Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-10-26
2002-12-24
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C435S001100, C435S174000, C435S177000, C435S325000, C435S366000, C435S395000
Reexamination Certificate
active
06497875
ABSTRACT:
BACKGROUND OF THE INVENTION
Adult skin consists of an epidermis generated principally by keratinocytes [1] and a complex dermis, populated by fibroblastic cells of mesenchymal origin [2] interspersed with vasculature, hair follicles, and other accessory structures. Within the dermis are histologically distinct regions: the papillary dermal layer just below the epidermal basement membrane, and the reticular dermal layer extending deeper to the hypodermal areas containing muscle and fat. There is no formal lineage map for dermal fibroblasts. Although types of dermal cells in culture have been described by elaborate morphological and biochemical criteria [3] the lineage progression from a mesenchymal dermal progenitor cell to reticular, papillary and follicular dermal cells is not understood.
Among the dermal fibroblasts appear to be a restricted population of mesenchymal stem cells (MSCs) [4] first identified as pluripotent, adherent cells of the bone marrow stroma [5]. MSCs in the adult are cells capable of giving use to a variety of mesenchymal phenotypes, including bone, cartilage, muscle, tendon, ligament, adipocytes, connective tissues, and dermis. Fleming et al. [4]) at Case Western Reserve University, have demonstrated that a small sub-population of the fibroblastic cells residing in the dermis react with monoclonal antibody SH2, a reagent that specifically labels MSCs in bone marrow [6]. The MSCs are clustered near vasculature, hair follicles, and adjacent to the epidermal basement membrane, although the significance of this pattern of localization has not yet been determined. Interestingly, Fleming and coworkers [4] also suggest that the number of MSCs in dermis, based on SH2 reactivity, decreases with the age of the patient to undetectable levels after age 20. This observation may contribute to our understanding of skin aging and its potential for self-renewal.
Relatively little is known about the embryologic development of human skin, although Holbrook and coworkers [2,7]have described a sequence of layer appearance with focus on the vasculature and appendage elements. Markers for extracellular matrix molecules, cell surface proteins, and growth factors have been used to help characterize the layers of skin during development, but the lack of model systems for in vitro differentiation has hampered progress in the field. Skin organ cultures [7] or embryonic side spheroids are the best system reported to study embryonic s development. These cultures consist of patches of full-thickness side introduced into suspension culture, where they round up to form spherical bodies. These cultures have epidermis on the outside and dermis on the inside, and they progress through a relatively normal sequence of developmental events. Because of the geometry of these bodies, it is difficult to use the spheroids to establish unequivocally the lineage progression of dermal cells.
In recent years, living skin equivalents [1] have been established, and the technology for reconstituting the epidermal layer from autologous or allogeneic keratinocytes has become highly advanced. The feeder layers for these keratinocyte cultures are generally fibroblasts in a formulation suitable for co-culture. While these skin equivalents can function in grafts, the fibroblastic feeder layers are not the same as a true, multi-layered dermis.
The principal needs for skin repair and regeneration methods and products are severe burns and skin ulcers. While there is substantial demand for improved therapy, there are no completely satisfactory products either on the market or in clinical development. The scope of the need in the United States is estimated as follows:
Type of injury
Estimated U.S. patient population
Partial thickness burns
2,000,000
Hospitalized burn patients
100,000
Burns requiring skin grafts
70,000
Skin grafts performed (reflects
150,000
multiple sites per patient)
Pressure (decubitus) ulcers
1,500,000
Venous ulcers
500,000
Diabetic ulcers
600,000
Moh's surgical wounds
100,000
Partial thickness burns constitute those where the burn involves the surface layer of skin (epidermal layer) and into, but not through the underlying dermal layer. Most of these injuries are treated without graft or other tissue replacement. This conservative approach is effective because keratinocytes (the primary cell type of the epidermis layer) required to repair the epidermal layer are present in the dermis, particularly in the tissue surrounding hair follicles and sebaceous glands.
Patients with more extensive burns generally can not be adequately treated through spontaneous healing because (1) these burns frequently destroy the underlying dermal layer which provides the source of keratinocytes, (2) healing for full thickness wounds must occur from the margins, which is a long process that exposes the patient to a high risk of infection through unprotected tissue and (3) spontaneous healing will lead to serious scar-ring and skin contraction that is both cosmetically unattractive and may be physically restrictive due to loss of flexibility and range of motion.
Severe burns are a primary application for mesenchymal stem cell therapy because they represent a serious medical threat, they result In a high cost of treatment, and they require a long recovery period. Serious burns are frequently referred to hospitals with specialized burn units or for serious cases, the major burn centers.
Decubitus (pressure) ulcers are one of the continuing problems associated with treatment in nursing homes and hospitals dealing with bed-ridden patients. They occur due to localized pressure that restricts blood circulation to the skin. The ulcers may be quite large in area and penetrate to the full thickness of the dermal layer. They are difficult to heal and require substantial nursing resources.
Venous ulcers result from poor circulation, particularly in the legs, associated with aging. Age-deteriorated veins can lose the “valve” function which keeps blood moving towards the heart. When this occurs, there is pooling of blood in the extremities and ineffective removal of toxins. This results in deterioration of the skin cells fed by the affected blood vessels.
Diabetic ulcers occur through an analogous process. Diabetes causes deterioration of the arteries through accumulation of advanced glycosylation end products (excess sugar that binds to proteins) and possibly sorbitol. As these arteries deteriorate they are unable to supply skin cells adequately, leading to cell death. As in the case of venous stasis, there is an underlying circulatory defect that requires correcting to gain fill healing. However, even if the defect is corrected, the s ulcers may persist unless properly treated.
A skin replacement is the ideal product for treating dermal ulcers. Repeated applications may be needed because the underlying defects are frequently not curable and the ulcers recur in 20-50% of cases,
Surgical wounds associated with the excision of skin cancers represent another major application for mesenchymal stem cell skin regeneration. Surgical wounds are frequently deep and cosmetically disfiguring. Treatment to accelerate healing and minimize scarring (there is a disproportionate incidence of skin cancers lesions on the face and neck) represents a significant need.
There are limited numbers of skin replacement products currently on the market and none of those in development appear likely to fully meet clinical needs, especially for full- and partial-thickness products. The measures of clinical success in skin replacement include (1) the ability to treat a wide range of dermal injuries; (2) the ability to replace or regenerate both the epidermis and the dermis skin layers: (3) a high degree of “take” or acceptance and growth by the underlying tissue; (4) shortening of the natural healing process; and (5) minimal scarring.
There is little evidence that current products shorten the time to healing. Therefore, the potential exists to s
Caplan Arnold I.
Sorrell J. Michael
Case Western Reserve University
Lillie Raymond J.
Naff David M.
Olstein Elliot M.
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