging strategies to control both the uniformity and microstructure of hydrogel building blocks (e.g., controlled radical polymerization techniques, telechelic polymers, self-immolative polymers) as well as fabricate hydrogels on well-defined length scales particularly within the nanoscale and microscale size regimes (e.g., microfluidics, 3D printing, electrospinning, and other techniques) are anticipated to further enable the production of hydrogels with novel properties and thus new potential applications.


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemical EngineeringMcMaster UniversityHamiltonCanada

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