WO2016130861A1

WO2016130861A1 - Composition and method for use of energy activated wound dressing

Info

Publication number: WO2016130861A1
Application number: PCT/US2016/017634
Authority: WO
Inventors: Tien Nguyen; Ary Chernomorsky; Stanley R Conston; Ronald Yamamoto
Original assignee: Medterials, Inc
Priority date: 2015-02-13
Filing date: 2016-02-11
Publication date: 2016-08-18

Abstract

A wound dressing is provided that adheres or bonds directly to tissue when activated by energy without the use of an adhesive layer. The wound dressing may be applied to a mucosal surface or to wounds due to trauma or surgery to protect the wound, promote healing, and reduce pain. The wound dressing comprises crosslinked gelatin with additives, such as a plasticizer, a surfactant and/or cysteine. Pharmaceutical agents to treat the wound may also be added. Applying energy, such as plasma, ultrasound, radio frequency, light or heat energy, causes the wound dressing to adhere or bond to an underlying wound or tissue and may also increase the flexibility or elongation of the wound dressing. The wound dressing may be generally planar, convex or concave to match the shape of the wound to be treated and may have through holes and/or a coating on an external surface of the film.

Description

Composition and Method for Use of Energy Activated Wound Dressing Related Applications:

Any and all applications for which a foreign or domestic priority claim is identified in the

Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1 .57.

Background of Invention:

Wound dressings are applied to areas of trauma or surgery to physically protect the wound, provide a barrier to infection, promote healing and in some cases deliver medication. Typically, wound dressings comprise several layers, including an adhesive layer to provide securement. However, some tissue surfaces are not suitable for the use of adhesive wound dressings. These surfaces include mucosal tissues, exudative tissue surfaces and bleeding tissue surfaces.

Mucosal tissues are sensitive to chemical irritation, especially from reactive adhesives capable of bonding to moist surfaces. Many adhesives, such as those used on the skin, are not effective when the underlying tissue is moist or producing fluid. In addition, applications where the wound dressing is within the body or in a location in which the dressing may be internalized such as the nasopharyngeal cavity, it is desired to have a dressing that is non-toxic and may be readily metabolized or eliminated by the body through natural processes. Due to these constraints, there are no satisfactory wound dressings for use after nasopharyngeal surgery, organ resection, or gastrointestinal surgery.

Known prior art:

United States Patent 5,071 ,417

Sinofsky; Edward L. December 10, 1991

Laser fusion of biological materials

United States Patent 5,156,613

Sawyer; Philip N. October 20, 1992

Collagen welding rod material for use in tissue welding

United States Patent 5,209,776

Bass; Lawrence S, et al May 1 1 , 1993

Tissue bonding and sealing composition and method of using the same Summary of the Invention: The present invention provides a wound dressing that adheres or bonds directly to tissue when activated by energy without the use of an adhesive layer. The invention comprises natural biological materials and provides adhesion through direct interaction and integration with the wound surface. The wound dressing may be applied to wounds due to trauma, arthroscopic surgery, spinal surgery, tracheobronchial surgery, neurosurgery, and surgery used in otolaryngology, urology, gynecology, gastroenterology, reconstructive surgery, and general surgery to protect the wound, promote healing, and reduce pain. The wound dressing may be applied in conjunction with nasopharyngeal surgery such as tonsillectomy, adenoidectomy, uvulopalatoplasty, uvulectomy and base of the tongue reduction. The wound dressing may also be used to stabilize and protect organs after resection such as lung reduction surgery, excision of solid tumors, and surgical repair of the gastrointestinal system. Some embodiments provide a wound dressing composition comprising gelatin and a plasticizer, wherein the composition is in the form of a film and crosslinked by physical or chemical means. In some embodiments, the film further comprises through holes. In some embodiments, the composition has a transition upon the application of energy to adhere or bond to an underlying wound. In some embodiments, the composition has a transition to a material with increased flexibility or elongation properties after the application of energy. Some embodiments provide a wound dressing composition comprising gelatin, a plasticizer, and a surfactant, wherein the composition is in the form of a film and crosslinked by physical or chemical means. Some embodiments provide a wound dressing composition comprising gelatin and cysteine, wherein the composition is the form of a film and crosslinked by physical or chemical means. In some embodiments, the film further comprises through holes. Some embodiments provide a wound dressing composition comprising gelatin, wherein the composition is in the form of a film and crosslinked by physical or chemical means. In some embodiments, the film further comprises a coating on the external facing surface of the film. Some embodiments provide a wound dressing composition comprising gelatin, wherein the composition is in the form of a film and crosslinked by physical or chemical means and further comprises a coating on the external facing surface of the film. In some embodiments, the coating comprises a material which prevents sticking of a probe or instrument applying energy to the wound dressing. In some embodiments, the coating material comprises a lipid, oil, fatty acid or emulsion. Some embodiments provide a wound dressing composition that contains additives including antiinflammatory agents, antibiotics, antimicrobial agents, anesthetics, analgesics, agents to prevent post-operative surgical adhesion, wound healing mediators, or other pharmaceutical agents. Some embodiments provide a wound dressing composition of the disclosed compositions in a generally planar configuration, a convex curved configuration or a concave curved configuration to match the shape of the wound that is being treated with the wound dressing. Some embodiments provide a method for application of a wound dressing composition comprising gelatin and a plasticizer wherein the wound dressing is applied to a mucosal surface and energy is applied to create adherence or bond to the underlying mucosal surface. Some embodiments provide a method for application of a wound dressing composition comprising gelatin and a plasticizer wherein the wound dressing is applied to a surface of an organ and energy is applied to create adherence or bond to the underlying organ surface.

Brief Description of the Drawings: Features and aspects, and advantages of the embodiments of the present disclosure are described in detail below with reference to the drawings of various embodiments, which are intended to illustrate and not to limit the invention. These drawings depict only several embodiments in accordance with the disclosure and are not to be considered limiting of its scope. FIG. 1 depicts an energy source for the activation of the wound dressing. FIG. 2 illustrates energy activation of the wound dressing in the nasopharyngeal cavity. FIG. 3a illustrates the wound dressing being placed onto a post-tonsillectomy wound. FIG. 3b illustrates activation energy emitted by the wand applied to the external facing surface of the wound dressing to activate the wound dressing. FIG. 4a illustrates a perspective view an embodiment of the present invention with a plurality of through holes. FIG. 4b illustrates a perspective view of an embodiment of the present invention with two layers. FIG. 5 illustrates a perspective view of an embodiment of the present invention with a coating of a wand interfacing material as the surface exposed to the environment external to the wound. FIG. 6 illustrates a wound dressing configured for energy activation on the periphery of the dressing.

Description of the Invention: The present invention is a composition for a wound dressing that may be activated by energy to create adherence or a direct bond of the wound dressing to the underlying tissue on which it is placed. In some embodiments, the wound dressing may bond to the tissues and integrate with the wound surface. The composition of the present invention comprises gelatin and a plasticizer formed into a thin film that conforms to the surface of the wound. While not wishing to be bound to a particular theory of operation, it is believed that the application of energy to the wound dressing while in intimate contact with the wound allows interaction of the dressing components and the wound to provide adherence or bonding. The energy source may be a source of plasma, radiofrequency (RF) electrical energy, ultrasound, light or heat. Some embodiments use an energy source with minimum effect on the underlying tissue such as saline plasma (e.g. Coblator, ArthroCare Corporation), gas plasma, radio frequency electrical energy, light or ultrasound, which provide sufficient energy to activate adherence or bonding of the wound dressing. With reference to Fig.1 , the energy source system includes a power supply module 1 providing power to a probe 2. The probe 2, also called a wand, includes a combination connector housing and handle 3 at its proximal end and a probe cable 4 connected to the power supply 1. Power supply 1 has an operator controllable power level adjustment 5 to change the applied power output, which is observable at a power display 6. Power supply 1 may optionally include a foot pedal control 7 attached with a cable 8 to the power supply 1. In one embodiment, the ultrasound activation of the wound dressing is enabled by cavitation of the wound and tissue fluids or additional fluid from irrigation. Regardless of the energy source, a means for control of the intensity of the applied energy may be used to provide the appropriate amount of energy without significant damage to the underlying tissue. In some embodiments, a small amount of energy may be delivered to the tissue through the wound dressing to increase bonding to the wound dressing or to provide hemostasis simultaneous with the activation of the wound dressing. Typically, the wound dressing composition is in the physical form of a film, with a first surface for application to a wound or tissue surface and an opposing second surface exposed to the environment external to the wound. Other forms suitable for specific applications of the wound dressing may also be used. The thickness and energy conductive properties of the film are selected to allow penetration of the energy source applied to the second surface to reach the first surface and bond the wound dressing to the underlying tissue. Appropriate film thickness ranges from about 30 to 250 microns, about 40 to 200 microns or about 50 to 150 microns. The film may be in a generally planar configuration or may be curved to match the approximate shape of the wound to be treated. The wound dressing may have a concave curved configuration to fit a tissue excision site such as after tonsillectomy or have a convex curved configuration to match the exterior of a resected organ such as the lung. The film can be fabricated by molding of the gelatin composition including film casting from solution. In one embodiment, the gelatin is prepared in a heated solution with a physiologically compatible buffer to provide a pH and tonicity to allow prolonged contact with tissue without irritation. Suitable buffer systems include phosphate buffer, HEPES, bicarbonate buffer and glycine buffer. Tonicity may be adjusted to the physiological range by the addition of sodium chloride and/or potassium chloride. In order to provide physical integrity and protection to the wound, the film is crosslinked after formation to form the wound dressing. Crosslinking may be performed by exposure to chemical agents such as formaldehyde, dialdehydes, including glutaraldehyde, diisocyanates, carbodiimides and difunctional epoxides. Physical methods include vacuum treatment, freeze- thaw, dehydrothermal and ultraviolet (UV) irradiation. Chemical methods in which ionic groups of the gelatin are utilized often increase hydrophobic properties of a gelatin based material. UV irradiation has been found to provide a hydrophilic surface after crosslinking, which provides good surface contact with a moist wound surface and mucosal tissue. Crosslinking is desired to be sufficient to provide physical integrity to the wound dressing material, but without crosslinking to a degree in which mobility of the material and tissue bonding properties are reduced. Suitable crosslinking has been found to be achieved with 2.5 to 10 minutes of UV exposure at a wavelength of 254 nm and an intensity of 950 milliwatts per cm². Additives may be added to the film composition to increase UV crosslinking, such as photo initiators or reactive sugars. The extent of crosslinking may be determined by the equilibrium water absorption of the wound dressing material. Equilibrium water absorption of about 70.5% to 741 .1 %, about 313.9% to

741 .1 % or about 491 .6% to 630.0% has been found to provide tissue bonding properties upon the application of energy. Close apposition of the wound dressing to the wound surface promotes bonding. Since wounds may have a variable configuration, the wound dressing is desired to be conformal. The addition of plasticizers to the gelatin composition allows the mechanical properties to be adjusted to allow conformance to the wound. Suitable plasticizing agents include glycerol, water, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol and polyethylene-propylene glycol copolymers. Plasticizers in the amount of approximately 4.7% to 12.8% by weight (wt %) of the dry composition have been found to provide flexibility to the wound dressing composition to provide improved tissue adherence or bonding. A surfactant may be added to the composition to aid film fabrication and, for some surfactants, to provide added plasticization effect. Suitable surfactants are non-toxic and include fatty acids, alkyl carboxylates-fatty acid salts, alkyl sulfates, alkyl ether sulfates, fatty acid esters, sorbitan fatty acids (Span^®), polyoxyethylene sorbitan fatty acids (Tween^®). It has been found that surfactant in a concentration as low as 0.1 wt % of the dry film in combination with a plasticizer improved tissue adherence of the wound dressing. During the application of energy to the wound dressing, it has been found beneficial to provide a path for fluid and gas at the interface of the tissue and wound dressing to be transported away from the interface. With reference to Fig. 4a, the wound dressing 12 has a first surface 15 intended for application to a tissue surface and a second surface 16 that is exposed to the external environment. The wound dressing 12 has a plurality of through holes 17 traversing the thickness of the wound dressing to connect the first surface 15 with the second surface 16. Through holes from the first surface to the second surface provide a path for fluid and gas flow. In addition, the holes may, in some embodiments, provide a pathway for applied energy to the wound and wound dressing interface to promote tissue bonding. Holes in the range of 0.41 mm to 0.71 mm diameter, corresponding to a cross-sectional area range of 0.13 mm² to 0.40 mm² have been found to provide sufficient transport properties. The holes may have various geometries, such as circular, polygonal, oblong, or slotted, with characteristic cross-sectional dimensions. The holes of various geometries may have a characteristic cross-sectional dimension, such as a diameter or an axial length in the range of 0.41 mm to 0.71 mm or a cross- sectional area in the range of 0.13 mm² to 0.40 mm². A plurality of holes may be incorporated into the wound dressing. A density of holes ranging from 8 to 16 holes per square cm has been found to provide transport properties without significant reduction of the barrier benefits of the wound dressing. A property of the wound dressing composition is the transition of the material properties after application of energy. The wound dressing composition has been found to increase in flexibility or elongation properties after exposure to energy. Flexibility is evident from the increased elongation properties during mechanical characterization. The transition allows the material to better conform to the microarchitecture of the wound surface. In some embodiments, the wound dressing integrates into the wound surface to provide a resurfacing of the wound. The transition effect is also useful in that a stiff wound dressing is more easily applied to the wound, but results in a conformal and flexible protective barrier on the wound surface after energy activation. In some embodiments, the surface of the wound dressing intended for contact with the wound surface is textured. Surface textures may be selected to facilitate integration of the wound dressing into the wound or promote wound healing. Textured surfaces may be fibrous, porous, dimpled, striated or other textures, including combinations thereof. In some embodiments, the texture is molded into the film used to fabricate the wound dressing. In some embodiments, the film may be etched or imprinted to impart texture. In some embodiments, the wound dressing may be composed of more than one layer. A layer adjacent the first surface intended for application to tissue may be comprised of several layers, each having a structure and composition the same as or different from another layer. Each layer may be structured to achieve specific properties. Similarly, a layer adjacent the second surface exposed to the environment may be a barrier layer comprised of several layers, each having a structure and composition the same as or different from another layer. With reference to Fig. 4b, the wound dressing 12 comprises two layers. Layer 18 comprises a first surface intended for application to a tissue surface with through holes 17. Layer 19 comprises a porous material to function as the second surface exposed to the environment external to the wound. In some embodiments, there may be additional layers between the tissue contact layer and the external barrier layer. In some embodiments, one or more layers of the dressing may be colored to provide ease of use or to identify the different layers. In some embodiments, part or all of the dressing may be colored to help a physician or patient confirm that the dressing is still in place, how much of the dressing has dissolved, or the like. In some embodiments, the wound dressing composition of the present invention may be used as a portion of a composite wound dressing. In one embodiment, the wound dressing composition of the present invention is used to form a perimeter of a composite wound dressing where the center of the dressing has a different composition and function, but the perimeter acts to secure the dressing to the wound. With reference to Fig. 6, the wound dressing 12 comprises a peripheral area 21 for energy activation and adherence of the dressing to underlying tissue and a central area 22 for treatment of the wound. The central portion of the composite wound dressing may be tailored to absorb exudate, deliver medications or transmit signals that may be magnetic, electrical or optical in nature. In some embodiments, the second surface of the wound dressing exposed to the environment is designed for contact with the probe or wand transmitting the energy to activate the wound dressing. In reference to Fig. 5, the wound dressing 12 comprises a base layer 18 comprising a first surface intended for application and adhesion to a tissue surface with through holes 17. Coating 20 comprises a wand interfacing material to function as the second surface exposed to the environment external to the wound. In some instances, the probe makes physical contact with the wound dressing and may stick to the wound dressing material, especially during or after energy activation. A layer of material on the second surface may be designed to interface with the probe and prevent adherence to the wound dressing material. Such probe interfacing materials may be a liquid, semi-solid or a solid such as oil, lipid, lipid derivative, fatty acid, fatty acid derivative, surfactant or an emulsion. The oil may comprise naturally derived oil or a synthetic oil such as low molecular weight

polydimethylsiloxane. The probe interfacing material is desired to be non-toxic and eliminated by the body by natural processes. The interfacing material may have a temperature transition from solid to liquid during activation of the wound dressing with energy such as lauric acid, palmitic acid and stearic acid. A coating of the probe interfacing material may also aid application of the wound dressing by acting as an electrical insulator or thermal conductor to promote even distribution of the energy to activate the wound dressing. The interfacing material may be applied as a coating on the second surface by thin film deposition, film casting or spray coating.

Alternatively, the probe interfacing material may be applied to the probe surface as a coating or sleeve that may be applied to the probe prior to activation of the wound dressing. With reference to Fig. 2, the wound dressing may be used in the nasopharyngeal cavity 11 , with the wand 2, hand held by the operator 9 and positioned against the tonsil tissue 10 of the patient. With reference to Fig. 3a and Fig. 3b, the wound dressing 12 is placed onto a post-tonsillectomy wound 13 and activation energy 14 emitted by the wand 2 applied to the second surface of the wound dressing 12 to activate the wound dressing. For use in the nasopharyngeal cavity, it is desired that the wound dressing is not a risk for obstruction if dislodged, which could cause choking or aspiration of the material. The transition of the material to a material of greater flexibility, integration into the wound and the plurality of through holes provides an adherent wound dressing that is difficult to remove in a single or several large pieces. Attempts to remove the bonded dressing with forceps results in loss of small fragments that are not a risk for obstruction. Additives may be incorporated into the wound dressing composition to enhance performance or provide other functional benefits. Advantageously, addition of the amino acid cysteine, cysteine derivatives including cystine, or other cysteine containing compounds increases the tissue bonding properties of the composition. While not wishing to be bound to a particular theory, cysteine incorporated into the dressing may provide for disulfide bonds between the wound dressing and the macromolecules of the underlying tissue. Mucin present on mucosal surfaces has high disulfide bond content and may be receptive to disulfide bonding to the cysteine- containing composition. In some embodiments, the energy source when applied to the wound dressing creates oxidative conditions to promote disulfide bonding between the wound dressing composition and the interfacing tissue. It has been found that a cysteine content of 0.044 wt % to 1 1 .8 wt % of the dry film provided increased adherence of the wound dressing to tissue. Other additives may be incorporated into the wound dressing, such as anti-inflammatory agents, antibiotics, antimicrobial agents, anesthetics, analgesics, agents to prevent post-operative surgical adhesion, and wound healing mediators. In some embodiments where the wound dressing is placed in the nasopharyngeal cavity, flavorings may be incorporated. In one embodiment, a steroid is added to the wound dressing composition to provide a local antiinflammatory effect and energy activated to adhere or bond to tissue using a low temperature energy source such as saline plasma or ultrasound. A low temperature energy source may be used to minimize degradation of drug during activation of the wound dressing. The additives may be incorporated into the wound dressing composition directly or alternatively in a separate layer attached to the second surface of the wound dressing. The additives may be introduced into the wound dressing that will elute out of the dressing at a desired rate once the dressing is applied to tissue. The wound dressing compositions of the present invention provides strong adherence to tissue, regardless of the moisture conditions during bonding. In tests performed with saline plasma energy activation, the wound dressing composition was thoroughly wet by the saline flow from the probe during energy activation, however the composition demonstrated strong tissue adherence. Wound dressing compositions containing cysteine in particular demonstrated strong tissue adherence under wet and high moisture conditions.

Examples:

Example 1 : Gelatin Wound Dressing Composition and Fabrication Wound dressings according to the invention were made from films dried from aqueous solutions of 10% by weight (wt %) gelatin and 10 mM HEPES buffer. The solution was prepared in a 100ml_ Wheaton glass bottle by adding 0.5ml_ of 1 M HEPES (Sigma H0887), 5g gelatin (Gelita Medella Pro 260 Bl NF), and 49.5ml_ deionized water. The solution was heated at 50 to 65°C for several hours until the gelatin dissolved into solution. A drop of water soluble dye colorant (blue or green) was added to the solution to aid the visual detection of film adhesion to tissues. Aliquots of 1 mL were dispensed to small weigh boats (anti-static polystyrene, VWR 89106-760), and allowed to dry at ambient conditions. The resultant films were harvested after drying was complete. The resultant dry films had a composition of 97.7 wt % gelatin and 2.3 wt % HEPES. Different types of gelatin were used to make films. Film types are denoted by their gelatin type and bloom number. For example, gelatin A277 was type A with bloom 277; gelatin B225 was type B with bloom 225.

Example 2: Adhesion Testing of Wound Dressings Various films were prepared by casting and drying of aqueous solutions containing 10 wt % gelatin as described in Example 1 . Wound dressings were prepared by crosslinking films to increase their strength by exposure to saturated formaldehyde vapor for 30 min. Through holes 0.71 mm diameter were introduced to each film by using a 25 gauge needle punch, at a density of 8 holes per cm². Resultant wound dressings were tested for tissue adherence by placing the film onto freshly cut beef tongue. An Arthrocare Coblator II Plasma Generator with a PROcise mAx Plasma Wand, set at a power setting level of "1 " and with low saline flow, was used to apply energy to the dressing while pressing down lightly on the dressing. The wound dressings were wetted by the saline flow during energy activation. A few minutes after the dressing was treated with the Coblator wand, the film was evaluated by using a pair of forceps to gently peel the film from the tissue, and the results were qualitatively scored for adherence to the tissue using the following scoring format.

Table 1 . Tissue Adherence Test Scoring Format

Table 2. Tissue Adherence Testing of Gelatin Film Compositions

10 wt % Gelatin A277 only 74 +/-

10 wt % Gelatin A277 + 1 wt %

84 +

glycerol

10 wt % Gelatin A277 + 0.01 wt %

102 - Tween^® 20

10 wt % Gelatin A277 + 1 wt %

91 ++

glycerol + 0.01 wt % Tween^® 20

Gelatin films placed on tissue without energy activation showed no adherence. Gelatin films without additives (100% gelatin) were slightly adherent to tissue after energy activation. However, the addition of 1 wt % glycerol, and 1 wt % glycerol plus 0.01 wt % Tween^® 20 to the solution used for film fabrication increased the tissue adherence of resultant films. Films formed from 10 wt % gelatin solution with the addition of 1 wt % glycerol had a resultant dry composition of 90.9 wt % gelatin and 9.1 wt % glycerol. Films with the addition of 1 % glycerol and 0.01 wt % Tween^® 20 had a resultant dry composition of 90.8 wt % gelatin, 9.1 wt % glycerol and 0.1 wt % Tween^® 20.

Example 3: Adhesion of Gelatin Films with Plasticizer Gelatin films containing Tween^® 20 without plasticizer were stiff and not compliant to the tissue surface. It was found that the addition of both Tween^® 20 and glycerol resulted in soft, compliant gelatin films. Gelatin films were fabricated from gelatin A277 with 10mM HEPES buffer, 0.01 % Tween^® 20, and different concentrations of glycerol using the fabrication method described in Example 1 . Films were dried from a 1 ml_ dispensed volume. Wound dressings were prepared by crosslinking the films by UV irradiation in a UV chamber (Bio-Rad GS Gene Linker) for 5 min on each side and forming 8 holes/cm² with a hole diameter of 0.71 mm. The resultant wound dressings had a glycerol and gelatin composition as listed in Table 3. The wound dressings were tested for energy activated tissue adherence as described in Example 2.

Table 3. Gelatin Wound Dressings with Various Levels of Plasticizer

The results demonstrate that energy activated tissue adherence was observed at a concentration range of glycerol in the dry film of 4.7 to 12.8 wt % and a weight ratio of gelatin to glycerol of 20:1 to 6.67:1 . Example 4: Thickness of Gelatin Film Wound Dressings

Films from Gelatin A277 (Gelita MedellaPro) were prepared by drying of an aqueous solution of 10 wt % gelatin, 1 wt % glycerol, 0.01 wt % Tween^® 20 and 10mM HEPES buffer as described in Example 1 . Different volumes, 0.5 to 1 .5 ml_, were dispensed into small weigh boats, and allowed to dry. The dry films had a composition of 88.9 wt % gelatin, 8.9 wt % glycerol, 0.1 wt % Tween^® 20 and 2.1 wt % HEPES. Their thickness were measured at 3 to 5 different locations on the films, and averaged. Wound dressings were prepared by crosslinking the films by exposure to saturated formaldehyde vapor for 30 min. Needle punches were used to introduce holes with different diameters and hole densities to each dressing, before they were tested for tissue adherence, using the Coblator system as described in Example 2.

Table 4. Tissue Adherence of Films of Variable Thickness and Hole Configuration

The results demonstrated tissue adherence was observed in the thickness range of 46 to 140 microns, with the optimal range of approximately 100 microns.

Example 5: Crosslinking of Gelatin Film Wound Dressings Chemical cross-linking was performed on the films of Example 3 by exposure to saturated formaldehyde vapor for 15 min to 60 min. Physical crosslinking was performed by irradiating films with UV light at 254 nm wavelength and intensity of 950 milliwatts/cm² for 2.5 min to 15 min on each side. Films of A277 gelatin were prepared as described in Example 3 with 1 ml_ dispensed volume. Dried films were UV crosslinked at various times to form wound dressings. Each crosslinked wound dressing contained 8 holes/cm² with a hole diameter of 0.71 mm. The films were tested for adhesion after activation by the Coblator system as described in Example 2.

Table 5. Wound Dressing Crosslinking with Formaldehyde

The results indicate that a formaldehyde vapor crosslinking time of 15 to 90 minutes exposu produced films adherent to tissue after energy activation.

Table 6. Wound Dressing Crosslinking by UV Irradiation

The results demonstrated that tissue adherence was observed for UV crosslink time for 2.5 to 10 min at an intensity of 950 milliwatts/cm² for each side of approximately 100 micron thick film.

Example 6: Textured Film Textures were introduced to films by overlaying nylon or polypropylene mesh on top of the dispensed gelatin solution before the drying process, as described in Example 1 . Circular mesh with 400 to 2000 micron opening sizes were used. The mesh was removed from the film after drying, resulting in a film with a textured surface. Wound dressings were formed by crosslinking the films for 10 minutes of UV exposure on each side as described in Example 5. Example 7: Effect of Cysteine Additive to Composition

Gelatin solutions at a concentration of 10 wt % with 1 wt % glycerol, 0.01 wt % Tween 20, and 10 mM HEPES was prepared with various concentrations of cysteine. Films were prepared from a 1 mL dispensed volume and formed as described in Example 1 . Wound dressing were prepared from the films by UV crosslinking for 5 min on each side, and the formation of 8 holes/cm² with a hole diameter of 0.71 mm. The wound dressings were tested for tissue adherence after activation by the Coblator system as described in Example 2.

Table 7. Adherence of Gelatin A277 with Cysteine

The results demonstrate that cysteine increased tissue adherence in the concentration range of 0.1 wt % to 1 1 .8 wt % of the dry wound dressing composition.

Table 8. Adherence of Gelatin A277, A294 and B250 with Cysteine

NT - not tested

The results demonstrate that cysteine increased tissue adherence in the concentration range of 0.044 wt % to 0.44 wt % of the dry wound dressing composition. The adherence was improved for both type A and type B gelatin compositions. The adherence of the type B gelatin compositions was greater than the type A gel both with and without cysteine.

Example 8: Gelatin Films with Dextrose Solutions of 10 wt % A277 gelatin, containing various concentrations of dextrose, 0.01 wt % Tween^® 20 and 10mM HEPES buffer were used to prepare films as described in Example 1 . Films were prepared from 1 ml_ dispensed volume. Wound dressing were fabricated from the films by UV crosslinking for 5 min on each side as described in Example 5, and the introduction of through holes (8/cm², 0.71 mm diameter). The wound dressings were tested for tissue adherence after activation by Coblator system as described in Example 2.

Table 9. Adherence of Wound Dressings Containing Dextrose

The addition of dextrose, in place of glycerol, did not significantly affect tissue adherence in films formed from gelatin solution with 0.01 wt % Tween^® 20 and 10mM HEPES. Additional films were fabricated from films dried from a solution of 10 wt % gelatin A277, 1 wt % dextrose, 0.01 wt % Tween 20, and 10mM HEPES with various levels of cysteine. Wound dressings were prepared from the films by UV crosslinking for 10 min on each side as described in Example 5 and the introduction of 8 holes per cm² with a hole diameter of 0.71 mm. The wound dressings were tested for energy activated tissue adherence as described in Example 2.

Table 10. Adherence of Wound Dressings Containing Dextrose and Cysteine

The results demonstrated that cysteine increased tissue adherence in dextrose-containing gelatin films.

Example 9: Wound Dressing Activation with Different Energy Sources Wound dressings were prepared from gelatin films prepared from A294 gelatin in 1 wt % glycerol, 0.01 wt % Tween^® 20 and 10 mM HEPES as described in Example 1 . Films were dried from a 1 ml dispensed volume. Wound dressings were prepared from the films by UV cross-linking for 2.5 min on each side and punching to form 8 holes/cm² with a diameter of 0.71 mm. The Coblator system was used to activate the wound dressings as described in Example 2 and the tissue adherence was determined. An ultrasound energy source was also used to activate the wound dressings. Low frequency ultrasound (LFUS) energy between 23 kHz and 28 kHz was generated from an ultrasound generator using piezoelectric transducers to which signals were applied. A titanium waveguide with a flat distal surface at the tip was attached to the ultrasound generator. The wound dressing was placed on the test tissue and the flat surface of the distal end of the waveguide was pressed to the surface of the wound dressing and moved over the desired area for wound dressing activation.

Table 1 1 . Wound Dressing Activation with Saline Plasma and Ultrasound

Example 10: Tensile Testing of Films

Gelatin films were fabricated according to Example 1 using two gelatin types, A294 (Gelita

MedellaPro) and B250 (Rousselot Peabody Inc.). The films were dried from an aqueous solution of 10 wt % gelatin solution in 1 wt % glycerol, 0.01 wt % Tween^®20, 10mM HEPES, and 0.05 wt % Cysteine (4mM), with a one ml dispensed volume. Each film was cross-linked by UV at 254 nm, 950 milliwatts/cm², for 5 min on each side. The films averaged 100 microns in thickness. The films were cut into test strip samples measuring 5 mm wide by 30 mm long. A total of 6 test strips of each gelatin type were prepared. The films were divided into three groups for mechanical (tensile) testing under various conditions. The films were tested dry, hydrated and treated with a saline plasma system. The film tensile properties were measured using a Mark-10 Corporation (Copiague, NY) mechanical test system consisting of an ESM301 Test Frame with an M5-50 Force Gauge. The force gauge output was recorded by the Mark-10 Mesur-Lite software program on a laptop computer and the data was transferred to Microsoft Excel for analysis. Two Mark-10 Miniature Component Grips were used to hold the film samples. The test system was set up with a gauge length of 15 mm and a cross-head speed of 10 mm/min.

The first test group was tensile tested in the dry state. The second test group was hydrated in deionized, filtered water for 30 minutes. The third test group was treated using the Coblator system as described in Example 2. The test strips were held in place on a sheet of polytetrafluoroethylene (Teflon) with a pair of forceps. The plasma wand was triggered away from the test strips and then swept over the films, without touching them, to treat.

The hydrated samples were tested at 30 minutes of hydration and the plasma treated samples were tested immediately after treatment. After mechanical testing, the data was processed to determine the peak tensile strength in grams-force and the percent elongation at break. The results were averaged and the results are presented in the following table.

Table 12. Tensile Testing of Wound Dressing Composition

The energy activation of the wound dressing composition demonstrated increased flexibility in handling and increased elongation at break or failure in tension as compared to the composition in dry and hydrated conditions prior to energy activation.

Example 1 1 : Extent of Crosslinking

Gelatin films prepared as described in Example 1 were chemically crosslinked by exposure to formaldehyde. Film samples were placed in containers saturated with formaldehyde vapor for 5, 10 and 15 minutes. The films were removed and allowed to equilibrate at ambient temperature and humidity. Small portions of the films were weighed and placed in deionized water for 30 minutes. The films were removed and excess water removed by blotting against a dry surface. The hydrated weight of the sample was measured and the water absorption of the samples determined. Three samples were measured for each crosslinking condition and then averaged.

Table 13. Water Absorption of Wound Dressing Composition, Chemical Crosslinking

CV- coefficient of variation Testing of formaldehyde crosslinked wound dressing films as described in Example 5 demonstrated energy activated tissue adherence after 15, 60 and 90 minutes of formaldehyde exposure, corresponding to a water absorption of 70.5 % to 146.7%.

Gelatin films prepared as described in Example 1 were physically crosslinked by exposure to 254 nm wavelength UV light at an intensity of 950 milliwatts/cm² for a variable amount of time. The equilibrium water absorption of the samples was determined as previously described for chemical crosslinking with formaldehyde vapor.

Table 14. Water Absorption of Wound Dressing Composition, Physical Crosslinking

Testing of UV crosslinked wound dressing films as described in Example 5 demonstrated energy activated tissue adherence after 2.5, 5, 10 minutes of UV exposure on each side of the film, corresponding to a water absorption of 741 .1 % to 315.0%.

Example 12: Probe Interface Oil Coatings Gelatin films were fabricated according to Example 1 using gelatin B250 (Rousselot Peabody Inc.). The films were dried from an aqueous solution of 10 wt % gelatin solution in 1 wt % glycerol, 0.01 wt % Tween^® 20, 10mM HEPES, and 0.05 wt % Cysteine (4mM), with 1 .0, 1 .2, 1 .5 and 2.0 ml dispensed volume to produce a films of approximately 56, 87, 102 and 145 micron thickness. Each film was cross-linked by UV at 254 nm, 950 milliwatts/cm², for 5 - 10 min on each side. Films were punched to form 8 through holes/cm² with a diameter of 0.71 mm. Selected films were coated with low molecular weight silicone fluid, cannola oil, sunflower oil or flaxseed oil with sufficient fluid to coat the surface. The resultant wound dressings were tested for tissue adherence by placing the film onto freshly cut beef tongue. A Valley lab Force EZ electrosurgical system by Covidien/Medtronic was used to apply energy in coagulation mode to the dressing while pressing down lightly on the dressing with the electrosurgical probe. A few minutes after the dressing was treated, the film was evaluated by using a pair of forceps to peel the film from the tissue, and the results were qualitatively scored for adherence to the tissue using the scoring format described in Example 2. The oil coating effectively prevented adhesion of the probe surface to the film during and after treatment.

Table 15. Probe Interface Oil Coating

Example 13: Probe Interface Fatty Acid Coatings

Additional films were coated with a fatty acid. A solution of palmitic acid was prepared in hexane at a concentration of 0.2 molar. The palmitic acid solution was warmed to 37 degrees C and pipetted onto films with surface area of 8 cm². Approximately 12.5 mg of palmitic acid was deposited onto the films, resulting in a surface concentration of approximately 1 .6 mg per cm². On some films, the coating process was repeated two or three times, resulting in surface coatings of approximately 3.1 mg per cm² and 4.7 mg per cm² respectively. The resultant wound dressings were tested for tissue adherence by placing the film onto freshly cut beef tongue and activated using a Valleylab Force EZ electrosurgical system as described in Example 12. The fatty acid coating effectively prevented adhesion of the probe surface to the film during and after treatment. The fatty acid coating was observed to transition from solid particles to a liquid during energy activation.

Table 16. Probe Interface Fatty Acid Coating

thickness, with holes

Palmitic acid coating (1 .6 mg/cm ), 145 micron

20 - high thickness, with holes + +

Additional films coated with a fatty acid were tested for tissue adhesion using the Coblator systems as described in Example 2. The fatty acid coating effectively prevented adhesion of the probe surface to the film during and after treatment.

Table 17: Probe Interface Coatings with Coblator

Example 14 - Wound Dressing Adhesion to Area of Excised Tissue

An area of freshly cut beef tongue was excised with either the Cut mode of the Valley lab Force EZ electrosurgical system or the Coblate mode of the Coblator system. A film with composition described in Example 13, with 1 .6 mg per cm² palmitic acid, was placed on the wound so that the film covered the excised area and 0.5 - 1 cm surrounding the wound. The film contained 8 through holes per cm² with a holed diameter of 0.71 mm. The coag mode of each system was used to activate the wound dressing.

Table 18. Wound Dressing Adherence to Excised Tissue

Claims

Claims: What is claimed is:

1 . A composition for a wound dressing comprising crosslinked gelatin and a plasticizer

configured as a thin film with a first surface for application to a tissue surface and an opposing second surface exposed to the environment external to the wound, characterized by a transition of the composition upon the application of energy to the second surface to a composition with increased flexibility as evidenced by an increase in elongation at failure.

2. The composition of claim 1 additionally comprising cysteine or cysteine derivatives.

3. The composition of claim 8 where the cysteine or cysteine derivatives is in the range of 0.044 wt % to 1 1 .8 wt % of the dry composition.

4. The composition of claim 1 where the film comprises a plurality of through holes between the first surface and the second surface.

5. The composition of claim 4 where the through holes have a characteristic dimension of 0.41 to 0.71 mm.

6. The composition of claim 4 where the through holes have a density of 8 to 16 holes per square cm.

7. The composition of claim 1 where the thin film has a thickness of 30 to 250 microns.

8. The composition of claim 1 where the plasticizer comprises glycerol, water, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol or polyethylene-propylene copolymers.

9. The composition of claim 8 where the plasticizer is in the range of 4.7 to 12.8 wt % of the dry composition.

10. The composition of claim 1 additionally comprising a surfactant.

1 1 . The composition of claim 10 where the surfactant comprises a fatty acid, alkyl carboxylates- fatty acid salt, alkyl sulfate, alkyl ether sulfate, fatty acid ester, sorbitan fatty acid (Span) or polyoxyethylene sorbitan fatty acid (Tween^®).

12. The composition of claim 10 where the surfactant is approximately 0.1 wt % of the dry

composition.

13. The composition of claim 1 additionally comprising a buffer.

14. The composition of claim 13 where the buffer comprises phosphate buffer, HEPES,

bicarbonate buffer or phosphate-citrate buffer.

15. The composition of claim 1 where the crosslinking produces a composition with equilibrium water absorption of 70.5% to 741 .1 %.

16. The composition of claim 1 where the gelatin is crosslinked with chemical cross-linking

agents.

17. The composition of claim 1 where the gelatin is crosslinked by exposure to UV irradiation.

18. The composition of claim 1 where the first surface is textured.

19. The composition of claim 1 additionally comprising a second layer attached to the second surface.

20. The composition of claim 1 additionally comprising a probe interface coating on the second surface.

21 . The composition of claim 20 where the probe interface coating comprises an oil, a lipid, a lipid derivative, a fatty acid, a fatty acid derivative or an emulsion.

22. The composition of claim 21 wherein the probe interface coating has a surface density of at least 1 .6 mg per cm².

23. The composition of claim 1 and an activation energy source, where the energy source is selected from the group consisting of plasma, radio frequency, ultrasound, light, thermal.

24. The composition of claim 1 additionally comprising a pharmaceutical agent.

25. The composition of claim 24 where the pharmaceutical agent is an anti-inflammatory agent, antibiotic, antimicrobial agent, anesthetic, analgesic, agent to prevent post-operative surgical adhesion or wound healing mediator.

26. The composition of claim 1 additionally comprising a dye or flavoring.

27. A method for application of a wound dressing comprising placing the first surface of the wound dressing of claim 1 on a tissue surface and applying energy to the second surface of the wound dressing to activate bonding of the wound dressing to the underlying wound.

28. The method of claim 27 where the wound dressing is applied to an internal organ or tissue.

29. The method of claim 27 where the wound dressing is applied to a tissue surface in the

nasopharyngeal cavity.

30. The method of claim 29 where the wound dressing is applied to a wound after tonsillectomy, adenoidectomy, uvulopalatoplasty, uvulectomy or base of the tongue reduction.

31 . A process for fabricating a wound dressing comprising, preparing an aqueous solution

comprising gelatin and a plasticizer, where the gelatin to plasticizer ratio by weight is from 20:1 to 6.67:1 , casting the solution and drying to form a film of thickness of 46 to 140 microns, crosslinking the film and forming through holes in the film to form a wound dressing, where the resulting dry film has a gelatin content of 85.1 wt % to 93 wt % and a plasticizer content of 4.7 wt % to 12.8 wt %.

32. The process of claim 31 where the aqueous solution additionally comprises a surfactant to produce a dry composition comprising 0.1 wt % of the surfactant.

33. The process of claim 31 where the aqueous solution additionally comprises cysteine to

produce a dry composition comprising a cysteine content of 0.044 wt % to 1 1 .8 wt %.

34. The process of claim 31 where the crosslinking is performed by UV irradiation to provide a water absorption of the resultant wound dressing composition in a range from 741 wt % to 315 wt %.