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. 2024 Sep 12;13(31):2400827. doi: 10.1002/adhm.202400827

An Environmentally Stable, Biocompatible, and Multilayered Wound Dressing Film with Reversible and Strong Adhesion

Baohong Chen 1, Bingzhi He 1, Alexander M Tucker 2,3, Ian Biluck 2, Thomas H Leung 4, Thomas P Schaer 5, Shu Yang 1,✉
PMCID: PMC11650397  PMID: 39263787

Abstract

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, a biocompatible, multilayered, reversible wound dressing film that conforms to skin and is waterproof is designed. The inner layer is capable of instant adhesion to various substrates upon activation of the dynamic boronic ester bonds by water; intermediate hydrogel layer and outer silicone backing layer 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 to be biocompatible with mouse skin. Skin injuries on the 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 the 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.

Keywords: elasticity, multilayered, reversible adhesion, waterproof, wound dressing

A biocompatible, multilayered adhesive film is developed as wound dressing that conforms to skin and is waterproof. The inner layer offers instant adhesion activated by water; the intermediate hydrogel layer and outer silicone layer enhance the dressing's elasticity and load distribution for adhesion. On animal skin, the film promotes fast healing and can be removed without causing additional tissue damage.

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1. Introduction

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.[ 1 ] Reversibility can be achieved through non‐covalent interactions,[ 2 ] introduction of dynamic covalent bonds in hydrogels and elastomers,[ 3 ] and use of plasticizers[ 4 ] 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.[ 5 ] Key metrics for evaluating adhesive's performance and practicality include the ease of activation/deactivation,[ 6 ] toughness,[ 7 ] shear strength,[ 8 ] and the number of cycles of reversible applications without significantly losing its efficacy.[ 9 ]

Various reversible adhesives have been developed for tissues. For example, silicone‐based adhesives[ 10 ] are tacky and offer gentle adhesion that can minimize patient's discomfort.[ 11 ] For example, medical grade silicone gels with low adhesion strength of 1–10 N m−1[ 12 ] can remain on the 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, for example, elderly patients or neonatal.[ 13 ] 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.[ 14 ] 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[ 15 ] and have been used as dressings for burns and chronic wounds.[ 16 ] 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.[ 17 ] Injectable surgical adhesives have been created from gelatin and chondroitin sulfate, two commonly used extracellular matrix biopolymers, demonstrating temperature‐responsive adhesion and self‐healing.[ 18 ] Compared to silicon‐based adhesives, hydrogel adhesives are much softer with shear strength in the range of 1–100 kPa that is close to the skin's modulus.[ 19 ] However, hydrogel adhesives can exhibit a high peel toughness ranging from 10 to 103 N m−1.[ 15c ] Therefore, they are capable of closing multiple types of wound in body.[ 20 ] 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.[ 21 ] Such a hydrogel tape can be strained and dehydrated. When wetted by water, it can not only bond to the wound but also provide a contract force to hasten healing.[ 22 ]

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.[ 15 , 23 ] Therefore, some hydrogels are made for under water applications.[ 24 ] In air, a hydrophobic protection layer is often introduced.[ 25 ] It can protect the adhesive from external stresses and help to distribute the load across the surface, thus reducing the risk of localized failures.[ 26 ] It also helps to minimize moisture loss to maintain a better environment for healing,[ 27 ] improving gas permeation to prevent the buildup of exudate, and facilitate wound respiration[ 28 ] and handling of the dressing in clinic operations.[ 29 ] For example, a woven cotton gauze provides both the mechanical support and absorbency of fluid around the wound.[ 30 ] The hydrogel sheets can retain moisture for delicate wounds.[ 29b ] The silicone membranes offer oxygen permeation and can be used to release drugs, while preventing moisture loss.[ 31 ] The polyurethane films are often used as the supporting layer as they offer flexibility, breathability, and transparency for wound monitoring.[ 32 ] Typically, these protection layers are applied separately on top of the wound dressing without chemical bonding to the dressing film.

We previously have developed a strong and reversible adhesive 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.[ 33 ] However, the PVA/BA adhesive film could 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.

2. Results and Discussion

2.1. Multilayer Adhesives

2.1.1. Design and Fabrication

As illustrated in Figure 1A,B, the wound dressing film comprises three layers, where the covalently crosslinked PAAm hydrogel acts as the intermediate layer between 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 reputation 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) originate 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.[ 34 ] Meanwhile, BA can form dynamic covalent bonds between PVA and the skin.[ 33 ] Further, the long PVA polymer chains will provide a bridging effect between the adhesive and the skin to enhance adhesion.[ 35 ] The hydrophilic PAAm hydrogel and the hydrophobic PDMS elastomer are chemically bonded here, which will be elaborated in more details later.

Figure 1.

Figure 1

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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.

The fabrication of the multilayered adhesive film is outlined in Figure 1C. 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, which is chosen according to our previous study.[ 33 ] PVA/BA aqueous solutions have a fixed 20 wt% of PVA and BA in total, which offers a desired viscosity for film fabrication. PAAm hydrogels 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 µm 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 the surface of PAAm hydrogel is ≈100 µm. The unmasked multilayer film is then dried for storage to extend the shelf life.

2.1.2. Functionality of Each Layer

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.[ 36 ]

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,[ 37 ] to precisely control the adhesion and wound healing processes. Microfluidic channels can be patterned in PDMS to transport and deliver biological cues or chemicals to enhance adhesion and wound healing process.[ 38 ]

The application of the multilayered adhesive film is illustrated in Figure 1D. 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.[ 33 ] The film can be peeled off simply after the adhesive is fully wetted by water.

2.1.3. Mitigation of Swelling‐Induced Deformation in the Hydrogel/PDMS Bilayers

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 (Figure 2A,D‐ii). 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 = Ebh 3/12, 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 (Figure 2B,D‐iii; Video S1, Supporting Information).

Figure 2.

Figure 2

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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) Mitigation 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 will become flat. D‐i) The flat state of the multilayer before swelling; D‐ii) the buckling state of the multilayer after swelling; D‐iii) the multilayer applied on two glass slides and the glass slides pulled by hand to test the adhesion, and no buckling is observed; D‐iv) a multilayer naturally buckles and rolls into a tube after fabrication; and D‐v) the multilayer is flat after swelling and after application on the glove.

The second strategy is to pre‐stress the hydrogel layer to balance the swelling‐induced deformation (Figure 2C). 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 toward the pre‐stretched hydrogel side due to the pre‐stress and drying (Figure 2D‐iv). 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 (Figure 2D‐v; Video S1, Supporting Information).

2.2. Adhesion Study

2.2.1. Biocompatibility

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 (Figure 3A; Figure S6A, Supporting Information) because PAAm and PDMS are known to be 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 (Figure 3B). 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.

Figure 3.

Figure 3

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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 among 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, and 330 ± 17 kPa. The sample size of each experiment n = 3.

2.2.2. Wound Closure Efficacy

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 the PVA/BA film is applied to the other wound (Figure 3C–E; Figure S6A, Supporting Information). 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 can easily destroy the film. Thus, the wound is not closed. In contrast, PAAm/PVA/BA film not only adheres to the mouse skin but also closes the wound. Photos shown in Figure 3D,E were taken one day after the applications of the PVA/BA and PAAm/PVA/BA films.

2.2.3. Failure of Adhesion

The mechanical environment around the wound determines 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 bridging the skins over the wound is under tensile stress, and the portions of the adhesive film contacting the skin are under shear stress (Figure 3F). 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 (Figure 3G). The failure of adhesion consists of two modes: cohesive failure and interfacial failure, corresponding to the two stress 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 contrast, 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.

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 Figure 3E. Residue stresses plateau in 3 h, up to 12 kPa, but the residual normal stress is as high as 2 MPa (Figure 3H). After drying for 6 h, the adhesion strength of the PAAm/PVA/BA film (L/W = 1, W = 20 mm, h = 0.3 mm) on glass is measured by stretching the glasses apart. The adhesion strength (τs) reaches ≈ 300 kPa (Figure 3I). The ultimate strength (σst) is measured as 9 MPa from the normal stress–strain curve of the dried PAAm/PVA/BA film under the uniaxial tension (Figure 3J). The aspect ratio of the film (length/width = L/W) affects the failure modes (Figure 3K). By the force balance of different potions of the film, the critical length (L c) of the cohesive‐interfacial failure transition is L c =  2σst h/τs. 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 L c = 25.7 mm, close to the experimental observation (Figure 3K; adhesion measured after 30 min). Thus, a longer adhesive film provides a more stable adhesion.

2.2.4. Adhesion Characterization

We then conduct lap shear (Figure 4A), shear/tension mix (Figure 4D), dry peel (Figure 4G), and wet peel (Figure 4J) 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 is kept the same (0.5 mm) with or without the PDMS backing layer. The shearing adhesion (Figure 4B,C) is stronger than the peel adhesion (Figure 4H,I), indicating a Velcro‐like behavior. We therefore refer our adhesive as the molecular dynamic Velcro to differentiate it from the prior study, molecular staple for adhesion.[ 39 ] In fact, many non‐covalent bonds can be regarded as molecular Velcro. 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 τ is calculated as τ  = F s /A, (N/m2), where F s is the shear force and A is the contact area. The 180° peel adhesion toughness G is calculated as G  =  2F p/W (N/m), where F p is the peel force. Apparently, the two quantities are not in the same unit, and thus cannot be compared directly. The force ratio is F s/ F p =  2τA/GW. As τ and G are measured as constants in Figure 4, as long as the length L  =  A/W > G/2τ  =  1/2 cm, F s will be larger than F p. Apparently, this requirement can easily be satisfied. For example, a film has a contact area of 6 cm2 and a width of 2 cm; then L  =  3 cm.

Figure 4.

Figure 4

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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 m−2, 148.2 ± 20.35 J m−2; 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 m−2, 36.2 ± 24.4 J m−2; p = 0.2844. 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 (A,D,G,J).

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 (Figure 4A–C) but enhances the adhesion strength in the shear/tension mix tests (Figure 4D–F). The peel force or adhesion toughness is also enhanced by the PDMS backing layer (Figure 4G–I). When water is added at the crack front, the removal force is decreased from 100 J m−2 (the dry film, see Figure 4H) to 20 J m−2 (see Figure 4K; Video S2, Supporting Information). The backing layer increases the removal force up to 40 J m−2 (Figure 4L). All the above experiments are done at the room temperature at a relative humidity of 30%.

2.2.5. Effect of Water to Adhesion Strength

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 Figure S1, Supporting Information, we dip the dry PAAm hydrogel in the PVA/BA solution for a given time period, t im. After taking 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, and 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 t wait. In our experiments, we use t im = 24 h and 3 s, and t wait = 1, 10, and 30 min for comparison.

Adhesion strength at t wait = 1, 10, and 30 min is measured for samples from the same batch (t im = 24 h; Figure S1A–D, Supporting Information). Adhesion is vaguely established when the waiting time is short (t wait = 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 large enough that it takes time to build up adhesion (t wait = 10 min), the PAAm/PVA/BA between the two glass slides is 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 Figure 3. When the adhesive is dried for the longest time (t wait = 30 min), the adhesive becomes glassy, and the debonding occurs when the adhesion force peaks. For samples with t im = 3 s, we control the time to dry the samples (t dry) before applying them to the glasses (Figure S1E–H, Supporting Information). The waiting time for adhesion before measurement is fixed to t wait = 1 min. This is equivalent to the operation shown in Figure S1A, Supporting Information and longer drying time helps to build up stronger adhesion.

Therefore, it is reasonable to attribute the partial adhesion strength to the content of water remaining 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 Figure 5A. 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 (Figure 5B), 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. Further, 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 (Figure 5C,D).

Figure 5.

Figure 5

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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.

2.3. Waterproofness

We test the waterproofness of the dressing by comparing the weight loss of the bare, dry PVA/BA films adhered on a glass slide (Figure 6A–C) and the dry PVA/BA film covered by a PDMS layer (0.2 mm thick, 7.5 cm × 7.5 cm), respectively (Figure 6D–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 (Figure 6C; Table S1, Supporting Information) with a dissolving rate being 88 µg s−1. In contrast, the weight of PVA/BA dry film covered by PDMS is increased by 1.7 times after 5 days (Figure 6F) due to the absorption of water through the edges.

Figure 6.

Figure 6

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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 immersing 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. The picture shows the state of the double layered film in water (E). Mass change of the PVA/BA shown in (E) after immersion in water over time (F). G–I) The experiment of evaporation of water in the multi‐layered hydrogel films with and without a PDMS protection layer over 36 h. Mean ± SD from left to right in (I) are 30.98 ± 7.3%, 1.59 ± 0.91%, and 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 h with and without a PDMS protection layer. Mean ± SD from left to right in (L) are 80 ± 13.16% and 5.29 ± 5.61%. For 12 h, p = 0.0008. A two‐sample t‐test obtains p‐values, indicating the significant level between bar plots as ** p < 0.01 and *** p < 0.001. The sample size for each experiment n  =  3 (I,L).

We observe that both the PAAm/PVA/BA hydrogel and the PVA/BA adhesives lose water over 12 h, with and without a PDMS protection layer (Figure 6G–I). Without the PDMS protection layer (Figure 6G), 30.98 ± 7.3 wt% of water is lost due to evaporation from the PAAM/PVA/BA hydrogel within 12 h at room temperature with 60% relative humidity, corresponding to a moisture transmission rate of 0.05 mg min−1 in air (Figure 6I). When protected by the PDMS layer (Figure 7H), the loss of water is significantly reduced to 1.59 ± 0.91 wt% in 12 h and 6.58 ± 2.08 wt% in 36 h, corresponding to a moisture transmission rate of 0.002 mg min−1 in air (Figure 6I). A similar water retention effect by elastomer on hydrogel has been reported by Floch et al.[ 40 ]

Figure 7.

Figure 7

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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.

We also observe that the PAAm/PVA/BA hydrogel swells with or without the protection of PDMS over 12 h (Figure 6J–L). Without PDMS (Figure 6J), hydrogel absorbs 80 ± 13.16 wt% water in 12 h, corresponding to a water absorption rate of 0.18 mg min−1 in water (Figure 6L). However, when protected by the PDMS layer (Figure 6K), the weight increment of hydrogel is significantly reduced to 5.29 ± 5.61 wt% in 12 h, with a water absorption rate of 0.005 mg min−1 in water (Figure 6L).

2.4. Adhesion on the Pig Skin

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 (Figure 7A,B), followed by shear tests of the adhesive film on the untreated skin (Figure 7C,D). Pig skin exhibits a high degree of homology to human skin and thus, pigs have become an accepted model of wound healing.[ 41 ] The pig skin is stiff and rough with elastic modulus ranging from 50 kPa to 1 MPa,[ 42 ] 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 (Video S3, Supporting Information). 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 (Figure 7E,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 (Video S3, Supporting Information).

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 (Figure 8A,B; Video S4, Supporting Information). The amount of water flowing over the adhesive film and the interval of time tested here are much greater than that of 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 (Figure 8C). When water get around the PDMS backing layer from the edge and diffuses 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 (Figure 8D), 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 will be pulled off as well, causing the pain sensation.

Figure 8.

Figure 8

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A–D) Observation of adhesives on the skin. Photos of removing the multilayered PDMS/PAAm/PVA/BA film from the back of a hand after flushing under water for 1 min. The film edges are exposed to the environment (A). The multilayered film under tap water for 1 min (B). The film remained on the skin (C). 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 (D). E–H) Photos of the multilayered adhesive film are placed on the pig skin. After cutting, the wound skin is stitched by sutures, followed by application of the PAAm/PVA/BA film with an elastomer layer on top (F). 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 (G,H).

Lastly, we test the performance of the multilayered adhesive film on the pig skin harvested from a freshly euthanized pig at ambient conditions (Figure 8E). 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 (Figure 8F). The skin‐adhesive composite is kept at the room temperature at a relative humidity of 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 will 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 (Figure 8G,H), suggesting that the dressing on the pig skin remains to be moisturized.

3. Conclusion

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 optimized. For instance, the hydrogel layer can be reinforced with cellulose nanofibers and incorporated with, for example, neomycin, which would provide antimicrobial properties and act as a cross‐linker.[ 43 ] 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.

4. Experimental Section

Materials

Polyvinyl alcohol (PVA, molecular weight, 13000–23 000 g mol−1, 87–89% hydrolyzed), acrylamide (AAm), benzophenone, 2‐hydroxy‐4′‐(2‐hydroxyethoxy)−2‐methylpropiophenone (I‐2959), and N,N'‐methylenebisacrylamide (MBAA) were purchased from Millipore Sigma. Boric acid (BA, DNase, RNase, Protease free, 99.5%) was ordered from Fisher Scientific. Polydimethylsiloxane (PDMS, Sylgard184) was purchased from Dow.

Fabrication of the Individual Component of the Bilayer Tape

For fabrication of PVA/BA films, 7.26 g PVA and 0.242 g 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.

For fabrication of high entanglement polyacrylamide (PAAm) hydrogel films, 19.67 g AAm was added in 10 mL water and heated at 50 °C to dissolve for 1 h. The molar ratio between water and AAm was controlled as 2. Then, 27.67 𝜇L MBAA aqueous solution (0.1 mol L−1) and 11 𝜇L I‐2959 ethanol solution (0.1 mol L−1) were added into the AAm solution. The molar ratio between MBAA and AAm was controlled as 10−5. The molar ratio between I‐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.

With respect to preparation of the PDMS backing layer, Sylgard184 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, the ratio of 20:1 was used. The homogeneous mixture was then poured into a petri dish with 1 mm thickness and cured at 70–80 °C for 4 h.

For fabrication of PAAm/PVA/BA hydrogel films, the PAAm/PVA/BA precursor was made by mixing 10 mL H2O, 2.34 g PVA, 0.078 g BA, 19.67 g AAm, 27.67 𝜇L MBAA solution (0.1 m), and 11 𝜇L I‐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.

For fabrication of the PDMS/hydrogel bilayer, photoinitiator, benzophenone, was first dissolved in ethanol at 1 wt%. The solution was brushed onto the surface 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.

For 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−1), water (50% v/v), and ethanol (50% v/v) for more than 5 h. The time depended 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 the swelling–drying process, the final sample was swollen again in water to maintain the same weight percentage of water as an as‐prepared hydrogel.

For coating of the tacky PDMS layer on the PDMS backing layer, Sylgard184 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 was 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, the coated film was cured at 60 °C for 4 h.

Experiments

Adhesion experiments were conducted. Both shearing and peeling test were carried out on the tensile machine (Instron 5564) at a loading speed of 5 mm min−1. The load cell was ± 2 kN. The sample was cut into a rectangular shape (2 cm wide × 5 cm long).

For the purpose of mouse model, female C57BL/6 mice (24.6 ± 2.5 g per mouse) and aged ≈3 months were housed in groups of four to six 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). The mice were treated in accordance with the NIH guidelines for the humane care of animals. The hair on the dorsum was clipped (Figure S2, Supporting Information). 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 3 M Coban. For wounding, mice were anesthetized using 3–4% inhaled isoflurane. The back was prepped with 10% povidone–iodine. Using a scalpel, two full‐thickness dorsal back incisions, each ≈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, 3 M 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 min. Euthanasia was performed by cervical dislocation, in accordance with protocols approved by the IACUC.

With respect to 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 µm 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, the slides were baked for 30 min at 60 °C, 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 the Department of Dermatology, University of Pennsylvania, where hematoxylin and eosin (H&E) staining of the slides was performed.

The swine model consisted of skeletally mature minipigs euthanized for reasons unrelated to this study and used as fresh cadavers. A series of 5 cm full thickness skin incisions was 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 the authors’ PAAm/PVA/BA dressing.

Statistical Analysis

Raw data were processed and plotted in MATLAB to calculate the mean and standard deviation (SD). The results were presented as mean ± SD. Each statistical analysis was performed with a sample size n = 3. A two‐sample t‐test (two‐tailed) was conducted to assess significant differences between two sets of test samples. The p‐value was calculated at a 95% confidence level. The null hypothesis H0 stated that the means of the two sample sets was equal, while the alternative hypothesis H1 posited that the means were not equal. The two‐sample t‐test (assuming equal variance) was carried out using summarized data in Origin.

Conflict of Interest

B.C., A.M.T., and S.Y. are co‐inventors of a provisional patent submission.

Author Contributions

B.C. and S.Y. conceived the concept. B.C. fabricated materials and did materials characterization and mechanical measurements. B.H. conducted experiments during the review‐revision stage. A.M.T., I.B., and T.H.L. did procedures on mice. T.H.L. did the histological analysis. A.M.T. and T.P.S. did procedures on pig. B.C. and S.Y. drafted the manuscript. All authors participated in the discussion and editing of the manuscript.

Supporting information

Supporting Information

ADHM-13-0-s004.pdf (2.9MB, pdf)

Supplemental Video 1

Download video file (13.7MB, mp4)

Supplemental Video 2

Download video file (2.3MB, mp4)

Supplemental Video 3

Download video file (17.4MB, mp4)

Supplemental Video 4

Download video file (18.8MB, mp4)

Acknowledgements

The authors acknowledge the support by the Center for Engineering Mechano‐Biology (CEMB), a Science and Technology Center funded by the National Science Foundation (NSF), #CMMI‐1548571, and the Center for Health, Devices and Technology at the University of Pennsylvania (Penn Health‐Tech) Accelerator program. Christopher Wun is acknowledged for drawing of the schematic of the skin shown in Figure 1D.

Chen B., He B., Tucker A. M., Biluck I., Leung T. H., Schaer T. P., Yang S., An Environmentally Stable, Biocompatible, and Multilayered Wound Dressing Film with Reversible and Strong Adhesion. Adv. Healthcare Mater. 2024, 13, 2400827. 10.1002/adhm.202400827

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.

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Supplementary Materials

Supporting Information

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Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.

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