Patent Publication Number: US-2021169701-A1

Title: Nanomodified transfer drape for epidermal grafting

Description:
BACKGROUND 
     The present invention relates generally to dressings for transferring epidermal skin grafts from a donor site to a recipient site, and more particularly to such dressings that can facilitate the retention of the epidermal skin grafts and migration of keratinocytes in the grafts to surrounding tissue. 
     Skin grafting is a surgical procedure in which a section of skin is removed from one area of a person&#39;s body (autograft), removed from another human source (allograft), or removed from another animal (xenograft), and transplanted to a recipient site of a patient, such as a wound site. Chronic wounds are often observed in elderly patients and/or in patients with severe comorbidities. A common feature of different types of chronic wounds is impaired re-epithalization. Autologous epidermal grafting provides a solution to wound closure by transferring the patient&#39;s own epidermal cells to the wound site. 
     In one technique, a plurality of epidermal micrografts (also known as microdomes) are generated by raising a plurality of blisters through openings of an orifice plate attached to an end of a low-pressure chamber. The raised blisters can be harvested and transplanted onto a wound site. A device marketed by the assignee of the present application under the trade designation CelluTome® can be used to create and harvest such epidermal micrografts in an automated and precise manner. 
     Following transfer of the epidermal micrografts to a wound site, a medical professional needs to monitor re-epithalization of the site to ensure its proper healing. In some cases, such a medical professional may have difficulty differentiating between the microdomes and slough several days following the micrograft transfer and may mistakenly wipe away the micrograph outgrowth believing that the wound site contained slough. This can lead to a poor outcome. 
     Accordingly, there is a need for improved dressings for skin grafting. 
     SUMMARY 
     In one aspect, a dressing for transferring skin grafts from a donor site to a recipient site is disclosed, which comprises a substrate having a surface configured for contact with one or more epidermal skin grafts, a plurality of capture sites distributed across said substrate surface, wherein each of said capture sites is configured for capturing at least one epidermal skin graft, and a plurality of topographical features distributed over said substrate surface and coupled to at least one of said capture sites so as to provide at least one of inducing proliferation and facilitating migration of keratinocytes in the captured epidermal skin grafts to surrounding tissue. 
     In some embodiments, the topographical features comprise a plurality of channels extending outwardly from said at least one capture site. In some embodiments, all capture sites are associated with one or more such channels. In some embodiments, the topographical features comprise a plurality of ridges extending outwardly from the capture sites. 
     In some embodiments, the capture sites include a plurality of wells configured for receiving one or more epidermal skin grafts. In other embodiments, the capture sites can include flat portions of the substrate surface to which an adhesive has been applied. 
     In some embodiments, at least one of the topographical features, e.g., at least one of a plurality of channels, can interconnect two or more of the capture sites, e.g., two or more of a plurality of wells provided on the substrate surface as capture sites. 
     In some embodiments, one or more of the skin-graft capture sites can include an adhesive for facilitating the capture of one or more skin grafts. In some such embodiments, the adhesive can exhibit a tackiness gradient extending from the center of a capture site to a periphery thereof. For example, the tackiness can decrease from the center of the capture site to its periphery. 
     In some embodiments, the adhesive can be applied to one or more capture sites as an adhesive film for at least partially coating at least one surface of the capture site(s) for facilitating the capture of epidermal skin grafts. By way of example, an adhesive film can be applied to the bottom surface of one or more wells provided on the substrate surface as capture sites. In some such embodiments, the adhesive film exhibits a thickness gradient characterized by a decreasing thickness from a center of a capture site, e.g., a well, to a periphery thereof. 
     In some embodiments, the adhesive film can exhibit a gradient in at least one chemical ingredient, which in turn imparts a tackiness gradient to the adhesive film. 
     In some embodiments, the adhesive film can have a surface density in a range of about 10 to about 200 grams/m 2 , e.g., a surface density in a range of about 15 to about 90 grams/m 2 . 
     By way of example, in some embodiments, the adhesive comprises a medical grade pressure-sensitive adhesive, such as a polyurethane adhesive, an acrylic adhesive, a high-tack silicone adhesive and a hydrocolloid-based adhesive. 
     In some embodiments, the capture sites, e.g., the wells, can have a width in a range of about 1 mm to about 5 mm, e.g., in a range of about 1 mm to about 4 mm or in a range of about 2 mm to about 3 mm. Further, in some embodiments, the topographical features can have a width in a range of about 100 nm to about 500 microns, e.g., in a range of about 200 nm to about 400 microns, or in a range of about 300 nm to about 300 microns. 
     In some embodiments in which the captures sites are in the form of a plurality of wells, the wells can have a depth in a range of about 1 micron to about 100 microns. 
     In some embodiments, at least one of the capture sites, e.g., the wells, and/or the topographical features can include a bioactive material. For example, the bioactive material can be applied to the bottom surface of at least one of the wells. In some such embodiments, the bioactive material can exhibit a concentration gradient along said at least one topographical feature. A variety of different bioactive materials can be employed. Some examples include, without limitation, collagen, keratinocyte growth factor (KGF), and epidermal growth factor (EGF). 
     In some embodiments, the substrate of a dressing according to the present teachings can include a plurality of perforations. In some such embodiments, the perforations can be distributed between the capture sites and the topographical features. By way of example, the perforations can have a width in a range of about 0.2 mm to about 2 mm, though other sizes can also be employed. In some embodiments, the perforations can have a cross-sectional area in a range of about 0.25 square millimeters to about 3 square millimeters. The perforations can have a variety of different cross-sectional shapes, such as polygonal, circular, etc. 
     A dressing according to the present teachings can be fabricated using fabrication techniques known in the art. For example, the topographical features can be formed via any of calendaring, film casting, extrusion, thermoforming during processing of a polymeric material to form said substrate. In some embodiments, the topographical features can be formed via any of chemical modulation, or embossing of said substrate surface. 
     In many embodiments, the substrate can be formed of a suitable polymeric material. Some examples of suitable polymeric materials include, without limitation, polyurethane, polypropylene, cellulosics, polyamides, polyvinyl alcohol, silicone elastomers, acrylics, and copolymers thereof. 
     In some embodiments, the substrate can have a thickness in a range of about 25 microns to about 200 microns. 
     In a related aspect, a method of transferring skin grafts from a donor site to a recipient site is disclosed, which comprises generating a plurality of epidermal skin blisters, placing a skin-graft contacting surface of a dressing on said epidermal skin blisters, where the dressing comprises a substrate having a surface configured for contact with one or more epidermal skin grafts, a plurality of capture sites distributed across said substrate surface, wherein each of said capture sites is configured for capturing at least one epidermal skin graft, and a plurality of topographical features distributed over said substrate surface and coupled to at least one of said capture sites so as to provide any of inducing proliferation and facilitating migration of keratinocytes in the captured epidermal skin grafts to surrounding tissue. The method further includes the step of cutting the epidermal skin blisters so as to capture said cut blisters at said capture sites of the transfer dressing. 
     In the above method, the dressing can have one or more of the properties discussed above. For example, in some embodiments of the above method, the capture sites can have a width in a range of about 1 mm to about 5 mm and the topographical features can have a width in a range of about 100 nm to about 500 microns. Further, the topographical features can include a plurality of channels extending outwardly from said at least one capture site. Further, at least one of the capture sites can include an adhesive. Moreover, at least one of the capture sites and/or the topographical features can include a bioactive material. 
     Further understanding of various aspects of the invention can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a schematic, perspective view of a transfer dressing according to an embodiment of the present teachings, 
         FIG. 1B  is a schematic top view of the dressing depicted in  FIG. 1A , 
         FIG. 2  is a schematic cross-sectional view of the dressing depicted in  FIGS. 1A and 1B , 
         FIG. 3  schematically depicts a capture site and associated topographical features extending outwardly from the capture site of the dressing depicted in the above figures, illustrating that the topographical features exhibit an increasing width from their proximal ends to their distal ends, 
         FIG. 4  is a schematic, perspective view of a transfer dressing according to another embodiment of the present teachings in which some of the topographical features connect a plurality of the capture sites, 
         FIG. 5  is a schematic, cross-sectional view of a transfer dressing according to another embodiment in which the skin-graft capture sites are in the form of flat portions of the substrate surface to which an adhesive has been applied, 
         FIG. 6  is a schematic, perspective view of a transfer dressing according to another embodiment in which the substrate includes a plurality of perforations between the capture sites and the topographical features, 
         FIG. 7  is a schematic top view of a capture sites and its associated topographical features to which a bioactive material has been applied, 
         FIG. 8  is a flow chart depicting various steps in a method according to the present teachings for transferring skin grafts from a donor site to a recipient site, 
         FIG. 9A  is a schematic view of a device for generating a plurality of epidermal skin blisters, and 
         FIG. 9B  shows a multi-plate cutter mechanism employed in the device of  FIG. 8A . 
     
    
    
     DETAILED DESCRIPTION 
     The present invention relates generally to a transfer dressing having a plurality of skin-graft capture sites, where the capture sites are associated with a plurality of topographical features, e.g., channels, that extend outwardly from the capture sites and can help induce proliferation and facilitate migration of keratinocytes in the capture epidermal skin grafts once the grafts are transferred to a recipient site. Various terms are used herein consistent with their ordinary meanings in the art. 
     The term “topographical feature,” as used herein, refers to a structure, such as a channel or a ridge provided on a substrate surface. The term “about,” as used herein, indicates a variation of at most 5% around a central value. 
       FIGS. 1A and 1B  schematically depict a transfer dressing  10  (herein also referred to as a transfer drape) according to an embodiment that includes a substrate  12  having two opposed surfaces  12   a  and  12   b,  where the top surface  12   a  is configured for receiving epidermal skin grafts from a donor site. For example, as discussed in more detail below, the surface  12   a  can receive a plurality of epidermal blisters that were raised through the openings of an orifice plate positioned at the distal end of a vacuum chamber and cut via a cutting mechanism. 
     The substrate  12  can be formed of a variety of different materials. For example, in some embodiments, the substrate  12  can be formed of a suitable biocompatible polymeric material. By way of example, the substrate  12  can be formed of any of polyurethane, polyethylene, cellulosics, polyamides, polyvinyl alcohol, silicone, elastomers, acrylics, polypropylene, polyvinyl chloride and copolymers thereof. 
     The substrate  12  can have a variety of different sizes selected, for example, based on an intended application. By way of example, in some embodiments, the substrate  12  can have a width (W) in a range of about 5 cm to about 15 cm, and a length (L) in a range of about 5 cm to about 10 cm, though other sizes can also be employed. In some embodiments, the substrate 12 can have a thickness (T) in a range of about 25 micrometers (microns) to about 200 microns, though other thicknesses can also be employed. 
     With continued reference to  FIGS. 1A, 1B  as well as  FIG. 2 , in this embodiment, the dressing  10  includes a plurality of skin-graft capture sites  14  distributed across the top surface  12   a  of the substrate  12 . As discussed in more detail below, in this embodiment, the skin-graft capture sites  14  are in the form of a plurality of wells having an adhesive film  16  that at least partially coats the bottom surfaces of the wells so as to facilitate the capture of the skin-grafts by the wells. 
     More specifically, as shown schematically in  FIG. 2 , in this embodiment a thin film of adhesive  16  that is disposed on the bottom surface of the wells  14  exhibits a decreasing thickness from the center of the well to a periphery thereof. 
     Although in this embodiment the wells  14  have flat bottom surface, in other embodiments, they can have different shapes, e.g., a hemispherical shape. In this embodiment, the wells  14  can have a width (w) in a range of about 1 mm to about 5 mm, and a depth in a range of about 1 micron to about 100 microns, though other sizes can also be employed. 
     In this embodiment, the wells  14  are distributed as a regular array across the top surface  12   a  of the substrate  12 . By way of example, in some applications, the spacing between the wells  14  can be selected such that the wells will be in substantial register with a plurality of blisters formed through the orifice plate of a cellutome® device when the substrate surface  12   a  is placed over the blisters. This will allow each of the wells to capture a corresponding blister when the blisters are cut. 
     Referring again to  FIGS. 1A and 1B , the dressing  10  further includes a plurality of topographical features  18  distributed across the skin-graft receiving surface  12   a  of the substrate  12 . In this embodiment, the topographical features  18  are in the form of a plurality of channels that extend radially outwardly from the wells  14 . 
     As shown schematically in  FIG. 3 , a proximal end (PE) of each channel  18  (e g , channel  18   a  depicted in this figure) is coupled to one of the wells  14  (e.g., well  14   a  depicted in this figure). The channel  18   a  terminates in a distal end (DE) at a length (L), which can be, for example, in a range of about 0.5 mm to about 10 mm, from the proximal end. In this embodiment, the channels  18  exhibit a varying width, which increases from the proximal end of each channel (i.e., the end coupled to one of the wells) to its distal end. By way of example, the illustrative channel  18   a  has a minimum width (W mm ), e.g., 10 nm, at its proximal end and a maximum width (W max ) at its distal end. The transition from the minimum width (W m. ) to its maximum width (W max ) can be linear or non-linear. By way of example, in some embodiments, the minimum width (W m ) can be in a range of about 50 nm to about 100 nm and the maximum width (W max ) can be in a range of about 400 microns to about 500 microns, though other sizes can also be employed, e.g., based on an intended application of the dressing. 
     As noted above, the bottom of the wells  14  can be coated with an adhesive film, which can facilitate the capture of epidermal skin grafts within the wells. In many embodiments, the channels  18  are not, however, coated with an adhesive film so as to not inhibit the migration of cells along the channels. For example, the adhesive film disposed at the bottom of the wells  14  can exhibit a decreasing thickness from the center of the wells to their periphery such that the channels are substantially free of such adhesive film. 
     In some embodiments, at least some of the topographical features disposed on the skin-graft receiving surface of the substrate interconnect two or more of the capture sites. By way of example,  FIG. 4  schematically depicts a dressing  20  according to such an embodiment, which includes a substrate  22  having a skin-graft receiving surface  20   a  on which a plurality of skin-graft capture sites  24 , e.g., in the form of a plurality of wells, such as the wells discussed above with regard to the transfer dressing  10 , are distributed. The illustrative dressing  20  further includes a plurality of channels  26  that extend outwardly from the skin-graft capture sites  24 . In this embodiment, a plurality of the channels  26 , i e, channels  26   a,    26   b,    26   c,  and  26   d  provide pairwise connections between some of the wells, e.g., the nanostructured channel  26   a  connects the well  24   a  to the well  24   b  and the channel  26   b  connects the well  24   a  to the well  24   c.  In other embodiments, more of the channels  26 , and in some cases all of the channels  26 , can provide pairwise interconnections between the skin-graft capture wells  24 . The interconnection of at least some of the wells via the channels can facilitate the migration of the epidermal grafts between the wells. In some embodiments, this can in turn induce a faster rate of wound coverage that could be more visible to a caregiver assessing the progress of the treatment. 
     In some embodiments, the skin-graft capture sites can be flat portions of the top surface  12   a  of the substrate  12 . By way of example,  FIG. 5  schematically depicts such a dressing  30 , which includes a plurality of substantially flat capture sites  32  to each of which an adhesive  34  is applied to facilitate the capture of a plurality of epidermal skin grafts. Although in this illustrative embodiment, the adhesive films  34  are depicted as having a uniform thickness across each capture site, in other embodiments the thickness of the adhesive films  34  can exhibit a gradient characterized by a greater thickness at the center of the wells and a lower thickness at the periphery. Further, similar to the previous embodiments, the dressing  30  includes a plurality of topographical features (not shown in this figure) in the form of channels that radiate outwardly from the capture sites. 
     In some embodiments, the substrate of a transfer dressing according to the present teachings can include a plurality of perforations distributed between the capture sites and their associated topographical features. By way of example,  FIG. 6  schematically depicts a transfer dressing  100  according to another embodiment, which includes a perforated substrate  120  having a skin-contacting surface  120   a  and an opposed surface  120   b.  Similar to the transfer dressing depicted in  FIGS. 1A and 1B , the dressing  100  includes a plurality of skin-graft captures sites  140  and a plurality of topographical features  180  extending from the skin-graft capture sites. A plurality of perforations in the form of cylindrically-shaped holes  200  are distributed in the substrate  100 . In some embodiments, the holes  200  can have a diameter in a range of about 0.2 mm to 2 mm. In some embodiments, the holes  200  can have a cross-sectional area in a range of about 0.25 mm 2  to about 3 mm 2 . In other embodiments, the perforations can have a polygonal cross-sectional shape. In some embodiments, the holes  200  extend from the surface  120   a  to the opposed surface  120   b.  In other embodiments, one or more of the holes  200  have openings at the surface  120   a  and extend partially into the substrate (that is, they do not extend all the way to the opposed surface  120   b ). The perforations  200  can advantageously facilitate the exudate drainage at the recipient site (e.g., a wound). 
     As discussed in more detail below, a dressing according to the present teachings, such as dressings  10 ,  20  and  30  can provide a number of advantages. For example, the skin-graft capture sites can confine the captured microdomes and the topographical features can concurrently present topographic cues to the keratinocytes/primary human cells, thereby guiding and facilitating their migration. 
     Moreover, once the dressing is placed on a recipient site, the sandwich-type transplants (i.e., the harvested microdomes sandwiched between the transplant site and the dressing) may result in an even distribution of microskin grafts, greatly improving the “take” rate of microskin tissue, thereby promoting re-epithalization. In addition, the void area in the functionalized dressing, i.e., the area of the dressing that does not contain topographical structures, can be suitable for exudate drainage in wound. 
     Moreover, the pattern of wells and topographical features can help a clinician distinguish between re-epithalized tissue and slough, thus inhibiting the removal of re-epithalized tissue by mistake. 
     In some embodiments, a bioactive material can be disposed in one or more of the capture sites and/or the topographical features. By way of example,  FIG. 7  schematically depicts a capture site  300  and its associated topographical features  302 , where a bioactive material  310  is applied to the capture site  300  and a plurality of its associated topographical features  302 . A variety of different bioactive materials can be employed. Some examples include, without limitation, collagen, keratinocyte growth factor (KGF), and epidermal growth factor (EGF). 
     With reference to the flow chart of  FIG. 8 , in one embodiment, a plurality of epidermal microblisters can be formed. By way of example, a cellutome® device can be employed to form such epidermal microblisters. For example, with reference to  FIGS. 9A and 9B , such a device  1000  can include a head  1020  that can be removably and replaceably attached to a harvester (not visible in this figure) to form a hollow chamber  1060  into which a plurality of blisters can be drawn. In particular, the head  1020  can include a suction coupling  1080  that allows coupling the head via a suction tubing  108   a  to a vacuum source (not shown) to generate a negative pressure within the chamber. The harvester includes an orifice plate  1100  having a plurality of openings  1100   a  through which a plurality of epidermal microblisters can be raised into the hollow chamber  1060 . The harvester further includes a cutter plate  1120  disposed between the orifice plate  1100  and an upper plate  1140 . Both the cutter plate  1120  and the upper plate  1140  include a plurality of openings  1120   a  and  1140   a,  respectively, through which the blisters can protrude. Once the blisters are formed, the cutter plate  1120  can be moved relative to the orifice plate and the upper plate to cut the blisters. Further details regarding such a blister-generating device can be found, e.g., in U.S. Pat. No. 9,173,674 titled “Devices for Harvesting a Skin Graft,” which is herein incorporated by reference in its entirety. 
     More specifically, once the blisters are formed, the application of reduced pressure to the chamber  1060  can be discontinued, and the head portion  1020  can be removed to expose the epidermal blisters. A dressing according to the present teachings can then be placed over the epidermal blisters (step 2 in the flow chart of  FIG. 7 ). In some embodiments, the number of the capture sites provided on the dressing is equal to the number of the formed epidermal blisters and the distribution of the capture sites across the skin-graft receiving surface of the dressing is such that there is a one-to-one correspondence between the capture sites and the epidermal blisters. 
     The epidermal blisters can then be cut and the cut blisters can be captured by the skin-graft capture sites of the dressing (step 3 in the flow chart of  FIG. 7 ). The dressing can then be placed on a recipient site, e.g., a wound site, to transfer the harvested blisters to a recipient site, e.g., a wound, so as to promote re-epithalization of the recipient site. 
     In some embodiments, the topographical features can be generated by means of thermoforming, film casting, calendaring, or a combination of these techniques. In another embodiment the topographical features can be created post-polymer processing by means of chemical modulation and/or embossing. By way of example, a thin layer of pressure sensitive adhesive can be coated onto the substrate to maintain the topographical features. In addition, the topographical features can be introduced on a pressure-sensitive adhesive coated polymeric film by means of embossing or engraving (positive or negative)/rotogravure process. 
     Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the invention.