A biocompatible, multilayered tape with reversible and strong adhesion for advanced wound care

Abstract

To address the vulnerability of water-activated adhesives to environmental conditions, presented here are adhesive tapes that include an adhesive portion comprising a water-activated reversible adhesive; and a hydrophobic backing secured to the adhesive portion. Also presented are methods, the methods including affixing an adhesive tape according to the present disclosure to a subject. Other disclosed methods include fabricating an adhesive tape according to the present disclosure.

Description

A BIOCOMPATIBLE, MULTILAYERED TAPE WITH REVERSIBLE AND STRONG ADHESION FOR ADVANCED WOUND CARECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to and the benefit of United States patent application no. 63 / 586,126, “A Biocompatible, Multilayered Tape With Reversible And Strong Adhesion For Advanced Wound Care” (filed September 28, 2023). All foregoing applications are incorporated herein by reference in their entireties for any and all purposes.GOVERNMENT RIGHTS

[0002] This invention was made with government support under 1548571 awarded by the National Science Foundation. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates to the field of adhesive wound dressings.BACKGROUND

[0004] Reversible adhesives have witnessed increased interest in diverse industries, emphasizing waste reduction and sustainable practices. However, their vulnerability to fluctuating conditions poses challenges in specific applications, and this vulnerability has particular relevance to the use of reversible adhesives in wound dressing applications. Accordingly, there is a long-felt need in the art for improved adhesives, particularly in the context of wound dressings.SUMMARY

[0005] Reversible adhesives have witnessed increased interest in diverse industries, emphasizing waste reduction and sustainable practices. However, their vulnerability to fluctuating conditions poses challenges in specific applications.

[0006] To address this issue, backing layers have been developed to provide mechanical support, distribute load, and offer additional functionalities.

[0007] In this context, we introduce a novel biocompatible, multilayered tape with a hydrophobic backing layer, with the tape offering reversible and strong adhesion. The tape, featuring dynamic bonds, is capable of instant adhesion to various substrates; the biocompatible, hydrophobic and elastic backing layer enhances its adhesion strength while protecting it from exposure to water. The adhesive's reversible nature ensures painless removal and easy repositioning. The integration of a hydrophobic backing layer further enhances the tape's performance and promotes wound healing. With the ability to further customize aesthetics and incorporate additional functionalities, this tape enhances patient comfort and treatment efficacy in advanced wound care applications.

[0008] In meeting the described long-felt needs, the present disclosure provides an adhesive tape, comprising: an adhesive portion comprising a water-activated reversible adhesive; and a hydrophobic backing secured to the adhesive portion.

[0009] Also provided is a method, comprising affixing an adhesive tape according to the present disclosure to a subject.

[0010] Further disclosed is a method, the method comprising fabricating an adhesive tape according to the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various aspects discussed in the present document. In the drawings:

[0012] FIG. 1. The structure and material compositions of the bilayer tape.

[0013] FIG. 2. General procedures for large scale fabrication of the bilayer tapes.

[0014] FIG. 3. Illustrations of the Approach 1 to prepare the bilayer adhesive tape.

[0015] FIG. 4. Illustrations of the Approach 2 to prepare the bilayer adhesive tape.

[0016] FIG. 5. Illustrations of the Approach 3 to prepare the bilayer adhesive tape.

[0017] FIGs. 6A-6D. The design, manufacture, and application of the reversible wound dressing film. (A) Schematic illustrations of the design and composition of the multilayered dressing film. (B) Chemical structures of each component in (A). (C) Schematics of the fabrication process. (D) Illustrations of the application and removal of the dressing film on skin.

[0018] FIGs. 7A-7D. Approaches to address the buckling issue of the multilayered adhesive film during uses. (A) Illustration of the buckling of the multilayer after dip into water, causing swelling. (B) Mitigating of buckling by increase of the modulus and thickness of the PDMS elastomer. (C) The pre-stretched hydrogel network that contains adhesives before bonding with the PDMS elastomer makes the bilayer buckle in the opposite direction in a dry state. After swelling in water, the hydrogel network of adhesive will expend, and the multilayer become flat. (D) i) the flat state of the multilayer before swelling; ii) the buckling state of the multilayer after swelling; iii) the multilayer is applied on two glass slides, and the glass slides are pulled by hand to test the adhesion, and no buckling is observed; iv) a multilayer naturally buckles and rolls into a tube after fabrication; v) the multilayer is flat after swelling and after application on the glove.

[0019] FIGs. 8A-8K. Characterization of the biocompatibility and the adhesion of wound dressings. (A-B) Biocompatibility of PVA / BA film on a mouse with shaved skin. (C-E) Comparison of the wound closure performance between PVA / BA film, PAAm / PVA / BA film, and Dermabond™ glue on the mouse with unshaved skin. (F) Tension and shear stress states of the PAAm / PVA / BA film on the skin. L, W, and h represent the length, width, and thickness of the film, respectively. (G) Model for measurements to mimic the stress states of the film on mouse skin. (H) The stress states of a PAAm / PVA / BA film during and after the drying process. PAAm is immersed in PVA / BA for 24 h. (I) The shear adhesion strength of the dried PAAm / PVA / BA film on the glass substrates tested after drying for 6 h. (J) The stress-strain curve of a dried PAAm / PVA / BA film. (K) The comparison of interfacial and cohesive failures of the adhesion. Mean ± SD from left to right in (K) are 456.6 ± 137.3 kPa, 234.4 ± 106.5 kPa, 301.1 ± 111.9 kPa, 330 ± 17 kPa. The sample size of each experiment n = 3.

[0020] FIGs. 9A-9L. Adhesion experiments of PAAm / PVA / BA films with and without the PDMS elastomer layer. (A-C) The lap shear tests. Mean ± SD from left to right in (A) are 23.7± 0.26 kPa, 20.55 ± 1.89 kPa; p = 0.0459. (D-F) The shear / tension mix tests. Mean ± SD from left to right in (D) are 8.09 ± 1.136 kPa, 64.65 ± 2.23 kPa; p < 0.0001. (G-I) The peel tests from the dry films. Mean ± SD from left to right in (G) are 73.86 ± 12.81 J / m2, 148.2 ± 20.35 J / m2; p = 0.0059. (J-L) The peel tests when water is added at the crack front of the films. Mean ± SD from left to right in (J) are 18.46 ± 4.85 J / m2, 36.2 ± 24.4 J / m2; p = 0.2844. (A, D, G, J) A two-sample t-test obtains p-values, indicating the significant level between bar plots as * p < 0.05, ** p < 0.01, and **** p < 0.0001. The sample size for each experiment n = 3.

[0021] FIGs. 10A-10D. The effect of water on adhesion. (A) The PAAm hydrogel film with 34% water is used for adhesion experiments after 1 min of adhesion time. (B) The dried PAAm hydrogel is immersed in water for 3 s and tested for adhesion after 1 min of application. (C) The PDMS-PAAm bilayer with 34% water is applied on glass for adhesion experiment after 1 min waiting. (D) The PDMS-PAAm bilayer with 34% water is applied on glass, and the adhesion is tested after 30 min waiting. The sample size for each experiment n= 3.

[0022] FIGs. 11A-11L. The protection effect of a PDMS backing layer on the PAAm / PVA / BA adhesive. (A) The PVA / BA film is adhered to a glass slide (dipping in water), dried and then attached to the petri dish, followed by immersion in water. (B) Pictures of the PVA / BA film before and after immersion in water. (C) Mass change of the PVA / BA film shown in (A) after immersed in water over time. (D-F) The dry PVA / BA film is covered by a layer of PDMS with a tacky surface attached to the petri dish, followed by immersion in water. (E) The picture shows the state of the double layered film in water. (F) Mass change of the PVA / BA shown in (E) after immersed in water over time. (G-I) The experiment of evaporation of water in the multi-layered hydrogel films with and without a PDMS protection layer over 36 hours. Mean ± SD from left to right in (I) are 30.98 ± 7.3 %, 1.59 ± 0.91 %, 6.58 ± 2.08 %. For 12 h, p = 0.0023, for 36 h, p = 0.0051. (J-L) The swelling effects of the hydrogel immersed in water for 12 hours with and without a PDMS protection layer. Mean ± SD from left to right in (L) are 80 ± 13.16 %, 5.29 ± 5.61 %. For 12 h, p = 0.0008. (I, L) A two-sample t-test obtains p-values, indicatingthe significant level between bar plots as ** p < 0.01 and *** p < 0.001. The sample size for each experiment n = 3.

[0023] FIGs. 12A-12F. Mechanical testing of the PAAm / PVA / BA films applied to the pig skin. (A-B) The mechanical property of pig skin. The thickness of the measured pig skin is ~ 5 mm. (C-D). The adhesion experiment of the multilayered film bridges two pieces of pig skins. (E) The crack can be observed in the shear experiments. The crack is typically initiated from the edge of film. (F) After debonding of the film from pig skin, there are residues of pig skin on the adhesive side of the film, which is regarded as the stratum corneum of the skin. The sample size for each experiment n= 3.

[0024] FIGs. 13A-13H. Observation of adhesives on skin (A-D). Photos of removing the multilayered PDMS / PAAm / PVA / B A film from back of a hand after flushing under water for 1 min. (A) The film edges are exposed to the environment. (B) The multilayered film under tap water for 1 min. (C) The film remained on skin. (D) During pulling, fibrils are formed on adhesive. The opaqueness of the film is due to a layer of white paper used as the matrix of PAAm / PVA / BA. There is no other special purpose of the paper. (E-H) Photos of the multilayered adhesive film is placed on the pig skin. (F) After cutting, the wound skin is stitched by sutures, followed by application of the PAAm / PVA / BA film with an elastomer layer on top. (G-H) After 10 days in air at a relative humidity of 30% and the room temperature, both the cut pig skin and the adhesive film are flexible for bending. White arrow indicates the adhesive film, and red dot line encloses the area of the film.

[0025] FIGs. 14A-14H. A). The PAAm hydrogel is immersed in a PVA / BA solution for 24 h and applied to glasses to make the adhesion. The test is done after twait time. B-D). Tests of samples prepared in (A) after tWait=lmin, 10 min, and 30 min, respectively. E). The PAAm hydrogel is immersed in PVA / BA solution for 3 s and dried for tdry time before applied to glasses to make the adhesion. F-H). Tests of samples prepared in (E) after tdry= 1 min, 10 min, and 30 min, respectively.

[0026] FIG. 15. Optical images showing tests on animal models. A) A live mice model, (i) Applying the Dermabond glue, (ii) Mouse applied with the PVA / BA film, (iii) Mice without (left) and with (right) the PVA / BA film before being sacrificed for histological tests. B) A just sacrificed pig model, (i) Cutting and stitching the pig skin, (ii)The profile of the cut. (iii) Stitching the wound with a suture, (iv) Applying the PAAm / PVA / BA film on top of the sutured wounds.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0027] The present disclosure may be understood more readily by reference to the following detailed description of desired embodiments and the examples included therein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0029] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0030] As used in the specification and in the claims, the term "comprising" can include the embodiments "consisting of' and "consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as "consisting of' and "consisting essentially of' the enumerated ingredients / steps, which allows the presence of only the named ingredients / steps, along with any impurities that might result therefrom, and excludes other ingredients / steps.

[0031] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it isunderstood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0032] Unless indicated to the contrary, the numerical values should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.

[0033] All ranges disclosed herein are inclusive of the recited endpoint and independently of the endpoints. The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0034] As used herein, approximating language can be applied to modify any quantitative representation that can vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about” and “substantially,” may not be limited to the precise value specified, in some cases. In at least some instances, the approximating language can correspond to the precision of an instrument for measuring the value. The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” can refer to plus or minus 10% of the indicated number. For example, “about 10%” can indicate a range of 9% to 11%, and “about 1” can mean from 0.9-1.1. Other meanings of “about” can be apparent from the context, such as rounding off, so, for example “about 1” can also mean from 0.5 to 1.4. Further, the term “comprising” should be understood as having its open-ended meaning of “including,” but the term also includes the closed meaning of the term “consisting.” For example, a composition that comprises components A and B can be a composition that includes A, B, and other components, butcan also be a composition made of A and B only. Any documents cited herein are incorporated by reference in their entireties for any and all purposes.

[0035] Any embodiment or aspect provided herein is illustrative only and does not limit the scope of the present disclosure or the appended claims. Any part or parts of any one or more embodiments of aspects can be combined with any part or parts of any one or more other embodiments or aspects.

[0036] Reversible adhesives have gained popularity in recent years, particularly in industries such as packaging, construction, and transportation, where there is a growing emphasis on reducing waste and improving sustainability. The reversible nature of these adhesives allows for easy removal and repositioning, reducing the risk of damage or waste to the underlying substrate. However, introduction of dynamic covalent bonds or non- covalent bonds that make these adhesives reversible can also be a potential weakness: when the environment is changed, e.g., in temperature, humidity, or chemical exposure, the adhesive could lose its grip.

[0037] To address this issue, backing layers have been introduced to provide additional support and maintain the mechanical properties of the adhesives. The backing layer acts as a barrier that protects the adhesive from external stresses, and helps to distribute the load across the surface, thus reducing the risk of localized failure. Depending on the application and the specific adhesive being used, the backing layer can be made from cellulose plastics, silicon elastomers, papers, fabrics, and coppers.

[0038] Among them, the plastic backing layers are commonly used for polymer adhesives, as they offer high strength and flexibility. In addition to providing mechanical support, backing layers can be designed to offer additional functionality, for example, electrical conductivity for the use in electronics. Others are designed for clean and easy removal of the adhesive without leaving residues or damaging the underlying surface.

[0039] In the case of wound dressing, a backing layer can provide mechanical support and integrity around wound, minimize moisture loss to maintain a better environment for healing, allow gas permeation to prevent the buildup of exudate and facilitate wound respiration, and improve the handling of the dressing in clinic operations.

[0040] Various materials can serve as the backing layer for wound dressing. For example, polyurethane films offer flexibility, breathability, and transparency for wound monitoring. Woven cotton gauze, a traditional wound dressing material, provides themechanical support and absorbency for fluid around the wound. Silicone membranes offer oxygen permeation while preventing moisture loss and can be used to release drug molecules. Hydrogel sheets are conformable and can offer moisturizing backing alternatives for delicate wounds. The backing layers, however, typically do not have strong adhesion on skin directly.

[0041] Hydrogel-based adhesives have been studied for biomedical applications. But such films dry over time in ambient conditions, thus limiting their clinical applications.

[0042] International patent applications PCT / US2022 / 051155 and PCT / US2023 / 067474 (incorporated herein by reference in their entireties) describe a strong and reversible adhesive film from poly(vinyl alcohol) (PVA) and boric acid (BA), forming boronic ester dynamic covalent bonds that can be opened by water and form adhesion on glass and mouse skin upon drying. However, when water in the adhesive is completely evaporated, the film becomes dry and stiff, resulting in skin-stretching sensation. Meanwhile, it is useful to protect the PVA / BA adhesive layer and wound site from continuous exposure to water, which can dissolve and completely remove the adhesive.

[0043] To address the aforementioned limitations, here, we develop a biocompatible, multilayered tape that is made of a biocompatible poly(dimethyl siloxane) (PDMS) elastomer backing layer as the matrix coated with the PVA / BA adhesive layer, which allows for instant adhesion to a wide range of substrates, including plastics, fabrics, glass, metals, ceramics, and skin.

[0044] Upon activation by water or moisture, the adhesive forms an immediate bond with the substrate, while the biocompatible and elastic backing layer provides a strong contract force to close wounds on adherends. The combination of the adhesive and backing layer offers a higher adhesion strength than the current topical wound dressing products available in the market. Meanwhile, the hydrophobic PDMS will keep moisture around the skin from evaporation, thus the tape remains soft and not too dry, which in turn improves patient comfort and promote the healing process.

[0045] The disclosed tape is not only functional but also versatile in terms of aesthetics. It can be transparent, allowing for observation on the site of application, or tailored in different colors using different colored elastomer backing layers. This openspossibilities for customization and personalized use. Additionally, our tape can provide additional functions such as drug delivery, monitoring, and stimulation, further expanding its potential applications.

[0046] As depicted in exemplary FIG. 1, an example tape includes multiple components, including instant adhesives consisting of elastic polyacrylamide (PAAm), water-activated instant sealant layer (PVA / BA), water-proof layer, and the hydrophobic backing layer (PDMS). PDMS is oxygen-permeable, thermal, and electrical insulating and hydrophobic, ensuring that the adhesive layers are protected from external moisture and other environmental factors. The resulting tape has excellent adhesion strength and can be easily peeled off without causing pain or discomfort to the user. Here, we synthesize a double network hydrogel comprised of PVA / BA and a covalently crosslinked, highly elastic PAAm hydrogel. The hydroxyl groups from PVA and BA can form covalent bonds with the substrates or adherends with hydroxyl groups, such as wood, skin, and glass. The multilayer tape can be dried after preparation to extend shelf life. It also facilitates the customization and the sterilization. For example, a quick dip of the tape in clean or sterilized water will activate the adhesion of the tape to a substrate.

[0047] PAAm hydrogel can be used as the matrix layer because the material provides certain advantages. First, the matrix layer can reinforce the mechanical and adhesive strength of the tape, thereby reducing the likelihood of detachment or failure during use. Second, the matrix can bond to the hydrophobic backing layer to enhance the overall stability and durability of the tape. Third, the matrix can retain a certain amount of moisture, which will help to keep the skin or other adherends hydrated. Fourth, the matrix layer can serve as a reservoir or carrier for drugs, biomolecules, or other active agents, which can be released for therapeutic applications.

[0048] Besides PAAm, other example biocompatible materials that are suitable for use as matrix layers include neutral hydrogels such as poly (2 -hydroxy ethyl methacrylate) (PHEMA), polyelectrolyte hydrogels such as polyacrylic acid (PAA), polyampholyte hydrogels, block copolymers, bottle-brush copolymers, conducting polymers, ionoelastomers, zwitterionic polymers, ionic liquid gels and organogels. The choice of the matrix material depends on intended applications, the desired properties of the tape, the nature of the backing layer and the compatibility of the matrix with theadhesive and the substrate. The versatility and flexibility of the matrix materials allows one to further tailor the properties and functionalities of the adhesives.

[0049] The silicone-based elastomer, PDMS, is chosen as the hydrophobic backing layer as it imparts additional mechanical support to the adhesive, which is relevant to ensuring that the tape remains to be adhered to the skin or the wound site during extended uses. It also acts as a barrier to protect the adhesive from undesired environments, such as extended exposure to moisture and microbes. PDMS can also be colored to protect the photosensitive drugs in the underlying layers from light exposure.

[0050] Heating circuits can be introduced to the backing layer to induce local heating for more precise control of the adhesion and wound healing processes. Vascular structures can be embedded to transport and release biological or chemical indicators for monitoring the environment, adhesion, and wound healing process. Other hydrophobic elastomers can also be used as the hydrophobic backing layer, including Eco-flex, dragon skin, natural and vulcanized rubbers, and polyurethane elastomers. These materials offer unique mechanical and chemical properties that can be tailored to a specific application of the tape.

[0051] To improve the adhesion and the insolation properties of tape, we add a water-sealant and a water-proof coating at the boundary of the tape. The water-sealant can be a hydrogel with or without adhesion. Polyelectrolytic hydrogels, such as PAA is chosen here because it absorbs water due to the hydrolysis of the carboxylic groups and the osmotic pressure of network. Meanwhile, PAA hydrogels form good adhesions with many substrates through the hydrogen bonding. Here, the adhesion does not need to be instant. The water-proof coating at the edge of the tape can be hydrophobic PDMS with a low crosslinker density (resin: crosslinker > 30 : 1 wt / wt), viscous commercial silica gels, or hydrophobic ionoelastomers.

[0052] If a wound on skin is caused by the removal of a melanoma tumor, photodynamic therapy can be applied through the bandage. Verteporfm is a medication used as a photosensitizer for photodynamic therapy.. Verteporfm, which can be loaded in the porous adhesives, can potentially penetrate the epidermal layers of skin, and get in the melanoma tumor cells. Once activated by the light of a specific wavelength, Verteporfm can generate reactive oxygen species to kill the remaining cancer cells, promoting a more thorough treatment of the condition. The tape can be transparent for observation on site.

[0053] Delivery of drugs and monitoring of conditions are functions that can be further added into our tapes. However, the backing layer can also be color changeable. For example, our future work considers the integration of on the backing layer that can change colors or patterns upon external stimuli (i.e., mechanical stretching or compression) to entertain children.

[0054] The innovative tape can be manufactured at scale, e.g., as outlined in FIG. 2. There are several different approaches to combine these procedures in the production of our tapes, and three examples are shown in FIGs. 7-9. Each example showcases one recipe for the adhesive and backing layers.

[0055] First, we prepare each component separately, which can be casted into a mold, followed by photo- or thermal polymerization. The chemistry is slightly modified from the conventional recipe to ensure bonding of the multi -components at a later step. The instant adhesive then can be hot-pressed to remove water and form a dry tape. The instant adhesive made from PVA / BA can be reswollen by water to form a PVA / BA hydrogel is formed. If the hydrogel network of adhesive needs to be porous for the purpose of drug-carrier loading, the instant adhesive will be further lyophilized and reswelled. At last, adhesives and backing layer are bonded together through chemical reactions. The unreacted monomers are washed out during the integration of the bilayer tape, and the pH of hydrophilic adhesives are tuned to be 7.4, which is the natural pH of human body.

[0056] During the application of the multilayer tape, the tape buckles after absorbing a certain amount of water (FIG. 3a). In medical or daily applications, it is impossible to precisely control the amount of water absorbed by adhesives or the contact time of the tape in water.

[0057] To address this issue, one can use various strategies. The first strategy is to tune the bending stiffness of the bilayer tape. The bending stiffness of a material, K is defined as K= Ebh3 / 12, where E is the Young’s modulus, b is the width, and h is the thickness of the film. Thus, to resist the buckling, we increase the bending stiffness of the backing layer by increase the elastic modulus or the thickness. Alternatively, one can reduce the elastic modulus and thickness of the hydrogel adhesives. One can increase the bending stiffness of the backing layer, and the bilayer tape can be flat after swelling (FIG. 3b).

[0058] A second strategy is to pre-program the deformation or pre-stress the adhesive layer to balance the swelling-induced deformation (FIG. 3c). To do so, we apply an equal-biaxial stretch to the hydrogel adhesive before the bonding. Alternatively, a pressure applied in the thickness direction can serve the same purpose. A typical equal - biaxial stretch ratio applied here is ~ 1.3. After the bonding between the adhesive and the backing layers, the bilayer buckles towards the pre-stretched adhesive layer side due to the pre-stress. When dipped in water, the hydrogel network swells. As the osmotic pressure balances the pre-stress inside the hydrogel network, the bilayer tape becomes flattened.

[0059] After tape fabrication, we measure its adhesion strength. In our studies, we have conducted both shearing and peeling tests between two identical tapes prepared in Strategy 1. Our findings suggest that the shearing adhesion is stronger than the peeling adhesion (FIG. 4), indicating a Velcro-like behavior. Here, our molecular Velcro is a combination of dynamic covalent bonding between the hydroxyl groups from substrates and boronic ester from the adhesive and hydrogen bonding between the substrate and the adhesive. The shearing adhesion strength is measured by the shearing force (Fs) dividing the contact area (A), T = Fs / A, (N / m2), and the 180° peeling adhesion toughness is measured by the peeling force (Fp) dividing the width (D) of sample G = 2Fp / D (N / m). Apparently, the two quantities are not in the same unit, thus cannot be compared directly. The easiest way is to compare the forces: Fs / Fp= 2TA / GD. Since T and G are measured constant in FIG. 4, as long as A / D > G / 2T = 1 / 800 (m), the shear force will be larger than the peeling force. Apparently, this requirement can easily be satisfied. For example, a tape has a contact area of 6 cm2and a width of 2 cm, then A / D = 3 / 100.

[0060] Quantitative measurement of adhesion strength on skin is crucial to assess the effectiveness of these tapes in various applications, including wound healing, drug delivery, and wearable devices.

[0061] As an example, pig skin was taken and its mechanical properties were measured (FIG. 5a), followed by lap shear tests of the tape on the untreated skins (FIG. 5b-5c). The pig skin is stiff and rough: its Young’s modulus reaches several MPa, which is compatible to that of the adhesive with a PDMS backing layer. This results in the good conformability of the bilayer tape on pig skin. The adhesion strength of the tape on pig skin is measured by lap shear tests, where two pierces of pig skin are clamped on the Instron machine, and a bilayer tape is applied between them.

[0062] By stretching the pig skin, ~ 10 kPa adhesion strength is obtained before the two pieces of pig skin are completely separated. After debonding, there are lots of residue of skin left on the surface of the adhesives (FIG. 5c). These residue skins are the stratum comeum layer of the pig skin. The debonding of stratum corneum layer limits the adhesion strength of tape. Thus, cracks between the bilayer tape and the pig skin are typically initiated from the edge of the tape.

[0063] To test the water-proof ability, we apply the bilayer tape on a hairy skin and rinse the tape under the tap water for at least 1 min (FIG. 6a). The amount of water flowed over the tape and the interval of time tested here are much greater than that the typical water contact that takes place in a typical wound sustained during daily life. After the rinse, the tape maintains the same state on skin, and hand movement has a negligible influence of the adhesion. The tape can be peeled off painlessly from skin by wetting the adhesives from the edge of the tape. This indicates the water -proof property of the bilayer tape.

[0064] We then test the performance of the bilayer tape on a pig skin in an ambient condition (FIG. 6b). The pig skin is cut and stitched by sutures first, followed by application of the tape, mimicking the real situation of wound after surgery. The skin-tape composite is kept at room temperature with a relative humidity 30% for 10 days. The composite remains highly flexible (FIG. 6b vi-viii). This indicates that the tape on pig skin is not totally dried.

[0065] In summary, the disclosed technology provides a biocompatible and reversible adhesive tape with a hydrophobic backing layer to enhance patient comfort and treatment effectiveness in wound care. T

[0066] he tape's adhesive property can be achieved through an adhesive composed of PAAm, PVA, and BA, where dynamic covalent bonds can be dissociated by water. The elastic PAAm hydrogel matrix layer reinforces the tape's mechanical strength and adhesive properties. To prevent discomfort caused by the tape's dryness, a hydrophobic backing layer, PDMS, is used to isolate the adhesive from environmental variations. The resulting tape remains adhesive, soft, and painlessly removable. The tape can be customized in various colors and can incorporate functionalities like drug delivery, monitoring, and stimulation. Also provided are industrial -scale production processingflows, including casting, polymerization, hot-pressing, and chemical bonding between adhesive and backing layer.

[0067] The following are exemplary embodiments of the disclosed technology. These embodiments are illustrative only, and the appended claims and the disclosed technology are not limited to any particular examples provided here.

[0068] Materials

[0069] Polyvinyl alcohol (PVA, molecular weight, 13000-23000 g / mol, 87-89% hydrolyzed), acrylamide (AAm), acrylic acid (AA), glycerol, benzophenone, verteporfin (VP) and 2-hydroxy-4'-(2 -hydroxy ethoxy)-2-methylpropiophenone (1-2959) and N,N'- methylenebisacrylamide (MBAA) are purchased from Millipore Sigma. Boric acid (BA, DNase, RNase, Protease free, 99.5%,) and pH buffer (pH=9, Hydrion) are ordered from Fisher Scientific. Polydimethylsiloxane (PDMS, SYLGARD®184) is purchased from Dow. VHB tapes (0.5 mm thick) are purchased from 3M.

[0070] Fabrication of the individual component of the bilayer tape

[0071] Fabrication of PVA / BA films. 7.26 g PVA and 0.242g BA powders (mass ratio of 30: 1) are mixed in 30 mL water. The mass concentration of PVA / BA in water is 20 wt%. The mixture is heated up to 90 °C. At the same time, the mixture is stirred until fully dissolved. The viscous solution is cast on a glass plate with 1 mm thickness and dried overnight at room or higher temperature.

[0072] Fabrication of PAAm hydrogel films. 42.64 g AAm is dissolved in 300 mL water to form an aqueous solution with a concentration of 2M. 0.77 g MBAA is dissolved in 50 mL water to form an aqueous solution with a concentration of 0.1 M. 0.224g 1-2959 is dissolved in 10 mL ethanol to form a solution with a concentration of 0.1 M. For 1 mL of AAm solution, 66 L MBAA solution and 1.5 L 1-2959 solutions are added. The solution is sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV light (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 2 h.

[0073] Fabrication of PAAc hydrogel films. 1.3 mL AAc is dissolved in 10 mL water to form an aqueous solution with a concentration of 2M. 0.77 g MBAA is dissolved in 50 mL water to form an aqueous solution with a concentration of 0.1 M. 0.224g 1-2959 is dissolved in 10 mL ethanol to form a solution with a concentration of 0.1 M. For 1 mL of AAc solution, 66 [iL MBAA solution and 1.5 [iL 1-2959 solutions are added. Thesolution is sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV light (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 2 h.

[0074] Fabrication of highly entanglement polyacrylamide (ePAAm) hydrogel films. 19.67 g AAm is added in 10 mL water and heated at 50 °C for 1 hour to dissolve. The molar ratio between water and AAm is controlled as 2. Then, 27.67 L as-prepared MBAA solution and I I L as-prepared 1-2959 solution are added into the AAm solution. The molar ratio between MBAA and AAm is controlled as 10'5. The molar ratio between 1-2959 and MBAA is controlled as 0.4. The solution is sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 6 hours. In some samples wherever specifically mentioned in context, the only variable is concentration of AAm.

[0075] Fabrication of ePAAm / PVA / BA hydrogel films. The ePAAm / PVA / BA precursor is made by mixing 10 mL H2O, 2.34 g PVA, 0.078 g BA, 19.67 g AAm, 27.67 j L MBAA solution (0.1 M) and I I L 1-2959 solution (0.1 M), where m(PVA) / m(BA)=30, m(PVA+BA)=20 wt.% in water, n(H2O) / n(AAm)=2, n(MBAA) / n(AAm)=10'5, and n(I-2959) / n(MBAA)=0.4. The solution is sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 6 h.

[0076] Fabrication of PAA hydrogel films. 5 g Acrylic acid, 0.5g N,N'- Methylenebisacrylamide (MBAA) crosslinker are mixed together with 0.05 g Irgacure 2959 photoinitiator and 10 mL distilled water. The solution is sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 2 h.

[0077] Fabrication of porous PAAm hydrogels. The PAAm hydrogels (1 mm thick) are fabricated as aforementioned, followed by freezing in liquid nitrogen. The samples are then freeze-dried in a lyophilizer (Labconco) at -80°C and 0.1 mbar for 1-2 days.

[0078] Fabrication of the PDMS / hydrogel bilayer. Photoinitiator, benzophenone, is first dissolved in ethanol at 1 wt%. The solution is brushed onto the surface of PDMS. The precursors of hydrogels are casted on top of PDMS, followed by UV curing (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 2 h.

[0079] Preparation of the PDMS backing layer. Sylgard 184 resin and the curing agent are mixed with a 10: 1 weight ratio, followed by stirring thoroughly until the mixture becomes homogenous. The mixture is then poured into a petri dish with 1 mm thickness and cured at 70-80°C for 1-2 h.

[0080] Fabrication of Ecoflex silicone gel. Ecoflex 00-30 is prepared by mixing the base and curing agent in a weight ratio of 10: 1, followed by stirring thoroughly until the mixture becomes homogenous. The mixture is then cast onto a target substrate (here, PDMS) and cured at room temperature for 1-2 days.

[0081] Removal of unreacted molecules in polymer films. The unreacted monomers in the polymer films are removed by first soaking the film in a tank of solution (i.e., water, ethanol, BA.) with a hundred-fold larger volume compared to the volume of polymer films for more than 5 hours each time. The time depends on the thickness of film. The swollen sample is placed on a glass plate and dried in an oven at 40 °C. After three cycles of swelling-drying processing, the final sample is swollen back with the same weight percentage of water.

[0082] Adhesion tests. Both shearing and peeling test are carried on the tensile machine (Instron 5564) at a loading speed of 5 mm / min. The load cell is ± 2 kN. The sample is cut into a rectangular shape (2 cm wide and 5 cm long).

[0083] Example Approaches For Large Scale Fabrication

[0084] The bilayer tape has a biocompatible and elastic backing layer, which provides a strong contract force to close wounds on adherends. The instant adhesion adhesive layer is activated by water or moisture and provides a high adhesion strength. The water sealant adhesive layer prevents water from penetrating through the tape and promotes the healing process. The hydrophobic adhesive layer allows for easy removal of the tape, while the oxygen-permeable backing layer isolates the adhesive layer and wound site from the external environment. Here we depict three approaches for the fabrication of bilayer tape.

[0085] Approach l is a straightforward and efficient method to fabricate the bilayer tape (FIG. 3). The adhesives and backing layers are prepared in a one-step process, which saves time and reduces the risk of contamination. Benzophenone acts as the bonding agent between the hydrophobic backing layer, PDMS, and the hydrogel layer. 1 wt% benzophenone / ethanol solution is brushed onto the surface of the hydrophobicbacking layer (PDMS). The precursor of PAAm hydrogel, including monomer AAm, crosslinker MBAA and photoinitiator 1-2959, is then casted on the benzophenone-treated PDMS, which are then sandwiched between two glass plates and irradiated under a UV light to polymerize. Next, the water sealant material, PAA, is cast on the same PDMS. The preparation of PAA is by replacing AAm monomers with AAc monomers and following the same recipe and procedures of making PAAm hydrogel. After polymerization, the unreacted monomers are removed by washing the bilayer in ethanol / water solution. After the sample is dried, the PAA hydrogel is masked on top. The bilayer tape is dipped in the adhesive (PVA / BA) solution to coat a layer of PVA / BA on the top of PAAm hydrogel. Then, the mask is removed, and the bilayer tape is sterilized. Finally, the hydrophobic adhesive (Ecoflex silicone gel) is coated directly on PDMS. The samples are sealed in plastic bags before use.

[0086] Approach 2 differs from the Approach 1 by preparing PVA / BA adhesive inside PAAm hydrogel layer at the first step (see FIG. 4). The adhesive hydrogel layer is prepared by mixing PVA and BA powders in PAAm precursor until fully dissolved. The precursor of PAAm hydrogel consists of monomer AAm, crosslinker MBAA, and photoinitiator 1-2959. Benzophenone acts as the bonding agent between the hydrophobic backing layer, PDMS, and the hydrogel layer. 1 wt% benzophenone / ethanol solution is brushed onto the surface of the hydrophobic backing layer (PDMS). The precursor of PAAm hydrogel, including monomer AAm, crosslinker MBAA and photoinitiator 1-2959, is then casted on the benzophenone-treated PDMS, which are then sandwiched between two glass plates and irradiated under a UV light to polymerize. Next, the water sealant material, PAA, is cast on the same PDMS. The preparation of PAA is by replacing AAm monomers with AAc monomers and following the same recipe and procedures of making PAAm hydrogel. After polymerization, the unreacted monomers are removed by washing the bilayer in ethanol / water solution. After the sample is dried, the PAA hydrogel is masked on top. The bilayer tape is dipped in the adhesive (PVA / BA) solution to coat a layer of PVA / BA on the top of PAAm hydrogel. Then, the mask is removed, and the bilayer tape is sterilized. Finally, the hydrophobic adhesive (Ecoflex silicone gel) is coated directly on PDMS. The samples are sealed in plastic bags before use.

[0087] Approach 3 differs from the previous two approaches that it uses a lyophilizing procedure to make the adhesive layer porous. The precursors of the PAAmhydrogels are sandwiched between two glass plates and cured under UV light. The hydrogel is frozen in liquid nitrogen and freeze-dried. The resulting porous hydrogel is reswollen in PVA / BA / AAm aqueous solution. The rest of the steps are the same as Approach 1.

[0088] Additional Disclosure

[0089] Reversible adhesives for wound care improve patient experiences by permitting reuse and minimizing further tissue injury. Existing reversible bandages are vulnerable to water and can undergo unwanted deformation during removal and readdressing procedures. Here, we design a biocompatible, multilayered, reversible wound dressing film that conforms to skin and is waterproof. The inner layer is capable of instant adhesion to various substrates upon activation of the dynamic boronic ester bonds by water; the intermediate hydrogel layer and the outer silicone backing layer both can enhance the dressing’s elasticity and load distribution for adhesion, and the silicone outer layer protects the dressing from exposure to water. The adhesive layer is found biocompatible with mouse skin. Skin injuries on mouse skin heal more rapidly with the film compared to no dressing controls. Evaluations of the film on skin of freshly euthanized minipigs corroborate the findings in the mouse model. The film remains attached to skins without delamination despite subjecting to various degrees of deformation. Exposure to water softens the film to allow removal from skin without pulling any hair off. The multilayered design considers soft mechanics in each layer and will offer new insights to improve wound dressing performance and patient comfort.

[0090] Reversible adhesives, characterized by their ability to alternate between adhesive and non-adhesive states are of interest for diverse applications, including wound dressings, transdermal drug delivery, and wearable electronics. Reversibility can be achieved through non-covalent interactions, introduction of dynamic covalent bonds in hydrogels and elastomers, and use of plasticizers to lower the elastic modulus such that the adhesive becomes tackier and can easily conform to a substrate for adhesion or peel off for removal. Key metrics for evaluating adhesive’s performance and practicality include the easy of activation / deactivation, toughness, shear strength, and the number of cycles of reversible applications without significantly losing its efficacy.

[0091] Various reversible adhesives have been developed for tissues. For example, silicone-based adhesives are tacky and offer gentle adhesion that can minimizepatient’s discomfort. For example, medical grade silicone gels with low adhesion strength 1-10 N / m can remain on skin for a few days, yet can be peeled off and repositioned easily, thus, allowing for non-traumatic adhesion to fragile and newly created tissues from, e.g., elderly patients or neonatal. Meanwhile, silicone is hydrophobic. When used in wet conditions, it can protect the wound from aqueous contaminations. Block copolymers containing a segment of polydimethylsiloxane (PDMS) and a segment of (modified) ionogenic poly(2-dimethylamino)ethyl methacrylate are used as hydrophobic adhesives in aqueous media. The drawback of silicone-based adhesives is the low adhesion on skin, which is relatively hydrophilic. Hydrogel adhesives are known for their hydrophilicity, biocompatibility, and moisture-retention capability, and have been used as dressings for burns and chronic wounds. Hydrogel adhesives can be synthesized with a wide variety of chemistry to offer more functionalities and tunability. Poly(acrylic acid-co-acrylamide) (PAA-PAAm) hydrogel with wrinkle patterns is designed to program the adhesion and the detachment by varying the water content. Injectable surgical adhesives have been created from gelatin and chondroitin sulfate, two commonly used extracellular matrix biopolymers, demonstrating temperature-responsive adhesion and self-healing. Compared to silicon-based adhesives, hydrogel adhesives are much softer with shear strength in the range of 1-100 kPa that are close to skin’s modulus. However, hydrogel adhesives can exhibit a high peel toughness ranging from 10-103N / m. Therefore, they are capable of closing multiple types of wound in body. For instance, poly(acrylic acid) grafted with N- hydroxysuccinimide ester crosslinked by biodegradable gelatin methacrylate is made into a double-sided tape for closing the wound on wet tissues. Such a hydrogel tape can be strained and dehydrated. When wetted by water, it can not only bond to the wound but provide a contract force to hasten healing.

[0092] In practice, to adopt any adhesive for wound closure or wound healing, the long-term stability of the adhesives under various physiological conditions is essential. Hydrogel-based reversible adhesives, however, may degrade or lose their adhesive properties in the presence of body fluids or extended exposure to water or environmental humidity. Therefore, some hydrogels are made for under water applications. In air, a hydrophobic protection layer is often introduced. It can protect the adhesive from external stresses and help to distribute the load across the surface, thus reducing the risk of localized failures. It also helps to minimize moisture loss to maintain a better environmentfor healing, improve gas permeation to prevent the buildup of exudate, and facilitate wound respiration and handling of the dressing in clinic operations. For example, a woven cotton gauze provides both the mechanical support and absorbency of fluid around the wound. The hydrogel sheets can retain moisture for delicate wounds. The silicone membranes offer oxygen permeation and can be used to release drugs while preventing moisture loss. The polyurethane films are often used as the supporting layer as they offer flexibility, breathability, and transparency for wound monitoring. Typically, these protection layers are applied separately on top of the wound dressing without chemical bonding to the dressing film.

[0093] In a reversible adhesive made from poly(vinyl alcohol) (PVA) and boric acid (BA), forming boronic ester dynamic covalent bonds that can be opened by water and form adhesion on glass and mouse skin upon drying, the PVA / BA adhesive film can dissolve and be completely removed under continuous exposure to water. To address this limitation, here we report the development of a multilayered wound dressing film consisting of a PVA / BA adhesive inner layer, an elastic, biocompatible hydrogel intermediate layer from PAAm, and a hydrophobic elastomer outer layer from PDMS. The combination of PAAm and PDMS provides a strong contract force to close the wound on the adherend. Importantly, the hydrophilic PAAm hydrogel layer will help to retain moisture at the wound and keep the dressing skin-like; the hydrophobic PDMS elastomer layer will prevent moisture from evaporation. After applying our film in a murine wound healing model, the wound is closed entirely in just 2 days. It is remarkable that, despite being deformed in different directions, the film retains its conformal fit to pig skins in the open air with negligible delamination. The ability of the multilayered wound dressing film to remain soft and flexible will offer great potentials to improve the skin’s comfort and promote the healing process. When wetted with water, the film is significantly softened and easy to be peeled off from the skin without pulling off the hairs on the back of the hand.

[0094] Results and Discussion

[0095] Multilayer Adhesives

[0096] Design and Fabrication

[0097] As illustrated in FIG. 6A-B, a wound dressing film can comprise three layers, where the covalently crosslinked PAAm hydrogel acts as the intermediate layerbetween the dynamic covalently bonded PVA / BA, the instant adhesive as the inner layer, and a covalently crosslinked PDMS as the outer layer. The inelastic PVA / BA adhesive and the elastic hydrogel are physically bonded together through the interpenetration (also known as topological entanglement) of the two polymer networks. To promote rapid interpenetration at the interface between PAAm and PVA / BA, we first prepare a double network hydrogel by doping PVA / BA into the PAAm hydrogel precursor. This ensures that the elastic PAAm network and the inelastic PVA / BA network are interpenetrated within the bulk of the hydrogel. We then coat an additional thin layer of PVA / BA onto the surface of the PAAm / PVA / BA hydrogel to serve as the adhesive inner layer. The coated PVA / BA readily crosslinks with the doped PVA / BA in the double network hydrogel at the interface through the dynamic covalent boronic ester bonds. Notably, pre-fabrication of a double network hydrogel is crucial because, otherwise, the slow reptation of the coated PVA / BA chains would limit their ability to diffuse into the PAAm network and form effective interpenetration, which is essential to enable effective force transduction during application. Meanwhile, the hydrogel network acts a reservoir of PVA / BA to provide adhesives to the surface when the PVA / BA in the surface layer is exhausted during readdressing. The interactions between PVA / BA and the substrate (or adherend) originated from the dynamic covalent bonds and non-covalent interactions between the hydroxyl groups in adhesives and on the surface of the substrate. It is shown that the hydroxyl groups on PVA chains would form hydrogen bonding with the biopolymers of the skin. Meanwhile, BA can form dynamic covalent bonds between PVA and the skin. Further, the long PVA polymer chains will provide a bridging effect between the adhesive and the skin to enhance adhesion. The hydrophilic PAAm hydrogel and the hydrophobic PDMS elastomer are chemically bonded here, which will be elaborated in more details later.

[0098] The fabrication of the multilayered adhesive film is outlined in FIG. 6C. To covalently bond the PDMS backing layer and the PAAm layer, we brush 1 wt% benzophenone / ethanol solution onto the surface of PDMS. Here, benzophenone is a radical generator. Precursor of PAAm with or without PVA / BA is prepared and cast into a mold. Unless specified, the mass ratio between PVA and BA in any adhesive film or solution studied here is fixed as 30 / 1. PVA / BA aqueous solutions have a fixed 20 wt% of PVA and BA in total, which offers a desired viscosity for film fabrication. PAAmhydrogels are always prepared together with PVA / BA, and the mass ratio between PAAm and PVA is fixed as 8.4 / 1 to optimize the elasticity of hydrogel. The elastic modulus of the as-prepared PAAm hydrogel is 0.29 ± 0.08 MPa. A dry PVA / BA film has an elastic modulus of 2.56± 0.51 GPa. The elastic modulus of PDMS backing layer is 0.63 ± 0.22 MPa. The multilayers are stacked together with a glass slide and photopolymerized to bond them together. After washing off the unreacted acrylamide in an ethanol / water bath, followed by drying, the hydrogel is masked to coat another layer of tacky PDMS (~ 50- 100 pm thick) on top of the existing PDMS film. After curing PDMS, mask 1 is removed, and another mask is covered on the inverse regions of mask 1. The masked bilayer is dipped in the PVA / BA aqueous solution to replenish the adhesive in the PAAm hydrogel matrix. The coating of PVA / BA on surface of PAAm hydrogel is ~ 100 pm. The unmasked multilayer film is then dried for storage to extend the shelflife.

[0099] Functionality of each layer

[0100] PAAm hydrogel is chosen as the intermediate layer because it fulfills several design requirements. First, the intermediate layer should reinforce the mechanical and adhesive strengths of the adhesive film, thereby reducing the likelihood of detachment or failure during uses. Second, the intermediate layer should be able to bond with the hydrophobic backing layer to enhance the overall stability and durability of the adhesive film. Third, the intermediate layer can retain a certain amount of moisture, which will help to keep the skin or other adherends hydrated. Fourth, the intermediate layer can serve as a carrier for delivery of drugs, biomolecules, or other active agents. Other biocompatible materials, including neutral hydrogels (e.g., poly(2-hydroxyethyl methacrylate), PHEMA), polyelectrolyte hydrogels (e.g., polyacrylic acid, PAAc), polyampholyte hydrogels, ionoelastomers, zwitterionic polymers, ionic liquid gels and organogels, can also be used depending on the intended applications.

[0101] PDMS is chosen as the hydrophobic backing layer because it imparts an additional mechanical support to the adhesive, which is critical for ensuring that the multilayer remains to be adhered to the skin or the wound site during the extended use. It also acts as a barrier to protect the adhesive from undesired environments, such as extended exposure to moisture and bacteria. PDMS can be colored to protect the photosensitive drugs in the underlying layers from light exposure. Heating circuits can be patterned onto PDMS to induce local heating, to precisely control the adhesion and woundhealing processes. Microfluidic channels can be patterned in PDMS to transport and deliver biological cues or chemicals to enhance adhesion and wound healing process.

[0102] The application of the multilayered adhesive film is illustrated in FIG. 6D. The adhesive is activated by water and pressed onto the skin to close the wound. No special treatment of the skin such as removal of hairs is necessary. In fact, hairs can enhance adhesion due to increased contact area. The film can be peeled off simply after the adhesive is fully wetted by water.

[0103] Mitigation of swelling -induced deformation in the hydrogel / PDMS bilayers

[0104] In our initial experiments, the multilayered adhesive film buckles after the PAAm / PVA / BA hydrogel layer absorbs a certain amount of water, leading to expansion in hydrogel layer, while the stiffer and hydrophobic PDMS elastomer layer resists such expansion (FIG. 7A, FIG. 7Dii). In clinical or daily applications, there is no time to precisely control the amount of water absorbed by adhesives or the contact time of the adhesive in water. To address this issue, we employ two strategies. The first is to tune the bending stiffness of the multilayered adhesive film. The bending stiffness of a rectangularly sectioned film is defined as K= Ebh3 / 12, where E is the Young’s modulus, b is the width, and h is the thickness of the film. To resist the buckling, we can increase the elastic modulus or film thickness of the PDMS elastomer layer. Alternatively, we can reduce the elastic modulus or the thickness of the PAAm / PVA / BA hydrogel layer. By increasing the bending stiffness of the PDMS elastomer layer (E ~ 1 MPa and h 1 mm) and reducing the thickness of PAAm / PVA / BA hydrogel layer h to 0.1 mm (E ~ 0.1 MPa,), we show that the swollen multilayer remains flat (FIG. 7B and FIG. 7Diii).

[0105] The second strategy is to pre-stress the hydrogel layer to balance the swelling-induced deformation (FIG. 7C). To do so, we apply an equal-biaxial stretch (typical ratio, 1.3-1.5) to the hydrogel before bonding it with a thin layer PDMS. After bonding the hydrogel and the PDMS elastomer layers, the multilayer buckles towards the pre-stretched hydrogel side due to the pre-stress and drying (FIG. 7Div). When dipped in water, the hydrogel network reswells. As the osmotic pressure balances the pre-stress inside the hydrogel network, the multilayer film is flattened (FIG. 7Dv).

[0106] Adhesion study

[0107] Biocompatibility

[0108] Next, we apply the PVA / BA adhesive on a shaved mouse skin. The direct contact of the skin with PVA / BA allows for investigation of the biocompatibility of PVA / BA (FIG. 8A) since PAAm and PDMS are known biocompatible. The adhesive is secured with a Coban wrap to prevent physical manipulation by the mouse. Five days later, the mouse is euthanatized, and the skin is harvested for histological analyses. Hematoxylin and eosin (H&E) staining reveal normal skin histology with no obvious inflammation or immune cell recruitment (FIG. 8B). Further, we do not observe any change in the thickness of the epidermis, a common protective response of the mouse skin to the adhesive, or disruptions in the normal structure of skin layers, such as the epidermis and dermis.

[0109] Wound closure efficacy

[0110] To evaluate the wound closure efficacy of the adhesives, we compare the performance of PVA / BA adhesive film and the PAAm / PVA / BA film (both are 0.3 mm thick) to that of Dermabond™, a commonly used clinical liquid glue in the mouse model. Two wounds are made in the skin of the dorsum of each animal; Dermabond is applied to one wound and PVA / BA film is applied to the other wound (FIG. 8C - FIG. 8E). After curing of Dermabond™, it does not completely close the wound. However, it can protect the wound from leaking or invasion by external objects. PVA / BA film, after dipping in water for 3 s, is applied to the cut. The film can adhere on the skin, but the blood or other fluids gushing out from the wound site could easily destroy the film. Thus, the wound is not closed. In contrast, PAAm / PVA / BA film not only adheres to the mouse skin but closes the wound. Photos shown in FIG. 8D and FIG. 8E are taken one day after the applications of the PVA / BA and PAAm / PVA / BA films.

[0111] Failure of adhesion

[0112] The mechanical environment around the wound determinates the measurement of the adhesion strength. We delineate the stress states of the adhesive film around the wound into two categories. While the wound is stretched to open, the portion of adhesive film bridges the skins over the wound is under tensile stress, and the portions of the adhesive film contacting the skin are under shear stress (FIG. 8F). To mimic the stress states of adhesive film around the wound and measure the adhesion strength, we use the PAAm / PVA / BA film to bridge two pieces of glasses (FIG. 8G). The failure of adhesion consists of two modes: cohesive failure and interfacial failure, corresponding to the twostress states of the adhesive film. If the normal stress in the bridge portion of the adhesive film is higher than the shear stress in the contact portion of the adhesive film, the covalent PAAm network will be broken. In contrary, if the shear stress in the contact portion of the adhesive film is higher, the non-covalent bonded interface between the PVA / BA and the glasses will be broken.

[0113] To quantify the adhesion, the dry PAAm / PVA / BA film is dipped in water for 3 s. After removing the excess water on the surface, the film is applied to the glass slides. We keep the glasses fixed on the tensile machine and allow the film to dry. A tensile residual stress builds up during the drying of PAAm / PVA / BA film overnight at room temperature. The residual stress of the film can provide the contraction on skin to close the wound as shown in FIG. 8E. Residue stresses plateau in 3 h, up to 12 kPa, but the residual normal stress is as high as 2 MPa (FIG. 8H). After drying for 6 h, the adhesion strength of the PAAm / PVA / BA film (L / W=l, W=20 mm, h=0.3 mm) on glass is measured by stretching the glasses apart. The adhesion strength (TS) reaches ~ 300 kPa (FIG. 81). The ultimate strength (<jst) is measured as 9 MPa from the normal stress-strain curve of the dried PAAm / PVA / BA film under the uniaxial tension (FIG. 8J). The aspect ratio of the film (length / width = L / W) affect the failure modes (FIG. 8K). By the force balance of different potions of the film, the critical length (Lc) of the cohesive-interfacial failure transition is Lc= 2osth / Ts. The critical shear strength for cohesive failure to happen is ~ 350 kPa (L / W=5 / 2). Thus, the critical length of the cohesive-interfacial failure transition is Lc= 25.7 mm, close to the experimental observation (FIG. 8K, adhesion measured after 30 min). Thus, a longer adhesive film provides a more stable adhesion.

[0114] Adhesion characterization

[0115] We then conduct lap shear (FIG. 9 A), shear / tension mix (FIG. 9D), dry peel (FIG. 9G), and wet peel (FIG. 9J) tests, respectively, for the as-prepared PAAm / PVA / BA films (with 34% water in bulk) within 10 min of contacting the substrates. The total thickness of PAAm / PVA / BA films are kept the same (0.5 mm) with or without the PDMS backing layer. The shearing adhesion (FIG. 9B-C) is stronger than the peel adhesion (FIG. 9H-I), indicating a Velcro-like behavior. Here, ours combines dynamic covalent bonds between the hydroxyl groups from the substrate and boronic ester from the adhesive and hydrogen bonds between the substrate and the adhesive. The shearing adhesion strength T is calculated as T = Fs / A, (N / m2), where Fsis the shear forceand A is the contact area. The 180° peel adhesion toughness G is calculated as G = 2Fp / W (N / m), where Fpis the peel force. Apparently, the two quantities are not in the same unit, thus cannot be compared directly. The force ratio is Fs / Fp= 2T.4 / G1 / / . Since T and G are measured as constants in FIG. 9, as long as the length L = 4 / 1 / / > G / 2T = 1 / 2 cm, Fswill be larger than Fp. Apparently, this requirement can easily be satisfied. For example, a film has a contact area of 6 cm2and a width of 2 cm, then L = 3 cm.

[0116] The adhesion strength of PAAm / PVA / BA with an elastomeric PDMS backing layer is different from that without. The PDMS layer does not contribute much to the lap shear adhesion strength (FIG. 9A-C) but enhances the adhesion strength in the shear / tension mix tests (FIG. 9D-F). The peel force or adhesion toughness is also enhanced by the PDMS backing layer (FIG. 9G-I). When water is added at the crack front, the removal force is decreased from 100 J / m2(the dry film, see FIG. 9H) to 20 J / m2(see FIG. 9K). The backing layer increase the removal force up to 40 J / m2(FIG. 9L). All above experiments are done at the room temperature at a relative humidity of 30%.

[0117] Effect of water to adhesion strength

[0118] The time to build up the adhesion is affected by the amount of water in the PAAm / PVA / BA film. We compare the different operation procedures and time for the adhesive and measure the adhesion strength in each case. As depicted in FIG. 14, we dip the dry PAAm hydrogel in the PVA / BA solution for a given time period, tim. After taken out from the solution, excess PVA / BA solution is removed, leaving only a thin coating of PVA / BA on the surface of PAAm. The PVA chains and BA molecules might diffuse into bulk PAAm hydrogel, or only entangle with PAAm at its surface, depending on the length of PVA chains, the kinetics of diffusion, and immersion time. We find the immersion process is most effective. The adhesive sample is cut into a rectangular shape (L=20 mm, W=20 mm, h=0.3 mm) and attached on the glass substrates for shear tests. The waiting time to engage adhesion before the experiment is recorded as tWait. In our experiments, we use tim= 24 h and, 3 s, and tWait= 1 min, 10 min, and 30 min for comparison.

[0119] Adhesion strength at tWait= 1 min, 10 min, and 30 min is measured for samples from the same batch (tim=24 h, FIG. 14A-D). Adhesion is vaguely established when the waiting time is short (tWait= 1 min). In this case, the hydrogel is almost fully swollen, and water content is high. The adhesive slips on the glass after the force peaks. When the adhesion time is short enough that the film is still wet, but the film size is largeenough that it takes time to build up adhesion (tWait= 10 min), the PAAm / PVA / BA between the two glass slides are highly stretched. Then the adhesive sample either breaks or slips on the glass slides. The dependence of these failure modes is analyzed as seen in FIG. 8. When the adhesive is dried for the longest time (twait= 30 min), the adhesive becomes glassy, and the debonding occurs when the adhesion force peaks. For samples with tim= 3 s, we control the time to dry the samples (tdry) before applying them to the glasses (FIG. 14E-H). The waiting time for adhesion before measurement is fixed to tWait= 1 min. This is equivalent to the operation shown in FIG. 14A, and longer drying time helps to build up stronger adhesion.

[0120] Therefore, it is reasonable to attribute the partial adhesion strength to the content of water remained in hydrogel. To confirm our hypothesis, we test the adhesion strength of both as-prepared and the wet-after-dry pure PAAm hydrogels. The as-prepared PAAm has a thickness of 0.3 mm. After drying, PAAm is less than 0.1 mm. We use the as-prepared PAAm film to physically connect two glass slides in the configuration shown in FIG. 10 A. After a rapid and small peak of force, the hydrogel slips on glass. When the dried PAAm film is dipped in water for 3 s (FIG. 10B), followed by removing the excess water on the surface using a paper towel, the adhesion strength of such a film (1.2 kPa) is slightly higher than that of the as-prepared hydrogel (0.8 kPa). After passing the peak force, the film slips on glass. Furthermore, we measure the as-prepared PAAm samples bonded with PDMS after UV polymerization. Thickness of the bilayer is controlled as 0.5 mm, where PAAm and PDMS have the same thickness. The PDMS / PAAm bilayer shows the adhesion strength of 9 kPa after 1 min of making close contact and 18 kPa after 30 min waiting (FIG. 10C-D).

[0121] Waterproofness

[0122] We test the waterproofness of the dressing by comparing the weight loss of the bare, dry PVA / BA films adhered on a glass slide (FIG. 11 A-C) and the dry PVA / BA film covered by a PDMS layer (0.2 mm thick, 7.5 cm x 7.5 cm), respectively (FIG. 11D-F). The PVA / BA film adhered on the glass is immersed in water for a certain interval of time, followed by complete drying at 100°C for 10 min before measuring the weight. The bare PVA / BA film is dissolved in less than 3 h (FIG. 11C) with a dissolving rate is 88 pg / s. See Table 1. In contrast, the weight of PVA / BA dry film covered byPDMS is increased by 1.7 times after 5 days (FIG. 1 IF), due to the absorption of water through the edges.Table 1. Stability of PVA / BA adhesive films after immersion in 50 mL DI water.

[0123] We observed that both the PAAm / PVA / BA hydrogel and the PVA / BA adhesives lose water over 12 hours, with and without a PDMS protection layer (FIG. 11G- I). Without the PDMS protection layer (FIG. 11G), 30.98 ± 7.3 wt % of water is lost due to evaporation from the PAAM / PVA / BA hydrogel within 12 hours at room temperature with 60% relative humidity, corresponding to a moisture transmission rate of 0.05 mg / min in air (FIG. 1 II). When protected by the PDMS layer (FIG. 12H), the loss of water is significantly reduced to 1.59 ± 0.91 wt % in 12 hours and 6.58 ± 2.08 wt % in 36 hours, corresponding to a moisture transmission rate of 0.002 mg / min in air (FIG. 1 II).

[0124] We also observe that the PAAm / PVA / BA hydrogel swells with or without the protection of PDMS over 12 hours (FIG. 11 J-L). Without PDMS (FIG. 11 J), hydrogel absorbs 80 ± 13.16 wt % water in 12 hours, corresponding to a water absorption rate of 0.18 mg / min in water (FIG. 1 IL). However, when protected by the PDMS layer (FIG. 1 IK), the weight increment of hydrogel is significantly reduced to 5.29 ± 5.61 wt % in 12 hours, with a water absorption rate of 0.005 mg / min in water (FIG. 1 IL).

[0125] Adhesion on the pig skin

[0126] Quantitative measurement of the adhesion strength of the adhesive films on the skin is crucial to assess their effectiveness for various applications, including wound healing, drug delivery, and wearable devices. Here, we measure the mechanical properties of a freshly harvested pig skin with a wound (FIG. 12A-B), followed by shear tests of the adhesive film on the untreated skin (FIG. 12C-D). Pig skin exhibits a high degree of homology to human skin and thus, pigs have become an accepted model ofwound healing The pig skin is stiff and rough with elastic modulus ranging from 50 kPa to 1 MPa, which is compatible to those of PAAm hydrogel (~ 0.1 MPa) and PDMS elastomer (~ 1 MPa) we used, respectively. Thus, the multilayered adhesive film conforms well on the pig skin. The adhesion strength of the film on the pig skin is measured by the mixed shear / tension test, where two pieces of pig skin are clamped on the Instron machine, and a 0.3 mm thick PAAm / PVA / BA film is applied to bridge them. By stretching the pig skin, an adhesion strength of ~ 10 kPa is obtained before the two pieces of pig skin are completely separated. After debonding, there are lots of residuals of the pig skin, that is the loose and porous stratum corneum layer, left on the surface of the adhesives (FIG. 12E-F). The debonding of stratum corneum layer from the pig skin limits the measurement of adhesion strength. Cracks between the film and the pig skin are typically initiated from the edge of the film.

[0127] We subject the multilayered adhesive film applied on the back of a hand with hairy skin to tap water for ~ 1 min to test its removability (FIG. 13A-B). The amount of water flowing over the adhesive film and the interval of time tested here are much greater than that the typical water contact expected at the wound site. After the rinse, the film remains on the skin, and the movement of the hand has a negligible impact on the adherence of the film on the skin (FIG. 13C). When water get around the PDMS backing layer from the edge and diffuse through the hydrogel layer, the PVA / BA is softened and becomes viscous. When the film is peeled, the viscous PVA / BA deforms and forms many fibrils on the skin. The film can be peeled off easily from the skin. Importantly, the hairs on the hand can be easily detached from the adhesive film rather than being pulled out of the skin (FIG. 13D), a clear benefit of the viscoelasticity of the wetted PVA / BA layer. In contrast, Dermabond™, the commonly used wound adhesive on the face and scalp, where strong adhesion is necessary, is glassy after curing. Therefore, the degree of deformation of Dermabond™ is limited. When peeling Dermabond™ off the skin, hairs would be pulled off as well, causing the pain sensation.

[0128] Lastly, we test the performance of the multilayered adhesive film on the pig skin harvested from a freshly euthanized pig at ambient conditions (FIG. 13E). The pig skin is incised with a scalpel and then closed with suture followed by application of the adhesive film, mimicking the real situation of closing the acute wound after surgery (FIG. 13F). The skin-adhesive composite is kept at the room temperature at a relative humidityof 30% for 10 days. The area of the PDMS backing layer is larger than that of the PAAm / PVA / BA film. This way, evaporation of water in the hydrogel film would be minimized and moisture around the wound can be retained. The composite film remains highly flexible without delamination from the pig skin after 10 days, despite being bent in various directions (FIG. 13G-H), suggesting that the dressing on the pig skin remains to be moisturized.

[0129] 3. Conclusion

[0130] In summary, we prepare a biocompatible and multilayered wound dressing film that can adhere instantly to various substrates upon water activation. The elastic hydrogel layer plays a crucial role in addressing the inherent weaknesses of reversible wound dressings by reinforcing the adhesive’s mechanical strength. The hydrophobic elastomer backing layer provides mechanical support and integrity around the wound, protecting the adhesive from extensive exposure to water, and minimizing moisture loss for an optimal healing condition. The resulting multilayered film remains adhesive and flexible yet can be easily removed from different types of skin, including mouse, pig, and human hand. Our dressing film is intended to dress and improve the shallow and acute wounds where wound liquid is minimal. The multilayered design will not only improve the handling of the dressing in clinical settings but also enhance patient comfort and recovery. We note that both the hydrophilic and hydrophobic layers in our design can be further modified. For instance, the hydrogel layer can, for example, be reinforced with cellulose nanofibers and incorporated with e.g., neomycin, which would provide antimicrobial properties and act as a cross-linker. The hydrogel layer can also function as a reservoir or carrier for drugs, biomolecules, or other active agents, allowing for controlled release for therapeutic applications. The hydrophobic layer would act as a protective barrier against environmental factors, such as prolonged exposure to microbes. The multilayered design presented here opens many new opportunities to introduce or enhance the functions of the wound dressings.

[0131] 4. Experimental Section

[0132] Materials

[0133] Polyvinyl alcohol (PVA, molecular weight, 13000-23000 g / mol, 87- 89% hydrolyzed), acrylamide (AAm), benzophenone, 2-hydroxy-4'-(2-hydroxyethoxy)-2- methylpropiophenone (1-2959) and N,N'-methylenebisacrylamide (MBAA) are purchasedfrom Millipore Sigma. Boric acid (BA, DNase, RNase, Protease free, 99.5%,) were ordered from Fisher Scientific. Poly dimethylsiloxane (PDMS, Sylgard®184) was purchased from Dow.

[0134] Fabrication of the individual component of the bilayer tape

[0135] Fabrication of PVA / BA films. 7.26 g PVA and 0.242g BA powders (mass ratio of 30: 1) were mixed in 30 mL water. The mass concentration of PVA / BA in water was 20 wt%. The mixture was heated up to 90 °C and stirred until fully dissolved. The viscous solution was cast on a glass plate with 1 mm thickness and dried overnight at room or higher temperature.

[0136] Fabrication of highly entanglement polyacrylamide (PAAm) hydrogel films. 19.67 g AAm was added in 10 mL water and heated at 50 °C for 1 hour dissolve. The molar ratio between water and AAm was controlled as 2. Then 27.67 L MBAA aqueous solution (0.1 mol / L) and I I L 1-2959 ethanol solution (0.1 mol / L) were added into the AAm solution. The molar ratio between MBAA and AAm was controlled as 10'5. The molar ratio between 1-2959 and MBAA was controlled as 0.4. The solution was sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under ultraviolet LED light (DigiKey) at wavelength 365 nm for 6 h. In some samples wherever specifically mentioned in context, the only variable was the concentration of AAm.

[0137] Preparation of the PDMS backing layer. Sylgard®184 resin and the curing agent were mixed with a 10: 1 to 30: 1 weight ratio. The ratio depends on the desired stiffness of PDMS. Typically, we used the ratio of 20: 1. The homogeneous mixture was then poured into a petri dish with 1 mm thickness and cured at 70-80 °C for 4 h.

[0138] Fabrication of PAAm / PVA / BA hydrogel films. The PAAm / PVA / BA precursor was made by mixing 10 mL FEO, 2.34 g PVA, 0.078 g BA, 19.67 g AAm, 27.67 j L MBAA solution (0.1 M) and I I L 1-2959 solution (0.1 M), where m(PVA) / m(BA)=30, n(MBAA) / n(AAm)=10'5, and n(I-2959) / n(MBAA)=0.4. The solution was sealed between two glass plates with a rubber spacer of the thickness of 1 mm and irradiated under UV (light source: ultraviolet LED (DigiKey), wavelength 365 nm) for 6 h.

[0139] Fabrication of the PDMS / hydrogel bilayer. Photoinitiator, benzophenone, was first dissolved in ethanol at 1 wt%. The solution was brushed onto thesurface of PDMS. The precursors of hydrogels were casted on top of PDMS, followed by UV curing (ultraviolet LED (DigiKey), wavelength 365 nm) for 2 h.

[0140] Removal of unreacted molecules in polymer films. The unreacted monomers in the polymer films were removed by first soaking the film in a mixture of aqueous solution of BA (2 mg / mL), water (50% v / v), and ethanol (50% v / v) for more than 5 h. The time depends on the thickness of film. The swollen sample was placed on a glass plate and dried in an oven at 40 °C. After three cycles of swelling-drying process, the final sample was swollen again in water to maintain the same weight percentage of water as an as-prepared hydrogel.

[0141] Coating of tacky PDMS layer on the PDMS backing layer. Sylgard®184 resin and the curing agent were mixed with a weight ratio 35: 1, followed by thorough stirring until the mixture became homogenous. A parafilm mask is put on top of the hydrogel region in the PAAm-PDMS bilayer. The bilayer was taped onto a petri dish, which was sucked on the spin coater (WS-650Mz-23NPPB, Laurell Technologies Corporation). The mixture of tacky PDMS was then poured on the masked bilayer (1 mm thick), followed by spin coating at 1500-2500 rpm for 2 min. Then coated film is cured at 60 °C for 4 h.

[0142] Experiments

[0143] Adhesion experiments. Both shearing and peeling test were carried on the tensile machine (Instron 5564) at a loading speed of 5 mm / min. The load cell is ± 2 kN. The sample was cut into a rectangular shape (2 cm wide x 5 cm long).

[0144] Mouse model. Female C57BL / 6 mice (24.6 ± 2.5 grams per mouse) age approximately 3 months were housed in groups of 4-6 in individually ventilated cages with ad libitum access to food and water. All experiments were conducted in accordance with institutional guidelines with approval from the Children’s Hospital of Philadelphia’s Institutional Animal Care and Use Committee (IACUC) (Protocol #21-000907) and the University of Pennsylvania’s IACUC (Protocol #805620). Mice were treated in accordance with the NIH guidelines for the humane care of animals. The hair on the dorsum was clipped (FIG. 15). For the histological study, Nair was used to remove remaining hair. The PVA / BA film was adhered to the dorsal skin and the animal was wrapped by 3M Coban. For wounding, mice were anesthetized using 3-4% inhaled isoflurane. The back was prepped with 10% povidone-iodine. Using a scalpel, 2 full-thickness dorsal back incisions, each approximately 1 cm long, were created. The anterior incision was closed with Dermabond™ glue and the posterior wound was closed with the dressing film. Once the adhesives had dried 3M Coban was wrapped around the abdomen of the mouse to protect the dressings. Analgesia was provided with subcutaneous buprenorphine. The animals recovered from anesthesia and were then returned to their cages. After days of caging, the wounds of mouse were observed and studied. Before sacrifice, mice were anesthetized with isoflurane administered via inhalation for 5 minutes. Euthanasia was performed by cervical dislocation, in accordance with protocols approved by the IACUC.

[0145] Histology. The skin of mice was cut after 5 days of the application of PVA / BA film. Standard histology and immunostaining protocols were performed, and investigators were blind to tissue origin during histologic staining. In brief, the fresh skin tissue was fixed overnight at 4 °C in 4% paraformaldehyde (J19943-K2, Thermo Scientific). Full thickness skin was removed from the mouse onto a paper towel. The skin was fixed by inverting the paper towel onto the surface of the fixative (4% paraformaldehyde in PBS), and incubated overnight at 4 °C. The following day, the skin was trimmed, placed into tissue cassettes, processed (VIP5b, Sakura) and embedded into wax (Leica Paraplast X-tra) blocks. Blocks were cut using disposable blades (D554P, Sturkey) on a rotary microtome (RM2235, Leica) set at 5 pm thickness. Sections were floated on a water bath (145702, Boekel) set at 43 °C and collected onto positively-charge glass slides (Fisherbrand Superfrost Plus). Following overnight drying at room temperature, slides were baked for 30 minutes at 60 degrees centigrade, followed by H&E staining using an automated Stainer (Leica auto-stainer XL). Slides were processed by the Skin Biology and Disease Resource-Based Core (SBDRC) at Department of Dermatology, University of Pennsylvania who performed hematoxylin and eosin (H&E) staining of the slides.

[0146] Swine model. Skeletally mature mini pigs euthanized for reasons unrelated to this study were used as fresh cadavers. A series of 5cm full thickness skin incisions were made using a surgical scalpel preserving the underlying muscle on their dorsum. The subcutaneous tissues and skin were closed using standard technique with 2-0 Vicryl for deep layers and 2-0 Monocryl for the skin. Then, the wounds were dressed with our PAAm / PVA / BA dressing.

[0147] Statistical analysis. Raw data are processed and plotted in MATLAB to calculate the mean and standard deviation (SD). The results are presented as Mean ± SD. Each statistical analysis is performed with a sample size n = 3. A two-sample t-test (two- tailed) is conducted to assess significant differences between two sets of test samples. The p-value is calculated at a 95% confidence level. The null hypothesis HO states that the means of the two sample sets are equal, while the alternative hypothesis Hl posits that the means are not equal. The two-sample t-test (assuming equal variance) is carried out using summarized data in Origin.

[0148] Aspects

[0149] The following Aspects are illustrative only and do not limit the scope of the present disclosure or the appended claims. Any part or parts of any one or more Aspects can be combined with any part or parts of any one or more other Aspects.

[0150] Aspect 1. An adhesive tape, comprising: an adhesive portion comprising a layer of water-activated reversible adhesive configured to contact a subject; and a hydrophobic backing associated with the adhesive portion.

[0151] Example water-activated reversible adhesives include, for example, those described in international patent applications PCT / US2022 / 051155 and in PCT / US2023 / 067474, both of which are incorporated herein by reference in their entireties for any and all purposes. Further disclosure can be found in B. Chen et al., “An Environmentally Stable, Biocompatible, and Multilayered Wound Dressing Film with Reversible and Strong Adhesion,” Advanced Healthcare Mater. 2024, 2400827 (forthcoming in 2024). One or both of the hydrophobic backing and the adhesive portion can be transparent. The hydrophobic backing can be gas-permeable.

[0152] Aspect 2. The adhesive tape of Aspect 1, wherein the adhesive portion further comprises a polymeric matrix material, the polymeric matrix material optionally bonding to the hydrophobic backing.

[0153] Aspect 3. The adhesive tape of Aspect 2, wherein the polymeric matrix material comprises any one or more of polyacrylamide, a thermoresponsive polymer, a neutral polymer, a cellulose ether, a polyelectrolyte hydrogel, a polyampholyte hydrogel, a block copolymer, a bottle-brush copolymer, a conductive polymer, an ionoelastomer, a zwitterionic polymer, a hydrophilic polyurethane-type polymer, a silicon hydrogel, an ionic liquid gel, or an organogel, the polymeric matrix material optionally comprising anelastic hydrogel. The matrix material can be, for example, a copolymer of any two or more of the above, a double network of any two or more of the above, or even a triple network of any three of the above.

[0154] Aspect 4. The adhesive tape of any one of Aspects 2-3, wherein the water-activated reversible adhesive defines a first polymeric network, wherein the polymeric matrix material defines a second polymeric network, and wherein the first polymeric network and the second polymeric network are topologically entangled.

[0155] Aspect 5. The adhesive tape of Aspect 4, wherein the polymeric matrix material defines a hydrogel, the hydrogel optionally having an elasticity greater than an elasticity of the layer of water-related reversible adhesive.

[0156] Aspect 6. The adhesive tape of any one of Aspects 4-5, wherein the adhesive portion comprises water-activated reversible adhesive disposed within the polymeric matrix material, and further wherein the adhesive portion comprises crosslinks between water-activated reversible adhesive disposed within the polymeric matrix material and the layer of water-activated reversible adhesive.

[0157] Aspect 7. The adhesive tape of any one of Aspects 1-6, further comprising a water sealant portion, the water sealant portion disposed about the adhesive portion.

[0158] Aspect 8. The adhesive tape of Aspect 7, wherein the water sealant portion comprises a hydrogel, the hydrogel optionally comprising any one or more polyacrylic acid (PAA), chitosan, alginate, poly-lysine, alginate, collagen, poly-lysine, and polyvinyl alcohol, polyethylene glycol, acrylate- based polymers, silicon hydrogel, hyaluronic acid, polyurethane, and cellulose.

[0159] Aspect 9. The adhesive tape of any one of Aspects 1-8, further comprising a waterproof portion, the waterproof portion disposed about the adhesive portion.

[0160] Aspect 10. The adhesive tape of any one of Aspects 7-9, further comprising a waterproof portion, the waterproof portion disposed about the water sealant portion.

[0161] Aspect 11. The adhesive tape of any one of Aspects 9-10, wherein the waterproof portion comprises any one or more of poly(dimethylsiloxane) (PDMS), a silica gel such as Ecoflex, dragon skin, or a hydrophobic elastomer such as poly(styrene-butadiene-styrene) (SBS), fluosilicone, fluorinated ethylene propylene, Fluoro-Elastomer (FKM) rubber such as Viton™, hydrophobic thermoplastic polyurethane (TPU), liquid crystal elastomers, or a plastic film such as poly(ethylene-vinyl acetate) (PEVA), polylactic acid (PLA), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyamide (Nylon), polystyrene (PS), cellophane, polyvinyl chloride (PVA), polycarbonate (PC), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK), polyglycolic acid (PGA), polydioxanone (PDO), or any hydrophilic-hydrophobic composites such as hydrogel-elastomer composite, bi-continuous phase polymers, and a hydrophilic-hydrophobic hybrid poly(ionic liquid).

[0162] Aspect 12. The adhesive tape of any one of Aspects 1-11, further comprising a bonding agent that promotes bonding between the hydrophobic backing and the adhesive portion, the bonding agent optionally comprising a radical initiator. Such an agent can, for example, include a radical initiator that generates radicals upon exposure to ultraviolet radiation or heat.

[0163] Aspect 13. The adhesive tape of any one of Aspects 1-12, wherein at least one of the hydrophobic backing and the adhesive portion comprises a dopant that promotes adhesion between the at least one of the hydrophobic backing and the adhesive portion and the other of the hydrophobic backing and the adhesive portion. A dopant in the hydrophobic backing layer and the adhesive portion can be, for example, an initiator that can generate radicals upon UV exposure or heat, such as benzophenone. Another example dopant is a monomer with a functional group such as copolymerize hydrophilic saline in adhesive polymer and copolymerize hydrophobic saline in hydrophobic backing. Saline chemistry can assist the bonding between adhesive potion and hydrophobic backing.

[0164] Aspect 14. The adhesive tape of any one of Aspects 1-13, wherein the adhesive portion comprises: a first network that comprises at least two hydroxyl -bearing chains of a first polymer, the at least two hydroxyl-bearing polymer chains being crosslinked by crosslinks that comprise one or more ester bonds, a second network that comprises at least two hydroxyl-bearing chains of a second polymer, and the second polymer optionally hydrogen bonding to the first polymer.

[0165] Aspect 15. The adhesive tape of Aspect 14, wherein ester bonds are derived from reaction between (i) a boric acid, a boronic acid, or tannic acid and (ii) a hydroxyl of the first polymer.

[0166] Aspect 16. The adhesive tape of any one of Aspects 1-15, wherein (a) the hydrophobic backing and the adhesive portion are essentially transparent, (b) the hydrophobic backing is gas-permeable, or both (a) and (b).

[0167] Aspect 17. The adhesive tape of any one of Aspects 1-16, further comprising any one or more of (a) a medicament, the medicament optionally disposed in the adhesive portion, and (b) a portion that exhibits a color change in response to a stimulus, the stimulus optionally being a temperature.

[0168] Aspect 18. A method, comprising affixing an adhesive tape according to any one of Aspects 1-17 to a subject.

[0169] Aspect 19. A method, further comprising contacting the adhesive portion of an adhesive tape according to any one of Aspects 1-18 with an amount of water so as to effect at least partial release of water-activated reversible adhesive from a subject.

[0170] Aspect 20. A method, comprising fabricating an adhesive tape according to any one of Aspects 1-19.

Claims

What is Claimed:

1. An adhesive tape, comprising: an adhesive portion comprising a layer of water-activated reversible adhesive configured to contact a subject; and a hydrophobic backing associated with the adhesive portion.

2. The adhesive tape of claim 1, wherein the adhesive portion further comprises a polymeric matrix material, the polymeric matrix material optionally bonding to the hydrophobic backing.

3. The adhesive tape of claim 2, wherein the polymeric matrix material comprises any one or more of polyacrylamide, a thermoresponsive polymer, a neutral polymer, a cellulose ether, a polyelectrolyte hydrogel, a polyampholyte hydrogel, a block copolymer, a bottle-brush copolymer, a conductive polymer, an ionoelastomer, a zwitterionic polymer, a hydrophilic polyurethane-type polymer, a silicon hydrogel, an ionic liquid gel, or an organogel, the polymeric matrix material optionally comprising an elastic hydrogel.

4. The adhesive tape of any one of claims 2-3, wherein the water-activated reversible adhesive defines a first polymeric network, wherein the polymeric matrix material defines a second polymeric network, and wherein the first polymeric network and the second polymeric network are topologically entangled.

5. The adhesive tape of claim 4, wherein the polymeric matrix material defines a hydrogel, the hydrogel optionally having an elasticity greater than an elasticity of the layer of water-related reversible adhesive.

6. The adhesive tape of claim 4, wherein the adhesive portion comprises water- activated reversible adhesive disposed within the polymeric matrix material, and further wherein the adhesive portion comprises crosslinks between water-activated reversible adhesive disposed within the polymeric matrix material and the layer of water-activated reversible adhesive.

7. The adhesive tape of any one of claims 1-3, further comprising a water sealant portion, the water sealant portion disposed about the adhesive portion.

8. The adhesive tape of claim 7, wherein the water sealant portion comprises a hydrogel, the hydrogel optionally comprising any one or more polyacrylic acid (PAA), chitosan, alginate, poly-lysine, alginate, collagen, poly-lysine, and polyvinyl alcohol, polyethylene glycol, acrylate- based polymers, silicon hydrogel, hyaluronic acid, polyurethane, and cellulose.

9. The adhesive tape of any one of claims 1-3, further comprising a waterproof portion, the waterproof portion disposed about the adhesive portion.

10. The adhesive tape of claim 7, further comprising a waterproof portion, the waterproof portion disposed about the water sealant portion.

11. The adhesive tape of claim 9, wherein the waterproof portion comprises any one or more of poly(dimethylsiloxane) (PDMS), a silica gel, dragon skin, a hydrophobic elastomer, fluosilicone, fluorinated ethylene propylene, Fluoro-Elastomer (FKM) rubber, hydrophobic thermoplastic polyurethane (TPU), liquid crystal elastomers, a plastic film, polylactic acid (PLA), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyamide (Nylon), polystyrene (PS), cellophane, polyvinyl chloride (PVA), polycarbonate (PC), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK), polyglycolic acid (PGA), polydioxanone (PDO), or a hydrophilic- hydrophobic composite, optionally a hydrogel -elastomer composite, a bi- continuous phase polymers, and a hydrophilic-hydrophobic hybrid poly(ionic liquid).

12. The adhesive tape of any one of claims 1-3, further comprising a bonding agent that promotes bonding between the hydrophobic backing and the adhesive portion, the bonding agent optionally comprising a radical initiator.

13. The adhesive tape of any one of claims 1-3, wherein at least one of the hydrophobic backing and the adhesive portion comprises a dopant that promotesadhesion between the at least one of the hydrophobic backing and the adhesive portion and the other of the hydrophobic backing and the adhesive portion.

14. The adhesive tape of any one of claims 1-3, wherein the adhesive portion comprises: a first network that comprises at least two hydroxyl -bearing chains of a first polymer, the at least two hydroxyl -bearing polymer chains being crosslinked by crosslinks that comprise one or more ester bonds, a second network that comprises at least two hydroxyl-bearing chains of a second polymer, and the second polymer optionally hydrogen bonding to the first polymer.

15. The adhesive tape of claim 14, wherein ester bonds are derived from reaction between (i) a boric acid, a boronic acid, or tannic acid and (ii) a hydroxyl of the first polymer.

16. The adhesive tape of any one of claims 1-3, wherein (a) the hydrophobic backing and the adhesive portion are essentially transparent, (b) the hydrophobic backing is gas-permeable, or both (a) and (b).

17. The adhesive tape of any one of claims 1-3, further comprising any one or more of(a) a medicament, the medicament optionally disposed in the adhesive portion, and(b) a portion that exhibits a color change in response to a stimulus, the stimulus optionally being a temperature.

18. A method, comprising affixing an adhesive tape according to any one of claims 1-3 to a subject.

19. A method, further comprising contacting the adhesive portion of an adhesive tape according to any one of claims 1-3 with an amount of water so as to effect at least partial release of water-activated reversible adhesive from a subject.

20. A method, comprising fabricating an adhesive tape according to any one of claims

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