Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1994-09-13
2004-02-10
Kemmerer, Elizabeth (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100
Reexamination Certificate
active
06689351
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods which enable the promotion of accelerated wound healing in patients who have suffered injury. Specifically, the present invention describes methods for promoting accelerated wound healing in patients suffering from a variety of wounds using the hematopoietic colony stimulating factor and GM-CSF.
BACKGROUND OF THE INVENTION
A. Wounds and Wound Healing
The human skin is composed of two distinct layers, the epidermis and dermis. Below these layers lies the subcutaneous tissue. The primary functions of these tissues are to provide protection, sensation, and thermoregulation to an animal. Secondarily, these layers protect the internal organs of the organism from shock or trauma by cushioning impacts from external forces and objects.
The outermost layer of skin, the epidermis, is approximately 0.04 mm thick, is avascular, is comprised of four cell types (keratinocytes, melanocytes, Langerhans cells, and Merkel cells), and is stratified into several epithelial cell layers [Leeson et al., (1985) Textbook of Histology, WB Saunders Co., Philadelphia]. The inner-most epithelial layer of the epidermis is the basement membrane, which is in direct contact with, and anchors the epidermis to, the dermis. All epithelial cell division occurring in skin takes place at the basement membrane. After cell division, the epithelial cells migrate towards the outer surface of the epidermis. During this migration, the cells undergo a process known as keratinization, whereby nuclei are lost and the cells are transformed into tough, flat, resistant non-living cells. Migration is completed when the cells reach the outermost epidermal structure, the stratum corneum, a dry, waterproof squamous cell layer which helps to prevent desiccation of the underlying tissue. This layer of dead epithelial cells is continuously being sloughed off and replaced by keratinized cells moving to the surface from the basement membrane. Because the epidermal epithelium is avascular, the basement membrane is dependent upon the dermis for its nutrient supply.
The dermis is a highly vascularized tissue layer supplying nutrients to the epidermis. In addition, the dermis contains nerve endings, lymphatics, collagen protein, and connective tissue. The dermis is approximately 0.5 mm thick and is composed predominantly of fibroblasts and macrophages. These cell types are largely responsible for the production and maintenance of collagen, the protein found in all animal connective tissue, including the skin. Collagen is primarily responsible for the skin's resilient, elastic nature. The subcutaneous tissue, found beneath the collagen-rich dermis, provides for skin mobility, insulation, calorie storage, and blood to the tissues above it.
Whenever there is an injury to the skin and/or the underlying soft tissue, a process to repair the resultant wound is immediately initiated in healthy organisms. In humans, this process does not lead to total regeneration of the injured outer integument unless the injury is confined to the epidermis and the basement membrane is left intact [Wokalek, H., (1988) CRC Critical Reviews in Biocompatibility, vol. 4, issue 3: 209-46]. Therefore, when a wound is characterized by more extensive tissue damage, the injured, destroyed, or lost tissue will not be reconstituted with like tissue, but will instead be replaced by scar tissue. Wounds characterized by tissue disruption penetrating completely through both the epidermis and dermis are known as full thickness wounds, while those which only extend through the epidermis but do not completely pass through the dermis are called partial thickness wounds.
The mechanisms of soft tissue injury can be divided into two general categories, mechanical and thermal. Mechanical forces are of three types, compression, shear, and tension. Compression, if enough force is applied, crushes the contacted tissue and produces serious wounds, such as those caused by blunt force trauma and gun shots. Wounds caused by shearing are the most common type of skin penetrating injury. Incisions, both surgical and nonsurgical, are examples of wounds produced by shearing forces. Because little energy is transferred to the surrounding tissue, little tissue devitalization occurs and healing is typically uncomplicated. Tension wounds occur when the skin is torn away from its subcutaneous base, either completely or leaving a flap with at least one edge still attached. The severity of a tension wound is dependent upon the amount of blood supply disruption to the flap and upon the size, thickness, and ratio of flap base width to flap length.
Thermal forces capable of producing wounds include cold, conduction, convection, electricity, and radiation. Generally, the severity of thermal wounds is dependent on the source, temperature, duration of exposure, and the ability of the skin to resist heat transfer [Trott, A. (1988) Ann. Emer. Med., vol 17: 1279-83].
Wound healing is the process through which the repair of damaged tissue(s) is accomplished. Wounds in which there is little or no tissue loss are said to heal by first or primary intention, while deep wounds suffering tissue loss heal by second or secondary intention. The wound healing process is comprised of three different stages, referred to as inflammation, granulation tissue formation, and matrix formation and remodeling [Ten Dijke et al., (1989) Biotechnology, vol. 7: 793-98].
The inflammatory response to soft tissue injury is initiated immediately upon infliction of the wound as tissue edges are separated and blood spills into the wound, activating the clotting cascade which leads to hemostasis. Initially there is a short phase of vasodilation in tissues surrounding the wound site followed by vasoconstriction. Platelets present in the wound, which aggregate to form the clot, also release a number of vasoactive compounds, chemoattractants, and growth factors [Goslen, J. B., (1988) J. Dermatol. Surg. Onco., vol 9: 959-72]. The clot itself is critical for eventual wound repair, as the provisional fibronectin matrix is used by fibroblasts and epithelial cells for ingress into the wound. Additionally, capillary permeability peripheral to the wound is increased, and because of the reduced blood flow, polymorphonuclear leukocytes (PMNs) adhere to the capillary walls and migrate into the wound, as do monocytes [Eckersley et al., (1988) British Medical Bulletin, vol. 44, No. 2: 423-36].
PMNS, such as neutrophils, are the predominant cell type found in the wound initially. PMNs and macrophages begin the process of cleaning the wound. This cleansing process is accomplished mostly through the phagocytosis of devitalized tissue and other debris. By days 3-5 post-injury, PMNs have largely been replaced by macrophages, which continue to remove dead and foreign material. In 1972, Simpson and Ross [J. Clin. Invest., vol 51: 2009-23] showed that an almost total absence of PMNs in the wound site did not inhibit wound healing. However, the role of macrophages in wound repair may be critical [Diegelmann et al., (1981) Plast. Reconstr. Surg., vol. 68: 107-113]. In experimental monocytopenic wounds, granulation tissue formation, fibroplasia, and collagen disposition are markedly impaired and healing is delayed [Leibovich et al., (1975) Am. J. Path., vol 78: 71-100; Mustoe et al., (1989) Am. J. Surg., vol 158: 345-50; Pierce et al., (1989) Proc. Nat. Acad. Sci. USA, vol. 86: 2229-33].
When found in wounds, macrophages are known to release a variety of biologically active substances that serve as chemoattractants for both monocytes and fibroblasts, such as transforming growth factor-&bgr; (TGF-&bgr;) and platelet-derived growth factor (PDGF) [Rappollee et al., (1988) Science, vol. 241: 708-12; Pierce et al., supra; Pierce et al., (1989) J. Cell Biol., vol. 109: 429-40]. See Obberghen-Schilling et al., (1988) J. Biol. Chem., vol. 263: 7741-46; Paulsson et al., (1987) Nature, vol. 328: 715-17;
Altrock Bruce W.
Pierce Glenn
Amgen Inc.
Amgen Inc.
Kemmerer Elizabeth
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