Self-healing hydrogels are a specialized type of polymer hydrogel. A hydrogel is a macromolecular polymer gel constructed of a network of crosslinked polymer chains. Hydrogels are synthesized from hydrophilic monomers by either chain or step growth, along with a functional crosslinker to promote network formation. A net-like structure along with void imperfections enhance the hydrogel's ability to absorb large amounts of water via hydrogen bonding. As a result, hydrogels, self-healing alike, develop characteristic firm yet elastic mechanical properties. Self-healing refers to the spontaneous formation of new bonds when old bonds are broken within a material. The structure of the hydrogel along with electrostatic attraction forces drive new bond formation through reconstructive covalent dangling side chain or non-covalent hydrogen bonding. These flesh-like properties have motivated the research and development of self-healing hydrogels in fields such as reconstructive tissue engineering as scaffolding, as well as use in passive and preventive applications.
Synthesis A variety of different polymerization methods may be utilized for the synthesis of the polymer chains that make up hydrogels. Their properties depend on how these chains are crosslinked.
Crosslinking Crosslinking is the process of joining two or more polymer chains. Both chemical and physical crosslinking exists. In addition, both natural polymers such as proteins or synthetic polymers with a high affinity for water may be used as starting materials when selecting a hydrogel.Hennink, W.E., van Nostrum, C.F. (2002) Advanced Drug Deliveries Review 54: 13-36.Abstract Different crosslinking methods can be implemented for the design of a hydrogel. By definition, a crosslinked polymer gel is a macromolecule that solvent will not dissolve. Due to the polymeric domains created by crosslinking in the gel microstructure, hydrogels are not homogenous within the selected solvent system. The following sections summarize the chemical and physical methods by which hydrogels are crosslinked.
Chemical crosslinking Method Process Radical polymerization Radical polymerization is a method of chain growth polymerization. Chain-growth polymerization is one of the most common methods for synthesizing hydrogels. Both free-radical polymerization, and more recently, controlled-radical polymerization have been utilized for the preparation of self healing hydrogels. Free radical polymerization consists of initiation, propagation, and termination. After initiation, a free radical active site is generated which adds monomers in a chain link-like fashion.Compared to free radical polymerizations, controlled living radial polymerizations offer the benefits of longer growing chain life for macromolecular engineering. A handful of controlled radical polymerizations currently utilized for self healing hydrogel synthesis include: Atomic transfer radical polymerization (ATRP) Reversible addition fragmentation transfer (RAFT) polymerization. Other chain growth methods include anionic and cationic polymerization. Both anionic and cationic methods suffer from extreme sensitivity toward aqueous environments and therefore, are not used in the synthesis of polymeric hydrogels. Addition and Condensation Polymerization Water-soluble monomers can be converted into hydrogels using crosslinking agents such as TEMED. Polyfunctional crosslinking agents react with monomer functional groups in a stepwise addition reaction. Condensation polymerization is the second type of step growth polymerization. Like addition polymerization, functional groups react in a step-wise manner to form a covalently linked gel network. Polyurethanes, polyesters, or nylon polymers are most commonly synthesized for hydrogel applications. Gamma and Electron Beam Polymerization High energy electromagnetic irradiation can crosslink water-soluble monomer or polymer chain ends without the addition of a crosslinker. During irradiation, using a gamma or electron beam, aqueous solutions of monomers are polymerized to form a hydrogel. Gamma and electron beam polymerizations parallel the initiation, propagation, and termination model held in free radical polymerization. In this process, hydroxyl radicals are formed and initiate free radical polymerization among the vinyl monomers which propagate in a rapid chain addition fashion. The hydrogel is finally formed once the network reaches the critical gelation point. This process has an advantage over other crosslinking methods since it can be performed at room temperature and in physiological pH without using toxic and hard to remove crosslinking agents
Physical crosslinking Method Process Ionic interactions Using ionic interactions, the process can be performed under mild conditions, at room temperature and physiological pH. It also does not necessarily need the presence of ionic groups in the polymer for the hydrogel to form. The use of metallic ions yield stronger hydrogel. Crystallization This method is specific to use the Poly(vinyl alcohol) (PVA) where the aqueous solution of this polymer when undergoing a freeze-thawing process creates a strong and highly elastic gel is formed. Stereocomplex Formation For stereocomplex formation, a hydrogel is formed through crosslinking that is formed between lactic acid oligomers of opposite chirality. Hydrophobized polysaccharides Examples of polysaccharides reported in literature used for the preparation of physically crosslinked hydrogels by hydrophobic modification are chitosan, dextran, pullulan and carboxymethyl curdlan. The hydrophobic interactions results in the polymer to swell and uptake water that forms the hydrogel. Protein interaction Protein engineering has made it possible for engineers to prepare a sequential block copolymers that contains repetition of silk-like and elastine-like blocks called ProLastins. These ProLastins are fluid solutions in water that can undergo a transformation from solution to gel under physiological conditions because of the crystallization of the silk-like domains. Hydrogen bonds Poly Acrylic Acid (PAA) and Poly Methacrylic Acid (PMA) form complexes with Poly Ethylene Glycol (PEG) from the hydrogen bonds between the oxygen of the PEG and carboxylic group of PMA. This interaction allows for the complex to absorb liquids and swell at low pH which transforms the system into a gel.
Interface chemistry of self-healing hydrogels
Hydrogen bonding Hydrogen bonding is a strong intermolecular force that forms a special type of dipole-dipole attraction. Hydrogen bonds form when a hydrogen atom bonded to a strongly electronegative atom is around another electronegative atom with a lone pair of electrons. Hydrogen bonds are stronger than normal dipole-dipole interactions and dispersion forces but they remain weaker than covalent and ionic bonds. In hydrogels, structure and stability of water molecules are highly affected by the bonds. The polar groups in the polymer strongly bind water molecules and form hydrogen bonds which also cause hydrophobic effects to occur. These hydrophobic effects can be exploited to design physically crosslinked hydrogels that exhibit self healing abilities. The hydrophobic effects combined with the hydrophilic effects within the hydrogel structure can be balanced through dangling side chains that mediates the hydrogen bonding that occurs between two separate hydrogel pieces or across a ruptured hydrogel.
Dangling side chain A dangling side chain is a hydrocarbon chain side chains that branch off of the backbone of the polymer. Attached to the side chain are polar functional groups. The side chains "dangle" across the surface of the hydrogel, allowing it to interact with other functional groups and form new bonds. The ideal side chain would be long and flexible so it could reach across the surface to react, but short enough to minimize steric hindrance and collapse from the hydrophobic effect. The side chains need to keep both the hydrophobic and hydrophilic effects in balance. In a study performed by the University of California San Diego to compare healing ability, hydrogels of varying side chain lengths with similar crosslinking contents were compared and the results showed that healing ability of the hydrogels depends nonmonotonically on the side chain length. With shorter side chain lengths, there is limited reach of the carboxyl group which decreases the mediation of the hydrogen bonds across the interface. As the chain increases in length, the reach of the carboxyl group becomes more flexible and the hydrogen bonds can mediated. However, when a side chain length is too long, the interruption between the interaction of the carboxyl and amide groups that help to mediate the hydrogen bonds. It can also accumulate and collapse the hydrogel and prevent the healing from occurring.
Surfactant effects Most self-healing hydrogels rely on electrostatic attraction to spontaneously create new bonds. The electrostatic attraction can be masked using protonation of the polar functional groups. When the pH is raised the polar functional groups become deprotonated, freeing the polar functional group to react. Since the hydrogels rely on electrostatic attraction for self-healing, the process can be affected by electrostatic screening. The effects of a change in salinity can be modeled using the Gouy-Chapman-Stern theory Double Layer .
: Zeta Potential : Salinity of solution : Distance between molecules, if the polar functional group is one molecule and an ion in solution is the other. To calculate the Gouy–Chapmanm potential, the salinity factor must be calculated. The expression given for the salinity factor is as follows:
: charge of ion
: number of ions per cubic meter : dielectric constant of solvent : , the permittivity of free space : , Boltzmann constant : thermodynamic temperature
These effects become important when considering the application of self-healing hydrogels to the medical field. They will be affected by the pH and salinity of blood.
These effects also come into play during synthesis when trying to add large hydrophobes to a hydrophilic polymer backbone. A research group from the Istanbul Technical University has shown that large hydrophobes can be added by adding an electrolyte in a sufficient amount. During synthesis, the hydrophobes were held in micelles before attaching to the polymer backbone. By increasing the salinity of the solution, the micelles were able to grow and encompass more hydrophobes. If there are more hydrophobes in a micelle, then the solubility of the hydrophobe increases. The increase in the solubility lead to an increase in the formation of hydrogels with large hydrophobes.
Physical properties
Surface properties
Surface tension and energy The surface tension (γ) of a material is directly related to its intramolecular and intermolecular forces. The stronger the force, the greater the surface tension. This can be modeled by an equation:
Where ΔvapU is the energy of vaporization, NA is the Avogadro constant, and a2 is the surface area per molecule. This equation also implies that the energy of vaporization affects surface tension. It is known that the stronger the force, the higher the energy of vaporization. Surface tension can then be used to calculate surface energy (uσ). An equation describing this property is:
where T is temperature and the system is at constant pressure and area. Specifically for hydrogels, the free surface energy can be predicted using the Flory–Huggins free energy function for the hydrogels.
For hydrogels, surface tension plays a role in several additional characteristics including swelling ratio and stabilization.
Swelling