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This chapter is an introduction to polymeric gels. The chemical and physical characteristics of this colloidal state of matter are outlined. The specific properties of the different types of gels are briefly reported, and the derived potential applications are displayed at the end of the chapter. The most promising ones are linked to biomedical applications.

Gels are popular: shampoos, beauty creams, shower soaps, tooth pastes, glues or mastics, colorful and tasty desserts… The name “gel” appears on so many different packs of everyday life and general use products! Consumers appreciate their “soft texture”, “transparency” – as synonymous with “pureness” – or “lightness” – contrary to calorie-rich food – the exceptional adhesive properties of “instantaneous glues” in technical applications… So many enjoyable qualities are, under the general perception, attributed to gels! Besides, smart gels have applications in drug delivery, tissue engineering, actuators and detectors… They are better known by specialists.

This chapter aims to introduce the different types of polymeric gels, types of macromolecules, gelation mechanisms, and gel properties and explain some innovations making use of gels.

The chapter is composed of four parts: an introduction (Section 1.1) with a brief history of the word “gel” and the criteria of the definition. Section 1.2 is a classification of different types of structures, polymers and mechanisms associated with gels. Section 1.3 reports on the remarkable properties of gels and finally in Section 1.4 some innovative applications are introduced. We conclude with perspectives.

The first definition of this colloidal state of matter goes back to Thomas Graham, a British chemist, in the Philosophical Transactions of the Royal Society in 1861.1  Graham included in the category of colloidal substances (from the Greek κoλλα: glue) starch, gelatin, albumen, gum, supersaturated solutions of inorganic particles or clay dispersions… because he recognized that these were slowly diffusing substances. The molecular structure of these substances was not yet identified.

Only much later, in 1920, Hermann Staudinger,2  a German organic chemist, demonstrated the existence of “macromolecules”, which he characterized as “polymers”. For this work, he received the Nobel Prize in Chemistry in 1953. He demonstrated that rubber and other polymers such as starch, cellulose and proteins are long chains of short repeating molecular units, linked by covalent bonds, contrary to colloidal dispersions of small molecules associated with physical interactions.

A more formal classification of the gel state was noted in 1949 by P. H. Hermans3  but still stresses the traditional colloidal viewpoint. According to Herman's definition, gels should be coherent two component systems formed by solid substances finely dispersed or dissolved in a solvent, they should exhibit solid-like behaviour and the dispersed component and the solvent form bi-continuous paths.

Much later, Paul John Flory, an American chemist, the leading pioneer in understanding the physical chemistry of macromolecules, Nobel Prize in Chemistry in 1974, proposed a more detailed classification of polymeric gels.4  He set apart four different types of structures:

  1. Well-ordered lamellar structures, including gel mesophases.

  2. Covalent polymeric networks, completely disordered.

  3. Polymer networks formed through physical aggregation, predominantly disordered, but with regions of local order.

  4. Particulate aggregated structures.

This classification still includes a large choice of molecules. This is why studying gels has been, from the beginning, a highly multidisciplinary activity.

As said, initially, gels were an aspect of colloid science since aggregation and association of small particles can lead to physical, colloidal networks. After the recognition of polymers, gels became part of the new polymer science and found uninterrupted development based on organic synthesis and physical characterization. As stated in Flory's definition, two types of interactions can generate the gel network: covalent bonds between polymers and physical aggregation between polymers or small particles.

Studying gels requires a large number of techniques. Investigations of the mechanical properties require nondisrupting techniques for soft materials, understanding thermodynamics (solubility, partial crystallization, phase separation, glass transition, conformational changes…) is fundamental, spectroscopic and other characterization techniques must be used to measure both static and dynamic characteristics of networks, imaging techniques at variable scales have been worked out, and statistical physics and mathematical models allow modelling the connectivity of networks. Above all, an increasing number of gels have found new applications in many different areas and required specific investigations of their functional properties: gels used for drug delivery, for tissue engineering, as sensors and actuators, etc. The present book illustrates some of the latest developments in various domains where gels are currently used with an emphasis on the nuclear magnetic resonance (NMR) properties and application in magnetic resonance imaging (MRI).

Firstly, we propose a simple classification of polymer gels according to the mechanisms of network formation or crosslinking: chemical gels, physical gels and other types of complex networks.

Gels are nowadays considered a distinct category of the soft matter classification. From Wikipedia (https://en.wikipedia.org/wiki/Soft matter): “Soft matter or soft condensed matter is a subfield of condensed matter comprising a variety of physical systems that are deformed or structurally altered by thermal or mechanical stress of the magnitude of thermal fluctuations. They include liquids, colloids, polymers, foams, gels, granular materials, liquid crystals, and a number of biological materials. These materials share an important common feature in that predominant physical behaviors occur at an energy scale comparable with room temperature thermal energy. At these temperatures, quantum aspects are generally unimportant. Pierre-Gilles de Gennes, who has been called the “founding father of soft matter,” received the Nobel Prize in physics in 1991 for discovering that methods developed for studying order phenomena in simple systems can be generalized to the more complex cases found in soft matter, in particular, to the behaviors of liquid crystals and polymers.Materials termed soft matter exhibit this property due to a shared propensity of these materials to self-organize into mesoscopic physical structures”.

In this chapter, we present some of the properties listed in the definition of “soft matter” that highlight remarkable features attributed to gels: self-organization, mesoscale structure, entropic elasticity and order phenomena … all of them being controlled by thermal energy around room temperature.

Networks connecting the polymers throughout the solvent develop various local arrangements which are directly related to the mechanisms of gel formation. Networks have permanent (chemical) crosslinks, non-permanent (labile or reversible) crosslinks and both types of crosslinks in “hydrogels”. Water is the solvent in many cases, although not exclusively. We review briefly in this section different types of crosslinks.

Chemical gels are irreversibly crosslinked networks. Crosslinking may occur through polymerization of monomers having functionalities of more than two (by condensation) or by covalent bonding between polymeric chains by irradiation, by sulphur vulcanization in rubbers or reactions by adding different chemicals.5 

One of the most important classes of chemical gels derives from acrylamide polymerization. Poly(acrylamide) (PAm) is used in various fields of engineering and technology as a flocculant for separation and clarification of liquid–solid phases, as a thickening agent and in film formation. Specifically, it has been used extensively in the analytical biochemistry field, in particular for electrophoresis (the PAGE technique is PolyAcrylamide Gel Electrophoresis) and macromolecular separation.

Polymerization of acrylamide monomers is performed by free radical chain reactions.6  The method generates free radicals under mild conditions by one-electron transfer reactions, the most effective of which is redox initiation. Free-radical polymerizations must be conducted with the exclusion of oxygen (in a vacuum or by deaerating with an inert gas). The polymerization proceeds by way of a chain reaction using tetramethyl ethylene diamine (TEMED). The first step is the activation of TEMED by ammonium persulfate (NH4)2(SO4)2, which leaves the TEMED molecule with a reactive unpaired electron. TEMED acts as an electron carrier providing an unpaired electron and converting the acrylamide monomer to a free radical state. The activated monomer in turn reacts with an unactivated monomer and the chain begins to grow; the active site shifts to the free end. Bis-acrylamide (BIS), which consists of two acrylamide units joined through their –CONH2 groups, generates the crosslinks of the networks. Solutions containing acrylamide monomers and BIS are able to form permanent networks. BIS can be incorporated into two growing chains; when the ratio of BIS monomers/acrylamide monomers is approximately 2% and the concentration of acrylamide is around 5% g cm−3, a gel is formed. Adding more of the crosslinker gives a topologically complex configuration, with loops, branches and interconnections. An example of the free radical polymerization reaction with BIS is illustrated in Figure 1.1.

Figure 1.1

Poly(acrylamide) (PAm) gel synthesis: (a) the molecules in solution and the mechanisms of free radical chain reaction; and (b) topology of the polymer network showing the BIS crosslinks and the growing chains. Adapted from ref. 7 with permission from Scientific American, a division of Springer Nature America, Inc.

Figure 1.1

Poly(acrylamide) (PAm) gel synthesis: (a) the molecules in solution and the mechanisms of free radical chain reaction; and (b) topology of the polymer network showing the BIS crosslinks and the growing chains. Adapted from ref. 7 with permission from Scientific American, a division of Springer Nature America, Inc.

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Radiation is a tool used to modify polymers without any chemical reagent and can be used to generate permanent networks. The effects of ionizing radiation on macromolecules in solution have been reported since the early sixties.8  By irradiation, polymers in solution may undergo changes similar to those observed in the solid state: degradation of the main chain, decomposition of side groups, and intramolecular or intermolecular crosslinking. The mechanisms responsible for these changes are complex and may result from direct or indirect action of radiation, or from both. Viscosity measurements are used to reveal these changes: degradation of the main chain causes a decrease in the reduced viscosity (viscosity of solution/viscosity of solvent), whereas the formation of intermolecular crosslinks increases the viscosity. It is shown in many cases that the viscosity at first decreases because of the greater influence of the degradation at small doses and at much higher doses the viscosity increases again and a continuous network may build up. When degradation of the main chain and intermolecular crosslinking occur simultaneously, there is a critical value of the ratio Rcrit of the degradation rate/crosslinking rate, above which no continuous network can build up. The ratio R depends on the nature of the solvent and the concentration of the polymer. In the case R> Rcrit one observes formation of branched macromolecules and microgels, together with linear fragments of different chain lengths. The interpretation of the viscosity data must be handled with caution in this case.

The general mechanisms of crosslinking in solution follow a well-known path:9 

The primary reactions occurring in the irradiation of a polymer in solution are the excitation and dissociation of both the polymer P and the solvent S by direct action of radiation:

P* and S* being electronically excited or ionized molecules. Dissociation in the main chain of P leads to free “main chain” macro radicals, while decomposition of a side group yields a free “side group” macro radical and a free radical of low molecular weight. In the case when energy is transferred from the polymer to the solvent the polymer is protected. Energy transfer in the opposite direction results in sensitization of the decomposition of the polymer. Sensitization also occurs when free radicals resulting from the radiolysis of the solvent attack the polymer, for instance by hydrogen abstraction. This process will enhance the formation of free side group macro radicals. The solution becomes strongly turbid during irradiation. The turbidity is explained by the formation of microgels. Water is expected to be the most effective solvent for network formation for a dissolved polymer. Highly reactive H-atoms and OH-radicals form easily and abstract hydrogen atoms from the polymer. In aqueous solutions, therefore, free side group macro radicals will be formed by indirect action at a high yield. Extremely fast crosslinking then occurs in aqueous solutions.

Another attribute of radiation, as an alternative mode for activating chemical reactions, is the immediacy and the control of the spatial distribution for generating active centres. However, small changes in the composition of water, changes in pH or the presence of dissolved oxygen, can significantly affect the radiation effects. To avoid the influence of O2, solutions must be purged with inert gas such as N2 or Ar.

Some examples of radiation-induced crosslinking and degradation of gels are shown below. Another example can be found in Section 1.4.

Matusiak et al.10  report on radiation synthesis and characterization of poly(acrylic acid) (PAA) nanogels and microgels using a γ-source (60Co) and short pulses of fast electrons. These methods are an interesting way of synthesizing polymeric carriers for biomedical applications. Starting from dilute aqueous solutions of PAA with a molecular weight Mw=4.5 105 Da, under suitable conditions (dose 0–5 kGy) the intramolecular recombination leads to the formation of nanogels and microgels. Adjusting the PAA concentration and the absorbed doses, the authors were able to control the molecular weight and dimensions of the nanogels.

Figure 1.2 shows the influence of the absorbed dose on the radius of gyration of nanogel particles. The authors conclude that under continuous irradiation at low dose rates, intermolecular recombination is the dominant reaction and results in the formation of nanogels or in macroscopic gelation, depending on the polymer concentration.

Figure 1.2

Radius of gyration Rg of PAA as a function of absorbed dose of 60Co gamma rays (dose rate 0.55 kGy h−1, in the range 0–5 kGy) for various concentrations (in mM) in Ar-saturated aqueous solutions at pH 2; Rg values determined at 25 °C in aqueous solution at pH 10. Reproduced from ref. 10 with permission from Elsevier, Copyright 2017.

Figure 1.2

Radius of gyration Rg of PAA as a function of absorbed dose of 60Co gamma rays (dose rate 0.55 kGy h−1, in the range 0–5 kGy) for various concentrations (in mM) in Ar-saturated aqueous solutions at pH 2; Rg values determined at 25 °C in aqueous solution at pH 10. Reproduced from ref. 10 with permission from Elsevier, Copyright 2017.

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On the contrary, Aliste et al.11  examined radiation effects on agar, alginate and carrageenan in powder (solid-state irradiation) within a dose range of 0–10 kGy and at a high dose rate of 8.4 kGy h−1. Agar is used mainly as a gelling agent in confectionery to prepare jellies, marshmallows and candies and also in special diet food. Alginates are thickening or gelling agents. Carrageenans are used for emulsion stabilization, in particular in dairy applications. Irradiation is viewed as being an effective after packaging process able to control pathogenic and spoilage organisms. The authors investigated the effects of 60Co ionizing radiation on the rheological behaviour of agar, alginate and carrageenan dissolved in aqueous solutions, after being irradiated in the solid state.

The experiments reveal, as shown in Figure 1.3 for agar solutions, a continuous decrease of viscosity with increasing absorbed doses below 10 kGy for all the polysaccharides investigated. The authors conclude that irradiation of the polysaccharide in powders induces degradation with the breakage of glycoside bonds.

Figure 1.3

Viscosity of agar solutions vs. radiation dose, at a dose rate of 8.4 kGy h−1, at 45 °C, at a concentration of 1%. Adapted from ref. 11 with permission from Elsevier, Copyright 2000.

Figure 1.3

Viscosity of agar solutions vs. radiation dose, at a dose rate of 8.4 kGy h−1, at 45 °C, at a concentration of 1%. Adapted from ref. 11 with permission from Elsevier, Copyright 2000.

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Vieira and Del Mastro12  investigated the effects of γ-radiation from a 60Co source on bovine powder gelatin at dose rates of 7 kGy h−1 for doses up to 50 kGy. The radiation effects were evaluated by following the viscosity of aqueous solutions at 40 °C; the authors also observed a decrease in viscosity, meaning degradation of the protein chains, similar to Aliste et al.11 

In totally different conditions, Cataldo et al.13  and Bessho et al.14  observed radiation-induced crosslinking of gelatin solutions and formation of a stable hydrogel. A series of samples with 3 wt% gelatin solution in water were irradiated at doses between 12 and 200 kGy, much higher than in the examples reported by Vieira and Del Mastro,12  at room temperature in the absence of air, with a dose rate of 2.2 kGy h−1. At radiation doses below 25 kGy, a gel is formed with poor mechanical properties and which tends to break easily. Above 25 kGy the hydrogel starts to shrink and to release water due to the increase of the crosslinking density. The results are shown in Figure 1.4. At 50 kGy and at higher doses the hydrogel is shrunken with a significant fraction of released water (about 40%). The fraction of released water increases gradually with the amount of radiation dose administered, reaching a value around 80% at 150–200 kGy. Above 50 kGy the gel becomes opaque. It is assumed that the crosslink formation derives from three main reactions: formation of disulphide bonds coming from thiol oxidation, tyrosine dimerization and phenylalanine dimerization. These reactions are due to formation and action of OH radicals in water, when oxygen is absent as explained in Section 1.2.1.2. FTIR spectroscopy shows that gelatin undergoes only minor structural changes even at 200 kGy.

Figure 1.4

Mass fraction of a gelatin hydrogel at an initial gelatin concentration of 3 wt%, at different radiation doses: above 25 kGy the gel shrinks and releases water due to the increased crosslinking density. At 200 kGy the gel mass is only 20% of the initial mass. Adapted from ref. 13 with permission from Springer Nature, Copyright 2008.

Figure 1.4

Mass fraction of a gelatin hydrogel at an initial gelatin concentration of 3 wt%, at different radiation doses: above 25 kGy the gel shrinks and releases water due to the increased crosslinking density. At 200 kGy the gel mass is only 20% of the initial mass. Adapted from ref. 13 with permission from Springer Nature, Copyright 2008.

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From these examples we may conclude that ionizing radiation produces a whole range of chemical modifications which depend on the molecule (protein, polysaccharide, synthetic polymer), on the dose (0–200 kGy), on the dose rate and on the environment (solvent, water, polymer concentration). Irradiation is performed in the absence of oxygen, either in the solid state of the polymer or in solution.

Other methods to generate permanent networks are photopolymerization,15  use of chemical crosslinkers in polymer solutions (for instance glutaraldehyde or a bis-epoxide) or use of multi-functional reactive compounds. Examples are shown in Section 1.2.3 with hydrogels. The type and degree of crosslinking influence many of the network properties, like the swelling properties, elastic modulus and transport of molecules, which are presented in Section 1.3.

A large number of mechanisms give rise to the formation of physical, non-permanent gels from synthetic to biological polymers.16  Thermoreversible gels show great sensitivity to the molecular environment, solvent, thermal history, etc. Physical networks are considered as metastable states and their properties are almost always time dependent. Some gels are heat set (due to the so-called hydrophobic effect) and others are cold set (due to conformation changes of the biopolymers) or to local crystallization. One can classify them in the following list.

Conformational changes from coils to multiple helices concern biopolymers like gelatin and polysaccharides. For gelatin, triple helices, reminiscent of native collagen structure, induce gelation;17  the double helices in agarose18–25  create the network by forming bundles, and the aggregation of carrageenan helices26–32  or the formation of an “egg box” structure in alginates33–37  by complexation with Ca++ ions are other examples of the mechanisms of gelation for polysaccharides. Gelatin and agarose form gels by lowering the temperature; carrageenan and alginate gelation require temperature changes and specific ionic environments.

Gelatin is denatured collagen, the most abundant protein in mammalians. Gelatin gels are used in a large number of applications; some are the traditional ones, as a normal ingredient of food preparation, and others are innovative applications, which will be highlighted in this chapter. Gelatin chains dissolved in water at temperatures around 50 °C are random coils. When gelatin solutions are cooled below room temperature, the protein undergoes a coil to triple-helix transition, and a polymer network begins to grow and form a gel when the concentration is above approximately 5 wt%. The helices are reminiscent of the triple helical native structure of tropocollagen, stabilized by hydrogen bonds. They are randomly oriented and do not further assemble within higher organization levels as in the native collagen fibres. The polypeptide chains only partly recover their native conformation and no equilibrium is reached even after many days (practically, 50% of the amino acids can be converted into a helical conformation). The gel is a metastable state and evolves with time at a fixed temperature; the elastic modulus increases. Gelation is thermoreversible: the gels melt when the temperature is raised back to the dissolution temperature.

Agarose is a linear polysaccharide which can be extracted by treating agarophyte red algae with an alkali. It consists mainly of repeated sequences of the two residues β-1,3 linked d-galactose and α-1,4 linked 3,6-anhydro-αl-galactose. Agarose is widely employed as a medium for microbial growth. At low temperatures a double helix structure is found from X-ray analysis. Each chain in the double helix forms a left handed 3-fold helix. However, the agarose network is described as arising both from double helix formation and the subsequent aggregation of these helices into bundles. The appearance of the gel is slightly turbid, because of the light scattered from aggregated helical regions. Figure 1.5 shows schematically the structures of gelatin and agarose gels.

Figure 1.5

Schematic networks in fibrillar gels: (a) collagen type triple helices and random coils in gelatin gels, and (b) bundles of double helices in agarose gels.

Figure 1.5

Schematic networks in fibrillar gels: (a) collagen type triple helices and random coils in gelatin gels, and (b) bundles of double helices in agarose gels.

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Particulate and fibrillar systems are formed from proteins in aqueous (or electrolyte) solution that were partly denatured by physical or chemical treatments. In heat-induced denaturation, the protein size and shape are only mildly perturbed; some of the hydrophobic groups, which at ambient temperatures are buried in the protein core, become exposed by unfolding or at the denaturation temperature. This “hydrophobic effect” leads to aggregation to form either fine stranded networks or branched particulate structures of the physical gel. Under mild denaturing conditions a protein denatures via various intermediates and then partially renatures in a slightly different manner to create non-covalent interactions between different proteins, and this leads to gelation. Most investigations deal with serum albumen (particularly from bovine sources, BSA38,39 ) or milk protein β-lactoglobulin, β-Lg.40  Typically between 60 and 80 °C denaturation takes place and leads to the formation of inter-protein β-sheets, giving rise to a polymeric network. In this case the “strands” of the network are typically a few protein diameters wide, around 5–10 nm, so these differ from those of gelatin, typically 1 nm in width (triple helix).

Particulate networks are observed also in the casein networks formed in milk clotting or cheese making. Such aggregation is usually irreversible but shares some characteristics with the phase separation of model colloidal systems with attractive particles.41,42 

Flocculation of casein micelles and subsequent gel formation can be induced either at neutral pH and temperatures above 20 °C by the addition of a proteolytic enzyme (rennet) which acts specifically to cleave off the glycomacropeptides (κ-casein) or by lowering the pH. After acidification of a milk dispersion to the isoelectric pH of the casein particles, a physically stable suspension of casein particles is produced at low temperatures. Gelation results from the aggregation of the casein particles at temperatures above 10 °C, but these particles have a complex structure due to the association of numerous different molecules.43 

Figure 1.6 shows schematically the different stages leading to formation of the network of casein particles.

Figure 1.6

Different steps in enzymatic coagulation of milk: (a) casein micelles and enzymes in solution, (b) proteoloysis of κ-casein, and (c) aggregation of the casein particles into clusters and release of κ-casein.

Figure 1.6

Different steps in enzymatic coagulation of milk: (a) casein micelles and enzymes in solution, (b) proteoloysis of κ-casein, and (c) aggregation of the casein particles into clusters and release of κ-casein.

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The hydrophobic effect concerns also amphiphilic synthetic polymers. The insertion of hydrophobic functional groups into a water soluble (hydrophilic) polymer induces self-association of the co-polymers in micelle-like domains when the temperature is raised. Solutions with amphiphilic polymers (such as polysaccharide derivatives with alkyl side chains, random block copolymers and hydrophobically modified polyelectrolytes) have remarkable rheological properties and are used as thickeners in cosmetic, pharmaceutical or detergent formulations. Networks with labile junctions exhibit shear thinning properties; the junctions are disrupted and re-associate spontaneously under shear.

Triblock linear copolymers poly(ethylene oxide)n–poly(propylene oxide)m–poly(ethylene oxide)m (PEOn–PPOm–PEOn), often called Pluronics® (BASF) or poloxamers, have numerous industrial applications as detergents, dispersants, stabilizers, foaming agents, or emulsifiers. Variable lengths of the PEO and PPO sequences are available. Pluronics behave as non-ionic surfactants and aggregate into micelles above a certain temperature, called the critical micellization temperature, which depends on the composition and concentration of the copolymer. The rupture of hydrogen bonds of PPO during heating increases the hydrophobicity, while the PEO chains remain hydrophilic.44  The whole sequence under heating PEOn–PPOm–PEOn solutions with n=98 and m=67, concentration 20 wt%, is shown in Figure 1.7. Starting at low temperature and measuring by micro differential scanning calorimetry (µDSC) and rheology the scenario is the following:

  • Step 1: between T=5 °C and T=14 °C, when the temperature increases, the viscosity of the solution decreases; the dehydration of PPO in solution is observed by infrared spectroscopy.

  • Step 2: between T=14 °C and T=23 °C, the solution remains a Newtonian fluid, and micelles are formed progressively, which is clearly measured by an important endothermic peak; the loss modulus G′′ increases.

  • Step 3: at the end of this period, all the copolymer molecules have undergone progressive association into spherical micelles.

  • Step 4: a stable gel is formed suddenly, which coincides with the temperature of the secondary endothermic peak. At this temperature, micelles form a crystalline structure after their total volume reaches the maximum volume fraction for random packing of spheres (around 63%). The storage G′ and loss modulus G′′ simultaneously increase at T=23 °C. A high storage modulus is reached G′≈20 kPa in the gel above room temperature. The solutions are solid-like materials at body temperature (36 °C), which is an interesting property for biomedical applications.

Figure 1.7

Gelation of poloxamer PEO98–PPO67–PEO98 in solution at concentration 20 wt%. The different steps correspond to increasing temperatures from 5 °C to room temperature.

Figure 1.7

Gelation of poloxamer PEO98–PPO67–PEO98 in solution at concentration 20 wt%. The different steps correspond to increasing temperatures from 5 °C to room temperature.

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Physical crosslinks can be also created when polymer solutions undergo a phase transformation under specific circumstances:

  • ■ When phase transformation is incomplete: for instance, when a crystalline polymer fraction coexists with an amorphous part, the solution may exhibit gel-like properties.

  • ■ When phase separation takes place in polymer solutions which exhibit an upper critical solution temperature UCST below the critical temperature. Alternatively, solutions which exhibit a lower critical solution temperature (LCST), heated above their critical temperature.

  • ■ In solutions containing a polymeric mixture: generally, solutions tend to phase separate immediately after mixing. At its final stage, liquid–liquid phase separation generates two fluid layers.

In order to obtain a gel, the final stages of the phase separations are not reached and, instead, they are arrested at a certain point where the network is formed. Many synthetic polymers and mixtures of biopolymers exhibit such behaviours.

A typical example is shown below with a solution of polystyrene PS (atactic PS) in trans-decalin (TD).45  The solutions exhibit a UCST with a critical temperature T=15 °C. The phase diagram is shown in Figure 1.8, top: lines A, B and C correspond to three different concentrations. In Figure 1.8, bottom, scanning electron microscopy (SEM) images show the structures observed after cooling at −40 °C. Cooling solution A into the binodal region results in the formation of spherical particles; the solutions are turbid, and the particles eventually sediment in the tube after some time. Solution B, being at the critical polymer concentration (6 wt%) phase, separates through a spinodal mechanism. In this case the typical spinodal morphology is observed, which consists of two continuous interconnected phases creating a network, with pores of about 1 µm. The network of interconnected phases no longer deposits in the tube.

Figure 1.8

Phase separation of a polymer solution in organic solvent (aPS-TD). Top: the phase diagram showing the binodal and the spinodal curves near the critical point. Three experiments of quenching solutions from above the critical point to below the spinodal: (A) c=4.4 wt%; (B) c=6.7 wt%; and (C) c=16 wt%. Bottom, from left to right: SEM images for the A, B and C samples. The white bar is 1 µm for A and B and 10 µm for C. Reproduced from ref. 45 with permission from John Wiley and Sons, Copyright © 1993 Hüthig & Wepf Verlag, Basel.

Figure 1.8

Phase separation of a polymer solution in organic solvent (aPS-TD). Top: the phase diagram showing the binodal and the spinodal curves near the critical point. Three experiments of quenching solutions from above the critical point to below the spinodal: (A) c=4.4 wt%; (B) c=6.7 wt%; and (C) c=16 wt%. Bottom, from left to right: SEM images for the A, B and C samples. The white bar is 1 µm for A and B and 10 µm for C. Reproduced from ref. 45 with permission from John Wiley and Sons, Copyright © 1993 Hüthig & Wepf Verlag, Basel.

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In case C with c=16 wt% cooling is performed in two steps: first, the solution is cooled into the binodal region (C1) and kept overnight. Under these conditions, the concentrated phase forms a continuous matrix. In a second step, the solution is quenched under the spinodal (C2). The SEM image (C3) taken after freezing at −40 °C shows a complex, porous material, with pore sizes around 10 µm.

Phase separation occurs in single polymer solutions or binary polymer solutions when the solvent becomes poor, for instance by lowering the temperature or by using selected mixed solvents. Generally, liquid–liquid phase separation is inhibited by the high viscosity or visco-elasticity of the mixtures. Moreover, either glass transition or crystallization of the polymers may interfere with the phase separation.16  These frustrated phase separations are also metastable. Freeze thawing procedures can also be used to control the microstructure of the networks, as reported in Section 1.4.

Most of the “hydrogels” used in biomedical applications are both chemically and physically crosslinked. They can be prepared from natural, synthetic or synthetic/natural polymer mixtures in aqueous solutions. Some examples are shown in the following sections.

Introducing covalent crosslinks between gelatin chains aims to “fix” the network. Different approaches can be used: incorporation of using bifunctional reagents such as glutaraldehyde (GTA) and diisocyanates, carbodiimides and polyepoxy compounds.46  GTA is the most widely used agent, known for its efficiency of stabilization of collagen-based biomaterials in spite of its cytotoxicity. Crosslinking of collagenous samples with GTA involves the reaction of lysine or hydroxylysine residues with the aldehyde groups of GTA. GTA is easily available and inexpensive and its aqueous solutions can effectively crosslink collagenous tissues in a relatively short period. Released after biodegradation, GTA is however toxic. A crosslinking agent able to form stable and biocompatible crosslinked products without cytotoxicity problems is genipin, which can be obtained from gardenia fruits. It has been used in the fabrication of food dyes or gelatin capsules.46 

An alternative way of crosslinking gelatin is by using an enzyme, transglutaminase (TGase), which catalyzes intra- and intermolecular crosslinking between lysine and glutamine residues of peptides or proteins.47,48  Naturally, TGase forms extensively crosslinked, insoluble protein macromolecules which are vital for an organism to create barriers and stable structures in physiological processes such as haemostasis and wound healing.

An extensive investigation of the rheological and structural properties of gelatin hydrogels crosslinked with a bifunctional reactant bis(vinylsulfonyl)methane (BVSM) has been published: the vinyl double bonds of the BVSM link to the amine groups of the protein to form a covalent network.49,50  These investigations aimed to elucidate the behaviour of crosslinked chemical gels in hot solutions, in the absence of triple helices (sol state) and in the physical gel state (low temperature). The rheological results are discussed in Section 1.3.2.3. It was shown that crosslinking of the physical gels by BVSM proceeds preferentially on sites located along the triple helices, rather than along the amorphous coils. Figure 1.9 shows schematically the structures that are preferentially formed in hydrogels with identical concentrations of gelatin and BVSM but following different protocols.

Figure 1.9

Gelatin hydrogels (crosslinker BVSM): (a) hydrogel at room temperature where crosslinking was performed in the sol state, anterior to physical gelation (triple helices); (b) hydrogel at room temperature where crosslinking with BVSM was posterior to physical gel formation; (c) hydrogel crosslinked with BVSM after physical gelation, heated back to 40 °C. The shear moduli of the first two hydrogels are different, although they correspond to identical gelatin and BVSM concentrations; in (c) the hydrogel has a higher modulus than when it was crosslinked directly in the sol state (40 °C). Reproduced from ref. 49 with permission from American Chemical Society, Copyright 2006.

Figure 1.9

Gelatin hydrogels (crosslinker BVSM): (a) hydrogel at room temperature where crosslinking was performed in the sol state, anterior to physical gelation (triple helices); (b) hydrogel at room temperature where crosslinking with BVSM was posterior to physical gel formation; (c) hydrogel crosslinked with BVSM after physical gelation, heated back to 40 °C. The shear moduli of the first two hydrogels are different, although they correspond to identical gelatin and BVSM concentrations; in (c) the hydrogel has a higher modulus than when it was crosslinked directly in the sol state (40 °C). Reproduced from ref. 49 with permission from American Chemical Society, Copyright 2006.

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It is expected that the behaviour observed in gelatin hydrogels crosslinked with BVSM reveals a general mechanism where the physical and chemical crosslinks compete for access to the nucleation sites of the triple helices and/or reactive amino acids.

Poly(acrylamide) – PAm – polymers are hydrophilic (Section 1.2.1.1), but substituting the acrylamide monomer for a more hydrophobic one, like for instance N-isopropylacrylamide (NIPAm), results in new materials exhibiting interesting properties due to their hydrophobic effect. Pure gels with poly(NIPAm) are sufficiently hydrophobic that they tend to phase separate on heating: the aqueous solutions possess lower critical solution temperature (LCST) behaviour. At low temperature, the hydrogen bonding between the polymer polar groups and water molecules leads to dissolution of the polymer, whereas above the LCST dehydration of the hydrophobic groups induces the collapse of the chains and partial aggregation in more concentrated solutions. Chemical crosslinks (such as by BIS monomers) are able to stabilize the interconnections between polymers in solution. The crosslinked gels can swell or shrink reversibly with the temperature according to their LCST. A list of different synthetic or natural polymers which exhibit a LCST is proposed by Jeong et al.,51  including poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), methyl cellulose (MC) and others.

Thermoreversible heat set hydrogels are widely investigated for drug delivery applications52  and tissue engineering because their LCST can be controlled by copolymerization with monomers with different hydrophobicity. Such hydrogels have adjustable swelling and deswelling properties versus temperature, which may be adapted to body temperature.

Polyelectrolyte complexes (PECs) involve mixtures of two polymeric components, one of which is positively charged (cationic) and the other negatively charged (anionic). When two polymers are oppositely charged, it is favourable for the two species to “neutralize” so that the two macromolecules are bound together by electrostatic interactions. This property may be used to prepare small complexes or multi-layered structures, “fixed” by adding covalent interactions.

Among positively charged polymers, chitosan is of major interest for many biomedical applications. The most commonly used anionic polymers include alginates, pectins, xanthans or proteins, such as collagen or gelatin, or synthetic polymers, such as PAA; even DNA has also been investigated.53 

Hydrogels prepared in view of biomedical applications should have tailored and reproducible chemical (pH sensitivity, ionic composition, etc.) and physical (swelling and mechanical) properties, besides good biocompatibility (biodegradation and immune response).54  These networks can be modified with the incorporation of biofunctions, and their transport properties (for drug delivery) can be adjusted through the polymer chain lengths and crosslinking density.

In summary, this section provides an overview of the numerous molecular compositions and processes that have been worked out for hydrogels especially in the biomedical field.

Section 1.3 highlights some remarkable properties of gels.

A particular aspect of gels that has been studied extensively by chemists and physicists for several decades is the sol–gel transition; the sol–gel transition was examined in the framework of critical phenomena. The theory of critical phenomena describes the very special limit when a solution switches from a liquid state, where the polymers are free to diffuse, to a solid-like medium, where the network of polymers entraps the solvent. The transition from one state to the other may happen suddenly. Many theoretical and experimental publications deal with the question of determining the “gel point”. The first approach is called the classical theory developed by Flory55,56  and Stockmayer;57  the classical theory predicts that the critical degree of conversion of the reactive groups at the gel point depends only on the functionality of the crosslinks in the network (the functionality is the number of branches connected to a crosslink), which is necessarily ≥3 if an infinite network is created. At the end of the seventies, physicists specialising in phase transitions (critical point of the liquid–vapour diagram or magnetic transitions) came up with an encouraging proposal: the sol–gel transition should obey universal “laws” similar to those established for phase transitions, at least within a narrow range of crosslinking, governing network formation close to the transition. In thermodynamics, temperature drives second order transitions. In the case of gelation, the microscopic parameter controlling the network formation is a crosslinking parameter. P. G. de Gennes58  developed a new and unified theory of gelation in terms of what is now known as “percolation”. The term percolation was given by the mathematician J. M. Hammersley59  to a statistical geometric model which reminded him of the passage of a fluid through a network of channels in which a random proportion of the channels was blocked (as a traditional Italian espresso pot). There is also an electrical analogy between percolation and the transition from conducting to non-conducting networks (i.e. when current pathways are cut randomly). Percolation deals with dramatic changes in the connectivity of systems of infinite size around this so-called percolation threshold.

Percolation is analogous to critical phenomena or second-order phase transitions. In second-order phase transitions, the “order parameter” determines the critical temperature at which a phase transition occurs. For instance, at the critical temperature of the vapour–liquid phase transition, the order parameter is the difference between the liquid and vapour densities, ρliq−ρvap, a difference which decreases smoothly towards 0 when the temperature approaches the critical point. For magnetic transitions, the spontaneous magnetization M is the order parameter, near the Curie point TC:

Equation 1.1

It was demonstrated that the spontaneous magnetization follows a power law behaviour with an exponent β:

Equation 1.2

Power laws are also predicted for several other parameters related to second order transitions. One of the most important exponents is the exponent describing the divergence of the correlation length of fluctuations of the order parameter when approaching the transition.

Percolation simulations were performed on lattices, where the sites, initially empty, are occupied randomly (filled sites), p being the fraction (proportion) of filled sites. Nearest neighbour filled sites are considered as connected and belong to a cluster. When more and more sites are occupied, the size of the clusters increases until it reaches all sides of the lattice at the percolation threshold pc. The spanning cluster is built at the percolation threshold.

The models predict that the average cluster size lav below the threshold diverges when approaching pc. Above pc, the cluster size is infinite. The critical region is located near the threshold with the condition that |(ppc)/pc|≪1. In this region, the important parameters describing the percolation follow different power laws versus the distance to the threshold pc. The fractal dimensionality of the cluster at the percolation threshold and the critical exponents are related. The fractal dimension reflects the ramified and open structure of the clusters right at the threshold. Away from the critical region, the fractal dimension fd=d where d is the spatial dimension.

A convenient way of comparing percolation and gelation is to imagine the process of increasing the number of connections, beginning with a totally unconnected state (sol state).

When the percolation model is adapted to gelation, the percolation threshold is associated with the gel point, the coordination number should be the functionality of the network, and the percolation probability becomes the gel fraction. Percolation applied to gelation requires evaluating the extent of reaction with an independent method such as spectroscopy or calorimetry. Very careful experiments are needed for an experimental determination of the critical exponents and of the gelation threshold. When dealing with kinetics of gelation, rheological measurements are limited by the time evolution of the system, and the limit of infinite time is not accessible to experiments.

One important prediction of percolation models deals with the increase of the equilibrium elastic modulus near the gel point by analogy with electrical conductivity σ:

Equation 1.3

The value predicted by percolation for exponent t in polymer gelation (entropic networks) is t=2 by analogy between the elasticity of networks of ideal springs and the conductivity of resistor networks.58 

Another widely used criterion to determine the gel point is known as the Winter–Chambon criterion.60  The Winter–Chambon criterion is primarily based on the frequency dependency of the shear elasticity modulus. They found that at a particular moment during the gelation reaction, both viscoelastic moduli, the storage G′ and the loss G′′ moduli, measured in the linear regime exhibit a power law dependence with the angular frequency ω over the entire accessible frequency range. According to the Winter–Chambon criterion the gel point is defined as the moment that the loss tangent is frequency independent.

They proposed to define the gel point by the following properties

Equation 1.4

where n and m are positive numbers <1.

The Kramers–Kronig relation requires that the two exponents n and m are equal. Then, the following situations may occur at the gel point:

Equation 1.5
Equation 1.6
Equation 1.7

The particular case where n=½ and G′=G″ was observed by these authors in their sample with an appropriate balanced stoichiometry.

The two theoretical approaches – percolation and the Winter–Chambon criterion – defining the gel point are based on two different descriptions. Most of the percolation models are essentially static theories. They do not consider the mobility of the molecules. The solutions are schematically represented by lattices where bonds are added at random and connect neighbouring sites simulating the progress of the reaction. The approach due to Winter and Chambon became familiar to many scientists working on gelation and the criterion has been often considered as a practical method of determining the gel point. This criterion has been applied in processes of physical gelation, chemical gelation and inorganic gel formation, although it was not specially designed in this context. Besides, dynamic measurements over the whole spectrum of the sample are not easy to perform in a dynamic process. In some examples, the gel point was estimated with n>½ or G″>G′ in the accessible frequency range (which is not infinite!) and this is contradictory to the definition of a solid-like material. Section 1.3.2.3 reports on the elasticity of a gelatin gel examined in the framework of the percolation models close to the gelation threshold.

Polymer gels are soft materials that can deform easily. Their elasticity is mainly related to the macromolecular conformations. We report here the different types of network elasticity in relation to their microstructure.

Crosslinked polymers above their glass transition temperature (called “elastomers” in the polymer materials field) and gel networks (containing solvent) are flexible solid-like materials that can be deformed by mechanical actions and recover their initial shape after the release of the mechanical force. This property, called “rubber like elasticity”, is directly related to the coil conformation of the polymers. When the networks are stretched, the number of possible microscopic orientations that the monomers can adopt decreases and therefore the entropy of the chain decreases. The free energy is decreased and the polymer behaves like a spring where the restoring force comes from entropy rather than from internal energy. In rubber-like elasticity when the force acts on a single polymer with an end-to-end distance the polymer reacts like a spring whose stiffness is given by:

Equation 1.8

where kB is the Boltzman constant, N is the number of monomers or units of the chain, and l is the monomer or unit size. The elastic coefficient of a single “ideal” chain, 3kBT/Nl2, is proportional to the absolute temperature T; the higher the temperature, the stiffer the spring. An extension of this molecular property to macroscopic networks made of crosslinked flexible chains states that the shear modulus relating the stress and the strain under shear deformation (similar to Young's modulus under elongation) is simply determined by:

Equation 1.9

where νe is the number density of elastically active chains and a is a prefactor close to unity. This very simple relation however includes a real difficulty when one tries to relate the elastically active chains to the number density of chains. The network topology is regarded as a major factor influencing the elasticity of networks, since the number of elastically effective junctions of the network is often very significantly different to the total number of junctions. The elastic properties are influenced both by the number of chemical junctions and by their spatial distribution, which can be uniform, random and clustered; the polymer chains can be entangled at large concentrations. Entanglements contribute to the elasticity. Therefore the contribution of crosslinks is difficult to establish, owing to either the complexity of the chemical reactions or to physically entangled solutions. In addition, “network defects” such as chain ends or closed loops do not in general contribute to the connectivity. To simplify, the shear modulus of chemical gels increases with the number density of elastically active chains.

Chemical gels are also mechanically weak. The experimental method to characterize the mechanical properties is mainly elongation. Large deformation measurements are difficult to perform: compression, extension or large amplitude oscillations. Large deformations are limited by the failure of the network. A new type of crosslinking was imagined by Okumura and Ito.61  These hydrogels contain PEG polymer chains and cyclic molecules, which are first threaded, and then the polymer chains were trapped by bulky end groups. In this way the authors synthetized a sliding, double ring crosslinked hydrogel, using two cyclodextrin molecules, each threaded on a different PEG chain and chemically crosslinked. Such gels possess freely movable, sliding links which produce outstanding mechanical properties, in particular a high stretching ratio without fracture. Such gels are neither covalently crosslinked nor physical gels; they are topologically interlocked gels which have “figure-of-eight” crosslinks. The sliding double ring crosslinks equalize the tension along the polymer chains (“pulley effect”) when they are stretched. Figure 1.10 shows that networks with sliding junctions stretch much more compared to the non-slip model (fixed crosslinks) under a given stress due to the movement of junctions along the polymer chains.61 

Figure 1.10

Schematic diagram of slide-ring gels at rest with freely movable figure-of-eight crosslinks functioning as pulleys. (a) The chains are end capped and thus topologically interlocked. (b–c) Comparison under tensile deformation between a sliding ring gel (b) and a chemical gel (c). The polymer chains in the sliding ring gel can pass through the figure-of-eight crosslinks. Under tension, the chemical gel is broken down gradually to a short polymer chain because the distribution of crosslinks localizes the stress of deformation. Adapted from ref. 61 with permission from John Wiley and Sons, Copyright © 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

Figure 1.10

Schematic diagram of slide-ring gels at rest with freely movable figure-of-eight crosslinks functioning as pulleys. (a) The chains are end capped and thus topologically interlocked. (b–c) Comparison under tensile deformation between a sliding ring gel (b) and a chemical gel (c). The polymer chains in the sliding ring gel can pass through the figure-of-eight crosslinks. Under tension, the chemical gel is broken down gradually to a short polymer chain because the distribution of crosslinks localizes the stress of deformation. Adapted from ref. 61 with permission from John Wiley and Sons, Copyright © 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

Close modal

The mechanical behaviour of these networks is quite different from the “entanglement” of polymer chains or the fixed junctions in chemical gels. The polymer chains in slide-ring gels can pass through the crosslinks but do not dissociate completely, due to topological restrictions.

Figure 1.11 compares the predictions of the normal stress σN (force per unit area of the initial state) versus elongation ratio λ until failure derived from the model developed by Koga and Tanaka62  for two types of networks, one with permanent crosslinks and the other with sliding links. The slide-ring gels support large deformations and also exhibit exceptional swelling properties.

Figure 1.11

Stress–strain relation under uniaxial deformation for the slip-link model (solid squares) and non-slip-link model (solid circles). Adapted from ref. 62 with permission from Springer Nature, Copyright 2005.

Figure 1.11

Stress–strain relation under uniaxial deformation for the slip-link model (solid squares) and non-slip-link model (solid circles). Adapted from ref. 62 with permission from Springer Nature, Copyright 2005.

Close modal

Physical gels are characterized by mesoscale structures which are determined by the mechanisms of self-association of the polymers. In gelatin, it seems obvious to try to relate the gel properties, in particular the shear modulus, to the fraction of residues in helical conformation. The task is however complicated because many parameters take part in the renaturation process such as the molecular weight of the gelatin, the temperature, the amino-acid composition/source of gelatin (mammalian, fish…), the extraction process (acid or basic), the iso-electric point, the time and the concentration. After an extensive investigation, it was established experimentally that the helix concentration is the unique parameter that controls the storage (elastic) modulus of gels. The helical fraction was measured independently by optical rotation or microcalorimetry, whereas the storage and loss moduli were determined by rheological means, with identical experimental protocols. It was found that all the experiments performed on gelatin solutions could be gathered on a single curve that relates the storage modulus G′ to the mass concentration of triple helices chelix (g helices cm−3 solution) formed in solution, whatever the conditions in which these triple helices have been renatured, with no fitting parameter.63,64  The thermal protocols must be identical in both types of experiments (structure and rheology) in order to establish this comparison, to account for the non-equilibrium state of the gels.

The plot in Figure 1.12, Figure 1.12 a), summarizes these results. The storage modulus is plotted on a logarithmic scale. The plot shows that the gelation threshold is around 0.003 g helices cm−3. Figure 1.13 shows a power law dependence of the storage modulus versus helix concentration close to the gelation threshold, with an exponent close to the value predicted by the percolation models. Far from the gel point the elasticity of gelatin networks can be interpreted as an entangled network of rigid rods, which can be deformed through the flexible links (coils), without bending of the rods. The helix concentration fully controls the elasticity at any time.

Figure 1.12

Shear moduli of fibrillar networks: (a) the shear modulus is plotted versus the concentration of triple helices in solution with gelatin concentrations in the range 4–22 wt%, measured with different cooling and heating protocols (filled squares: c=4.5–22 wt% during cooling; empty circles: c=4.5–22 wt% during heating; empty diamonds: isothermal maturation). The gelation threshold is 0.003 g cm−3. (b) Comparison between the storage moduli of different fibrillar gels; polysaccharide gels exhibit high moduli and they are brittle. In gellan gels, the type of counter ions (Na+ or K+) plays a role in the rigidity as well. (a) Adapted from ref. 65 with permission from John Wiley and Sons, Copyright © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 1.12

Shear moduli of fibrillar networks: (a) the shear modulus is plotted versus the concentration of triple helices in solution with gelatin concentrations in the range 4–22 wt%, measured with different cooling and heating protocols (filled squares: c=4.5–22 wt% during cooling; empty circles: c=4.5–22 wt% during heating; empty diamonds: isothermal maturation). The gelation threshold is 0.003 g cm−3. (b) Comparison between the storage moduli of different fibrillar gels; polysaccharide gels exhibit high moduli and they are brittle. In gellan gels, the type of counter ions (Na+ or K+) plays a role in the rigidity as well. (a) Adapted from ref. 65 with permission from John Wiley and Sons, Copyright © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Close modal
Figure 1.13

The storage modulus versus the distance to the gel point on a log–log scale. In the percolation model a power law dependence is predicted with a critical exponent t=2. The critical helix content or gel point in gelatin is ccrit=0.003 g helices cm−3. Adapted from ref. 63 with permission from American Chemical Society, Copyright 2002.

Figure 1.13

The storage modulus versus the distance to the gel point on a log–log scale. In the percolation model a power law dependence is predicted with a critical exponent t=2. The critical helix content or gel point in gelatin is ccrit=0.003 g helices cm−3. Adapted from ref. 63 with permission from American Chemical Society, Copyright 2002.

Close modal

Agarose and gellan gels have higher storage moduli and a lower gel point concentration than gelatin, as shown in Figure 1.12, Figure 1.12 b). It is interesting to compare the shear moduli of gelatin and polysaccharides, which can be considered as fibril type networks in the small strain limit, within a large concentration range, up to 25 wt% (for gelatin). The plot highlights that agarose gels have a very high modulus at low concentrations compared to gelatin: for instance at c=2 wt% the modulus is about 100 kPa for agarose and 1 kPa for gelatin. The fibrillar structures of agarose or gellan and gelatin differ, and this has substantial consequences for the rigidity of the gels. It is suggested that the fibrils in agarose gels are rigid and non-entangled. The rigidity of the network comes in this case from both the rods with variable thicknesses (aggregation of double helices) and from the junctions between the rods, which are probably much less flexible than gelatin loops or coils. In agarose gels almost all monomers are in the helical conformation.

Double-network hydrogels (DN) containing two interpenetrating networks are a new category of hydrogels. These gels have high potential in artificial cartilage. The mechanical properties of DN gels prepared from many different polymer pairs are enhanced compared to the individual components. DN gels are synthesized from monomers in the presence of a crosslinker via two-step network formation: the first step forms a tightly crosslinked network of a polyelectrolyte. Then, the gel is immersed in an aqueous solution of a second monomer with a low ratio of crosslinking agent and a second polymerization is carried out. The second polymer is a neutral polymer incorporated within a highly swollen polyelectrolyte network and has a high relative molecular mass. Under an optimized composition, the DN gels containing 90 wt% water possess an elastic modulus of 0.1–1 MPa, failure tensile stress of 1–10 MPa, failure strain of 1000–2000%, and failure compressive stress of 20–60 MPa. Although the double network structure has been found to be effective with many kinds of combinations, among all the polymer pairs studied so far, the one made of poly(2-acrylamido, 2-methyl, 1-propanesulfonic acid) (PAMPS) polyelectrolyte and PAm neutral polymer has outstanding properties when the molar concentration of the second network is 20–30 times that of the first network.66  The first network is tightly crosslinked, while the second network is loosely crosslinked, which requires also a very high molecular weight of the second polymer. An impressive picture is shown in Figure 1.14.

Figure 1.14

Photograph of a tough PAMPS/PAm DN gel. Reproduced from ref. 66 with permission from the Royal Society of Chemistry.

Figure 1.14

Photograph of a tough PAMPS/PAm DN gel. Reproduced from ref. 66 with permission from the Royal Society of Chemistry.

Close modal

The exceptional mechanical properties of these gels were explained by effective local relaxation of the stress and dissipation of crack energy through a combination of the two networks, which exhibit different structures and densities. It is interesting to notice however that the enhanced properties are mainly observed with a very narrow, optimum, proportion of the two components. The particular mechanisms underlying this achievement are still to be elucidated.67  Measurements of the elastic properties of a tough gel under high elongation are shown in Figure 1.15 in comparison with a single network of Pam.

Figure 1.15

Comparison between PAMPS/PAm DN and PAm single network gels with the same acrylamide concentration and initial Young's modulus (by adjusting the concentration of the crosslinker). The DN gel can withstand high levels of deformation; in contrast, the PAm gel breaks at low stresses. Adapted from ref. 67 with permission from American Chemical Society, Copyright 2006.

Figure 1.15

Comparison between PAMPS/PAm DN and PAm single network gels with the same acrylamide concentration and initial Young's modulus (by adjusting the concentration of the crosslinker). The DN gel can withstand high levels of deformation; in contrast, the PAm gel breaks at low stresses. Adapted from ref. 67 with permission from American Chemical Society, Copyright 2006.

Close modal

The swelling of a polymer network or a gel is governed by solvent induced expansion force (or more formally free energy) involving osmotic and in addition, for polyelectrolyte systems, ionic contributions. The net result is that a gel will tend to swell to an equilibrium degree, depending upon its nature, the amount of crosslinking, the nature of the solvent or the temperature. To achieve a high degree of swelling, the retractive force must be small, and so the degree of crosslinking near to the critical amount.

The simplest model for swelling was proposed by Flory and Rehner.68  When a chemically crosslinked gel is immersed in an excess of liquid and allowed to equilibrate, the size of the sample may increase, decrease or remain constant. If a cube of gel is immersed in a good solvent the volume will increase from an initial value of V0 to V. The swelling ratio q is defined as V/V0> 1. The gel is assumed to swell affinely. The “excluded volume” effect determines that the average coil dimensions tend to increase, in order to maximize the number of polymer segment–solvent interactions in a good solvent. For the unswollen gel, the chains will have approximately unperturbed dimensions and in a poor solvent the polymer shrinks and the volume decreases. However, the tendency to swell is counteracted by the elastic restoring force from rubber elasticity theory. The total swelling pressure Π can be written more formally as a sum of four individual pressure terms:

Equation 1.10

Starting with the free energy for swelling, π1 is the “excluded volume” (or mixing term) from Flory–Huggins theory69  with an associated polymer-solvent “quality” parameter (Flory parameter χ). Then, π2 of opposite sign reflects the change in configurational free energy with swelling (the rubber elasticity term). Further terms include π3, which is a measure of the difference in osmotic pressure between the gel and the solution. For a polyelectrolyte gel this includes the Donnan contribution from the mixing of ions with the solvent, where the gel acts like an osmotic semi-permeable membrane. For instance, if the polymer chains have a net negative charge there will be a net accumulation of cations inside the gel. Finally, a term, π4, comes from the free energy of electrostatic interactions. For gels in non-polar solvents, only the first two of these terms are required. The osmotic swelling force depends on the factor (χ−0.5) reflecting the solvent quality (χ=0.5 corresponds to the theta (θ) solvent69 ). Swelling equilibrium is accomplished for polyelectrolyte gels when the chemical potential of the solvent in the gel and in the surrounding solvent is the same.

For electrically charged polymers (so-called polyelectrolytes), the need to reduce charge–charge interactions along the chain contour makes the gel swell to a large extent in pure water, or in low ionic strength electrolyte solutions. An example of a PAA gel is shown in Figure 1.16. However, at high electrolyte concentrations, the gel will tend to de-swell; this effect can be amplified by adjusting the mix of ionic species (screening of the repulsive charges). For ionic gels containing weakly acidic pendent groups, the equilibrium degree of swelling increases as the pH of the external solution increases, while for gels containing weakly basic pendent groups the degree of swelling increases as the pH decreases. The volume changes are reversible.

Figure 1.16

PAA gel swollen in pure water: on the left hand of the picture, the initial size of the gel; on the right hand, the final size: after swelling for several days immersed in distilled water, the volume of the gel after swelling increased by a factor of 25.

Figure 1.16

PAA gel swollen in pure water: on the left hand of the picture, the initial size of the gel; on the right hand, the final size: after swelling for several days immersed in distilled water, the volume of the gel after swelling increased by a factor of 25.

Close modal

The nature of the junctions in gel networks has also a great influence on the swelling at equilibrium. A very large volume change is observed in sliding ring gels, as shown in Figure 1.17; the gel absorbs water up to ca. 400 times its dry weight. This property is particularly remarkable because these gels are non-ionic and their swelling is only related to the topography of the crosslinks.

Figure 1.17

Volume change of a sliding ring gel: top left: before volume change; top right: the dry gel; and bottom: the water-swollen gel (ca. 400 times the dry weight). Adapted from ref. 61 with permission from John Wiley and Sons, Copyright © 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

Figure 1.17

Volume change of a sliding ring gel: top left: before volume change; top right: the dry gel; and bottom: the water-swollen gel (ca. 400 times the dry weight). Adapted from ref. 61 with permission from John Wiley and Sons, Copyright © 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

Close modal

In 1981 Tanaka and co-workers7  discovered the volume phase transition of chemical gels, in which the swelling and shrinking behaviours exhibit discontinuous profiles with hysteresis. This novel discovery regarding crosslinked polymeric materials has attracted considerable interest in the field of polymer science and smart materials (see Section 1.4). Partly hydrolyzed polyacrylamide (PAm) gels are weakly polyelectrolyte in nature. Mixtures of good solvent (water) and poor solvent (acetone) were investigated. As small amounts of acetone are added to a PAm gel, the gel de-swells. Moreover, for certain amounts of alkaline hydrolysis, the de-swelling becomes discontinuous – there is a sudden de-swelling over a very narrow range of acetone/water compositions. The authors imagine from these observations many potential applications of these hydrogels: cycles of expansion and contraction might be powered by changes in temperature, solvent composition, pH, ionic strength or electric field. They believed that such devices may be particularly appealing for use as an artificial muscle. Because the change in volume is discrete and predictable, a gel might also serve as a memory element or a switch. An important factor in most such applications is the speed of the phase transition. A gel with dimensions of about a centimetre requires several days to reach a new equilibrium volume. As the diffusion time is proportional to the square of the linear dimensions of the gel, a cylindrical gel of 1 µm diameter would swell or shrink in a few thousandths of a second! These predictions were fully explored in the domain of “biosensors” and “micro-electro-mechanical systems” (MEMS).

The swelling of physical gels with non-permanent crosslinks is much more complex. Because the physical links are labile junctions, they can redistribute progressively under osmotic pressure and the junctions may partially dissolve, releasing polymer chains into solution. The ultimate state of swelling of physical networks should lead to dispersions of polymeric aggregates or simply to a polymer solution.

Besides the traditional uses in food and home care products, known to a large public, gels have found numerous novel applications in medical, biomedical and analytical areas, which are briefly introduced now.

‘Polymer gel phantoms’ have been formulated to serve as radiation dosimeters capable of measuring the entire 3D dose distribution with enough spatial precision for dose verification of radiotherapy cancer treatments. The gel dosimetry experiment should be performed in a similar way to the patient treatment.70  The absorption of the dose in soft tissues is also similar to the absorption of the dose in water, not entirely surprisingly as our soft tissues consist predominantly of water. For that reason, in radiotherapy, also standard dosimetry is performed with water as a standard medium. In radiotherapy, “tissue equivalence” and “water equivalence” are used intertwined. Two exceptions of tissues that are not entirely water equivalent are bone and lungs (see for instance ref. 71).

In radiologically tissue equivalent gels, the amount of radiation-induced copolymerization depends on the absorbed radiation dose. To this end, PAm gels, based on the copolymerization of acrylamide and BIS monomers, were incubated inside a gel matrix of agarose; the systems were first developed with the acronym of BANANA (Bis, Acrylamide, Nitrous oxide ANd Agarose).

Later, polymer gel dosimeters with gelatin as a gel matrix were introduced and received the acronym PAG (PolyAcrylamide-Gelatin gels) or BANG (Bis (3%), Acrylamide (3%), Nitrogen and Gelatin (5%)) for the commercialized versions. In another version, the comonomers were replaced by methacrylic acid, which received the names MAG and BANG-2 gels. In order to restrict chain propagation during polymerization, to keep the radiation-induced changes local, an unusually high concentration of the crosslinker (BIS) was introduced (same mass of monomers of Am and BIS). Upon irradiation of PAG gel dosimeters insoluble polymeric agglomerates are created which precipitate in the gel. The polymeric aggregates have sizes comparable to the wavelength of visible light, causing increased optical turbidity. It is observed that polymerization is confined mostly within the site of initiation and the polymer does not diffuse through the gel pores. Gelatin gels are more transparent than agarose and the optical effect due to the polymer precipitation is more pronounced and is more easily visualized.

Gel dosimeters were prepared with volumes up to 10 L.72,73  The absorbed radiation dose can be read out by several methods such as quantitative magnetic resonance imaging (MRI), optical computed tomography (optical CT) or X-ray CT. The intrinsic NMR R2 value (1/T2) of agarose is significantly higher (a factor of 10) than that of gelatin; the intrinsic R2 of agarose causes an enormous offset in the dose-R2 response, which results in a poor dose resolution.74,75  The atomic composition, electron density and average atomic number of the BANG-2 gels are close to human muscle tissue.76  It is important to notice that agarose or gelatin alone has no significant response to radiation at the doses reported for dosimeter gels (in contrast with the results shown in Section 1.2.1.2). The function of agarose and gelatin in polymer gel dosimeters is limited to the spatial fixation of the polymer aggregates. For polymer gel phantoms, it is expected that the parameters chosen for evaluation of radiation effects are proportional to the absorbed doses.

Figure 1.18 compares the relative response curves (in arbitrary units) of irradiated PAm gels. Comparison between Raman, R2 measurements from MRI and X-ray CT during polymerization of PAm gels demonstrates the similarity of the dose response after normalization with the different methodologies with a relatively linear dose response in a dose region between 0 and 10 Gy, although some scatter was detected especially towards the highest doses. Baldock et al.78  follow by FT-Raman vibrational spectroscopy the copolymerization of PAm samples in their vials during seven days post-irradiation to ensure complete polymerization of the samples. A detailed analysis of the crosslinking in polyacrylamide gels versus the BIS content is reported in ref. 79. Potential physicochemical errors in polymer gel dosimeters are listed by Sedaghat80  and Vandecasteele and De Deene.81  Irradiation takes approximately 1 hour, and storage and stabilization 3 to 5 days, away from daylight. For all these reasons, the preparation and observation procedure have to be rigorously controlled due to the complex chemistry and the non-equilibrium of the phases in these gel systems.82 

Figure 1.18

Comparison between MRI (R2), X-ray CT and Fourier transform Raman spectroscopy on irradiated PAm gels used in 3D radiation dosimetry by subtracting the 0 Gy value of the variables and normalizing the 10 Gy point to 1 for each set of data. Adapted from ref. 77 with permission from IOP Publishing, Copyright Institute of Physics and Engineering in Medicine.

Figure 1.18

Comparison between MRI (R2), X-ray CT and Fourier transform Raman spectroscopy on irradiated PAm gels used in 3D radiation dosimetry by subtracting the 0 Gy value of the variables and normalizing the 10 Gy point to 1 for each set of data. Adapted from ref. 77 with permission from IOP Publishing, Copyright Institute of Physics and Engineering in Medicine.

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In the new field of tissue engineering, polymers were designed to assist regeneration of three-dimensional tissues and organ structures integrated with biological demands. Engineering of tissues or organs to treat patients appears as a promising therapeutic approach that combines biomaterials, cells and environmental factors to promote tissue repair and/or functional restoration. Biomaterials called “scaffolds” play an important role as extracellular matrices which create the correct microenvironment and promote tissue development. Scaffolds are designed to have optimal pore sizes depending on the cells which are expected to grow inside: for fibroblasts and hepatocytes, the pore size should be around 20 µm, for skin regeneration, between 20 and 150 µm, and for bone regeneration in the range of 100–250 µm. For smaller pore sizes (10–100 nm) and weak mechanical properties, biochemists and pharmacists use hydrogels. Polymer scaffolds allow the diffusion of nutrients, metabolites and growth factors.83  Specific cells isolated from a small tissue biopsy from the patient are incorporated into the polymer scaffold: the surgeon makes incisions which enable placement of the polymer/cell assembly.

Fabrication of scaffolds needs particular processing in order to generate highly interconnected networks of pores, with controlled size distributions and extensive interconnectivity. Ideally, scaffolds should disappear after the tissue is restored and eliminated within the timeframe of the tissue rebuilding. The pore sizes needed for cell growth are significantly larger than the hydrogel matrix size. Specific strategies have been developed to create scaffolds adapted for each application. We briefly analyze here the scaffolds for skin regeneration. Gelatin and chitosan are the main components which are used as scaffolds for skin regeneration. Gelatin, being denatured collagen, the major constituent of the epidermis, is entirely absorbable and moreover inexpensive and abundant. Gels however have weak mechanical properties. Chitosan consisting of partially deacetylated (90%) chitin – a major constituent of shell crustaceans – is a linear polysaccharide made of glucosamine and N-acetylglucosamine, similar to glycosaminoglycans (GAG), another important constituent of the extracellular matrix of numerous tissues. Chitosan is biocompatible, biodegradable, very absorbent, anti-bacterial, and non-toxic. Mixing the two biopolymers dissolved in water creates an incipient phase separation at the same time as gelatin gelation starts. The concentrations of gelling agents total 2–3 wt% creating weak structures which facilitate biodegradation. Other components are introduced in solution to promote cell adhesion to the scaffolds (like for instance, hyaluronic acid or Aloe vera extract). An important step in scaffold preparation is freezing of the weak gelling solutions after being spread as thin layers approximately 3 mm thick, at room temperature, over stainless steel pans (freeze dryer shelf). The cooling rates of the freeze dryer shelf can be varied, as shown in Figure 1.19; the temperature in the sample was recorded during freezing at distinct positions and the average values were reported for four freezing rates.84 

Figure 1.19

Rapid freezing of gel films spread on a cold plate. Temperature is recorded versus time for different cooling rates of the cold plate. Ice crystals grow during the isothermal step at 0 °C. Undercooling is also observed. Adapted from ref. 84 with permission from Elsevier, Copyright 2003.

Figure 1.19

Rapid freezing of gel films spread on a cold plate. Temperature is recorded versus time for different cooling rates of the cold plate. Ice crystals grow during the isothermal step at 0 °C. Undercooling is also observed. Adapted from ref. 84 with permission from Elsevier, Copyright 2003.

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In the example the freezing process (growth of ice crystals at 0 °C) takes variable periods of time (Figure 1.19). At the surface of the pan the lowest temperature, −40 °C, is reached after 120 min at the lowest cooling rate (−0.6 °C min−1) and after 20 min at the highest rate (−4.1 °C min−1). Ice crystal growth rates control the pore size distribution of the scaffolds and their heterogeneity should be minimized. Formation of ice crystals is influenced by both the rate of nucleation of ice crystals and the rate of heat and biopolymer diffusion. The nucleation rate defines the number of ice crystals that form and the rate of heat and polymer transfer away from the point of nucleation defines the size of the ice crystals. A large undercooling (below water freezing temperature) increases the rate of nucleation of ice crystals and decreases heat and polymer diffusion. Therefore, small ice crystals are formed, leading to a scaffold with small average pore diameters. However, a predominant direction of heat transfer leads to the formation of columnar ice crystals. Figure 1.20 shows the surface and the cross-section of a scaffold after quenching the films down to −190 °C. Pores aligned in columnar channels created by ice crystals nucleated near the cold plate and growing towards the surface can be seen. The channels are not interconnected. To allow transport of cells and metabolites the scaffold must have a large pore volume fraction (generally greater than 90%) and an interconnected pore network.

Figure 1.20

Surface (left) and cross-section (right) images of scaffolds frozen at −190 °C measured by SEM. The bar is 1 mm. Reproduced from ref. 85, http://dx.doi.org/10.1590/1980-5373-MR-2015-0793, under the terms of a CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/deed.en.

Figure 1.20

Surface (left) and cross-section (right) images of scaffolds frozen at −190 °C measured by SEM. The bar is 1 mm. Reproduced from ref. 85, http://dx.doi.org/10.1590/1980-5373-MR-2015-0793, under the terms of a CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/deed.en.

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After freeze drying, it is necessary to add a chemical crosslinking step. When the active process succeeds in forming a stable and homogeneous porous sponge, the final test resides in evaluation of the biological in vitro and in vivo properties. A variety of solutions are discussed in the literature.86–92 

Stimuli responsive properties of hydrogels have been exploited to make smart materials for various applications including controlled drug release systems, sensors or cell culture substrates. The gels require a molecular recognition element that initiates the responsive behaviour. In their recent review, Culver et al.93  describe various classes of responsive hydrogels and review recent applications of these materials, highlighting the versatility of this field. Improved sensitivity and selectivity should make hydrogels important diagnostic tools. For bioanalytical and biomedical applications, it is important to have hydrogels responsive to small metabolites, nucleic acids, proteins, or other chemical and biological molecules.94  For example, insulin release in response to glucose concentration changes is needed in treating diabetes. Hydrogels can be readily made into different forms including monoliths, thin films, or micro/nanoparticles. Each form has a different loading capacity, release kinetics and mechanical property. Micro/nanoparticles are useful for drug delivery, while thin films are ideal for cell culture and for making fast response transducers. Monoliths, on the other hand, are easy to handle, to observe, and to incorporate into devices. Stimuli-responsive hydrogels that undergo abrupt changes in volume in response to external stimuli such as pH, temperature and solvent composition have potential applications in biomedicine and the creation of “intelligent” materials, for example as media for drug delivery, separation processes and protein immobilization. A pioneering study is due to Takashi Miyata et al.,95  who synthetized a material which swells reversibly in a buffer solution, in response to a specific antigen. This effect is based on reversible binding between an antigen and an antibody which also controls the crosslinking of a semi-interpenetrating network (semi-IPN) of the hydrogel (Figure 1.21). Antibodies are complex proteins that the body uses to identify antigens, viruses and bacteria.

Figure 1.21

(a) Diagram suggesting the mechanism of swelling of an antigen–antibody semi-hydrogel in response to a free antigen; and (b) effects of the free antigen concentration on the hydrogel swelling ratio: the swelling ratio was measured in solution using an optical microscope. The maximum of the swelling ratio is 10%. Reproduced from ref. 95 with permission from Springer Nature, Copyright 1999.

Figure 1.21

(a) Diagram suggesting the mechanism of swelling of an antigen–antibody semi-hydrogel in response to a free antigen; and (b) effects of the free antigen concentration on the hydrogel swelling ratio: the swelling ratio was measured in solution using an optical microscope. The maximum of the swelling ratio is 10%. Reproduced from ref. 95 with permission from Springer Nature, Copyright 1999.

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The hydrogel swells in the presence of a free antigen because the intra-chain antigen–antibody binding can be dissociated by exchange of the grafted antigen for the free antigen.

In Figure 1.21 antibodies are shown as Y shaped components. Antigen–antibody is a unique specific interaction which is often called “the lock and key fit”. The semi-interpenetrated networks contain permanent crosslinks and, in addition, antibody and antigen molecules grafted on the polymer. After polymerization, the solution becomes an antigen–antibody semi-interpenetrated hydrogel, by complexation of the immobilized antibodies and antigens. When the gels are put into a buffer solution containing the corresponding free antigens, they swell: the underlying mechanism involves free antigens that competitively bind to the antibodies, breaking the previously existing complexation. This suggests that the binding due to the antigen–antibody hydrogel was much weaker than with free antigens, probably due to the denaturation of grafted antigens. These hydrogels possess the ability to recognize specific antigens and could be used to develop immunoassays and other antigen-sensing materials.

In a similar way, Liu94  reports on oligonucleotide-functionalized hydrogels as stimuli responsive biosensors. Incorporation of DNA sequences (less than 100 nucleotides) within smart hydrogel networks can serve as a reversible crosslinker, modulating the mechanical and rheological properties. DNA can selectively bind to a variety of different chemical and biological molecules and respond to stimuli in different ways: sol–gel transition, reversible volume changes, generation of optical signals, or controlled protein release.

Another area of active research is devoted to development of MEMS (micro-electro-mechanical systems) based on hydrogel structures of micron sizes. Stimuli-sensitive hydrogels are designed to respond to temperature, electrical fields, light, pH, solvents and specific ions. To fabricate functional hydrogel structures at the micro-scale, photo-patterning technologies and synthesis of microgels were developed.

Richter et al.96  describe a quartz crystal microbalance (QCMB) technique, based on a polyelectrolyte smart hydrogel. The pH sensitive material is made of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) spin coated in solution and thermally crosslinked. The thickness of the dry film is 390 nm and when swollen in water (pH 7) it was 1.1 µm. They demonstrate the suitability of PVA/PAA coated quartz as a pH sensor in the pH range of 2.55–3.45, with no hysteresis. In this range the measurement precision reaches a pH of 0.002! The amplitude, frequency and damping shift can be used as pH responsive indicators (Figure 1.22).

Figure 1.22

Sensor characteristics of PVA/PAA coated quartz in the range pH 2.55–3.45. Adapted from ref. 96 with permission from Elsevier, Copyright 2004.

Figure 1.22

Sensor characteristics of PVA/PAA coated quartz in the range pH 2.55–3.45. Adapted from ref. 96 with permission from Elsevier, Copyright 2004.

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Another example of hydrogel-based MEMS is microcantilevers.97  pH responsive hydrogels can be precisely patterned onto microcantilevers to create an ultra-sensitive pH microsensor. Photolithography is utilized to pattern networks of, for example, poly(methacrylic acid) (PMMA). The adhesion between the silicon substrate and the polymer is achieved by using a coupling agent. Ionization of the acid groups occurs when the pH is raised above the pKa of the anionic network. With deprotonation of acid groups, the electrostatic repulsion between chains increases the hydrophilicity of the network and water is absorbed. Swelling of the hydrogel is the actuation mechanism of the MEMS, inducing a deflection of the cantilever (Figure 1.23).

Figure 1.23

Left: example of a MEMS sensor based on a microcantilever patterned with a hydrogel at rest (thickness 2.2 µm) and in the swollen state; right: equilibrium bending versus pH. Adapted from ref. 97 with permission from Springer Nature, Copyright 2003.

Figure 1.23

Left: example of a MEMS sensor based on a microcantilever patterned with a hydrogel at rest (thickness 2.2 µm) and in the swollen state; right: equilibrium bending versus pH. Adapted from ref. 97 with permission from Springer Nature, Copyright 2003.

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For the highest sensitivity of 20 µm per pH unit, there is a resolution for optical based laser detection set-ups of 1 nm deflection for ΔpH=5×10−5! It is expected that the sensitivity of such devices could be tailored by changing the amount of crosslinking, by increasing the porosity of the network or the polymer film thickness.

This chapter provides a look through the literature on gels, from the very beginning, when this colloidal state was described first, towards the impressive developments in recent years with contributions from several distinguished scientists recognized by Nobel Prizes. In parallel, a great richness of inventive synthesis appeared which found many applications in every day life and in very specific areas. There is still room for future developments closely linked to biomedical applications. To enable future practical developments, basic knowledge of gelation mechanisms can be extended through different physico-chemical analytic techniques and computational modelling. NMR has proven to be a key emerging tool in the characterization of a large variety of gel systems. Gel research is an active area of interdisciplinary efforts which draws on the expertise of chemists, physicists, engineers, mathematicians and clinicians.

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