Acrylate based hydrogels are one of the most promising soft biocompatible material platforms that significantly contribute to the delivery of therapeutics, contact lenses, corneal prosthesis, bone cements and wound dressing, and are being explored widely for potential applications in the field of regenerative medicine. A significant number of these materials, which possess excellent water sorption properties, have been supported by the Food and Drug Administration (FDA) of the United States for different applications. Nonetheless, many of their physical and biological properties required for certain biomedical and bioengineering applications are often poor when they are in the hydrated state at the body temperature: tensile/compression performance, water diffusion, antimicrobial activity, antifouling capacity, biological response, porosity for the fabrication of supports or scaffolds for tissue engineering, electrical and/or thermal properties, among other properties. Consequently, new acrylic-based hydrogels have been designed as multicomponent systems such as interpenetrated polymer networks, composites and nanocomposite materials, which have exhibited superior properties able to substantially enhance potential uses of these materials in the biomedical and bioengineering industry.
- acrylic-based hydrogels
Hydrogels are hydrophilic polymer networks that are capable of absorbing large amounts of water and retaining them, which make them a versatile class of materials especially for biomedical applications. The physical and biological properties largely depend on composition, polymerisation methods and crosslinking but in general are mechanically weak materials. Acrylic-based hydrogels are utilised in numerous fields of biomedicine and examples include therapeutic delivery , intraocular lenses, contact lenses and corneal prosthesis in ophthalmology , bone cements for orthopaedics , wound dressing , and tissue
2. Mechanical properties of hydrogels
Hydrogels form a versatile platform for a large number of biomedical applications; however, they are in general mechanically weak and improvement of these properties is one of the most desirable aims in the field of hydrogel engineering. Current research is focussing in this complex scientific field  especially as the mechanical integrity drops rapidly in the hydrated state. Thus, hydrogels have been reinforced through many established kinds of methods and techniques: forming block copolymers, in which hydrophobic and hydrophilic domains alternate , increasing crosslinking density , using binary systems composed of two or more mixed polymers as interpenetrating polymer networks , plasma grafting of a hydrogel onto a hydrophobic substrate [12, 13, 14], self-reinforced composite materials composed of fibres embedded in a matrix  and by reinforcement through sol-gel reactions . Nevertheless, new procedures to enhance the mechanical performance of acrylics have been performed by incorporating 2D materials such as graphene (2010 Nobel Prize in Physics)  and other outstanding carbon-based materials such as carbon nanotubes (CNT) . Graphene derivatives, such as graphene oxide (GO) [19, 20, 21] or reduced GO (rGO) , have also shown excellent reinforcement for acrylics, especially in the hydrated state, and for the enhancement of many other physical and biological properties.
2.1 Interpenetrating polymer networks
Interpenetrating polymer networks (IPNs) lead to reinforced polymer networks that enhance the mechanical properties of hydrogels. In 2003, the first double-network (DN) hydrogel with enhanced mechanical properties was reported . This type of DN interwoven hydrogel architecture consisted of an interpenetrating polymer network (IPN) of a soft neutral polymer network within a more highly cross-linked network prepared by a two-step sequential free-radical polymerisation. This two-step chemical procedure consisted of synthesising a highly cross-linked polymer network, and subsequent swelling of this network in a water soluble monomer that was then polymerised inside. The second polymerisation step was conducted with or without the incorporation of a cross-linking agent. Therefore, an IPN is an advanced polymeric system that is often utilised in polymer engineering to enhance physical and biological properties by combination of functional properties. These multicomponent polymeric networks are composed of cross-linked polymers without covalent bonds between polymer networks. However, at least one of these networks is synthesised and/or cross-linked within the presence of the second network. In this field, six basic multicomponent polymeric morphologies can be distinguished: mechanic blends, graft copolymers, block copolymers, AB-cross-linked copolymers, semi-IPNs and full-IPNs . Both polymer networks are cross-linked in a full-IPN , while an IPN having a polymer network embedded within the first cross-linked network produces a semi- or pseudo-IPN [26, 27]. IPNs can be produced while the two networks are synthesised at the same time as simultaneous interpenetrating polymer networks (SINs), or by swelling of the first polymer network into a solution containing the mixture of monomer, initiator and activator, usually with a cross-linker, as sequential IPNs. Thus, reinforced SINs and semi-SINs of hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) networks have been synthesised with hydrophobic poly(ethylene glycol) polymer chains . The sequential mode of synthesis has been employed to produce reinforced hydrogels as full IPNs and semi-IPNs of weak gelatin with polyacrylic acid (PAA) for studies of biological response in rats . The mechanical properties of triple-network (TN) hydrogels synthesised from pseudo-SIPNs and pseudo-IPNs have exhibited that the presence of a loosely cross-linked third network modifies the mechanical performance of pseudo-SIPNs and pseudo-IPNs . Many types of IPN hydrogels have been also developed with the goal of improving the mechanical behaviour and swelling/deswelling response . For instance, IPN hydrogels of chitosan/poly(acrylic acid) (PAA) synthesised by UV radiation showed significant enhancement of mechanical properties, even in the hydrated state . ‘Smart’ hydrogels possess the special property of being able to modify their volume/shape in response to small alterations of certain parameters of the surrounding ambient. These responsive hydrogels find application in numerous biomedical and bioengineering fields such as biological and therapeutic demands [33, 34] and sensing applications . Encapsulation of cells for cartilage tissue engineering was reported using two biocompatible materials-agarose and poly(ethylene glycol) (PEG) diacrylate to form an IPN with superior mechanical integrity . Under unconfined compression, these hydrogel networks were found to be fourfold higher in their shear modulus relative to a pure PEG-diacrylate network (39.9 vs. 9.9 kPa) and a 4.9-fold increase relative to a pure agarose network (8.2 kPa). In the field of hydrogel materials, advanced stimuli-responsive materials based on interpenetrating liquid crystal-hydrogel polymer networks have been engineered by combination of cholesteric liquid crystalline network that reflects colour and an interwoven poly(acrylic acid) network that provides humidity and pH response .
2.2 Acrylic-based composite hydrogels
Fibre reinforcement is known to enhance mechanical properties and the incorporation of fabrics produces significant mechanical improvement to polymer hydrogels. Thus, hydrogels consisting of a polymer matrix embedded with high-strength fibres, such as glass, aramid and carbon, have exhibited significant reinforcement . In these kinds of materials, the mechanical properties are significantly enhanced and the biocompatibility of the acrylic polymer phase should remain unmodified. Thus, PHEMA hydrogels, which are one of the most studied hydrogel biomaterials, have been synthesised by incorporating various types of weaved and knitted fabrics and fibres, in order to enhance overall qualities in advanced biomedical wound dressing usage . Nevertheless, in the last decades, natural fibres have attracted much interest as reinforcement agents for polymer-based composites due to their advantages over other type of conventional fibres such as those made from glass or carbon . Thus, natural fibres such as flax, hemp, sisal, kenaf, jute, coir, kapok and banana, among many others, have shown many advantages over man-made glass and carbon fibres: lower cost, lower density, comparable specific tensile behaviour, less energy cost, non-abrasive, not irritating, lower health risk and sustainable properties such as renewability, biodegradability and recyclability . Thus, natural ultra-long chitin natural fibres obtained from marine-river crab shell wastes have been added into PMMA resins to produce nanocomposites with outstanding properties for biomedical and bioengineering applications .
2.3 Acrylic-based nanocomposite hydrogels
Nanoparticles have generated significant interest and are a promising strategy of reinforcing hydrogels. Nanocomposites made with nanomaterials such as silica, graphene and its derivatives, nanofibres and various other nanoparticles have been reported for biomedical applications. Silica is a biocompatible material which has been reported to possess bioactive properties . Silica possesses high biocompatibility and bioactive properties  and can also enhance the mechanical performance of hydrogels through filling or by the sol-gel process . Thus, for example, biphasic matrices of hybrid acrylic-based nanocomposite hydrogels consisting of an organic phase of poly(2-hydroxyethyl acrylate) and an inorganic phase of silica network obtained by the sol-gel process of tetraethoxysilane (TEOS) showed improved physical properties . Another reinforcement approach consists of combining IPNs with nanosilica filling. Thus, for instance, poly(acrylic acid) and alginate in the form of IPNs with the incorporation of nanosilica have shown improved compressive strength of the pure components . On the other hand, the development of graphene-based nanocomposite hydrogels has exponentially increased during the last decade. Thus, graphene (GN) is a two-dimensional monolayer of sp2-bonded carbon atoms , which has attracted increasing interest owing to its excellent electrical and thermal conductivity [48, 49] and superior mechanical performance . In addition, in the field of biomedicine, graphene is able to promote adherence of human osteoblasts and mesenchymal stromal cells . The addition of small amounts of the oxidised form of GN, graphene oxide (GO), can significantly improve the mechanical strength of poly(2-hydroxyethyl acrylate) (PHEA) hydrogels . Polyacrylamide (PAM) is generally a weak and brittle material; however, when reinforced with GO, it was reported to exhibit improved of mechanical properties . GO is also a 2D nanomaterial with excellent physical properties  like graphene, usually produced from natural graphite that can be easily exfoliated into monolayer sheets. Nevertheless, GO is more utilised than GN in the synthesis of composite materials because it possesses hydrophilic oxygenated functional groups, such as hydroxyl (-OH), epoxy (-C-O-C-), carbonyl (-C=O) and carboxyl (-COOH), which render easier its dispersion in water [54, 55, 56, 57]. Thus, the incorporation of GO nanosheets into poly(acrylic acid)/gelatin composite hydrogels significantly increased their Young’s modulus and maximum stress. In addition, the hydrogel with GO (0.2% w/w)/PAA (20% w/w) showed the highest Young’s modulus, whereas GO (0.2% w/w)/PAA (40% w/w) composites exhibited the highest maximum stress. These results suggest that GO nanosheets can be successfully used as reinforcing agents to improve the mechanical properties of hydrogel materials, which are often required for certain applications in tissue regeneration . Multifunctional hydrogels with high mechanical performance, environmental stability, and dye-loading capacity has also been proposed as innovative synthetic approach for the 3D self-assembly of GO nanosheets and DNA . Furthermore, the available oxygen-containing functional groups of GO have led to the synthesis of 3D cross-linked GO networks by coordination chemistry, as reinforcement micro-meter size carbon nanomaterials (CNMs) are able to enhance the mechanical performance of hydrogels, such as alginate, even more than single GO nanosheets . Other CNMs such as carbon nanotubes (CNTs), discovered by Iijima , in the form of single wall carbon nanotubes (SWCNTs) and multi-wall carbon nanotubes (MWCNTs), as well as carbon nanofibres (CNFs) are being explored for the enhancement of mechanical and other physical and biological properties of hydrogels [61, 62, 63, 64, 65, 66, 67, 68]. Plant fibre-based nanofibres are used as reinforcement agents to produce transparent hydrogels . Novel PAM-based nanocomposite hydrogels produced with natural chitosan nanofibres via in situ free-radical polymerisation exhibited that this type of nanofibres can act simultaneously as a multifunctional cross-linker and as a reinforcing agent achieving higher compression strengths and storage modulus than those of the pure hydrogel . Popular hydrogels such as polyvinyl alcohol (PVA) has been reinforced with nanoparticles of clay (usually 10 wt.% or less) for wound healing applications . These polymer-clay nanocomposite hydrogels with uniformly dispersed inorganic particles with at least one dimension in the nanometre scale exhibited superior mechanical and thermal properties when compared to pure polymers or conventional composites .
3. Electrical properties
Stimulus responsive biomaterials are highly desirable in biomedicine and bioengineering. Electrical stimulation can regulate physiological activities such as cell division , migration , differentiation and death . It has been reported that electrical stimulation helps both in spinal cord repair and cancer therapy. The ability to use electrically conducting polymers endogenously enables spatial control of stimulation [76, 77, 78]; hence, there is much focus on developing new conductive hydrogels for biomedical applications. Graphene is well-known for its excellent electrical conductivity . However, its current cost is still very high. Therefore, more new composite materials are expected to be developed using reduced graphene oxide (rGO), which is produced from GO. GO cannot be utilised for the design of conductive composite hydrogels because it possesses very low electrical conductivity due to the oxygen-containing functional groups located at the basal planes and edges. A recent paper reported a single-step procedure starting from a homogeneous water dispersion of GO, to form rGO during photopolymerisation of a resin induced by UV radiation . Grafting of poly(acryl amide)/poly(acrylic acid) onto the surface of GO followed by a reduction to rGO nanosheets by a two-step chemical reduction with increased conductivity has been performed in order to fabricate transparent conductive films . Advanced conductive DN hydrogels composed of rGO and poly(acrylic acid) have been synthesised by a two-step procedure with a reduction-induced in situ self-assembly . A nacre-inspired nanocomposite of rGO and PAA prepared via a vacuum-assisted filtration self-assembly process exhibited abundant hydrogen bonding between GO and PAA that resulted in both high strength and toughness, which are higher than that of pure reduced GO. Moreover, this composite also displayed high electrical conductivity with potential in many biomedical applications such as flexible electrodes and artificial muscles. Carbon nanotubes (CNTs), on the other hand, are being exploited for biosensing units because of their excellent electrical properties with a superb conductivity and remarkable mechanical properties . Ultrasensitive electrochemical biosensors have been developed with CNTs because of their unique electrical properties. Glucose biosensors for diabetics have been developed with nanofibrous membranes filled with multiwalled carbon nanotubes (MWCNTs) electrospun from mixtures of poly(acrylonitrile-co-acrylic acid) (PANCAA) and MWCNT . Dielectrophoretically aligned carbon nanotubes were proposed to control the electrical and mechanical properties of gelatin methacrylate (GelMA) hydrogels . In addition, in the field of biomedicine, these GelMA-based hydrogels exhibited excellent maturation of contractile muscle cells.
4. Thermal properties
Hydrogels placed in the human body do not need to endure temperatures higher than that of body temperature; however, it is of importance to have an understanding of the thermal properties and improvements can enhance its long-term performance. For instance, semi-IPNs of polyurethane incorporated into a polyacrylamide network showed improved thermal properties . Differential scanning calorimetry of PHEMA/SiO2 hybrids exhibited two glass transition temperatures (
5. Water sorption/diffusion
The behaviour of water in hydrogels is also very important for any biomedical applications because properties such as water sorption and water diffusion play a very important role in cell survival, especially relevant in tissue regeneration . Thus, acrylic hydrogels such as PHEMA or PHEA are important due to their unique properties of hydrophilicity, swelling and deswelling [90, 91, 92]. Their excellent water sorption behaviour has rendered this type of hydrophilic materials very promising for a wide range of biomedical and bioengineering applications such as wound healing, controlled drug delivery, regenerative medicine, etc. [6, 93]. Their hydrophilic functional groups attached to the polymeric backbone provide the ability to absorb water, while their resistance to dissolution arises from cross-linking of polymer chains . Nevertheless, these single-network hydrogels possess very weak mechanical properties and slow swelling response. Therefore, reinforcement of hydrogels is deemed necessary to exponentially increase their potential applications in biomedicine and bioengineering. However, the enhancement of mechanical properties can significantly affect the water sorption and diffusion of polymer hydrogels. Thus, reinforcement approaches combining hydrophilic and hydrophobic functional groups as multicomponent polymeric systems can yield to a decrease of water sorption. The enhancement of mechanical properties of hydrogels through the addition of GO nanosheets can also modify their water sorption performance. Thus, for instance, the swelling rates of graphene oxide/poly(acrylic acid-co-acrylamide) nanocomposite hydrogels increased with increasing GO content to about 0.30%
6. Antimicrobial and antifouling capacity
Microbial infections are becoming more and more serious because they often lead to implant failure, which may cause major economic losses and suffering among patients in spite of using antibiotics and aseptic conditions. Therefore, novel antimicrobial approaches are becoming more and more necessary in biomedicine in this antibiotics resistant era . Thus, much effort is being made on the development of new advanced biomaterial hydrogels with high antimicrobial activity and non-toxic for human beings. Thus, antibacterial hydrogels of polydextran aldehyde and branched polyethylenimine have been prepared in the form of syringe-injectable bioadhesive . These hydrogels have shown effective antibacterial activity against both Gram-negative and Gram-positive bacteria. Conductive injectable self-healed hydrogels based on quaternized chitosan-g-polyaniline (QCSP) and benzaldehyde group functionalized poly(ethylene glycol)-co-poly(glycerol sebacate) (PEGS-FA) have also shown antibacterial, antioxidant and electroactive action for cutaneous wound healing . Hydrogels based on chitosan and its derivatives have been broadly utilised as implant coatings because of their intrinsic non-toxic, osteoconductive properties, pH response, antimicrobial activity, biocompatibility and cell adhesive capacity [107, 108]. Novel hydrogel coatings produced by electrophoretic co-deposition of chitosan/alkynyl chitosan exhibited high antibacterial activity against
In the field of implanted biomedical devices, it is important to modify the hydrogel surface to achieve antifouling properties that make it resistant to protein adsorption and cell adhesion. Thus, for example, the antifouling activity of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) hydrogels was enhanced by surface grafting of a brush of poly(oligoethylene glycol methyl ether acrylate) [poly(OEGA)] . Copolymerisation of non-fouling zwitterionic carboxybetaine methacrylamide (CBMAA-3) and 2-hydroxyethyl methacrylate (HEMA) in the presence of uniformly dispersed clay nanoparticles (Laponite XLG) in water by UV radiation has produced novel antifouling highly wettable hydrogels with superior mechanical performance and self-healing capacity . In this field, it is highly desirable to produce hydrogels bearing antifouling properties and biocompatibility in order to prolong the lifetime of implanted materials, switchable antimicrobial property to eliminate infection and inflammation and outstanding mechanical performance to avoid the failure of the implanted material. To address these points, derivatives of zwitterionic carboxybetaine were developed with hydroxyl group(s), which can switch between the lactone form (antimicrobial) and the zwitterionic form (anti-fouling) . Besides, the intramolecular hydrogen bonds enhance the mechanical property of the zwitterionic hydrogel, making it a viable material for coatings. However, the current increasing rates reported by the World Health Organisation of antibiotic resistance in pathogenic microbes are becoming a global health threat. Therefore, more resources and efforts must be done worldwide in order to develop new antimicrobial approaches such as antimicrobial hydrogels, because they have shown to be very effective in preventing and treating clinically relevant multidrug-resistant pathogens.
The development of new advanced porous polymers has received much interest due to their potential to combine the properties of porous materials and polymers . Many industrial fields such as gas storage and separation materials [129, 130], control drug delivery , catalysts , supports for electrochemical sensing , low-dielectric constant materials , packing materials for chromatography , and engineered three-dimensional porous matrices (
8. Applications and future trends
Acrylate-based hydrogels are being widely investigated for their use in biomedical applications such as tissue engineering and systems for controlled delivery of biologically active agents. Hydrogels have been derivatized to enable crosslinking and photo-polymerisation, form electro-conducting networks and confer degradability to suit different biomedical applications. The pioneering work by Hubbel et al.  on bioerodible hydrogels based on copolymers of polylactic acid (PLA), copolymers of alpha hydroxyacids and polyethylene glycol (PEG) with acrylate end groups facilitated new tools for controlled release formulations and delivery platforms. These systems could be tuned to vary the degradation times from very short to long periods by changing composition of the hydrophobic ester block. Rational design using pH and thermoresponsive polymers have also been reported for drug delivery applications. A novel pH-responsive hydrogel based on carboxymethyl cellulose/2-hydroxyethyl acrylate was synthesised  as a transdermal delivery system for naringenin. The polymer exhibited different swelling ratio at different pH with Fickian diffusion characteristics, while mechanical properties could be controlled by varying cross-linking density and grafting. Photo-cross-linked hydrogels have also been used for the controlled release of various hydrophobic and hydrophilic drugs, including hydrogels based on methacrylate-terminated PEG  and PEG-poly(ε-caprolactone) multiblock copolymers . Another family of hydrogels that is being explored for possible applications is thiol-acrylate hydrogels that were tailored to vary degradation rates and enhance cell viability particularly for cranial defects [161, 162]. A study of the multiscale modelling of the reaction kinetics of these thiol-acrylates with the mechanical properties revealed that the stiffness was related to light intensity, concentration of thiol groups and pH, thereby making it possible to tune the hydrogel properties. More recently, the synthesis and characterisation of novel acrylate-terminated amide-linked PEG-PDLA and PEG-PLLA star block copolymers were reported by Buwalda et al. . Using PEG-PLA star block copolymer hydrogels through physical cross-linking and combining with photopolymerization, in situ gelation was achieved. Selected copolymers were initially physically cross-linked by stereocomplexation that on subsequent photopolymerization generated robust and stable hydrogels. This system was injectable and the hydrogels that were formed in situ were stable over periods of time that would be appropriate for long-term drug delivery.
Due to their versatile properties, acrylic-based hydrogels are currently used or proposed for a wide range of biomedical and bioengineering fields such as tissue engineering, orthopaedics, ophthalmology and dental materials. However, the number of applications of this type of biomaterials could be significantly increased if their properties would be improved, such as their mechanical strength in the hydrated state at the body temperature. In this regard, acrylic-based biomaterials have been developed as interpenetrating polymer networks, composites with incorporated particles such as fibres and/or advanced nanomaterials such as graphene, graphene oxide and carbon nanofibers, among many others, in order to improve their mechanical performance, electricity, thermal behaviour/degradation, water sorption/diffusion, biological interaction, antimicrobial activity and porosity values, required for certain applications. Furthermore, acrylic-based hydrogel scaffolds have been produced with the suitable morphology of pores and porosity for tissue regeneration by following developed protocols and sophisticated techniques. Nevertheless, in spite of the impressive advancements achieved so far, which are presented in this book chapter, many challenges still remain to design acrylate hydrogels with specific polymers for advanced applications in biomaterial science.
This work was supported by the 2019-231-003UCV grant from the Universidad Católica de Valencia San Vicente Mártir.