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Configuration of glycosaminoglycansRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, PolysaccharideConfiguration of glycosaminoglycans description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060100174, Configuration of glycosaminoglycans. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This Application is a Divisional Application and claim a Priority Date of Aug. 1, 2003 benefited from a patent application Ser. No. 10/632,599 filed by the same inventor of this Patent Application. Patent application Ser. No. 10/632,599 is a Formal Application and claim a Priority Date of Aug. 1, 2002 benefited from a Provisional Patent Application 60/400,078 filed by the same inventor of this Patent Application. FIELD OF THE INVENTION [0002] The present invention relates generally to structures composed of glycosaminoglycans with or without living cells, methods of producing glycosaminoglycan structures, and methods of treating subjects using these structures. BACKGROUND OF THE INVENTION [0003] Slow healing or lack of healing of dermal wounds (e.g., decubitus ulcers, severe burns and diabetic ulcers) and eye lesions (e.g., dry eye and corneal ulcers), is a serious medical problem, affecting millions of individuals and causing severe pain or death in many patients. Healing of surgical wounds can also be slow or otherwise problematic, particularly in aging and diabetic individuals. Although wounds may be quite dissimilar in terms of cause, morphology and tissue affected, they share a common healing mechanism. Each repair process ultimately requires that the correct type of cell migrate into the wound in sufficient numbers to have an effect: macrophages to debride wounds, fibroblasts for the formation of new collagen and other extracellular matrix (ECM) components in wounds where the extracellular matrix was damaged, capillary endothelial cells to provide the blood supply, and epithelial cells to ultimately cover the wounds. [0004] However, under certain circumstances, such as burn wounds, and hereto lacking of sufficient living skin to support the regeneration of the wound, and then the wounds will last longer and have chances to develop severe infection that some time causes the loss of the lives. Hence resulted hypertrophic burn scars are notoriously difficult to treat because of their extensive tissue involvement. [0005] The standard method for grafting extensive or deep burn wounds used full-thickness sheet grafts or narrowly meshed, thick, split-thickness skin grafts [Lattari, et al. J Burn Care Rehabil 18:147-155 (1997)]. This method, however, creates an additional complication-prone wound at the donor site. Donor sites can be painful and may develop infection, hypertrophic scarring, blistering, and hyper- or hypopigmentation. The problem of donor site scar hapertrophy occurs most frequently when a graft is taken at more than 0.012 inch thick, leaving a residual dermal bed that is too thin. Meanwhile, early and permanent coverage of extensive burn wounds is still difficult because of the shortage of the donor sites. [0006] The unwounded dermis owes much of its structure and strength to the interactions of cells with the ECM. It is well understood now that migration of fibroblasts and keratinocytes plays an important role in wound healing. The ECM is the key dynamic assemblage of interacting molecules that regulate cell functions and interactions in response to stimulation of wounds. This matrix includes several proteins known to support the attachment of a wide variety of cells, including fibronectin, vitronectin, thrombospondin, collagens, and laminin. Although fibronectin is found at relatively low concentrations in unwounded skin, plasma fibronectin deposition occurs soon after wounding. When tissue is damaged, the ECM must be replaced to provide a scaffold to support cell attachment and migration. In addition to providing a scaffold, extracellular matrices can also direct cellular proliferation and differentiation. An extracellular matrix can, therefore, direct healing of a tissue in such a way that the correct tissue geometry is restored. [0007] Acceleration of the healing process can be greatly aided by a better understanding of the factors that influence the synthesis of granulation tissue, which fills the wound before epithelialization. An important phase of early wound healing involves fibroblast secretion of glycosaminoglycans (GAGs), which form a hydrophilic matrix suitable for remodeling during healing. Tissue-engineering techniques generally focus on mimicking the ECM by creating a scaffolding of resorbable materials that serves to promote wound healing. However, the use of GAGs in such materials is hindered by the instability of free GAGs. [0008] Modification of GAGs, such as hyaluronan, in order to provide more stable structures has been an area of interest in this field. For example, U.S. Pat. No. 4,851,521 describes esters of hyaluronic acid in which all or only a portion of the carboxylic groups of the acid are esterified. See also Kuo J W et al., Bioconjugate Chem 2:232-241 (1991). These GAG modifications however, alter the biological activity of the GAGs and renders them less effective than their free counterparts. In addition, structures formed with these esterified GAGs are instable when in contact with liquid, such as body fluids, and thus structures composed of these molecules do not retain their integrity following application to a subject. [0009] There is a need in the art for compositions, devices and methods for providing site-specific GAG administration, and in particular for GAG structures that are stable and cell or tissue accessible in vivo and which provide bioavailable GAG. SUMMARY OF THE INVENTION [0010] The present invention provides stable glycosaminoglycan (GSG) structures and methods of use of such GAG structures. These structures comprise a core of free GAG, a coating of crosslinked GAG surrounding the core, and a layer of a positively charged moiety surrounding the crosslinked GAG layer. These GAG structures provide improved stability, both in in vivo an external use. Furthermore, resurfacing of the structures provides improved cell adhesion and thus improved delivery of the GAG into cells, tissues and/or organs. [0011] In one aspect of the invention, methods are provided for preparing compounds having of a core of free GAG, a surrounding layer of cross-linked GAG, and a layer of a positively charged moiety. The method comprises the steps of cross-linking an outer layer of a GAG substrate solution (premade into a structure of any shape) with a high concentration (e.g., between about 35% to 85%) of a cross-linker, which effectively crosslinks the GAGs on the periphery of the substrate while leaving the GAGs in the core of the substrate free, ie., not crosslinked. The GAG structures can be formed into a desired shape prior to cross-linking, and the crosslinkers help to fix and stabilize the structures in the particular shape. Preferably, the cross-linking reagent is an aldehyde, e.g., glutaraldehyde, formaldehyde and the like. GAG structures formed according to the invention, are particularly advantageous in that they do not dissolve upon contact with bodily fluids and provide cells access to bioavailable, free GAG. Also, as any excess crosslinking agent can be removed from the structures without affecting the structural integrity, these structures are non-toxic upon administration. [0012] A particular embodiment of the invention provides a composition comprising the GAG structures of the invention and an appropriate excipient. The excipient may be any acceptable carrier of the GAG structures of the invention, including water. [0013] It is thus an object of the present invention to provide a polymeric composition that can provide for directed release of GAGs and can serve as a substrate for cell growth. [0014] In a particular embodiment of the present invention, the GAG structures are used in or on devices and/or compositions that promote wound healing." The GAG structure can provide bioactive GAG in a controlled manner, e.g., by application externally to a dermal wound, or internally to a damaged organ or an incised vein or artery with or without living cells. The GAG structure can be cultured with various cells prior to use, e.g., hyaluronan (HyA) structures can be cultured with keratinocytes or fibroblasts for use in a liquid bandage. [0015] In one aspect of the invention, the GAG is introduced to a wound site using a delivery vehicle such as a solid wound dressing, a liquid bandage, an adhesive and the like, which delivery vehicles comprises the GAG structures of the invention. [0016] It is thus an object of the present invention to provide drug delivery devices, particularly wound dressings, comprising such polymeric delivery vehicles for release of wound-healing agents to aid in the wound healing process. [0017] In another embodiment of the invention, the GAG structures are provided to modulate other GAG-mediated events, e.g., resurfaced GAG structures may be introduced into the synovial fluid of a joint to alleviate arthritis. [0018] It is thus an object of the present invention to provide methods of treatment for GAG-mediated physiological conditions and/or disease. [0019] An advantage of the present invention is that the cross-linking agent is removed from the delivery device, thus limiting potential toxicity from the cross-liking agents. [0020] It is another advantage of the present invention that the GAG structures are stable in vivo for up to 6 months. [0021] It is yet another advantage that the GAG structures of the invention provide enhanced cell attachment. These and other objects of the invention will be apparent from the following description and appended claims, and from practice of the invention. Continue reading about Configuration of glycosaminoglycans... Full patent description for Configuration of glycosaminoglycans Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Configuration of glycosaminoglycans patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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