Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Waste or feces
Reexamination Certificate
2000-12-28
2002-12-31
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Waste or feces
C424S548000, C424S422000, C424S423000, C424S426000, C424S443000, C424S444000, C424S093700, C514S002600, C514S021800, C514S953000, C623S011110, C623S015120
Reexamination Certificate
active
06500464
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to biologically active wound dressings and more particularly to biologically active bilayered constructs useful as a wound dressing, as a skin equivalents or as skin substitutes. It relates also to the manufacture of such constructs in an economical, large scale, process.
BACKGROUND
Burn wounds, in general, are exceedingly painful and difficult to heal. Burns can be partial thickness burns, which destroy some, but not all of the epidermis and may destroy a portion of the dermis. Some partial thickness burn wounds will heal if treated properly with bioactive dressings, which can protect the wound and promote rapid epithelialization with minimal inflammation and scar formation. Full thickness burns, on the other hand, destroy all of the epidermis, the hair follicles, sweat glands and sebaceous glands and frequently much of the dermis. Full thickness burns ultimately require skin grafting.
Several types of skin grafts have been used to cover and repair damaged skin. Autografts are the most effective skin grafts and are tissue transplants derived from the injured individual, usually in the form of split-thickness skin grafts. A split-thickness skin graft consists of skin removed from a donor site and placed on a full thickness wound, after debridement of the dead tissue, to close and heal the wound. Split-thickness skin grafts, comprise the epidermis, part of the epidermal adnexal structures and part of the dermis. Typically, a split-thickness skin graft is meshed (short, alternating incisions) which allows for a maximum of 1:10 expansion of the graft tissue and usually an expansion of 1:3 or less. Other types of skin grafts include allografts, which are tissue transplants between individuals of the same species but different genotypes, and homografts, which are allografts from humans. Harvesting these grafts creates additional skin wounds which, in turn, need to be treated and may compromise the patient further.
Disadvantages of skin grafts, other than autografts, include infection and frequent rejection by the recipient requiring the use of immunosuppressive agents. Research efforts have been directed towards developing functional substitutes, that overcome the disadvantages of skin substitutes derived from animal skin, to provide permanent wound closure.
An effective bioactive wound dressing should facilitate the repair of wounds that may require restoration of both the epidermis and dermis. To be successful such a skin graft must be placed onto, and be accepted by, the debrided wound of the recipient and provide a means for the permanent re-establishment of the dermal and epidermal components of skin. The graft should not evoke an immune response, which can destroy the graft, and should include suitable dermal components to support the growth and development of a normal epidermis. The graft should suppress the formation of granulation tissue which causes scarring.
Additional criteria for biologically active wound dressings include: rapid adherence to the wound soon after placement; proper vapor transmission to control evaporative fluid loss from the wound and to avoid the collection of exudate between the wound and the dressing material. Skin substitutes should act as barrier to microorganisms, limit the growth of microorganisms already present in the wound, be flexible, durable and resistant to tearing. The substitute should exhibit tissue compatibility, that is, it should not provoke inflammation or foreign body reaction in the wound which may lead to the formation of granulation tissue. An inner surface structure should be provided that permits ingrowth of fibro-vascular tissue. An outer surface structure should be provided to minimize fluid transmission and promote. epithelialization. A variety of materials and constructions have been proposed to meet these requirements.
Synthetic polymeric materials in various forms have been tested for the development of skin structures having the ability to induce cellular migration and proliferation into the graft. This effort has been limited by the high incidence of infection and inability to promote vascularization and epithelialization. Epithelialization of the membrane graft provides a barrier to infection and contributes to the control of fluid loss.
Typical bioabsorbable materials for use in the fabrication of porous wound dressings, skin substitutes and the like, include synthetic bioabsorbable polymers such as polylactic acid or polyglycolic acid, and also, biopolymers such as the structural proteins and polysaccharides. Skin substitutes made from synthetic polymers have, for a number of reasons, met with limited success. The structural proteins have also met with limited success and include collagen, elastin, fibronectin, laminin and fibrin, as well as other proteins of the human connective tissue matrix. Of these, the material most studied has been collagen. Collagen is the most abundant animal protein and the major protein of skin and connective tissue. A high degree of homology exists between the various types of collagen found in different animal species and human collagen. Accordingly, animal collagen types such as bovine collagen are useful because they exhibit very low immunogenicity when implanted into humans or used as topical dressings on human wounds.
However, the use of collagen alone as a reconstituted collagen film, sponge or sheet for example, has not been demonstrated to serve as an effective wound covering for various reasons among which are the stimulation of the development of granulation tissue and production of a chronic inflammatory response before being resorbed or biodegraded.
Besides films or sheets, collagen may be prepared in a variety of physical forms including porous mats and sponges. Freeze drying an aqueous gel or an aqueous suspension of collagen may be used to produce a porous collagen sponge. Such collagen sponges are described, for example, by Chvapil and co-workers in J. Biomed. Mater. Res. 11 721-741 (1977).
Porous implants, made from biological, bioabsorbable components, are normally intended to be invaded by the cells of the host or recipient of the implant. By and large, these sponges have not proven to be very useful. Later developments, using sponges of appropriate structure and inoculated with suitable cell types have, however, shown considerable promise.
The prior art processes for preparation of a cell-impermeable film on a surface of lyophilized collagen sponge to support and anchor a cellular component, e.g. keratinocytes, generally done using complex and technically difficult procedures. Earlier work by others in this field includes the following:
Yannas, (U.S. Pat. No. 4,060,081) teaches the preparation of a fibrous layer of a mixture of collagen and chondroitin-6-sulfate (GAG) to which is attached a silicone component. The collagen/GAG component of this skin substitute was found to be biodegradable and was said not to be inflammatory or immunogenic. However, it required that the silicone “epidermis” be removed at a later date and that the dermal layer be covered with a thin autograft, to provide the epidermal component, for permanent wound closure.
In U.S. Pat. No. 4,505,266, Yannas discloses the preparation of a cross-linked, bi-layer sponge which has a silicone membrane coated on its surface to serve as a moisture barrier. A milled collagen dispersion is blended with chrondroitin 6-sulfate and the mixture poured into freezing trays. This was then lyophilized for a period of 24 to 48 hours to form a porous structure. When the lyophilization was complete, the sponge was cross-linked by heating for about 24 hours at 105° C. Finally a silicone adhesive was coated over the entire exposed surface of the cooled foam. After curing, the silicone formed an impermeable layer.
Berg discloses a surface coating of a collagen construct with a noncollagenous, non-bioabsorbable adhesive (U.S. Pat. No. 4,841,962).
Ksander, in U.S. Pat. No. 4,950,483, discloses that multilayer atelopeptide collagen sponge products can be formed by serially castin
Brown David J.
Ceres Ralph A.
Lesnoy Daniel C.
Lilore Ralph T.
Ortec International, Inc.
Witz Jean C.
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