Degradable and Removable Tough Adhesive Hydrogels

Abstract

The development of tough adhesive hydrogels has enabled unprecedented adhesion to wet and moving tissue surfaces throughout the body, but they are typically composed of nondegradable components. Here, a family of degradable tough adhesive hydrogels containing ≈90% water by incorporating covalently networked degradable crosslinkers and hydrolyzable ionically crosslinked main-chain polymers is developed. Mechanical toughness, adhesion, and degradation of these new formulations are tested in both accelerated in vitro conditions and up to 16 weeks in vivo. These degradable tough adhesives are engineered with equivalent mechanical and adhesive properties to nondegradable tough adhesives, capable of achieving stretches >20 times their initial length, fracture energies >6 kJ m^-2 , and adhesion energies >1000 J m^-2 . All degradable systems show complete degradation within 2 weeks under accelerated aging conditions in vitro and weeks to months in vivo depending on the degradable crosslinker selected. Excellent biocompatibility is observed for all groups after 1, 2, 4, 8, and 16 weeks of implantation, with minimal fibrous encapsulation and no signs of organ toxicity. On-demand removal of the adhesive is achieved with treatment of chemical agents which do not cause damage to underlying skin tissue in mice. The broad versatility of this family of adhesives provides the foundation for numerous in vivo indications.

Keywords: adhesives; biodegradable materials; bioinspiration; biomaterials; hydrogels.

Figure 1:. Overview of strategies to engineer degradable tough adhesives.

(a) Several strategies were explored to engineer degradable tough adhesives. To make the covalent network degrade, the non-degradable crosslinker of polyacrylamide is replaced with acrylate-functionalized degradable linkers. To make the ionic network degradable, oxidized alginate (algoxalate) was used. Chitosan degradation occurs under physiological conditions based on the degree of deacetylation of chitin. (b) For hydrolytically degrading tough gels, MBAA is replaced with either PEGDA, PoloxDA, or OxAlgMA. For enzymatically degrading hydrogels, MBAA is replaced with either GelMA or HAMA. Within the ionic network, alginate is replaced with its oxidized analog, algoxalate.

Figure 2:. Tough Hydrogels with Degradable Covalent Network Maintain High Toughness and Adhesion.

(a-d) The effect of different covalent crosslinkers on maximum stretch, stress, and fracture toughness. The covalent crosslinkers tested with associated concentrations (crosslinker/acrylamide wt.%) were: MBAA (0.06), PEGDA (0.06), PoloxDA (0.12), OxAlgMA (0.12), GelMA (0.03), and HAMA (0.06). *P<0.01 between time points. Mean values are shown and error bars represent ± s.d. (n=3-8 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. (e) The effect of covalent crosslinker on adhesion energy. *P<0.01 between groups. Mean values are shown and error bars represent ± s.d. (n=3-4 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. (f) The effect of crosslinker type on TA dry weight over time was evaluated with exposure to accelerated aging buffer. *P<0.01 between time points. Mean values are shown and error bars represent ± s.d. (n=3-4 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction.

Figure 3:. Tough Hydrogels with Degradable Covalent Network Demonstrate Tunable Degradation Profiles.

(a) Five different formulations of degradable tough hydrogels and non-degradable controls were implanted subcutaneously in mice and evaluated up to 16-weeks post implantation. (b-e) HFUS imaging evaluated changes in hydrogel thickness over time. *P<0.01 between groups. Mean values are shown and error bars represent ± s.d. (n=3-4 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. Scale bar = 1mm. (f) The effect of crosslinker type on TA dry weight post implantation. *P<0.01 between groups. Mean values are shown and error bars represent ± s.d. (n=3-4 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. Graphics generated in part with BioRender.

Figure 4:. Tough Hydrogels with Degradable Covalent Network Demonstrate Biocompatibility.

Tissue histology samples were collected over time. (a-c) In fast degrading gels, cell infiltration and capsule thickness were evaluated after 1, 2, and 8 weeks. *P<0.025 between groups. Median values are shown, and error bars represent IQR. (n=3-4 samples/group), as analyzed by a Scheirer-Ray-Hare test (nonparametric 2-way ANOVA) with Dunn’s tests for multiple comparisons. Histological images are sagittal sections of tough hydrogel, surrounding soft tissue, and skin tissues stained with hematoxylin and eosin. Larger image scale bar: 1000μm. Inset scale bar: 100μm. The tough hydrogel stains dark blue with the basic hematoxylin; (blue) nuclei of leukocytes clustered at the periphery of the gel are also dark blue. Surrounding tissue, fibrous capsule, and subcutaneous muscle appear red with the acidic eosin component of the stain. Arrows indicate capsule. Asterisks indicate cell infiltration. (d-f) In slow degrading gels, cell infiltration and capsule thickness were evaluated after 4, 8, and 16 weeks. *P<0.017 between groups. Median values are shown and error bars represent IQR. (n=3-4 samples/group), as analyzed by a Scheirer-Ray-Hare test (nonparametric 2-way ANOVA) with Dunn’s tests for multiple comparisons. Histological images are sagittal sections of tough hydrogel, surrounding soft tissue, and skin tissues. Larger image scale bar: 1000μm. Inset scale bar: 100μm. The tough hydrogel stains dark blue with the basic hematoxylin; (blue) nuclei of leukocytes clustered at the periphery of the gel are also dark blue. Surrounding tissue, fibrous capsule, and subcutaneous muscle appear red with the acidic eosin component of the stain. Arrows indicate capsule. Asterisks indicate cell infiltration.

Figure 5:. Removal agent treatments decrease tough adhesive toughness and adhesion energy on skin surfaces.

(a) Several strategies were tested to reduce the material properties and adhesion strength of the tough adhesives including the use of chemicals to chelate calcium ions from alginate and reduce molecular weight (b) Treatment with all chemicals decreased mechanical toughness. *P<0.01 between groups. Mean values are shown and error bars represent ± s.d. (n=3-6 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. (c) The adhesion energy following placement on porcine skin tissue was measured as a function of various treatments. *P<0.01 between groups. Mean values are shown and error bars represent ± s.d. (n=3-6 samples/group), as analyzed by a one-way ANOVA with post hoc t-tests with Bonferroni correction. (d) Following euthanasia, mouse skin was assessed using high frequency ultrasound and histology. (e) Control skin, and skin following removal of the TA (both without [TA] and with alginate lyase [TA+AL]), Dermabond [DB], and cyanoacrylate [CA] as assessed using high frequency ultrasound (left) and histology (right). Green arrows inside chitosan. Purple arrows indicate removal of the epidermis. Scale bar (HFUS) = 1mm. Scale bar (histology) = 100um. Graphics generated in part with BioRender.