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. 2023 Mar 8;102(5):497–504. doi: 10.1177/00220345221148684

Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery

DT Wu 1,2,3,*, BR Freedman 1,2,*, KH Vining 1,2,4, DL Cuylear 1,2, FPS Guastaldi 5, Y Levin 6, DJ Mooney 1,2,✉
PMCID: PMC10150439  PMID: 36883653

Abstract

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are common chronic inflammatory conditions, manifesting as painful oral lesions that negatively affect patients’ quality of life. Current treatment approaches are mainly palliative and often ineffective due to inadequate contact time of the therapeutic agent with the lesions. Here, we developed the Dental Tough Adhesive (DenTAl), a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended drug delivery of clobetasol-17-propionate, a first-line drug for treating OLP and RAS. DenTAl was found to have superior physical and adhesive properties compared to existing oral technologies, with ~2 to 100× adhesion to porcine keratinized gingiva and ~3 to 15× stretchability. Clobetasol-17-propionate incorporated into the DenTAl was released in a tunable sustained manner for at least 3 wk and demonstrated immunomodulatory capabilities in vitro, evidenced by reductions in several cytokines, including TNF-α, IL-6, IL-10, MCP-5, MIP-2, and TIMP-1. Our findings suggest that DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful oral lesions associated with chronic inflammatory conditions.

Keywords: biocompatible materials, tissue adhesives, surgical tapes, oral medicine, oral lichen planus, oral ulcers

Introduction

Oral mucosal lesions are prevalent conditions with several etiologies, including infection, trauma, immune reaction, metaplastic, or neoplastic conditions. Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are the 2 most common causes and are associated with painful lesions affecting several mucosal tissues in the oral cavity (Scully and Carrozzo 2008; Akintoye and Greenberg 2014). OLP is a T-lymphocyte–mediated chronic autoimmune disease affecting 1% of the global population with potential of progressing to a malignant condition (Peng et al. 2017; González-Moles et al. 2019; 2021). OLP affects various intraoral tissues, including oral mucosa, gingiva, and tongue, and manifests as white striations, plaques, or papules. In parallel, RAS presents as recurrent bouts of painful ulcers at intervals of a few days to a few months, classified into 3 clinical variants depending on their severity and duration: minor RAS, major RAS, and herpetiform ulceration (Stanley 1972). Ulcers may involve lips, soft palate, and oropharynx with painful lesions exceeding 1 cm in diameter (Preeti et al. 2011). In terms of pathogenesis, emerging evidence suggests that cell-mediated immune reactions play a key role in the onset and progression of RAS (Cui et al. 2016).

Current treatment approaches for oral mucosal lesions are primarily palliative and focus on reducing inflammation, infection, and pain by delivery of various drugs, including antimicrobials, immunomodulatory agents, topical anesthetics, anti-inflammatory agents, and systemic or local steroids (Scully and Carrozzo 2008; Preeti et al. 2011; Belenguer-Guallar et al. 2014). However, these strategies have significant drawbacks. In particular, systemic steroids, although effective, may induce intolerable and off-target side effects that lead to treatment cessation (Belenguer-Guallar et al. 2014). Topically delivered steroids in the form of mouth rinses, gels, or ointments have short exposure times and unpredictable drug distribution due to continuous salivary flow and mechanical stresses within the oral cavity (Belenguer-Guallar et al. 2014). In addition, other patch-based drug delivery solutions do not provide strong adhesion to wet oral surfaces or enable extended drug release (Cilurzo et al. 2010; Colley et al. 2018; Brennan et al. 2022). Thus, there is a therapeutic need for local delivery that prolongs the contact time between the drug and mucosal lesion in the context of intraoral mechanical disturbances and salivary flow.

There has been significant previous work to develop mucoadhesive delivery systems to facilitate a close contact between a drug-release system and oral mucosal lesions. These delivery systems include bioadhesive microparticles (Sander et al. 2013), mucoadhesive buccal tablets (Perioli et al. 2004; Al-Ani et al. 2021), and polymeric mucoadhesive membranes (Santocildes-Romero et al. 2017; Colley et al. 2018). Despite advances in the development of bioadhesives for oral drug delivery, strong adhesion to wet and dynamically moving mucosal surfaces and extended drug release remain challenging.

The aim of this study was to develop and evaluate an adhesive hydrogel patch, the Dental Tough Adhesive (DenTAl), with robust mechanical properties, strong adhesion to diverse wet and dynamically moving intraoral tissues, and extended drug delivery. Our approach exploits a bioinspired tough adhesive patch comprising of 2 layers: an adhesive surface and a dissipative matrix. Unlike existing adhesives, the tough adhesive offers a multicomponent adhesion strategy to achieve strong adhesion to underlying wet tissues (Li et al. 2017), with orders of magnitude improvements in matrix toughness and adhesion energy compared to in situ polymerizing hydrogel adhesives and bandages (Nam and Mooney 2021). We show that DenTAl has superior physical and adhesive properties compared to existing adhesives and can sustain release of clobetasol-17-propionate for at least 3 wk. These findings suggest that DenTAl may help manage painful oral lesions associated with chronic inflammatory conditions.

Materials and Methods

Fabrication and Testing of Dental Tough Adhesive

To prepare the DenTAl (60 × 15 × 1.5 mm3), a hydrogel was first fabricated to provide the dissipative matrix. Then, its surface was treated with the bridging polymer, chitosan (Heppe Medical Chitosan; 54046), and coupling reagents for carbodiimide coupling to the underlying tissue. Alginate-polyacrylamide (Alg-PAAm) hydrogels were synthesized following a previous method as described in the Appendix (Li et al. 2017). The mixture of the bridging polymer and coupling reagents (~300 µL) was applied to the surface of DenTAl prior to application. Compression was performed by applying approximately 5 kPa of pressure between 2 glass plates with approximately 5% strain for 5 min. Previous study reported a strong bond between the dissipative hydrogel matrix and the adhesive matrix (Li et al. 2017). During the wait time, the specimens were sealed in a plastic bag with 1× phosphate-buffered saline (PBS) without calcium chloride or magnesium chloride (Gibco 10010023) to prevent dehydration. The use of PBS does not affect the hydrogel, drug chemistry, or release kinetics.

The adhesion energy was measured with 180-degree peeling tests to assess interfacial toughness. Previous studies have comprehensively characterized the bulk mechanical properties of tough gels (Li et al. 2017; Freedman et al. 2022). A tough adhesive was adhered to oral tissues (n = 4–6 samples/group) with one end open for 5 min (see Appendix). The back of DenTAl was bonded with a rigid polyethylene terephthalate (PET) film with Krazy Glue, to limit deformation to the crack tip. The free tips were attached with sandpaper, to which the machine grips were attached. A mechanical testing setup (Instron model 2519; load cell = 50 N) was used to record the force (N) and extension (mm). The loading rate was kept constant at 100 mm/min. The adhesion energy was calculated as 2 times the plateau value of the ratio of the force and width. Interpenetration of chitosan into the tissue was imaged using fluorescein isothiocyanate (FITC)–labeled chitosan and confocal microscopy (see Appendix). Comparisons to existing oral wound–sealing technologies (GelFoam and OraAid) were evaluated (see Appendix).

In Vitro Cell Biocompatibility Study

Primary human gingival epithelial (GE) cells were cultured for 1 wk in CnT-Prime epithelial proliferation medium (CellnTech). Subsequently, GE cells were seeded at a density of 1 × 104 cells per well with 100 µL medium in 96-well plates and cultured for 24 h. To assess the biocompatibility, GE cells were treated with DenTAl-conditioned media at varying concentrations (0×, 0.001×, 0.01×, 0.1×, 1×) for 24 h. DenTAl-conditioned medium was obtained by incubating gels (thickness, 0.75 mm; diameter, 3 mm) with Dulbecco’s modified Eagle’s medium (DMEM) for 24 h (ISO-10993-5,12) and diluted to the following concentrations: 1 × 10−1, 1 × 10−2, and 1 × 10−3 of the original conditioned medium. Cell viability was assessed using the WST cell proliferation assay kit (2210 Millipore, Sigma) according to manufacturer’s instructions. Briefly, 10 µL WST-1 solution was added to each well for 4 h in standard culture conditions. The plate was shaken for 1 min and the absorbance was measured at 420 nm and 600 nm.

In Vivo Adhesion Study

The animal procedures were approved by the Institutional Animal Care and Use Committee of the Massachusetts General Hospital (Protocol #2017N000087) and in compliance with the ARRIVE (Animal Research: Reporting of In vivo Experiments) guidelines. Additional information regarding the animal study is provided in the Appendix. Two female Yucatan minipigs (age 6 mo; 30–35 kg) were prepared for intraoral surgery. Briefly, sterile surgical drapes were placed over the animals, leaving the mouth area exposed, and chlorhexidine 0.2% was used as an intraoral antiseptic. After this, retractors were used to keep the jaws opened, and DenTAl (2 × 2 cm2) was attached to healthy gingiva (maxilla and mandible) and monitored for a period of 7 d to evaluate the bonding capacity/strength/behavior over time.

Drug Loaded Tough Gel Preparation and Release

DenTAl (thickness, 0.75 mm; diameter, 3 mm) was loaded with a concentration of 10 or 100 mg/mL clobetasol-17-propionate (Toronto Research Chemical) dissolved in the Alg-PAAm solution prior to gel crosslinking. Two concentrations of drugs were used to demonstrate fast versus extended release based on previous studies (Freedman et al. 2022; Koh et al. 2022). Clobetasol release profiles were examined over a period of 1 mo with drug-loaded DenTAl soaked in Hank’s Balanced Salt Solution (HBSS) (pH 7.4). As the drug used is a small-molecule hydrophobic corticosteroid (clobetasol-17-propionate), the selection of buffer type would not be expected to affect drug chemistry. This release buffer was maintained at 37°C on a shaker and was subsequently sampled and replaced every 24 h to mimic the effect of continuous salivary flow. DenTAl with 10 mg/mL was placed in 2.65 mL HBSS and DenTAl, with 100 mg/mL placed in 26.5 mL HBSS, respectively, to maximize the flux of drug out of the gel. Near-sink conditions were maintained for the release study, as clobetasol has a water solubility of ~2 mg/mL (Patel et al. 2013). Released drug was sampled daily and evaluated using liquid chromatography–mass spectrometry (LC-MS) (Agilent 1290/6140, gradient method; SIM mode, 467 g/mol). Chromatographic separation was performed at room temperature using a high-performance liquid chromatography (HPLC) column (Agilent Zorbax Rx-C18; internal diameter 2.1 mm, length 150 mm). A 2-solvent linear gradient method was used (A: 0.02% formic acid; B: methanol). Drug concentrations were quantified by integrating the characteristic peak. Bioactivity was evaluated using a cytokine screening kit (see Appendix).

Statistical Analysis

A power analysis was done to determine sample sizes per condition in every experiment using G*Power (Version 3.1, Germany). One-way analysis of variance (ANOVA) with post hoc Student’s t tests with Bonferroni corrections (GraphPad Prism, Version 9) was used to evaluate the effect of intraoral tissue type on the adhesion energy and chitosan interpenetration, as well as to evaluate the effect of adhesive type on the adhesion energy and mechanical properties. Significance was set to P < 0.05 for all tests.

Results

DenTAl Adheres to Wet Intraoral Tissues

DenTAl patches were applied to diverse wet oral tissue surfaces ex vivo and in vivo (Fig. 1A) and remained strongly adherent after applying stretch (Fig. 1B). In addition, DenTAl maintained adhesion in the oral cavity up to 1 wk in a porcine model despite continuous salivary flow and mechanical stresses associated with daily physiological functions (Fig. 1C). In vitro and ex vivo mechanical testing demonstrated high adhesion energy between DenTAl and diverse porcine oral tissues, including the dorsal tongue, cheek, gingiva, and lip (Fig. 1D). Adhesion to dorsal tongue was the strongest (mean = 1,600 J/m2), followed by cheek, gingiva, and lip.

Figure 1.

Figure 1.

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Tough Gel Adhesive (DenTAl) attaches strongly to diverse oral tissues. (A) DenTAl is composed of a dissipative matrix and adhesive surface. (B) Mechanical stretching of DenTAl adherent to porcine gingiva ex vivo. (C) In vivo porcine study demonstrating robust oral adhesion for at least 1-wk postapplication. (D) Quantification of ex vivo adhesion energy between DenTAl and porcine oral tissues, including lip, tongue, cheek, and gingiva. Data shown as mean ± SD (n = 4–6 samples/group), as analyzed by a one-way analysis of variance (ANOVA) with post hoc t tests with Bonferroni corrections.

The penetration of the bridging chitosan was examined following adherence of DenTAl to diverse oral tissues, including tongue, cheek, gingiva, and lip. Visualization of the chitosan revealed the adhesive conformed to the unique curvatures of each corresponding tissue (Fig. 2A). Chitosan diffusion depths ranged from ~5 μm to 17 μm and was significantly greater in tongue compared to other tissues (Fig. 2B).

Figure 2.

Figure 2.

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Chitosan interpenetration into various tissues. (A) Visualization of the interpenetration of the bridging polymer chitosan into diverse oral tissues. Green: FITC-labeled chitosan. Blue: DAPI nuclear staining. White: tissue collagen. (B) Quantification of chitosan diffusion into lip, tongue, cheek, and gingiva (μm). Data shown as mean ± SD (n = 4–6 samples/group), as analyzed by a one-way ANOVA with post hoc t tests with Bonferroni corrections.

DenTAl Exhibits Robust Mechanical and Adhesive Properties

The mechanical and adhesive performance of DenTAl was then compared to commercially available Ora-Aid, a noneugenol protective dressing material for intraoral wound sealing, and Gel Foam, a hemostatic device prepared from purified porcine gelatin. DenTAl exhibited significantly enhanced stretchability (Fig. 3A) and improved adhesion (Fig. 3B) compared to both of these technologies when applied to porcine keratinized gingiva ex vivo.

Figure 3.

Figure 3.

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Dental Tough Adhesive (DenTAl) mechanical and adhesion properties outperform that of existing commercialized technologies. (A) The maximum stretch (mm/mm) before failure was measured for DenTAl, Gel foam in the wet and dry state, and OraAid (P < 0.001) and OraAid (P < 0.001). (B) Quantification of the adhesion energy of DenTAl, Gel Foam, and OraAid after adhesion to gingival tissue ex vivo. Data shown as mean ± SD (n = 4–6 samples/group), as analyzed by a one-way ANOVA with post hoc t tests with Bonferroni corrections.

The in vitro biocompatibility of clobetasol-loaded DenTAl was evaluated using a WST assay (ISO10993-5,12). There is no statistically significant difference in viability between gingival epithelial cells cultured in conditioned media (CDM) prepared with clobetasol-loaded DenTAl compared to control medium (Fig. 4).

Figure 4.

Figure 4.

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Effect of Dental Tough Adhesive (DenTAl) on cell viability. The effect of DenTAl on cell viability was assessed using an WST assay by adding varying concentrations of conditioned media (CDM) to gingival epithelial cell cultures. The negative control indicates the relative Optical Density (OD) for cells treated with ethanol. Data shown as mean ± SD, as evaluated by a one-way ANOVA with post hoc t tests with Bonferroni corrections.

Clobetasol-Loaded DenTAl Exhibit Extended Release of Active Drug

DenTAl was synthesized with encapsulated clobetasol (Fig. 5A) and examined for drug release using a release by dissolution principal previously applied (Freedman et al. 2022). With this dissolution-controlled release strategy, the tough hydrogel functions to immobilize nondissolved corticosteroid particles in close proximity, increasing local concentration gradients that limit the ability for the steroid to dissolve. Previous work has found that higher drug loadings result in further extended release. In fact, this tissue adhesive tough hydrogel drug delivery system allowed for very high drug loadings (up to 500 mg/mL) in contrast to other delivery systems (Freedman et al. 2022). DenTAl with high clobetasol concentration (100 mg/mL) exhibited cumulative release of 40% over a 21-d time period, while DenTAl with low clobetasol concentration (10 mg/mL) exhibited cumulative release of 90% to 95% within 14 d (Fig. 5B). Clobetasol released from DenTAl after 1 and 7 d was placed in contact with cultured RAW 264.7 cells that were challenged with lipopolysaccharide (LPS) and proinflammatory cytokine secretion analyzed. In the presence of clobetasol released from DenTAl, several proinflammatory cytokine levels, notably IL-6 and MCP-5, were reduced (Fig. 5C; Appendix Fig. 1).

Figure 5.

Figure 5.

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Dental Tough Adhesive (DenTAl) loaded with clobetasol enables extended release. (A) Clobetasol-17-propionate was incorporated into the tough gel layer of DenTAl. (B) The release of clobetasol was measured over time from gels loaded with 100 mg/mL or 10 mg/mL. Data shown as mean ± SD (n = 4–6 samples/group), as analyzed by a 2-way analysis of variance with post hoc t tests with Bonferroni corrections. (C) Treatment with clobetasol-releasing DenTAl-conditioned medium decreased the production several proinflammatory cytokines by RAW 264.7 cells. Control = cells cultured in basal medium. Lipopolysaccharide (LPS) = cells cultured with LPS for 24 h. LPS + D1 Clob = cells cultured in conditioned medium after 1-d release from clobetasol-loaded DenTAl. LPS + D7 Clob = cells cultured in conditioned medium after 7-d release from clobetasol-loaded DenTAl. Red indicates values greater than 1 (normalized to untreated control).

Discussion

Current strategies for the management of painful oral lesions associated with OLP and RAS include topical rinses, gels, and ointments. Recently, mucoadhesive patches have emerged as promising drug delivery strategies for the management of these painful lesions (Cilurzo et al. 2010; Colley et al. 2018; Brennan et al. 2022). This study demonstrated that DenTAl exhibits strong adhesion energy to numerous oral tissues ex vivo, including porcine tongue, cheek, gingiva, and lips. Robust adhesion was further shown in an in vivo porcine model up to 1 wk, despite the dynamic mechanical influences exerted by saliva and the surrounding soft tissue. Here, the hydrogel remained adherent after 1 wk when the animals were sacrificed. Similar studies in other animal models have demonstrated robust adhesion up to 4 wk (Lazow et al. 2021; Freedman et al. 2022). Given the current limitations of methods to deploy intraoral medications (Jones et al. 2009), the ability of DenTAl to improve retention in the oral cavity, which is expected to enhance drug bioavailability, will likely be of interest for the field of dental medicine.

The data presented here demonstrate physical penetration of the chitosan bonding agent and strong adhesion to diverse intraoral soft tissues. Surprisingly, chitosan penetration did not correlate to the adhesion energy. We speculate that since oral tissues have varying anatomy and composition, this may play a key role in mediating adhesion. For instance, the presence of papillae on dorsal tongue may increase surface area for adhesion. In addition, tissue microarchitecture may be important in adhesion. For instance, the degree of keratinization may alter adhesion, which could explain the difference between adhesion between the buccal mucosa, a nonkeratinized tissue, and the lip, a keratinized tissue.

We have previously shown that these tough adhesive gels can penetrate other wet dynamic tissues, form covalent and electrostatic bonds with functional groups on the adhered tissue surface, and lead to strong adhesion (Li et al. 2017). However, no previous studies have demonstrated high adhesion energies on a variety of tissues in the intraoral cavity. Compared to the standard-of-care commercially available intraoral wound dressing materials, DenTAl demonstrated significantly higher maximum stretch and adhesion energy. Similar comparisons were performed in the literature comparing tough adhesive hydrogels with existing surgical adhesives and demonstrated superior adhesion and mechanical properties (Li et al. 2017). The constant salivary flow and mastication processes can increase the susceptibility of the standard-of-care materials to dislodge or fail, and these materials exhibit low-adhesion energies to the gingiva. The in vivo residence time of the DenTAl in the porcine oral cavity is notable, as other patches and adhesive employed have not been maintained, presumably due to the dynamic nature of the intraoral cavity (Paris et al. 2021). A recent study reported the development of degradable and removable tough adhesive hydrogels that can be removed on demand via treatment with chemical agents, which do not cause damage to underlying tissues. Future work will allow the development of similar degradable DenTAl systems based on similar hydrogel chemistries (Freedman et al. 2021).

DenTAl was successfully loaded with clobetasol-17-propionate and exhibited extended cumulative release up to 4 wk. To date, the most employed agents for treatment of OLP are topical corticosteroids, which are considered first-line treatment (Lodi et al. 2020). Previous randomized clinical trials using topical clobetasol propionate have confirmed symptom and clinical improvements along with cost-effectiveness (Conrotto et al. 2006; Carbone et al. 2009). Based on clinical evidence, we selected clobetasol-17-propionate as the test drug to incorporate into the DenTAl and showed these adhesive hydrogels can load varying doses of clobetasol-17-propionate (10 mg/mL and 100 mg/mL) and provide sustained release for up to 4 wk. The ability to tune the amount and duration of clobetasol delivery is likely relevant to the treatment of chronic inflammatory conditions such as OLP, given the variable findings with other topical and mouth rinse formulations with high daily doses (Lodi et al. 2005). The mechanism of drug incorporation and release from DenTAl is likely physical entrapment and subsequent simple diffusion of the drug from the polymer matrix (Li and Mooney 2016). Previous studies have verified that the chitosan layer does not have an impact on the diffusion of uncharged corticosteroids and is not expected to affect release of clobetasol (Freedman et al. 2021). In comparison to the mucoadhesive patch by Colley et al. that delivers clobetasol-17-propionate, DenTAl provides superior adhesion and longer duration of adhesions in vivo (1 wk vs. 118 min), as well as allows for extended drug release (up to 4 wk vs. 360 min) (Colley et al. 2018; Brennan et al. 2022). Future in vivo and clinical studies are required to demonstrate the effectiveness of DenTAl for oral applications. In addition, future and ongoing studies will develop methods to a create barrier from the oral cavity side to direct drug release toward the target tissue while reducing drug leakage to the rest of the oral cavity.

The findings that clobetasol released from DenTAl significantly reduced proinflammatory cytokine secretion from macrophages challenged with LPS support the bioactivity of the encapsulated and released drug. Corticosteroids have multiple actions, including anti-inflammatory and immunomodulatory, and can inhibit the activity of several cytokines following inactivation of specific transcription factors such as activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB). The analgesic effect of corticosteroids is likely attributable to its effects on the inflammatory pathway and associated beneficial effects on mucosal healing (Ahluwalia 1998; Lodi et al. 2020). Our results demonstrate a significant reduction in the expression of proinflammatory cytokines, including TNF-α, IL-6, MCP-5, and MIP-2. Cytokines such as IL-6 and TNF-α have proinflammatory activity, while IL-1RA and IL-10 mainly play anti-inflammatory roles (Holdsworth and Gan 2015). Therapeutics manipulating cytokine levels (e.g., IL-6 and TNF-α) have been shown to attenuate joint inflammation and systemic inflammation, suggesting DenTAl as a promising vehicle for the treatment of inflammatory diseases (Holdsworth and Gan 2015). Interestingly, the expression of IL-10 and TIMP-2, which have typical anti-inflammatory roles, is also reduced. Although IL-10 is considered a potent anti-inflammatory cytokine that strongly inhibits the production of proinflammatory cytokine, recent studies have suggested that IL-10 also has immunostimulatory properties on CD4+, CD8+, and natural killer (NK) cells, increasing IFN-γ production (Lauw et al. 2000). For future studies, as part of the clinical translational efforts, we will validate these findings in large animals.

Conclusion

In conclusion, DenTAl is a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended delivery of clobetasol-17-propionate. DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful lesions associated with chronic inflammatory oral conditions. Future studies will examine efficacy of this material in animal models of OLP and RAS, as well as test degradable versions of DenTAl and adhesives based on noncovalent attachment (Freedman et al. 2021; Cintron-Cruz et al. 2022). Future clinical application of DenTAl may be expanded to local deliveries of antimicrobial and chemotherapeutic agents to treat periodontitis and precancerous or malignant lesions, respectively.

Author Contributions

D.T. Wu, B.R. Freedman, K.H. Vining, D.L. Cuylear, contributed to conception and design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; F. Guastaldi, Y. Levin, contributed to design, data acquisition, drafted and critically revised the manuscript; D.J. Mooney, contributed to conception and design, data interpretation, drafted and critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy.

Supplemental Material

sj-docx-1-jdr-10.1177_00220345221148684 – Supplemental material for Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery
Click here for additional data file. (89.1KB, docx)

Supplemental material, sj-docx-1-jdr-10.1177_00220345221148684 for Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery by D.T. Wu, B.R. Freedman, K.H. Vining, D.L. Cuylear, F.P.S. Guastaldi, Y. Levin and D.J. Mooney in Journal of Dental Research

Footnotes

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.T. Wu, K.H. Vining, D.L. Cuylear, F. Guastaldi, and Y. Levin declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. B.R. Freedman has the following interests: Amend Surgical, consulting, licensed IP; Limax Biosciences, equity. D.J. Mooney has the following interests: Lyell, equity; Attivare, equity; IVIVA Medical, consulting and equity; J&J, consulting; Boston Scientific, consulting; Limax Biosciences, equity; Epoulosis, equity; Revela, equity; Amend Surgical and Sirenex, licensed IP.

Funding: The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article: supported by National Institutes of Health (NIH) (NIA K99AG065495; National Institute of Dental and Craniofacial Research [NIDCR] K99DE030084) and the Osteology Foundation (21-032). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funder of the study had no role in the design of the study, collection, analysis, interpretation of data, and in writing the manuscript.

A supplemental appendix to this article is available online.

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Supplementary Materials

sj-docx-1-jdr-10.1177_00220345221148684 – Supplemental material for Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery
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Supplemental material, sj-docx-1-jdr-10.1177_00220345221148684 for Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery by D.T. Wu, B.R. Freedman, K.H. Vining, D.L. Cuylear, F.P.S. Guastaldi, Y. Levin and D.J. Mooney in Journal of Dental Research

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