Instant welding of gels by dry chitosan interlayers

Hydrogels are materials that consist of a network of crosslinked polymer chains, the interstitial voids being filled with water (1), which can constitute some 10 to 90% of the total volume of the material. The polymer chains can be natural in origin, such as polysaccharides or proteins, or synthetic, such as poly(vinyl alcohol). The crosslinking in natural gels is generally physical in nature, involving phenomena such as entanglement or hydrogen bonding, while in synthetic hydrogels, it tends to be covalent. Familiar examples of hydrogels are the protein-based gelatin, which is employed to produce gels in the culinary world, or the synthetic sodium poly(acrylate), which becomes a hydrogel upon fluid absorption, and is used extensively in baby diapers. Hydrogels have proven to be extremely useful materials in many areas of the biological and medical sciences (2). Commonalities with human tissue, especially concerning their extremely high concentration of water, have meant that they can play useful roles in such diverse biomedical applications as contact lenses (3), tissue repair (4), and even facilitating interfaces with silicon-based devices (5). Hydrogels are, however, notoriously challenging to attach to each other, or to other elastomeric materials (6). In PNAS, Freedman et al. (7) describe a rapid, simple, and versatile approach to hydrogel–hydrogel and hydrogel–elastomer adhesion, based on the use of a sandwiched, dry, chitosan film.

Previous approaches to hydrogel bonding have generally involved the use of chemical functionalization or irradiation to create covalent bonding between the adhering materials or “adherends” (5, 8). While these approaches can yield effective adhesion, they generally suffer from impracticability in the surgical environment, either due to lengthy reaction times or complex protocols. Recently, an alternative approach, dubbed “topological adhesion” and based on hydrogen bonding and entanglement, has been shown to provide both better (three to four times) adhesion strength and greater convenience than covalent methods. Using a liquid chitosan bridging layer, Yang et al. (9) showed that chitosan molecules could essentially “stitch” the hydrogel surfaces together at the molecular scale. An advantage of chitosan (10) is that it is a natural product—a bio-compatible natural polysaccharide, based on β-1,4-D-glucosamine and prepared by partial de-acetylation of chitin, which is the second-most widely occurring biopolymer in nature (after cellulose) and is present in a broad range of species ranging from shrimp to fungi. The mechanism of topological adhesion involves the diffusion of the chitosan molecules (pKa ≈ 6.5) into the more alkaline hydrogels, where the amine groups deprotonate and are thus more likely to participate in hydrogen-bonding interactions with the entangled hydrogel polymer chains. The approach suffers from a weakness, however, which is the time required for the large chitosan molecules to diffuse across the interfacial water into the hydrogel surfaces. This can lead to application times on the order of minutes to hours, which can be problematic during surgery, for example.

It has been shown in unrelated studies that the slow-diffusion issue for wet-surface adhesion can be circumvented by means of dry, adhesive, polymeric interlayers that rapidly absorb water, swell, and crosslink the adherends (11). In other words, rather than the topographical-adhesion polymers diffusing through the water, the water moves into the dry adhesion layer (Fig. 1), presumably driven by the hydrophilicity of the polymers and the significant capillary forces at work (12). In PNAS, Freedman et al. (7) have applied the dry-interlayer approach to the chitosan adhesive system, thereby substantially enhancing both the speed and utility of this non-covalent, biopolymer-based gel-bonding system.

Fig. 1.

Cartoon of the dry, topological adhesion of gels (orange) via a dry chitosan layer. Top: Interfacial water (blue) on the gel surfaces is rapidly driven into a dry chitosan film (green) by means of capillary forces. Bottom: Expanded, hydrated chitosan (pale green) forms multiple hydrogen bonds (yellow) and entanglements with the polymer chains in the two gel pieces, to yield a strong, adhesive bond between them.

Dual-network hydrogels, such as alginate-poly(acrylamide), are tough materials that lend themselves well to biomedical applications (13). Freedman et al. (7) bonded pairs of such gel samples with a dry chitosan film between them, by applying pressure for 30 s. These sandwich-like structures were then investigated regarding their mechanical properties and the nature of the bonding interface. Standard peel tests under uniaxial tension ultimately resulted in cohesive failure of the gels, which limited the measured adhesion-energy values to an impressive 3,000 J.m⁻². Confocal microscopy with fluorescently labeled chitosan and energy-dispersive spectroscopy showed that, following adhesion, the dry chitosan layer constituted a narrow, homogeneous layer at the interface of the adherent gels.

In PNAS, Freedman et al. describe a rapid, simple, and versatile approach to hydrogel-hydrogel and hydrogel-elastomer adhesion, based on the use of a sandwiched, dry, chitosan film.

Control experiments were carried out, in which the chitosan interlayer was substituted by amine or carboxylic acid-containing polymers, such as poly(amino styrene) or poly(acrylic acid), respectively. In these cases, adhesion was found to be far inferior to that obtained with chitosan. This suggests that under the particular pH conditions used (Hanks’ Balanced Salt Solution at pH 7.4), chitosan exists in a “sweet spot,” at which its amino and hydroxyl groups, together with any residual acetyl groups from the original chitin, are capable of forming effective hydrogen-bonding interactions with the gels. Interestingly, the thickness of the dry chitosan films appeared to play a minimal role in the adhesion strength, while incubation of the sandwiches in Dulbecco’s Modified Eagle Medium at 37 °C for up to 48 h showed somewhat lower measured adhesion. However, it should be noted that this was due to cohesive failure (i.e., of the gels) rather than failure at the adhesive interface. The surface concentration of polymer chains in the hydrogels seemed to be an important factor. Reducing this concentration, either by swelling the gels in water or, in particular, by enhancing the proportion of dangling, less-crosslinked surface chains by means of oxygen-containing molding materials (14), led to reduced adhesion. The latter effect may also be partially due to the lower entanglement with dangling chains on the gel surface than with a crosslinked gel network.

The authors extended this approach to adhesion between hydrogels and elastomers, since this represents another current clinical challenge in areas such as wound dressings and bioelectronics. Specifically, the commercial, acrylic elastomer foam tape VHB 4905 (3M) could be attached to the alginate-poly(acrylamide) dual-network gel, using the dry chitosan interlayer, to yield a bond with an adhesion-energy value of >4,000 J.m⁻², likely due to the combined hydrogen-bonding and van der Waals interactions between the chitosan and the polyacrylate network of the VHB. While the composition of the VHB is proprietary, an x-ray photoelectron spectroscopy measurement of its surface did not reveal the presence of nitrogen, implying that nitrogen-containing groups, such as amine, are not required for strong adhesion to the chitosan interlayer to take place. Little diminution of the adhesion energy was measured after 24 h incubation in culture medium. An interesting benefit of the elastomer coating was observed; using dry chitosan films to coat a hydrogel sample on both sides with VHB substantially reduced its rate of dehydration—a potential advantage when gel applications involve exposure to air.

Potential biomedical applications of the dry chitosan gel-adhesion approach have been demonstrated by Freedman et al. (7), including the wrapping of a gel piece around cylindrical objects (mimicking bowel, tendons, or nerves, for example) and fastening with the dry chitosan adhesive. This has the advantage that the gel remains firmly in place while not adhering to the object—ideal properties for the inhibition of post-surgical fibrotic adhesion formation. Such wrappings can also be applied for local cooling, thanks to their high water content. Potential is seen here for the treatment of burn injuries, since, in addition to cooling, the gel can also prevent rapid fluid loss. Finally, it was demonstrated that the combination of dry chitosan films and gels can be used as a mechanical support for liquid chitosan in the treatment of internal fluid leaks, thus effectively constituting a surgical “puncture-repair kit.” This approach was successfully tested on a swine aortic model through thousands of simulated cardiac cycles and demonstrated significantly higher burst pressures than other commonly used bio-adhesives.

While the properties of hydrogels are clearly of great biomedical interest and the materials are already familiar in clinical settings, practical difficulties with current technologies have limited their widespread application. It is to be hoped that the authors’ simple approach of using an adhesive layer consisting of a dry chitosan film will enable far more widespread medical applications of hydrogels, with consequent improvements in effectiveness for a broad range of gel-based treatments and human-interfaced diagnostics.