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  • 专利说明
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    • 专利摘要:
    DEVICE FOR OBTAINING A SKIN GRAFT The present invention generally relates to methods for preparing a skin graft. In certain embodiments, the methods of the invention involve collecting a plurality of skin grafts from an individual, applying the grafts to a first substrate, stretching the first substrate and transferring the grafts from the first substrate to at least a second substrate for application in a patient container location.
    公开号:BR112013002642B1
    申请号:R112013002642-1
    申请日:2011-08-05
    公开日:2021-02-02
    发明作者:Denis LaBombard；Josh M. Tolkoff；Sameer Ahmed Sabir；Andrew Ziegler
    申请人:3M Innovative Properties Company；
    IPC主号:
    专利说明:

    The present applications claim the benefit and priority of the non-provisional application U.S. serial number 12 / 851,621, filed on August 6, 2010, the content of which is incorporated by reference in this document in its entirety. FIELD OF THE INVENTION
    The present invention generally relates to methods of preparing a skin graft. BACKGROUND
    The skin is the largest organ in the human body, representing approximately 16% of a person's total body weight. Due to the fact that it interacts with the environment, the skin has an important function in the defense of the body, which acts as an anatomical barrier of pathogens and other environmental substances. The skin also provides a semi-permeable barrier that prevents excessive fluid loss while ensuring that essential nutrients are not washed out of the body. Other functions of the skin include isolation, temperature regulation and sensation. Skin tissue can be subjected to many forms of damage, which include burns, trauma, illness and depigmentation (for example, vitiligo).
    Skin grafts are often used to repair such damage to the skin. Skin graft application is a surgical procedure in which a section of the skin is removed from an area of a person's body (autograft), removed from another human source (allograft) or removed from another animal (xenograft), and transplanted in a patient's recipient site, such as a wound site. As with any surgical procedure, applying a skin graft includes certain risks. Complications can include: graft failure; rejection of the skin graft; infections in recipient or donor sites; or leakage of fluid and blood from donor sites of autograft as they heal. Some of these complications (for example, graft failure and skin graft rejection) can be mitigated by using an autograft instead of an allograft or xenograft.
    A problem encountered when using an autograft is that the skin is taken from another area of a person's body to produce the graft, which results in the generation of injury and trauma at the donor site. Generally, the size of the graft is correlated with the size of the recipient site, and thus a large recipient site requires the removal of a large section of skin from a donor site. As the size of the section of skin removed from the donor site increases, so does the likelihood that the donor site will not heal properly, which requires additional intervention and treatment. Additionally, as the size of the section of skin removed from the donor site increases, so does the possibility of infection. There is also an increased healing time associated with the removal of larger sections of hair, as a larger wound is produced.
    To solve these problems, techniques have been developed • 25, which allow the expansion of a skin graft so that a collected graft can treat a recipient site that is larger than a donor site. Such methods involve expanding a graft collected on a substrate and applying the expanded substrate that has the graft expanded to a container location. A problem associated with such techniques is that keeping the substrate used for graft expansion in a stretched configuration results in tension in the substrate, which is not ideal, since such tension negatively affects the interaction of the graft and the recipient site. In addition, the stretched substrate may not retain the same properties as the substrate's non-stretched configuration, that is, technological characteristics such as physical, environmental and performance characteristics could be affected by the stretching of the substrate.
    There is an unmet need for skin graft application methods and devices. SUMMARY
    The present invention generally relates to methods for preparing a skin graft that involves transferring a graft from a first stretched substrate to at least one other substrate. By transferring an expanded graft from a first stretched substrate to at least one other substrate, the methods of the invention minimize the manipulation and tension of the substrate that holds the graft in the container location, while still allowing the repair of a container location that it is larger than a donor site from which the graft is obtained. In certain embodiments, the methods of the invention involve collecting a single graft or a plurality of skin grafts from an individual, applying the graft (s) to a first substrate, stretching or expanding the first substrate, and transferring the graft (s) from the first substrate to at least one other substrate to • 25 apply to a recipient site. The methods of the invention minimize the generation of injury and trauma at a donor site, provide treatment for a recipient site that is larger than a donor site, and minimize the manipulation and tension of a medical dressing that attaches a graft to a recipient site.
    In certain embodiments, the methods of the invention make it possible to prepare a skin graft for transfer to a recipient site without cultivating the graft or applying biological products to the graft. Instead, certain methods of the invention use mechanical techniques for preparing a skin graft, for example, air pressure to stretch the substrate, which thereby expands the grafts.
    In certain embodiments, the methods of the invention further include ensuring that the orientation of the skin grafts is maintained during the transfer of the grafts from the first substrate to the second substrate. Graft orientation can affect graft rejection.
    The collection of skin grafts can occur by any method known in the art. In certain embodiments, collecting involves raising a plurality of bubbles, and cutting the bubbles to obtain a plurality of skin grafts. In certain embodiments, raising a plurality of bubbles involves applying heat, vacuum pressure, or a combination thereof. In certain embodiments, the bubble may be a fluid-filled bubble (for example, a suction bubble). In other modalities, the blister is not filled with fluid, that is, the raised skin has only air inside. Any type of raised bubble (filled with fluid or not filled with fluid) can be used with the methods of the invention.
    The methods of the invention are used to prepare any type of skin graft, such as an epidermal skin graft, a partial thickness graft, or a full thickness graft. In particular embodiments, the methods of the invention are used to prepare skin grafts that include only or, substantially only, the epidermal layer of the skin. The methods of the invention can be used for autografts, allografts, or xenografts. In 30 preferred modalities, the grafts are autografts.
    In certain embodiments, the methods of the invention involve transferring the graft material from a first substrate to at least one additional substrate for application in a container location. In certain embodiments, more than one transfer of the grafts is performed, such as at least two transfers, at least three transfers, at least four transfers, 5 or at least five transfers. By transferring the micrografts from the first stretched substrate to at least one other substrate, there is a minimization of manipulation and tension of the substrate that attaches the graft to the recipient site. The substrates can be of the same 10 materials, or different. In certain embodiments, the substrates are medical dressings. In other embodiments, at least one of the substrates includes a biological or chemical substance, such as an antibiotic or growth factor.
    The methods of the invention are used to prepare the skin grafts for any recipient site of the damaged skin. Exemplary types of skin damage include burns (for example, thermal or chemical), infections, injuries or depigmentation. In particular embodiments, the recipient site is an area of depigmented skin that has been prepared to receive a skin graft. BRIEF DESCRIPTION OF THE DRAWINGS
    Figure 1 is a drawing showing the anatomy of the skin.
    Panels A to C in Figure 2 are schematic that • show a device for generating and collecting a plurality of micro-grafts. Panel A provides an exploded view of the device. The panel B provides a top view of the assembled device. Panel C provides a side view of the assembled device.
    Figure 3 provides a schematic of an exemplary process for preparing a skin graft according to the methods of the invention. Panel A shows an epidermal blister excised on a sterile cutting surface with a sterile cutting tool above. Panel B shows the cutting tool when cutting the epidermal bubble to generate an array of micrografts. Panel C shows the arrangement of micrografts that was produced by the cutting tool on a first substrate. Panel D shows the first substrate placed in an expansion device. A second substrate is placed on the mounting cover above. Panel E shows the expansion process. As the first substrate expands, the micrografts move away. Panel F shows that, as the first substrate is flattened against the mounting cover, the micrografts are transferred to the second substrate. Panel G shows the expansion process completed, and that the micrografts were transferred to the second substrate. Panel H shows the removal of the mounting cover that has the second substrate and the expanded micro-grafts from the expansion device. Panel I shows the removal of the second substrate that has the micrografts expanded from the expansion device mounting cover.
    Panels A and B of Figure 4 are drawings showing a device of the invention for raising a suction bubble.
    Panels A to D of Figure 5 show different devices of the invention for raising a suction bubble.
    Figure 6 is a process diagram showing the steps for treating vitiligo using the methods of the invention. DETAILED DESCRIPTION
    The skin consists of 2 layers. The outer layer, or epidermis, is derived from ectoderm, and the thicker inner layer, or dermis, is derived from mesoderm. The epidermis constitutes about 5% of the skin, and the remaining 95% is the dermis. Figure 1 provides a diagram showing the anatomy of the skin. The skin varies in thickness, depending on the anatomical location, sex, and age of the individual. The epidermis, the outermost of the two layers, is a stratified squamous epithelium that consists mainly of melanocytes and 5 keratinocytes in progressive stages of differentiation from the deepest to the most superficial layers. The epidermis has no blood vessels; thus, it must receive nutrients by diffusion from the underlying dermis through the basement membrane, which separates the 2 layers.
    The dermis is a more complex structure. It consists of 2 layers, the most superficial papillary dermis and the deepest reticular dermis. The papillary dermis is thinner, which includes loose connective tissue that contains capillaries, elastic fibers, reticular fibers, and some collagen. The reticular dermis includes a thicker layer of dense connective tissue that contains larger blood vessels, closely intertwined elastic fibers, and branched and coarse collagen fibers arranged in layers parallel to the surface. The reticular layer also contains fibroblasts, 20 mast cells, nerve endings, lymphatics and some epidermal appendages. A fundamental gel-like substance that surrounds the components of the dermis is composed of mucopolysaccharides (mainly hyaluronic acid), chondroitin sulfates, and glycoproteins.
    In a graft, the characteristics of the donor site are most likely maintained after graft application in a recipient site as a function of the thickness of the graft's dermal component. However, thicker grafts require more favorable conditions for survival 30 due to the requirement for increased revascularization. It has been found, however, that a substantially epidermal graft, according to the invention, is more likely to adapt to the characteristics of the recipient site.
    The present invention provides methods and devices for preparing and using skin grafts. In certain embodiments, the invention relates to preparing a skin graft to transfer to a recipient site without cultivating the graft or applying biological products to the graft.
    In certain embodiments, the methods of the invention involve collecting a plurality of skin grafts from an individual, applying the grafts to a first substrate, stretching the first substrate, and transferring the 10 grafts from the first substrate to a second substrate for the application in a patient's container location.
    The collection of skin grafts can be achieved by any technique known in the field, and the technique employed will depend on the type of graft required (for example, epidermal graft, partial thickness graft, or full thickness graft). An epidermal graft refers to a graft that consists of substantially epidermal skin and does not include any substantial portion of the dermal layer.
    A partial-thickness graft refers to a graft that includes sheets of superficial (epithelial) and some deep (dermal) layers of skin. A full-thickness graft refers to a graft that includes all layers of the skin, which includes blood vessels.
    In certain embodiments, a device, as shown in Panels A to C in Figure 2, is used to obtain the plurality of skin grafts. Device 200 includes a frame 201 and a cover 202. The bottom plate 203 is fitted to the frame, a cutter grid plate 204, a cutter plate 205, and a top plate 206. The bottom plate 203, the the cutter plate 205, and the top plate 206, each includes a hole arrangement 211. Once assembled, the hole arrangement 211 of each of the plates 203, 205, and 206 is aligned. The size of the holes in the hole arrangement will depend on the size of the graft required, with larger holes used to produce larger grafts. A first substrate 207 interacts with the top plate 206 and will receive the collected grafts 5.
    The device 200 also includes an actuation block 208, actuation bar 209, and actuation block guides 210, The actuation components 208, 209, and 210 control the movement of the cutter plate 205. The frame 201 includes a limiter 10 vacuum 212, and cover 202 includes a suction hole burr 213. Once assembled, frame 201 and cover 220 are arranged in such a way that vacuum limiter 212 and suction hole burr 213 are aligned each other (panel B of Figure 1). A vacuum source is then connected to the device 200, such that negative pressure can be generated within the device. The device 200 can be secured together by screws with clamp 214. The device 200 can also include a heating element.
    To produce and collect the plurality of skin grafts, device 200 is placed in a donor site, such as an inner part of a patient's thigh. The vacuum source is turned on, which produces negative pressure inside device 200. Negative pressure causes the skin to be pulled towards the cover 202, with a plurality of different portions of skin being pulled through each arrangement of hole 211 in each of the plates 203, 205, and 206. Such action results in the generation of many microbubbles. The bubbles may or may not be filled with fluid. Any type of high bubble can be used with the methods of the invention.
    Once the microbubbles are raised, actuating components 208, 209, and 210 are engaged to move the cutter plate 205. The movement of the cutter plate 205 interrupts the alignment of the hole arrangement 211 in each of the plates 203, 205, and 206, and results in the cutting of the microbubbles. The cut microbubbles are captured on the first substrate 207, which is above the top plate 206. In this manner, a spaced array of micrografts was provided.
    The amount of negative pressure applied, the amount of time the vacuum is maintained, and / or the depth of the holes above the cutting surface (plate 206) determines which type of graft will be collected, for example, epidermal graft, 10 graft from partial thickness, or full thickness graft.
    Generally, each micrograft will have a lateral dimension less than about 2 mm, for example, from 100 to 2,000 microns.
    Once the grafts have been collected and applied to the first substrate, the first substrate is stretched or expanded, which results in an increased distance between the individual micrografts, which keeps them apart and results in the production of a skin graft that can repair a recipient site that is larger than the donor site from which the grafts were obtained. In the methods of the invention, the 20 individual grafts themselves are not expanded, that is, the graft tissue is not stretched; instead, stretching the substrate increases the space or distance between each individual micrograft. The methods of the invention thus minimize tissue manipulation. -25 The purpose of such processing is to use tissue from a donor site to cover an area of the wound that is larger than the donor site. The stretching of the substrate can be done manually, that is, by hand, or it can be done with the help of a machine. The stretch can be substantially uniform in all directions or can be influenced in a certain direction. In a particular embodiment, the stretch is substantially uniform in all directions. The stretching of the substrate can be carried out mechanically or achieved by applying a pressurized gas or fluid. In certain embodiments, air pressure is used to expand the first substrate. Exemplary methods and devices are described in Korman (U.S.5 5.914.264), the content of which is incorporated by reference in this document in its entirety.
    Any minimum distance can be provided between the micrografts after stretching the first substrate. The amount of the stretch can be large enough to provide a sufficiently large area of substrate containing the micrografts to allow a larger area of damaged tissue to be repaired with the use of a particular amount of tissue from the graft removed from the donor site, that is, the area of the first stretched substrate that contains the 15 separate micrografts can be much larger than the total area of the donor site. For example, the distance between adjacent micrografts on the first drawn substrate can be greater than about 0.5 mm, although small separation distances can also be used. For the repigmentation of skin tissue, an amount of stretch can be applied to the first substrate in such a way that the distance between adjacent micro-grafts is less than about 4 mm, due to the fact that it is known that melanocytes, when grafted in a depigmented region, can migrate up to * 25 about 2 mm from each micrograft to repigment the regions between the micrografts. This average distance may be greater if keratinocyte migration is involved with the treated tissue because keratinocytes typically migrate greater distances compared to 30 melanocytes.
    The ratio of the wound area to the donor site area is referred to as the expansion ratio. A greater expansion ratio is desirable to minimize trauma to the donor site, and to assist patients who have only a small amount of tissue available for graft application purposes. The amount of area expansion, for example, the ratio of an area of damaged tissue that can be repaired, compared to an area of graft tissue removed from a donor site, can be 50 0x or more. In particular embodiments, the expansion area can be from about 10x to about 100x, which provides a more uniform coverage and / or repigmentation of the container location. To repair burns or ulcerated tissue, the micro-grafts may be smaller than those used to repair other types of damaged tissue, and thus the distances between the adjacent micro-grafts may be greater after stretching the first substrate. In such an exemplary application, an area expansion of about 100X or more can be used.
    In other embodiments and depending on the material of the first substrate, keeping the first substrate in a stretched configuration can result in tension on the substrate 20 that is not ideal. In addition, the first stretched substrate may not retain the same properties as the unstretched configuration of the first substrate, that is, technological characteristics, such as physical, environmental and performance characteristics, could be affected by the stretch of the substrate. Additionally, the methods used to keep the substrate in its stretched condition can be physically uncomfortable and prevent the uniform application of the micrografts to uneven skin surfaces. Thus, in certain embodiments, once the first substrate is stretched, the spaced micrografts are transferred to a second substrate. By transferring the micrografts to a second substrate, the methods of the invention minimize the manipulation and tension of the substrate that holds the graft to the recipient site.
    After stretching the first substrate, the second substrate is brought into contact with the grafts on the first stretched substrate. The transfer is facilitated by the second substrate, which has greater affinity or more adhesive strength in the direction of the micrografts than the first substrate. In certain embodiments, the second substrate is coated with a hydrocolloid gel. In other embodiments, the first substrate is moistened with a fluid such as water or saline.
    Moistening the micrografts and the first substrate provides lubrication between the grafts and the first substrate, and allows easy transfer of the grafts from the first substrate to the second substrate. After moistening the first substrate, the grafts have a greater affinity for the second substrate than the first substrate. The first moistened substrate is then removed from the second substrate, and the grafts remain attached to the second substrate. The distance between the micro grafts is maintained after transferring the micro grafts from the first stretched substrate to the second substrate.
    The first substrate can be made from any material that is biocompatible and capable of being stretched by applying a moderate tensile force. The second substrate can be made from any material known in the art that is compatible with biological tissue. The second substrate may also be able to be stretched by applying a moderate tensile force. Exemplary materials for the first and / or second substrates include medical dressings, such as TEGADERM (medical dressing, commercially available from 3M, St. Paul, MN) or DUODERM (medical dressing, commercially available from 3M, St. Paul, MN ). The first and / or second substrates can also be gas permeable.
    In certain embodiments, the first and / or the second substrate includes an adhesive on one side that facilitates the attachment of the grafts to the substrates. The substrate material can have intrinsic adhesive properties, or alternatively, one side of the substrate can be treated with an adhesive material, for example, an adhesive sprinkler such as LEUKOSPRAY (Beiersdoerf GmbH, Germany). In certain embodiments, the first and second substrates are made of the same material. In other embodiments, the first and second substrates are made of 10 different materials. In certain embodiments, the materials of the first and second substrates are chosen to facilitate the transfer of the micrografts from the first substrate to the second substrate. For example, in certain embodiments, the material chosen for the first substrate 15 has a weaker adhesive than the material chosen for the second substrate.
    In certain embodiments, the material of the first substrate is a deformable, non-resilient material. A deformable non-resilient material refers to a material 20 that can be manipulated, for example, stretched or expanded, from a first configuration to a second configuration, and once in the second configuration, there is no residual stress on the substrate. Such materials can be stretched into an expanded configuration without returning to their original size, and thus, in these embodiments, it is not necessary to transfer the micrografts from a first substrate to a second substrate. Instead, the first expanded substrate that includes the micrografts is applied in a container location.
    Such deformable non-resilient materials tend to be soft, rigid, or both soft and rigid. Softness is measured on the durometer scale. An example of such a material is a soft polyurethane. A soft polyurethane is produced as follows. Polyurethanes in general usually have soft, hard segments. The hard segments are due to the presence of phenyl bridges. In a soft polyurethane, the phenyl bridge is replaced by an aliphatic one, which is more flexible, as its carbon ring 6 has no double bonds.
    Therefore, all segments are soft. On the Durometer Scale, a soft polyethylene is rated about Shore 8 0A. Other materials suitable for use with the methods of the invention include low density polyethylene, linear low density polyethylene, polyester copolymers, polyamide copolymers, and certain silicones. In these embodiments, the first expanded substrate that has the micrografts retains its extended position without any residual stress, and the first expanded substrate is applied in a container location.
    Finally, the grafts and substrate are applied to a container at a patient's site. Before applying the grafts to the recipient site, the site is prepared to receive the grafts using any technique known in the field. The necrotic, fibrotic or avascular tissue must be removed. The technique used to prepare the site will depend on the damage to the recipient site. For example, the epidermal tissue, if present at the recipient site, can be removed to prepare the area to receive the micrografts.
    Burnt or ulcerated sites may not require removal of epidermal tissue, although some site cleansing or other site preparation may be performed. The wounds must be described and then allowed to be pelleted for several days before the graft is applied. Most of the granulation tissue must be removed as it has a tendency to harbor bacteria. The application of silver sulfadiazine to the wound for 10 days before the graft application reduces the bacterial count by a lot.
    The size of the area at the container location can be about the same size as the area of the first stretched substrate that has micrografts adhered to it. This size will generally be larger than the tissue area of the original graft that was removed from the donor site to form the micrografts. Damaged or unpigmented skin may be subjected to dermabrasion with sandpaper or other rough material. Alternatively, the epidermal tissue can be removed from the recipient site by forming one or more bubbles over the area to be treated, for example, a suction bubble or a freezing bubble, and the raised epidermal bubble tissue can then be removed. removed by cutting or other procedure.
    The substrate that has the micrografts can be placed over the area to be treated to form a dressing.
    A portion of the substrate that has the micrografts can be positioned over the area to be repaired, for example, the area from which the epidermal tissue has been scraped or removed for repigmentation. The substrate can be fixed in place 20 over the treatment area, for example, using tape or the like. The substrate can be removed after sufficient time has elapsed to allow attachment and growth of the micrografts in the treatment area, for example, from several days to a few weeks.
    Another aspect of the invention provides to collect a single graft from a donor site, such as an epidermal graft, to generate an array of micro-grafts from the single graft, to place the graft on a first substrate, to expand a distance between the micro-grafts in a first 30 substrate, transfer the micrografts from the first substrate to a second substrate, and apply the micrografts to a recipient location. Figure 3 provides a schematic of an exemplary process for preparing a skin graft according to methods of the invention.
    The methods of the invention involve collecting a single graft from a donor site, such as an epidermal graft. The collection of skin grafts can be achieved by any technique known in the field, and the technique employed will depend on the type of graft required (for example, epidermal graft, partial thickness graft, or full thickness graft). In certain modalities, collecting a skin graft involves raising a blister and cutting the blister.
    In certain embodiments, the bubble may be a fluid-filled bubble (for example, a suction bubble). In other embodiments, the bubble is not filled with fluid. Any type of raised bubble can be used with the methods of the invention.
    In certain embodiments, suction bubble grafting is used. The application of suction bubble grafting involves raising a bubble, and then staining the raised bubble off. An exemplary suction bubble grafting technique is shown in Awad, (Dermatol Surg, 34 (9): 20 1,186 to 1,193, 2008), the content of which is incorporated by reference in this document in its entirety. This article also shows several devices used to form suction bubbles. A suction bubble device is also described in Kennedy et al. (U.S. 6,071,247), the content of "25 which is incorporated by reference in this document in its entirety. An exemplary device is commercially available from Electronic Diversities (Finksburg, MD).
    A device for raising a suction bubble is typically operated by using suction chambers that are attached to a patient's skin. An instrument typically contains a power source, a vacuum pump, temperature controls and all controls related to operating multiple suction chambers. The suction chambers are connected to the console by a flexible connection. Each of the chambers is controlled by a pre-set temperature control to provide an ideal skin heating temperature. Both chambers share a common adjustable vacuum source 5 that affects all chambers in the same way.
    Bubble formation is achieved by attaching the suction bubble device to a patient's skin. Typically, hook and loop fastening straps are used to hold the device in place. The 10-chamber heating system provides a slight heating of an orifice plate of the device, which is in direct contact with the surface of a patient's skin. The application of moderate negative pressure from the instrument console, inside the chamber, causes the patients' skin to be gently attracted through the opening (s) in the orifice plate. The results are typically suction bubbles, approximately the size of the opening (s) in the orifice plate. The area of the bubble and skin is generally undamaged, and patient discomfort is minimal.
    The negative pressure chamber is made of mostly plastic components, with two removable screw caps. The top cover is fitted with clear vision lenses so that the actual bubble formation can be observed. The opposite end of the chamber is ’25 fitted with a removable orifice plate that is placed on a patient’s skin. Since this plate is simply threaded at the end of the chamber, multiple plates with different opening patterns can be interchanged as desired.
    The interior of the device is heated and illuminated by an arrangement of low-voltage incandescent lamps. This lamp arrangement is controlled from the instrument's console temperature controller, using cycles as needed, to maintain the set point temperature. The heat from these lamps is radiated and conducted to the orifice plate, which then heats a patient's skin. The chamber is connected to the console by means of a low voltage electrical system and a composite vacuum. Quick connections are used for the electrical and vacuum system to facilitate removal and storage.
    The Negative Pressure Instrument console is an autonomous fan-cooled unit which is designed to operate at 120 VAC 60 Hz power. The vacuum is supplied by an industrial grade diaphragm vacuum pump, capable of a typical vacuum of 20 in Hg (0 to 65 kPa) at 0 m3 / minute (0 CFM). An analog controller that is pre-set at 40 ° C provides temperature control for 15 each suction chamber. This provides precise control of the orifice plate temperature. The instrument console has internal settings that allow the user to recalibrate the temperature setting if desired. Other temperatures can be pre-set if desired. The front panel 20 includes a vacuum trap and vacuum gauge adjustment to regulate the vacuum in both chambers. The front panel of the console also contains the connections for the camera mounts.
    Since the suction bubble is elevated, it is ’25 cut by methods known in the art (see, for example, Awad, Dermatol Surg, 34 (9): 1,186 to 1,193, 2008), and placed on the first substrate. Once on the first substrate, an array of micrografts is generated from the single graft. Panel A of Figure 3 shows a skin graft excised on a first substrate, with a sterile cutting tool above the graft. In certain embodiments, instead of being applied directly to the first substrate, the cut bubble is placed on a sterile surface, such as a glass slide, and the micrograft arrangement is generated on the sterile surface prior to transfer to the first substrate. In other embodiments, the cut bubble is trapped between two aligned metal screens. The screens are pushed together 5 to cut the bubble in a micrograft arrangement. The micrografts are then pushed out of the screens and deposited on the first substrate using an arrangement of pusher whose size and spacing correspond to the metal screens. In certain modalities, the cut bubble is collected 10 directly between the two screens to generate the micrograft arrangement.
    In other modalities, the cut bubble is collected directly in a molding and shearing or perforating device for the generation of micrografts. Molding and shearing or drilling includes an arrangement of flat-faced piston-like components that fit closely into the openings in a metal mesh / mesh. In this modality, the cut graft is collected in a piston array, and locations between the piston array and the screen / mesh. The screen / mesh is closed over the cut bubble and force is applied to the piston arrangement. The pistons are pushed through the holes in the mesh / mesh, and in the process, portions of fabric are drilled from the mesh / mesh openings and deposited on a substrate, which produces an array of micrografts on a * 25 substrate. Such modalities allow a simultaneous generation of the micrograft arrangement and deposition of the micrograft arrangement on the substrate.
    The array of micrografts can be generated by cutting or using other protocols to form the array of micrografts from the single graft. The cuts can pass partially or completely through the graft tissue. For example, to repigment the skin tissue, the micro-grafts used may have a presence of melanocytes. Consequently, a lateral dimension of such micrografts can be between less than about 1 mm, for example, 200 to 1000 microns. Other exemplary sizes are between 400 and 800 microns. The area of the micrografts can be between about 0.04 mm2 and about 1 mm2. Exemplary sizes can provide micrografts large enough that each micrograft is likely to contain some melanocytes, still small enough to provide a large number of micrografts 10 from a particular piece of graft tissue, which can facilitate a significant degree of expansion at the graft site.
    To treat burns or ulcers, where the presence and proliferation of keratinocytes are important, the 15 micrograft sizes may be smaller. For example, a lateral dimension of micrografts that contains keratinocytes can be between about 50 microns and about 1,000 microns, or between 100 microns and about 800 microns. The area of such micrografts can be between about 0.0025 mm2 and 20 about 1 mm2. The strips of exemplary size provide micrografts large enough to contain viable and undamaged keratinocytes, and small enough to facilitate the repair of a larger area of damaged skin.
    Panel B in Figure 3 shows an exemplary '25 cut tool. The cutting tool can be configured in any way, and this configuration will depend on the size of the micrografts to be produced and the desired arrangement pattern. The cutting tool includes a plurality of adjacent blades. The layout of the slides 30 will depend on the desired pattern for the arrangement of micrografts. The tool shown in panel B of Figure 3 is configured to produce a checkered grid of micrografts (See panel C of Figure 3). The spacing of the blades in the cutting tool will depend on the desired size of the micrografts. For example, the blades can be spaced by about 100 to 2,000 microns, or about 500 to 1000 microns. The cutting tool is pressed at least 5 times on the skin graft on the first substrate to produce the micrograft arrangement (See panels B and C in Figure 3).
    Other exemplary devices for producing a micrograft arrangement include mesh devices. Such 10 mesh devices include rigid and biocompatible material, such as stainless steel. The mesh includes a plurality of openings. The openings are sized to provide an array of micrografts of a desired size, such as side sizes between about 100 microns and about 1,000 to 15 microns or about 300 microns to about 500 microns. Similar to the cutting tool described above, the mesh is pressed at least once on the skin graft to produce the micrograft arrangement.
    Panels D to I of Figure 3 show the remaining 20 steps of the method. Once the micrograft array is on the first substrate, the distance between the micrografts is expanded. The expansion results in the increased distance between the individual micrografts, which separates them and results in the production of a skin graft that can repair a recipient site that is larger than the donor site from which the grafts were obtained. The expansion can be performed as described above. After the expansion of the first substrate, the second substrate is brought into contact with the grafts on the first stretched substrate for the transfer of the micro grafts from the first expanded substrate to the second substrate. The transfer can be carried out as described above. The distance between the micro grafts is maintained after transferring the micro grafts from the first stretched substrate to the second substrate. Once the grafts are transferred to the second substrate, the grafts and substrate are applied to a container at a patient's site. The preparation of the container site and the application of the micrograft arrangement to the prepared container site can be carried out as described above.
    In other embodiments, the transfer to a second substrate is not necessary because the material of the first substrate is a deformable non-resilient material. A deformable non-resilient material refers to a material that can be manipulated, for example, stretched or expanded, from a first configuration to a second configuration, and once in the second configuration, there is no residual stress on the substrate. Such materials can be stretched to an expanded configuration without returning to their original size. Exemplary materials are described above. In these embodiments, the first expanded substrate that has the micrografts retains its extended position 20 without any residual tension, and the first expanded substrate is applied in a container location. The preparation of the recipient site and application of the micrograft arrangement to the prepared recipient site can be carried out as described above.
    In certain respects, the methods of the invention maintain proper skin graft orientation. Epidermal skin includes a stratum corneum layer and a basal layer. The stratum corneum refers to the outermost layer of the epidermis, composed of large, flat, polyhedral envelopes 30 and similar to the plaque filled with keratin, which is made up of dead cells that have migrated from the granular stratum. This layer is composed mainly of dead cells that do not have nuclei. The thickness of the stratum corneum varies according to the amount of protection and / or tightness required by a region of the body. In general, the stratum corneum contains 15 to 20 layers of dead cells, and is between 10 and 40 μm thick.
    The basal layer (or germ layer or basal layer) refers to the deepest layer of the 5 layers of the epidermis. The basal layer is a continuous layer of living cells and can be considered as the stem cells of the epidermis. These cells are undifferentiated and proliferative, 10 that is, they create daughter cells that migrate superficially, which differentiates during migration. Keratinocytes and melanocytes are found in the basal layer.
    For a graft to become integrated in a container location, the graft must be able to receive nutrients.
    Since the cells in the basal layer are living cells, targeting an epidermal graft in such a way that the basal layer interacts with the recipient site allows the graft to receive nutrients, and thus remains viable. In contrast, since the stratum corneum cells are dead cells, 20 orienting an epidermal graft in such a way that the stratum corneum layer interacts with the recipient site prevents the graft from receiving nutrients, which results in the death of the graft tissue. and graft failure. The methods of the invention ensure that during the graft application process, the "basal layer of a graft interacts with a patient's recipient site, which allows the graft to receive nutrients and thus remain viable.
    Certain methods involve collecting an epidermal skin graft, and applying the epidermal skin graft to a recipient site in such a way that the basal layer of the skin graft makes direct contact with the recipient site. Collection can be accomplished by creating a bubble, such as a suction bubble. The suction bubble graft application is described above.
    In one embodiment, a vacuum is used to trap the stratum corneum side of the bubble, which can be released when the bubble is deposited on the cutting surface. In another 5 modalities, after raising the bubble and prior to cutting the bubble, an adhesive side of a substrate is placed in contact with the stratum corneum layer of the raised bubble. Upon counting the bubble, the stratum corneum layer of the graft becomes attached to the substrate, and the basal layer is oriented away from the substrate. Such a technique ensures that the basal layer of the graft is oriented away from the substrate and is thus available for interaction with a patient's recipient site.
    Other methods of the invention involve collecting a skin graft from a donor site, placing the skin graft on a first substrate in such a way that the basal cells of the graft make direct contact with the first substrate, transferring the graft from the first substrate for a second substrate in such a way that the 20 basal cells do not come in direct contact with the second substrate, and apply the second substrate in a container location, collection can be accomplished by creating a bubble, such as a bubble suction. The suction bubble graft application is described above, the bubble is cut and the basal layer * 25 of the graft is connected to an adhesive side of a first substrate. The basal layer of the graft becomes attached to the first substrate and the stratum corneum layer is oriented away from the first substrate, and is available for interaction with a second substrate.
    An adhesive side of a second substrate is brought into contact with the stratum corneum layer of the graft that is adhered to the first substrate. The transfer to the second substrate is achieved as described above. Briefly, in one embodiment, the first substrate is moistened with a fluid such as water or saline. Moistening the graft and the first substrate provides lubrication between the graft and the first substrate and allows easy transfer of the graft from the first substrate to the second substrate. After moistening the first substrate, the graft has a greater affinity for the second substrate than for the first substrate. The first moistened substrate is then removed from the second substrate and the grafts remain attached to the second substrate.
    Upon transfer, the stratum corneum layer of the graft becomes attached to the second substrate, and the basal layer is oriented away from the second substrate. Such a technique ensures that the basal layer of the graft is oriented away from the second substrate and is thus available for interaction with a patient's recipient site.
    Another aspect of the invention provides a device for obtaining a skin graft. The devices of the invention include a hollow body that has a distal configuration 20 configured to be placed on the skin, a mechanism for raising a bubble, and a cutter integrated in the body for cutting the bubble produced in the skin.
    In certain embodiments, a device as shown in panel A of Figure 4 is used to obtain a ‘25 skin graft. The device 400 includes a hollow body 401 and a mechanism for raising a bubble 402. The hollow body 401 includes a distal configuration 403 that is configured to be placed on the skin. Such a distal configuration may include an orifice plate 404. Orifice plate 404 determines the size and shape of the blister or blisters that will be raised. The orifice plate 404 can be of any shape or size and will depend on the bubble or bubbles to be raised. Generally, the diameter or lateral dimension of the bubble can be from about 6 mm to about 12 mm, although larger or less bubble sizes can be used.
    The mechanism for raising a bubble can be a vacuum component, a heating component, or a combination thereof. An exemplificative heating component is a light source. In a particular embodiment, the mechanism 402 is a combination of a vacuum component and a heating component.
    Hollow body 401 further includes a cutter 405, 10 which includes cutter plate 406 and a hole 407 (panel B of Figure 4). The device 400 also includes an actuation block 408, an actuation bar 409, and actuation block guides 410. Actuation components 408, 409, and 410 control the movement of the cutter 405.
    Bubble formation is achieved by attaching the distal configuration 403 of the hollow body 401 to a patient's donor site, such as an internal part of a patient's thigh. Hook and loop fastening straps can be used to hold the device in place. The heating component of the bubble lift mechanism 402 provides a slight heating of the orifice plate 404, which is in direct contact with the surface of a patient's skin. Applying moderate negative pressure to the interior of the chamber from the vacuum component of the '25 bubble lift 402 mechanism results in a patient's skin being gently attracted through the opening in the orifice plate 404. The result is a bubble or bubbles, approximately the size of the opening in the orifice plate 404. A produced bubble may be filled with fluid or may not contain any fluid, that is, a bubble that has air inside it. The area of the blister and skin is generally undamaged and the patient's discomfort is minimal.
    The cutter 40 5 is positioned in the hollow body 401 in such a way that, by raising the bubble, at least a portion of the bubble protrudes through hole 407 in the cutter plate 406. The actuating components 408, 409, and 410 are engaged to move the cutter plate 406. The movement of the cutter plate 406 interrupts the alignment of the hole 407 with the other components of the device 400, and results in the cutting of the raised bubble.
    Panel A of Figure 5 shows a device 500 which further includes a chamber 511 for capturing the cut bubble 10. Chamber 511 is positioned in hollow body 501 and above cutter 505. Chamber 511 can be removable from device 500. Chamber 511 can include multiple configurations. For example, chamber 511 may include a retractable bottom. The bottom is in an open position when chamber 511 is inserted into hollow body 501. In the open position, chamber 511 is capable of receiving the cut bubble. Once the cut bubble is in chamber 511, the bottom of the chamber is closed, which captures the bubble in chamber 511. Chamber 511 can then be removed from device 500.
    In another embodiment, chamber 511 includes a substrate 512 (panel C of Figure 5). In this embodiment, the device 500 is configured in such a way that the substrate 512 is positioned in the chamber 511, so that upon lifting the bubble, a portion of the bubble comes into contact with the substrate '25 and becomes attached to the substrate. The cutter 505 then cuts the bubble, and the cut bubble becomes attached to substrate 512 in chamber 511. Chamber 511 is then removed from device 500, and substrate 512 can be removed from chamber 511. In other devices, a vacuum, instead of a substrate, 30 is used to trap the cut bubble inside the chamber.
    In certain embodiments, the device 500 does not use a camera, instead, a substrate 512 is directly integrated with the device 500 in order to capture the cut bubble (panel D of Figure 5). Once captured, substrate 512 that has a cut bubble attached can be removed from device 500.
    The methods of the invention can be used to prepare a skin graft to repair numerous different types of skin damage. For example, the methods of the invention can be used to prepare grafts to treat burns (for example, both thermal and chemical burns), blistering, dermatological conditions (for example, epidermolysis bullosa or pyoderma gangrenosum), therapy ulcers by radiation, diabetic ulcers, ischemic ulcers, trophic ulcers, trauma, or depigmentation (eg vitiligo).
    In particular embodiments, the methods of the invention are used to prepare a skin graft (s) to treat vitiligo. Vitiligo is a chronic disorder that causes depigmentation of skin blemishes. This occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. Although the 20 spots are initially small, they often widen and change the shape. When skin lesions occur, they are more prominent on the face, hands and wrists. Some lesions have hyperpigmentation around the edges. Depigmentation is particularly noticeable around ’25 holes in the body, such as the mouth, eyes, nostrils, genitals and navel.
    Vitiligo is generally classified into two categories, non-segmental vitiligo and segmental vitiligo. In non-segmented vitiligo (NSV), there is usually some form of symmetry in the location of the depigmentation spots. New spots also appear over time and can be spread over large portions of the body or located in a particular area. Vitiligo where little pigmented skin remains is referred to as vitiligo universalis. Non-segmental vitiligo can appear at any age, unlike segmental vitiligo, which is much more prevalent in adolescence.
    Segmental vitiligo (SV) differs in appearance, etiology and predominance of associated diseases. Its treatment is different from that of non-segmented vitiligo. It tends to affect the areas of the skin that are associated with dorsal roots of the spine. It spreads much faster than non-segmented vitiligo and, without treatment, is much more stable / static in course and is not associated with autoimmune diseases.
    Figure 6 is a process diagram showing the steps for treating vitiligo using the methods of the invention. To treat vitiligo, an autograft is provided to the depigmented skin site. The graft includes melanocytes, and thus, upon acceptance of the graft by the recipient site, the graft will produce pigmented skin at the recipient site. As shown in Figure 6, a donor site of pigmented skin is cleaned aseptically before a skin graft is collected. Standard methods are used to clean the donor site. A typical donor site is an inner thigh, but any area of pigmented skin can be used.
    After cleaning, a grafted skin is collected by ‘25 raising a bubble, such as a suction bubble, and cutting the bubble. The devices described in this document can be used to lift and cut the bubble. Alternatively, commercially available bubble devices can be used. Once cut, the epidermal blister is placed in a sterile cutting device and divided into a micrograft arrangement. The micrografts are transferred to a first substrate for expansion. The transfer can take place as described above. In certain embodiments, the cut bubble is placed directly on the first substrate and the micrograft arrangement is generated directly on the first substrate. The micrografts are expanded as the surface area of the first substrate is expanded. The 5 expanded micrografts are transferred to a second substrate. Figure 6 shows an exemplary substrate, TEGADERM (medical dressing, commercially available from 3M, St. Paul, MN). However, any biocompatible substrate can be used.
    The depigmented skin area (ie, the recipient site), is prepared through aseptic cleaning and dermabrasion. The second substrate that includes the expanded micro-grafts is applied to the recipient site submitted to the dermabrasion. The donor site and the recipient site are covered with a dressing and wound care is provided. INCORPORATION BY REFERENCE
    References and citations to other documents, such as patents, patent applications, patent publications, diaries, books, newspapers, network content, were made by 20 of this entire disclosure. All such documents are hereby incorporated by reference in their entirety for all purposes. EQUIVALENTS
    The invention can be realized in other specific ways * 25 without deviating from the spirit or the essential characteristics of the same. Therefore, the aforementioned modalities should be considered as illustrative in all senses, rather than limiting the invention described in this document. The scope of the invention is therefore indicated by the appended claims rather than the aforementioned description, and all changes that are covered by the meaning and breadth of equivalence of the claims are therefore intended to be covered by it.
    权利要求:
    Claims (10)
    [0001]
    1. DEVICE FOR OBTAINING A SKIN GRAFT, characterized by comprising: a hollow body (401, 501), the hollow body (401, 501) having a distal end (403, 503) configured for placement on the skin; an orifice plate (404, 504) mounted on the distal end (403, 503) of the hollow body (401, 501) and with a plurality of openings through which the skin can be raised; a cutter (405, 505) integrated within the hollow body (401, 501) and being movable, the cutter (405, 505) comprising a cutter plate (406, 506) and a plurality of openings aligned with the plurality of plate openings orifice (404, 504); and a mechanism (402, 502) for raising at least one bubble through said plurality of openings, the bubble raising mechanism (402, 502) being one of: a source of vacuum to create suction, a source of heat to generate heat, and a combination of them.
    [0002]
    2. DEVICE, according to claim 1, characterized in that it further comprises a chamber (511), positioned in the hollow body and above the cutter.
    [0003]
    DEVICE, according to claim 2, characterized in that the heat source comprises at least one light source configured to heat the orifice plate (504) with radioactive energy.
    [0004]
    DEVICE, according to any one of claims 1 to 3, characterized in that it further comprises an actuator for moving the cutter plate (406, 506) to interrupt the alignment of the holes and cut the raised bubble.
    [0005]
    DEVICE, according to claim 2, characterized in that it further comprises a substrate (512) inside the chamber (511).
    [0006]
    6. DEVICE, according to claim 5, characterized in that the device is configured in such a way that, when cutting the bubble, the cut portion of skin is attached to the substrate (512).
    [0007]
    7. DEVICE according to claim 6, characterized in that the substrate (512) comprises an adhesive.
    [0008]
    DEVICE, according to claim 6, characterized in that the substrate (512) comprises a dressing.
    [0009]
    DEVICE, according to claim 4, characterized in that the substrate (512) is capable of being stretched.
    [0010]
    10. DEVICE, according to claim 1, characterized in that the hollow body (401, 501) is further adapted to be coupled to a vacuum source, so that a negative pressure can be generated inside the device when the hollow body (401 , 501) is placed on the skin of a donor to raise at least one blister.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112013002642B1|2021-02-02|device to obtain a skin graft
    US10603072B2|2020-03-31|Methods for preparing a skin graft without culturing or use of biologics
    US11083487B2|2021-08-10|Methods for preparing a skin graft
    US9414856B2|2016-08-16|Devices for generating and transferring micrografts and methods of use thereof
    JP5843295B2|2016-01-13|Skin graft collection device
    AU2017279616A1|2018-01-18|Methods of manufacturing devices for generating skin grafts
    RU2587906C2|2016-06-27|Methods of preparing a skin graft
    同族专利:
    公开号 | 公开日
    CN105997199B|2019-08-02|
    CN103402446B|2016-08-03|
    AU2018256579A1|2018-11-22|
    AU2016204210B2|2018-08-02|
    JP5878173B2|2016-03-08|
    US8617181B2|2013-12-31|
    CN103402446A|2013-11-20|
    JP2013543387A|2013-12-05|
    EP2600779A4|2014-05-28|
    WO2012019094A2|2012-02-09|
    AU2016204210A1|2016-07-21|
    CA2807411A1|2012-02-09|
    BR112013002642A2|2016-06-07|
    KR101880313B1|2018-07-19|
    US20120035618A1|2012-02-09|
    SG187216A1|2013-02-28|
    KR20130094314A|2013-08-23|
    CN105997199A|2016-10-12|
    AU2011285592A1|2013-02-14|
    EP2600779A2|2013-06-12|
    EP2600779B1|2016-09-21|
    KR20180085048A|2018-07-25|
    CA2807411C|2019-09-03|
    WO2012019094A3|2013-08-15|
    RU2013107157A|2014-09-20|
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    KR20170059026A|2015-11-19|2017-05-30|한국전자통신연구원|Skin expansion apparatus and method of skin expantion using the same|
    WO2017143229A1|2016-02-19|2017-08-24|Kci Licensing, Inc.|Transfected epidermal grafts and methods of making the same|
    CN106108984B|2016-09-09|2018-09-11|福州大学|A kind of personalized negative pressure sucker preparation method of leucoderma skin-grafting|
    US11065031B2|2016-10-28|2021-07-20|The General Hospital Corporation|Systems and methods for assembling tissue grafts|
    US20190275177A1|2016-11-29|2019-09-12|Kci Licensing, Inc.|Identification and visualization of micrografts for monitoring epithelialization|
    US11193858B2|2018-05-01|2021-12-07|Community Blood Center|Tissue planing assemblies and methods|
    法律状态:
    2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-10-01| B25A| Requested transfer of rights approved|Owner name: KINETIC CONCEPTS, INC. (US) |
    2019-10-15| B25A| Requested transfer of rights approved|Owner name: KCI HOLDING COMPANY, INC. (US) |
    2019-10-29| B25A| Requested transfer of rights approved|Owner name: KCI LICENSING, INC. (US) |
    2019-12-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-08-04| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2020-11-24| B09A| Decision: intention to grant|
    2021-01-26| B25A| Requested transfer of rights approved|Owner name: 3M INNOVATIVE PROPERTIES COMPANY (US) |
    2021-02-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/08/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US12/851,621|2010-08-06|
    US12/851,621|US8617181B2|2010-08-06|2010-08-06|Methods for preparing a skin graft|
    PCT/US2011/046737|WO2012019094A2|2010-08-06|2011-08-05|Methods for preparing a skin graft|
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