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Polymeric and Self Assembled Hydrogels
From Fundamental Understanding to Applications
By Xian Jun Loh, Oren A. Scherman
The Royal Society of ChemistryCopyright © 2013 The Royal Society of Chemistry
All rights reserved.
XIAN JUN LOH AND OREN A. SCHERMAN
Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Contact lenses, shoe sole cushions, vitamin capsules, baby diapers and wound dressings, all these objects have a material in common: hydrogels. The use of hydrogels has experienced phenomenal growth and they are now widely used by almost everyone and in almost every imaginable application. Yet, in spite of its wide applicability, there is still intense research work being carried out on hydrogels. Every year, for the past five years, more than 2000 publications are reported in the scientific literature, with the number growing year on year (Figure 1.1). Hydrogels can generally be classified by their origin and the type of cross-linking.
Hydrogels can originate from either natural or synthetic sources. In general, natural hydrogels can be protein or polysaccharide derived. Amino acids and saccharide monomer units are generally water soluble. Thus, along with the high molecular weight of these components and their high degree of inter-molecular interactions, they have a tendency to form self-assembled 3D structures that can swell in water. For example, the basis of human tissue scaffold is the extracellular matrix (ECM). The ECM provides structural and mechanical support to the cells and is the main component of connective tissue in animals. Polysaccharide gels and fibrous proteins fill up the interstitial matrix and act as a compression buffer against the stress placed on the ECM. Some examples of naturally derived hydrogels include collagen, gelatin, fibrin, hyaluronic acid and chitosan.
Common synthetic hydrogels can be classified into stable, biodegradable, peptide and stimuli-responsive hydrogels. Examples of stable gels are poly(vinyl alcohol) gels and acrylamide/acrylate-based gels, which are typically very stable and do not readily degrade. On the other hand, biodegradable gels are designed to disintegrate into their monomeric components after some time. The main constituents of these gels are polyesters such as poly(lactic acid), poly(ε-caprolactone) or poly[(R)-3-hydroxybutyrate]. Peptide hydrogels sit at the interface between natural and synthetic hydrogels. They can be prepared by standard peptide synthetic methods, which have been gaining research interest in the past few years. These peptide hydrogels are generally cyto-compatible and do not show significant immune response in biological systems. As a result of their folding capabilities to form α-helices, b-sheets and random coils, they offer unique insights into the molecular construction of a hydrogel, which can be exploited to form a variety of soft materials. Stimuli-responsive hydrogels such Pluronics/Poloxamer or poly(N-isopropylacrylamide) hydrogels offer a degree of control over the physical behaviour of the hydrogels upon application of an external stimulus, in this case, temperature. External control is useful for a variety of reasons, for example, the regulation of the behaviour of the hydrogels can allow users to fine-tune the rate of the release of a loaded cargo in the gel matrix. Potentially, dual-phased release can be realised with a system incorporating multiple stimuli-responsive moieties.
1.2 Type of Cross-Linking
Conventional hydrogels are 3D water-swollen structures that are cross-linked by non-reversible chemical bonds. However, these hydrogels can be brittle in nature, causing the swollen gels to shatter upon application of pressure. A non-covalent approach, based on physical interactions, offers an attractive alternative to producing hydrogels. This creates a self-correcting system which adjusts itself to external pressure, thus resolving the brittleness problem. Recently, a hydrogel system based on clay, water and a dendritic binder has been reported. The simple mixture of these three components leads to the formation of free-standing hydrogels with excellent mechanical properties. Supramolecular hydrogels or gel assemblies based on host–guest interactions have also been reported. Temperature-induced gelation based on hydrophobic/hydrophilic switching has also been investigated in great detail. Triggered hydrogel systems based on a change in pH have also been investigated but these are less common. Supra-molecular hydrogels have been reported with low molecular weight hydrogelators and the interested reader is referred to several notable papers and reviews.
1.3 Cutting-edge Research
Current cutting-edge research utilising hydrogels focuses on applications such as photonic gel films for mechanochromic sensing, soft circuits, 3D cell culture and as a sensor for a cell's mechanical behaviour. These new and exciting applications are all being developed to tackle real and very urgent world problems and some of these applications require hydrogels with unique physical properties. For example, there is a worldwide shortage of organs for transplant due to cultural and societal boundaries on organ donation and transplant acceptance. Tissue engineering has been proposed as a potential strategy to provide a partial solution to this problem. Instead of seeking organ donors, entire organs may be built in the laboratory (Figure 1.2). "Printable" organs have been suggested as a very realistic and attractive idea. The key components required to print an organ are a printer, ink, paper and a bioreactor. Recently, Alblas and her co-workers have developed a way to "print" stable cell-containing scaffolds. Thermogelling polymers were used as the polymer hydrogel "ink". These printed gel structures were heated to form gels and further cross-linked to form permanent gel structures. Stem cells were incorporated into the hydrogels and can be used to initiate tissue generation within the scaffolds. A cell-laden hydrogel can be used to build much more complex structures such as tissue grafts that have blood vessels built into them. With this technology, even the fabrication of an entire organ may soon be possible via a bottom-up approach. However, there are concerns as to whether the material is entirely useful for clinical applications as these gels are not natural gels, an aspect that requires further development.
In another new breakthrough in the field of hydrogels, Varghese and coworkers have developed the hydrogel version of Velcro, a self-healing hydrogel that binds in seconds and is able to be stretched repeatedly. This material utilises the ability of the carboxylic acid group to form hydrogen bonds with each other to create the self-healing effect. By varying pH levels, the pieces are able to weld and separate very easily. The process was successfully repeated many times without any reduction in material strength. Numerous potential applications of this material include medical sutures, targeted drug delivery, industrial sealants and self-healing plastics.
Hydrogels have also been making inroads into the field of soft electronics. Supercapacitors are complementary devices to batteries in energy storage and delivery schemes, providing quick bursts of power when required. A poly(aniline) based hydrogel was prepared and used as electrodes in a supercapacitor. The new material has a capacitance about three times greater than a typical carbon supercapacitor. Supercapacitors are fabricated from two closely spaced, porous carbon electrodes that charge and discharge rapidly. Poly(aniline) was cross-linked with phytic acid to form the conductive porous hydrogel. The polymer can be synthesised using inkjet printing or spray coating each solution on a surface. The fabrication of the hydrogel is feasible for large-scale energy storage applications or miniaturised for microelectronic applications. This hydrogel supercapacitor is more cost-effective than the carbon supercapacitor, as the electrolyte it uses is water-based and cheaper than the organic ionic liquids used in carbon supercapacitors.
Recently, Thomas and co-workers have unveiled a photonic-crystal hydrogel material that reflects a wide range of wavelengths in response to a variety of stimuli. By changing the external gel environment, the wavelength of reflected light can be shifted from the ultraviolet region to the near infrared region. The polymer gel comprises two constituent polymers that self assemble into a structure that can interact with light and change the colour of the gel. This hydrogel can potentially be used as a colourimetric chemical sensor on clothing.
As a class of substances, hydrogels have been around for some time and still their applications continue to grow as the versatility of hydrogels is recognised and as new research and development increases their impact across ever-widening fields in science and technology: from aerospace to agriculture, from electricity to the environment, from food to footwear and from medical to military applications. This vibrant field is more than mere laboratory curiosity as in this increasingly dynamic and interdependent world, close interactions are needed between laboratory researchers and industrial partners to bring technology to fruition.CHAPTER 2
Fabrication, Structure, Mechanical Properties, and Applications of Tetra-PEG Hydrogels
MITSUHIRO SHIBAYAMA AND TAKAMASA SAKAI
Hydrogels have been used in daily life for many years such as in diapers, contact lenses, cosmetics, foods, drug reservoirs, etc. Despite the unique characteristics of high water absorbency and water-retention capability, practical applications of hydrogels, especially as structural materials, are restricted because of their low mechanical strength and brittleness. There are several reasons why hydrogels are mechanically weak. In addition to their low content of polymer, e.g. 10 wt% of polymer in aqueous media, inhomogeneities in the network structure of gels lower their mechanical properties far below what they should be. The inhomogeneities are categorized into spatial, topological, connectivity, and motility inhomogeneities. Figure 2.1 (top) indicates concentration fluctuations in polymer solutions (left) and in gels (right). In polymer solutions, only thermal concentration fluctuations exist, of which the average is zero. On the other hand, gels contain both frozen concentration fluctuations (the low-frequency component in this figure; blue) introduced by cross-linking and thermal concentration fluctuations (high-frequency component; red). The introduction of cross-links brings about various types of inhomogeneities as shown in Figure 2.1 (bottom), i.e. spatial inhomogeneities (nonrandom spatial variations of cross-link density in a gel), topological inhomogeneities (defects of network, such as dangling chains, loops, chain entrapment, etc.), connectivity inhomogeneities, and motility inhomogeneities (local degree of mobility). In general, it is difficult to control and/or reduce these inhomogeneities, resulting in complexity and inferior physical properties of polymer gels. For example, because of the presence of dangling chains (topological inhomogeneities), they begin to break from the weakest link, thus reducing the whole mechanical strength.
Many attempts were made to obtain an ideal gel network consisting of unimodal strands, free from defects or entanglements. Some of these attempts included gelation by physical cross-linking, gelation from prepolymers, and gelation from polymers by γ-ray irradiation. Homogeneity could be relatively easily obtained in thermoreversible physical gels. However, the homogeneity cannot be controlled strictly even in physical gels because cross-links are introduced randomly. In addition, because physical cross-linking is generally weaker than chemical cross-linking, the resulting physical gels are soft and weak. Gelation from prepolymers seemed more promising than the others because the detailed network structure was controllable by designing constitutional units, and the gelation process was well predicted by Flory's tree approximation. He et al. reported the synthesis of jungle-gym-type polyimide organogels using tri-functional cross-linkers and telechelic rigid aromatic oligomers as backbones, which had a high compression modulus. As for hydrogels, there were numerous studies to obtain the homogeneous bio-compatible hydrogels. As far as can be determined, no hydrogels formed from macromers have compressive strength reaching a MPa range, which is one of the most important criteria for practical use. The fragility likely comes from inhomogeneity of the network structure as discussed above.
It should be noted that most gels made from prepolymers are obtained by coupling asymmetrical components such as multi-functional cross-linkers and telechelic polymers (Figure 2.2a). These asymmetrical combinations should give the network a high degree of freedom, allowing various micro-structures including loops and defects. These micro-structures deprive a gel of cooperativeness, weakening the gel. A new strategy for forming a homogeneous network by decreasing the degree of freedom of the micro-network structure has been employed. A gel was formed by combining two well-defined symmetrical tetra-functional precursors (i.e. modules) of the same size (Figure 2.2b). As each prepolymers has four end-linking groups reacting with each other, these two prepolymers must connect alternately to avoid the self-biting reaction. This gelation process is a simple A–B type reaction in accordance with Flory's classical theory. This gel is named "Tetra-PEG gel" after its structure [PEG = poly(ethylene glycol)] and the name of the components. The constitutional prepolymers and the reaction were biocompatible, and the compressive strength of resulting gel was in the MPa range, which was much superior to those of agarose gels or acrylamide gels having the same network concentrations. It is believed that this methodology, i.e. module assembling by cross-end-coupling, opens a new paradigm of gel preparation.
Section 2.2 will describe the synthesis and characterization of Tetra-PEG macromers and gels. In Section 2.3, the structure of Tetra-PEG gels is discussed on the basis of small-angle neutron scattering (SANS) results. Section 2.4 is devoted to the discussion on the relationship between the mechanical properties and structure of Tetra-PEG gels. In Section 2.5, a variety of medical applications of Tetra-PEG gels are demonstrated. Finally, future directions of the study and application of Tetra-PEG gels are given.
2.2.1 Synthesis of Precursors
Tetrahydroxyl-terminated PEG (THPEG; Figure 2.3a) was synthesized by successive anionic polymerization reactions of ethylene oxide from the sodium alkoxide of pentaerythritol. Tetraamine-terminated PEG (TAPEG; Figure 2.3b) and tetra-NHS-glutarate-terminated PEG (TNPEG; Figure 2.3c) were successfully synthesized by changing the end-group of THPEG to amine and N-hydroxysuccinimidyl (NHS) ester, respectively. Previous studies reported by Sakai et al. provide the detailed synthesis method that was carried out.
Excerpted from Polymeric and Self Assembled Hydrogels by Xian Jun Loh, Oren A. Scherman. Copyright © 2013 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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