**7. Porosity in scaffolds for tissue engineering**

Polyacrylic acid is a pH-sensitive and biocompatible polymer that is being used in many biomedical fields [26]. It has attracted considerable interest because of its therapeutic use, due to its ability to swell reversibly with changes in pH. Thus, GO functionalized with PAA (GO-PAA) by *in situ* atom transfer radical polymerization (ATRP) showed potential use as an intracellular protein carrier using bovine serum albumin (BSA) as a model protein [87]. This application is very important because proteins participate in all vital body processes and these perform an essential function inside cells as enzymes, transduction signals and gene regulation. Another pH-sensitive terpolymer hydrogel, poly(acryl amide-co-2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylamido glycolic acid), with applications in drug release showed a quasi-Fickian diffusion mechanism with partly chain relaxation controlled diffusion. These hydrogels demonstrated a sharp change in its water absorbency and molecular weight between cross-

The effect of temperature on swelling properties of acrylic hydrogels is also very important [86], and they can be modified to exhibit fast temperature sensitivity, and improved oscillating swelling-deswelling properties as, for example, in thermosensitive poly(N-isopropyl

In biomedicine, bacterial infections can lead to implant failure, which may cause major economic losses and suffering among patients despite the use of preoperative antibiotic prophylaxis and the aseptic processing of materials. Therefore, novel antibacterial materials are urgently needed for medical uses [90]. However, acrylics itself do not have antibacterial activity intrinsically, and therefore some fillers and antibacterial agents need to be incorporated by physical blending in order to produce an acrylic-based antibacterial material [91]. Thus, graphene has emerged as a novel green broad-spectrum antibacterial material, with little bacterial resistance and tolerable cytotoxic effect on mammalian cells. It exerts its antibacterial action via physical damages through direct contact of its sharp edges with bacterial membranes and destructive extraction of lipid molecules. The graphene-based nanocomposites have a wide range of biomedical applications such as wound dressing due to its superior

In the field of dental materials, since methyl methacrylate was firstly used in tooth restoration in 1937, methacrylate monomers having good biocompatibility and adhesive property have been extensively used as dental materials [91]. The most commonly used methacrylate monomers in commercial dental resin-based materials are methyl methacrylate (MMA), 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropyl)-phenyl]propane (Bis-GMA), 1,6-bis-[2-methacryloyloxyethoxycarbo nylamino]-2,4,4-trimethylhexane (UDMA) and tri-ethylene glycol dimethacrylate (TEGDMA) [93]. However, the dental materials produced with these monomers are not of antibacterial nature, which is very important in this biomedical field. Thus, another strategy to design acrylic hydrogels with desired antibacterial performance consists of adding silver nanoparticles (Ag NPs). This modification produced a strong antibacterial activity against *Escherichia coli* and also

links of the network with a change in pH of the swelling media [88].

acrylamide-co-acrylic acid) hydrogels [89].

antibacterial properties and good biocompatibility [92].

**6. Antibacterial activity**

84 Acrylic Polymers in Healthcare

Tissue engineering holds great promise for regeneration and repair of diseased tissues, making the development of new porous supports as scaffolds for tissue regeneration a topic of great interest in biomedical research. Hydrogels have emerged as leading candidates for engineered tissue scaffolds due to of their biocompatibility and similarities to native extracellular matrix. However, precise control of hydrogel properties such as high porosity, remains a challenge. Traditional techniques for creating bulk porosity in polymers have demonstrated success in hydrogels for tissue engineering. However, some problems related to direct cell encapsulation often occur. Emerging technologies have demonstrated the ability to control porosity and morphology in hydrogels, creating engineered tissues with structure and function similar to native tissues [99].

The applications of porous materials are nowadays widespread. The interconnection and geometry of pores, which depend on the tissue to regenerate, physicochemical properties and mechanical resistance of the material, play in these biomedical applications a major role. Thus, there are several methods to produce *scaffolds*, which include gas foaming [100], sintering fiber meshes [101], solvent casting [102], polymerization in solution [80, 103], porogen technique [104, 105], freeze-drying techniques [106, 107], electrospinning [108], 3D printing [109], 3D bioplotting of scaffold with cells [110], etc. For example, acrylic scaffolds with interconnected spherical pores and controlled hydrophilicity with interconnected porous structure were synthesized using a template of sintered PMMA microspheres of controlled size. In these scaffolds, the geometric characteristics (pore size, connectivity and porosity) and the physicochemical properties of the resulting material can be controlled in an independent way. Copolymerization of hydrophobic ethyl acrylate and hydrophilic hydroxyethyl methacrylate comonomers in the free space of the template and subsequent solution of the PMMA microspheres gave rise to the scaffold with the designed pore architecture (see **Figure 3**) [105].

Another example is the novel preparation of gelatin-PHEMA porous scaffolds by freeze-drying technique, in which morphology was assessed by SEM and μ-CT (**Figure 4**). Four types of novel hydrogels using different methacrylamide-modified gelatin/2-hydroxyethyl methacrylate ratios between 1/0 and 1/2 (w/w) (samples from C0 to C3) were prepared in this study, and the results indicated that the HEMA content in the initial polymerization mixtures modulates the architecture of the porous scaffolds from straightforward, top-to-bottom oriented channels for hydrogels possessing the lowest HEMA content to a complex and dense internal porosity of the channels in the case of higher HEMA loaded materials. It is important to notice that the covalently bound gelatin sequences significantly improve the biocompatibility of PHEMAbased hydrogels, which is very convenient for tissue engineering purposes.

Superporous acrylic scaffolds can also be prepared by the salt-leaching technique using NaCl or (NH4 ) 2 SO<sup>4</sup> as a porogen [111] or with many other porogenic agents such as ammonium oxalate crystals [112].

By submitting carbon dioxide (CO<sup>2</sup> ) to supercritical conditions (*P* = 160–260 bar, *T* = 60°C) after certain time and then rapidly depressurize, it is also possible to fabricate porous structures that are related to the supercritical parameters and to the polymer blend composition [113]. The use of carbon dioxide (CO<sup>2</sup> ) to create such scaffolds has received some attention in the past. But, many researchers believe that although CO<sup>2</sup> processing of polymers can lead to porous scaffolds, there is limited interconnectivity between the pores. However, highly porous (greater than 85%) and well-interconnected scaffolds were obtained in a blend of poly(ethyl methacrylate) and tetrahydrofurfuryl methacrylate (PEMA/THFMA) showing promise for potential applications in cartilage repair [114].

Probably the most sophisticated techniques to produce scaffolds are electrospinning, 3D printing and bioprinting. Electrospinning is composed of a high-voltage DC power supply, an infusion pumps and a syringe with a needle tip usually with a diameter of 0.5 mm, and for example, biodegradable nanofibrous poly(l-lactic acid) (PLLA) scaffolds have been prepared by this process for use in tissue regeneration [115]. 3D printing promises to produce complex biomedical devices according to computer design using patient-specific anatomical data. This 3D printing technique has slowly evolved to create one-of-a-kind devices, implants, scaffolds for tissue engineering and drug delivery systems among other important applications. However, several technological limitations, related to the kind of commercially printable materials available and other technical printing aspects, must still be overcome. The common 3D printing technologies such as three-dimensional printing, fused deposition modeling, selective laser sintering, stereolithography and 3D Plotting/Direct-Write/Bioprinting, are still Latest Improvements of Acrylic-Based Polymer Properties for Biomedical Applications http://dx.doi.org/10.5772/intechopen.68996 87

technique [104, 105], freeze-drying techniques [106, 107], electrospinning [108], 3D printing [109], 3D bioplotting of scaffold with cells [110], etc. For example, acrylic scaffolds with interconnected spherical pores and controlled hydrophilicity with interconnected porous structure were synthesized using a template of sintered PMMA microspheres of controlled size. In these scaffolds, the geometric characteristics (pore size, connectivity and porosity) and the physicochemical properties of the resulting material can be controlled in an independent way. Copolymerization of hydrophobic ethyl acrylate and hydrophilic hydroxyethyl methacrylate comonomers in the free space of the template and subsequent solution of the PMMA microspheres gave rise to the scaffold with the designed pore architecture (see **Figure 3**) [105].

Another example is the novel preparation of gelatin-PHEMA porous scaffolds by freeze-drying technique, in which morphology was assessed by SEM and μ-CT (**Figure 4**). Four types of novel hydrogels using different methacrylamide-modified gelatin/2-hydroxyethyl methacrylate ratios between 1/0 and 1/2 (w/w) (samples from C0 to C3) were prepared in this study, and the results indicated that the HEMA content in the initial polymerization mixtures modulates the architecture of the porous scaffolds from straightforward, top-to-bottom oriented channels for hydrogels possessing the lowest HEMA content to a complex and dense internal porosity of the channels in the case of higher HEMA loaded materials. It is important to notice that the covalently bound gelatin sequences significantly improve the biocompatibility of PHEMA-

Superporous acrylic scaffolds can also be prepared by the salt-leaching technique using NaCl

after certain time and then rapidly depressurize, it is also possible to fabricate porous structures that are related to the supercritical parameters and to the polymer blend composition

to porous scaffolds, there is limited interconnectivity between the pores. However, highly porous (greater than 85%) and well-interconnected scaffolds were obtained in a blend of poly(ethyl methacrylate) and tetrahydrofurfuryl methacrylate (PEMA/THFMA) showing

Probably the most sophisticated techniques to produce scaffolds are electrospinning, 3D printing and bioprinting. Electrospinning is composed of a high-voltage DC power supply, an infusion pumps and a syringe with a needle tip usually with a diameter of 0.5 mm, and for example, biodegradable nanofibrous poly(l-lactic acid) (PLLA) scaffolds have been prepared by this process for use in tissue regeneration [115]. 3D printing promises to produce complex biomedical devices according to computer design using patient-specific anatomical data. This 3D printing technique has slowly evolved to create one-of-a-kind devices, implants, scaffolds for tissue engineering and drug delivery systems among other important applications. However, several technological limitations, related to the kind of commercially printable materials available and other technical printing aspects, must still be overcome. The common 3D printing technologies such as three-dimensional printing, fused deposition modeling, selective laser sintering, stereolithography and 3D Plotting/Direct-Write/Bioprinting, are still

as a porogen [111] or with many other porogenic agents such as ammonium

) to supercritical conditions (*P* = 160–260 bar, *T* = 60°C)

) to create such scaffolds has received some attention in

processing of polymers can lead

based hydrogels, which is very convenient for tissue engineering purposes.

or (NH4 ) 2 SO<sup>4</sup>

oxalate crystals [112].

86 Acrylic Polymers in Healthcare

By submitting carbon dioxide (CO<sup>2</sup>

[113]. The use of carbon dioxide (CO<sup>2</sup>

the past. But, many researchers believe that although CO<sup>2</sup>

promise for potential applications in cartilage repair [114].

**Figure 3.** SEM micrographs of EA/HEMA copolymer scaffolds (30% HEMA) at different magnifications. Reprinted with permission from Ref. [105].

under deep research for the progress of each technology in tissue engineering. Bioprinting is the more advanced 3D printing technology because it consists of printing cells combined with custom 3D scaffolds for personalized regenerative medicine [109].

Mechanical resistance depends both on the material properties and on the interconnected pore structure of the scaffold. This problem is more serious in the case of porous acrylic hydrogels, which exhibit very poor mechanical properties in their swollen state [80]. Therefore, it is

**Figure 4.** Morphology of the gelatin-PHEMA porous scaffolds as obtained through μ-CT (panels (a)–(c): (a), top view; (b), bottom view; (c), side view) and SEM (panel (d)) analyses: panel (I), C0; panel (II), C1; panel (III), C2; panel (IV), C3. Reprinted with permission from Ref. [107].

usually necessary to enhance the mechanical properties of these porous structures by means of the methods, shown in Chapter 2, with nanomaterials or other techniques. For example, the use of a hybrid hydrogel nanocomposite of silica/poly(2-hydroxyethyl acrylate) as scaffold material matrix greatly improves the mechanical properties, and the silica phase of the scaffold was effectively interconnected and continuous, able to withstand pyrolysis without losing the pore architecture of the scaffold [37].

Other modifications of acrylics such as those of PHEMA with cholesterol methacrylate (CHLMA) and laminin have been developed in the presence of ammonium oxalate crystals to introduce interconnected superpores in the matrix in order to design superporous scaffolds that promote cell-surface interaction [116]. PHEMA has also been modified with lamininderived Ac-CGGASIKVAVS-OH peptide sequences to construct scaffolds that promote cell adhesion and neural differentiation. With the same goal, nanofiber scaffolds prepared by electrospinning were treated with oxygen plasma and then simultaneously *in situ* grafted with hydrophilic acrylic acid to obtain PLLA-g-PAA with a modified surface, which significantly improved cell adhesion and proliferation [115].

Recent studies of 3D microenvironment comprising fibronectin-coated PMMA/PC-based multicomponent polymeric systems promoted differentiation of primary human osteoblasts, which hereby renders a promising tool for tissue-specific *in vitro* preconditioning of osteoblasts designated for clinically oriented bone augmentation or regeneration. Furthermore, morphogenesis and fluorescence dye-based live/dead staining revealed homogenous cell coverage of the microcavities, whereas cells showed high viability up to 14 days, and Azur II staining proved formation of uniform sized multi-layered aggregates, exhibiting progressive intracellular deposition of extracellular bone matrix constituents comprising fibronectin, osteocalcin and osteonectin from day 7 onwards [117].

Polysaccharide hydrogels have become increasingly studied as matrices in soft-tissue engineering due to their known cytocompatibility. Thus, for example, crosslinkable dextran methacrylates and hyaluronan methacrylate hydrogels, which are candidates as matrices for soft-tissue reconstruction, were synthesized, showing that the *in vitro* degradation behavior of these kinds of hydrogels could be controlled by the polysaccharide structure and the crosslinking density. Furthermore, under *in vitro* conditions, these materials had no cytotoxic effects against fibroblasts, and the use of composite gels improved the adherence of cells [118].

Even though the great advances have been achieved in scaffold design of acrylic-based materials, much research has to be conducted still in order to find new ways and methods capable of providing suitable advanced porous materials for tissue engineering applications.
