Recent advances of on-demand dissolution of hydrogel dressings
Wound management is a major global challenge and a big financial burden to the healthcare system due to the rapid growth of chronic diseases including the diabetes, obesity, and aging population. Modern solutions to wound management include hydrogels that dissolve on demand, and the development of such hydrogels is of keen research interest. The formation and subsequent on-demand dissolution of hydrogels is of keen interest to scientists and clinicians. These hydrogels have excellent properties such as tissue adhesion, swelling, and water absorption. In addition, these hydrogels have a distinctive capacity to form in situ and dissolve on-demand via physical or chemical reactions. Some of these hydrogels have been successfully used as a dressing to reduce bleeding in hepatic and aortal models, and the hydrogels remove easily afterwards. However, there is an extremely wide array of different ways to synthesize these hydrogels. Therefore, we summarize here the recent advances of hydrogels that dissolve on demand, covering both chemical cross-linking cases and physical cross-linking cases. We believe that continuous exploration of dissolution strategies will uncover new mechanisms of dissolution and extend the range of applications for hydrogel dressings.
KeywordsWound management Wound dressing On-demand dissolution Hydrogel
Wound healing is intrinsically and closely related to survival; wounds such as the diabetic foot ulcers that fail to heal can lead to a lower 5-year survival rate than some cancers (e.g., breast and prostate) [1, 2]. Thus, many efforts have been devoted to developing new and effective strategies to promote wound healing. In clinical settings, the standard processes for wound treatment include as follows: (1) cleaning the wound, (2) debriding, (3) choosing suitable dressings for wound healing, and(4) binding the wound to avoid shedding of dressings . Dressings have long been considered as a critical part of wound care, and many of dressings can indeed be useful for topical therapies. In addition to the traditional cotton gauze dressings, a myriad of new dressings that are made of biological materials can also be selected by the clinicians. Over the past few decades, biomaterials and especially polymeric materials have rapidly become a key enabling technology in this push to develop advanced strategies for wound care [4, 5, 6]. Polymeric materials were mostly used as dressing to treat wounds, which can absorb wound exudates, prevent wound desiccation, and isolate the wound from the environment [6, 7, 8]. A range of commercially available polymer-based dressings, such as hydrocolloids, polymeric film, fibers, and hydrogels, have been widely used for the treatment [5, 9]. However, currently available dressings adhere to the wound, particularly burn wound surfaces, requiring cutting and mechanical debridement for a dressing change. This can lead to traumatization of newly epithelialized tissues, delayed healing, and personal suffering in the injured patient [10, 11]. Additionally, changing a wound dressing takes a long time. For example, the average duration of a burn dressing change is almost an hour . The dressing change for anesthesia can require even more time. More seriously, these painful dressing changes have to be conducted many times until an obvious improvement in the wound healing is observed. This means that opaque burn dressings in clinical applications should be changed every 2 days to observe the condition of wound and avoid excessive waste of dressings. In fact, doctors want to use transparent dressings to make it easier to monitor the condition of wound and to place it on the wound surface for a long time until it heals. If the wound is infected, the dressings are expected to be dissolved as soon as possible. The ideal dissolution time of dressings should be controlled within a few minutes, and the ideal time for dressing change is expected to be rapid. Consequently, strategies with gentler and less invasive approaches enable facile dressing change and avoid secondary damage.
Therefore, there is a critical unmet need for a topically applied material that (1) is easily applied and forms in situ, (2) is of sufficient mechanical flexibility to accommodate complex wound contours and volumes, (3) can be easily and atraumatically removed under controlled conditions for definitive surgical care, and (4) is non-toxic. In order to fulfill these requirements, the first dissolvable hydrogel dressings were introduced. These controlled dissolution of hydrogels is especially significant for (1) atraumatic removal after dressing function is completed, (2) targetable transit of sealed therapeutics (e.g., proteins, cells, and small molecules), and (3) customized administration of highly efficient agent . Despite an intense research focus on dissolvable cross-linked hydrogel, little effort has been made to summarize these systems. Here, we will outline the recent advances in hydrogels that dissolve on demand for nursing wounds, as this rapidly evolving field continues to make important contributions to biomedicine.
Dissolvable cross-linked hydrogels
In recent years, hydrogels have become attractive for wound healing applications owing to their biocompatibility, tunable biodegradability, and controllable mechanical properties [20, 21, 22]. Since the chemistries and performances of hydrogels are controllable and repeatable, synthetic hydrogels gain especially interests for wound care applications [23, 24]. These controllable features include mediating the hydrogel and dissolution rates [25, 26]. In particular, the controlled dissolution of hydrogels is important for their atraumatic removal from the wound after their function is complete. Generally, the dissolution of chemically cross-linked hydrogels can be achieved by incorporating cleavable moieties though the approach of ester hydrolysis or enzymatic degradation [27, 28]. Compared with chemically cross-linked hydrogels, the physically cross-linked hydrogels can undergo phase transitions by changing the external environment without coupling agent, optical irradiation, or organic solvents (which are usually harmful to the human body) [29, 30, 31]. However, mechanical properties of physically cross-linked hydrogels are weaker than chemically cross-linked hydrogels, so their application is limited [32, 33]. Consequently, we will review recent advances in developing dissolvable physically and chemically cross-linked hydrogels.
Chemically cross-linked hydrogels
Thiol-thioester exchange reaction, thiol-disulfide exchange reaction, retro-Michael reaction, and retro Diels-Alder (rDA) reaction have all been used to prepare dissolvable hydrogels. These hydrogels offer responsive synthetic processing for dissolution rates. Examples of these reactions as a method to synthesize on-demand dissolvable hydrogels are described below.
Grinstaff et al. studied dissolvable hydrogels made by thiol-thioester exchange reaction [36, 37]. In particular, they studied a hydrophilic poly(ethylene glycol) lysine sulfhydryl (PEG-LysSH) dissolvable hydrogel-made stem from thiol-thioester exchange (Fig. 2b). To prepare the PEG-LysSH, the PEG amine (Mw: 2 kDa) was introduced on the lysine-based peptide dendron possessing four terminal thiols by a standard peptide coupling reaction. The dendritic molecules were composed of repeating nanoscale motifs, which were somewhere between polymers and a small organic molecule systems. Dendrons formed easily via a variety of non-covalent interactions, and they could provide a macromer with many reactive sites to ensure the fast formation of hydrogels . The use of a dendritic macromonomer provides many advantages such as fine control of the composition, structure, and molecular weight. Then, the dissolvable thioester-linked PEG-LysSH hydrogel was fabricated spontaneously within seconds by mixing poly(ethylene glycol disuccinimidylvalerate) (SVA-PEG-SVA) with dendritic macromonomer with multiple reactive positions via native chemical ligation (NCL) reaction [39, 40]. The dissolution of PEG-LysSH-based hydrogel could occur in both l-cysteine methyl ester (CME) and 2-mercaptoethanesulfonate (MES) solutions. The dissolving mechanism of the hydrogel depended on thiol-thioester exchange reaction between the thioester bonds in hydrogel and thiolate solutions (e.g., CME, MES), and formed amide linkage to preclude re-formation of hydrogel. They found that the concentration of thiolate solutions and pH values had a significant effect on the dissolution behavior of PEG-LysSH hydrogel. The thioester bridges in the hydrogel could rapidly cleave, and the gel completely dissolved within 24 min at pH 8.5 in 0.3 M of MES solution. Since the hydrogel could be easily removed from the skin to avoid secondary damage, in vivo experiments had shown that this type of hydrogel possesses a potential application in wound repair. Recently, Konieczynska et al. synthesized a stimulus dissolvable dendritic thioester hydrogel burn dressing for second-degree burn healing . The hydrogel was composed of a lysine-based dendron and a PEG-based cross-linker. Moreover, the lysine-based dendron used in the hydrogel was capped with nucleophilic amines, which could overcome the limited storage life and fine controllable gel rate that allows the matrix to easily fill the complex geometry of the burned area. They further studied the performance of on-demand dissolution of this hydrogel. After the hydrogel was applied to a second-degree burn wound on a rat and left to gel for 1 h, a CME-soaked gauze was administered to half of the hydrogel for 30 min, resulting in the dissolution of the gauze-treated hydrogel.
Some of the main features of various crosslinking types of hydrogels. PBS phosphate buffer saline
Exogenous dissolution agents
In situ formation or not
Expected dissolution time
Potential for wound treatment
Chemically cross-linked hydrogels
Better application in vivo
Hydrogel are pure and less toxic
Low mechanical strength, less crosslinking species, less selectivity of polymer, long gelation time
Supramolecular self-assembly hydrogels
Mild chemical irrigant
Within 2 min
Better application in vivo
Hydrogels have better mechanical properties and less toxic effects
Self-assembly process is difficult to control
Physically cross-linked hydrogels
Within 25 min
Better application in vivo
A cheaper way for hydrogel dissolution
Dissolution times of hydrogel are too long, and toxicity of thiolate is unknown
Thiol-containing reducing agent
Within 10 min
Better application in vivo
Built-in redox-sensitivity as living cells
Cytotoxicity of hydrogels or dissolution agents are uncertainty
Glutamate, PBS (pH 7.4), or light
2 days (glutamate); 4 days (PBS)
4.5 min (light)
Further research is needed
Increased stability for sustained release under highly reducing conditions
Michael acceptors for retro Michael Reaction have been less studied, and the effect of hydrogel dissolution is poor with side reaction
0.4 h (100 °C)
Further research is needed
Hydrogels are formed need no catalysts or initiators
The dissolution temperatures of hydrogel are too high
Early preparations of on-demand disolving hydrogel according to thiol-disulfide exchange reaction were described by Hisano et al. . The soluble poly (acrylamide-co-N,N′-bisacrylcystamine) (P-S-S-P) hydrogel was formed through air oxidation of the thiols to disulfide bonds (24 h) or thiol-disulfide exchange reaction with poly(acrylamide-co-N-acryl-cysteamine) (P-SH) and low molecular weight disulfides (3,3′-dithiodipropionic acid, glutathione disulfide, or cystamine) . l-cysteine or glutathione (GSH) molecules were used to dissolve this hydrogel via thiol-disulfide exchange reaction (Fig. 3b). The dissolution time of hydrogel reduced with the increase of the concentrations of l-cysteine or GSH, and the hydrogel could be dissolved within 1 min by adding the l-cysteine or GSH at a concentration of 600 μmol/mL. Recently, Szilagyi et al. developed a redox-responsive disulfide cross-linked polysuccinimide (PSI) gels, which showed a reversible dissolution and gelation performance based on thiol-disulfide exchange reaction in a shorter time . The PSI gels were dissolved within 15 min with the reducing agent of dithiothreitol at 1 mM, and the regelation phenomenon occurred with the PSI gels were oxidized in air to disulfide linkages within 4–6 h. Anumolu et al.  designed analogous, and better hydrogels, which were composed of 8-arm-PEG-SH and either H2O2 or 8-arm-PEG-sulfur-thiopyridine (Fig. 3c). The hydrogels were in situ cross-linked in phosphate buffer saline (PBS) (pH 8.0) within 60 s and 10 s, respectively. GSH was added as the thiolate moiety to leave extant disulfide bonds (Fig. 3d) . The hydrogels were dissolved within 30–40 min, 15–20 min, and 10–15 min in the presence of the 1%, 3%, and 5% (w/v) glutathione solutions, respectively.
All of these works provide ways to synthesize on-demand dissolvable hydrogels according to thiol-disulfide exchange with the goal of wound dressing application. Unfortunately, as shown in Table 1, there are little data to speak to the toxicity of the dissolution agents. One more problem is that the thiol-containing hydrogel precursors are easily oxidized in air, causing trouble for the stable synthesis of the hydrogels.
One example of the dissolvable hydrogels based on succinimide-thioether cross-linking was formed in situ by using a mixture of thiolated 4-arm-PEG (Mw: 10 kDa) and MAL-functionalized low-molecular weight heparin (MAL-LMWH) (Fig. 4b) . With the addition of GSH, the hydrogels were dissolved, and the dissolution rate was governed by the reducing conditions . In another recent report, Kiick et al. investigated an on-demand dissolvable hydrogel, which could be fabricated in situ within seconds via a Michael-type addition reaction . The hydrogel was then dissolved though three different modes: GSH-reducing environment, photocleavage (visible and two-photon infrared light), and ester hydrolysis [49, 50]. Compared with disulfide-based hydrogels, these succinimide-thioether bond containing hydrogels exhibit higher stability. Current reports on the preparation of dissolvable hydrogels based on retro-Michael reaction focus on precursors containing maleimide, and more Michael acceptors (e.g., acrylates) for preparation of these hydrogels also need to be studied.
Wei et al. reported a dissolvable hydrogel that could be prepared via DA cyclization, and it could be dissolved at above 70 °C via rDA reactions by exposing it to dimethylformamide (DMF) . In order to make this class of functional hydrogels apply in a physiologically relevant environment, Finn et al. prepared the PEG-oxanorbornadiene (OND) hydrogels that could be dissolved in more than 1 day in a biologically relevant environment via rDA-mediated reactions (Fig. 5b) . The hydrogel was synthesized via the reaction between 4-arm thiol-terminated PEG (Mw: 10 kDa) and 7-OND cross-linkers. Interestingly, the authors observed that its dissolution rate was related to the temperature and OND moiety without swelling buffer, which was not related to pH values (5.0–9.0) during swelling process. Another related study of the dissolvable hydrogel with DA reaction was reported by Kirchhof et al. . The DA hydrogel was prepared by mixing equimolar amounts of furyl and MAL substituted multi-arm PEGs  (Fig. 5c). Moreover, the gelation time and mechanical properties of the DA hydrogel were related to the concentration of polymer, branching amount, and molecular weight of PEGs . The dissolution of hydrogel was triggered by the hydrolysis of chemically inert meleamic acid derivatives, and the process usually needs days to weeks .
Although there are other reversible open-loop addition reactions that are similar to the DA reaction and can be used to prepare dissolvable hydrogels, most can only be dissolved under radiation of the ultraviolet light (100–315 nm), which is harmful to humans . As shown in Table 1, the DA/rDA transformations provide an efficient, economical, and simple method for the formation and dissolution of hydrogels (e.g., the dissolution of hydrogels does not require any exogenous agents at elevated temperature). The slow dissolution of these hydrogels at biologically relevant conditions severely limits their biological applications.
Physically cross-linked hydrogels
Temperature-sensitive physically cross-linked hydrogels (TPCH)
Many environmental stimuli have been used to induce the volume or phase reversible transitions of the hydrogel systems, including pH, temperature, ions, electric fields, light, pressure, sound, and magnetic fields [67, 68]. Recently, the gel-sol phase reversible transitions of temperature-sensitive physically cross-linked hydrogels have been widely studied [69, 70]. Here, the TPCH are mainly introduced.
The temperature-sensitive behavior of physically cross-linked traditional hydrogels means that they can change their hydrophilicity, hydrophobicity, and volume of gel networks. They can also undergo gel-sol reversible transitions with the change of temperature . The polymer chains in TPCH can undergo sol-gel phase reversible transitions, which are sol at low temperature and gel at high temperature . Typical TPCH are composed of hydrophobic chains (e.g., poly(N-isopropylacrylamide)) and hydrophilic links (e.g., poly(tetramethyleneether glycol)), and their molecular architecture may include two-block, three-block, multi-block, and hyperbranched structures . The polymers can form a semi-rigid gel through the hydrophobic interactions or secondary bonding, and these bonds between the polymer chains can be changed with increased temperature . TPCH can undergo the hydrophilic-hydrophobic transition via the hydrophobic interaction when temperature is above the lower critical solution temperature (LCST) . The polymer solution has the low viscosity at room temperature, but it will turn into gel when the temperature is above the LCST. LCST values can be adjusted by changing the ratio of hydrophobic chain, hydrophilic chain, and molecular weight . Generally, TPCH are significant for wound care because they can be removed easily from the wound at a temperature below human physiological temperature (37 °C).
One example of TPCH preparation is a physical mixture of chitosan and glycerol phosphate (GP) disodium salt . The mixture remains in a transparent liquid state at room temperature, while gelation occurs at 37 °C. The gelation occurs because phosphates in GP neutralizes the amine groups of chitosan, leading to a rise in hydrophobic and hydrogen bonding between chitosan chains at a high temperature. Bhattarai et al. introduced an injectable chitosan-PEG (45–55 wt%) TPCH, which took advantages of the interactions among chitosan chains for gelation . The chitosan-PEG co-polymer was synthesized by chemically grafting monohydroxy PEG onto chitosan backbone via Schiff base and sodium cyanoborohydride chemistry. The mixture could be injected using a 22-G needle below the transition temperature, and gelation occurred at approximately 25 °C. The hydrogen bonds between PEG and water molecules are dominant at low temperatures, while the hydrophobic interactions between the polymer chains are dominant at high temperatures [78, 79], leading to the formation of hydrogels by the hydrophilic-hydrophobic transition. As wound dressing, this temperature-sensitive hydrogels can be dissolved on demand just by changing the temperature. Moreover, chitosan is able to promote faster wound healing and generate smooth scarring because of the enhancement of vascularization and the supply of chitooligomers at the lesion site [80, 81].
Such polymers can be used as an injectable hydrogels for treating the irregularly shaped wound; they can be injected around the wound at low temperatures, forming a gel at human physiological temperature. They can also be used as an in-situ gel sealant for emergency wound treatment, which can rapid gelation to attaching to the wound and be removed easily before subsequent treatment. However, as is shown in Table 1, one of the big problems is that the gelation time is rather long. Moreover, the dissolved temperature of TPCH should be further optimized.
Other stimuli sensitive physically cross-linked hydrogels
In addition to the wide application of TPCH discussed above, other stimuli have also been used for preparing dissolvable hydrogels with environmental sensitivity. However, the preparation of hydrogels purely on the basis of physical cross-linking is rare, and the variety of polymers is limited. Nevertheless, there are several other stimuli-sensitive physically cross-linked dissolving hydrogels that have been studied. For example, the pH values can affect swelling or shrinkage behavior of pH-sensitive hydrogels, because the pendant acidic (e.g., carboxylic acids) or basic (e.g., ammonium salts) groups in solution can accept or release protons with the change of pH values [72, 82]. These kinds of hydrogels have been most widely used in the field of controlled drug delivery and permeation switches . Glucose-sensitive hydrogels can undergo sol-gel phase reversible transitions depending on the glucose concentration in the environment . Some glucose-sensitive hydrogels can be formed by a reversible crosslink among the glucose-containing polymer chains via the non-covalent interaction between concanavalin A (Con A) and glucose. The glucose binding sites in Con A can combine free glucose or polymer-bound glucose depending on the concentration of free glucose . Magnetic-sensitive hydrogels may undergo phase transitions via a magnetic field, and one way to obtain such hydrogels is to add magnetic nanoparticles . Light-sensitive hydrogels are usually synthesized by introducing photo-responsive groups (e.g., azobenzene) [85, 86]. The self-assembly structure of the light-sensitive hydrogels can be destroyed with molecular isomerization upon ultraviolet irradiation; therefore, most of these hydrogels can undergo sol-gel phase transitions in the response process .
Supramolecular self-assembly hydrogels
Supramolecular hydrogels have been widely researched as wound dressing due to the advantages of degradable, injectable, adjustable gelation process, simple preparation, and without chemical reactions. More important, this self-assembled supramolecular hydrogels as wound dressing can be mildly removed after finishing its work. However, it is difficult to control self-assembly process. The optimization of the amphiphilic polymers of building blocks provides a possible for controlled self-assembly process, while the gelation time and dissolved response speed need to be further improved.
In this paper, four popular strategies for preparation of dissolvable chemically cross-linked hydrogels, environment-sensitive physically cross-linked hydrogels and supramolecular self-assembly hydrogels are introduced. All of them provide economical and effective methods for the synthesis of controlled and on-demand dissolving hydrogels for in vivo applications.
It should be pointed out that different types of wounds and different stages of the same wound have different requirements for hydrogel dressings, and it is difficult for a single material to meet the complex needs of the wound. Therefore, multifunctional dressings, which can be prepared by combining different functional materials, open up a method to meet the various demands in the healing process. Besides, new cross-linking and dissolution strategies should be considered in designing hydrogels for clinical purposes. Continued study and development of hydrogels is of great interest. Overall, the exploration of new type of on-demand dissolvable hydrogels is an area that displays the creativity of both chemists and biologist in materials and chemical biology.
This work is supported by the Science and Technology Innovation Plan of Southwest Hospital (No. SWH2016ZDCX2014 and SWH2017ZDCX1001), Third Military Medical University (Grant No. 2016XPY12).
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HL, DH, and JD contributed to the peer-reviewing and writing of the manuscript. All authors read and approved the final manuscript.
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The authors declare that they have no competing interests.
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