Biotherapeutic cell-coated microspheres

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form

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Details

424490, 435174, 435177, 435180, 4352401, 4352402, 43524023, 43524024, 623 15, A61K 916, C12N 1100, C12N 1102, C12N 1108

Patent

active

058305076

DESCRIPTION:

BRIEF SUMMARY
This application is a 3717 PCT/CA93/00187 filed Apr. 23, 1993


TECHNICAL FIELD

The present invention relates to the field of tissue implants and more particularly to the application of skin implants for the treatment of full- and partial-thickness skin injuries, such as burns and other wounds.


BACKGROUND ART

Full-thickness and partial-thickness skin injuries, such as burns and other wounds, represent a significant cost to health care systems. For example, about 2 million people in North America suffer from burns each year. Of these about 200,000 people are hospitalized, 15,000 of which die of burn-related causes. The overall hospital cost for treating these patients is in the order of $1000/percentage burned area ($U.S., 1992) so that the average burn patient with burns to 20 to 30% of their body generates initial hospital care costs of about $25,000, not including the cost of further treatment and potential loss of productivity and income. For instance, McMillan et al (J Burn Care Rehab 6:444-446; 1985) have demonstrated that operating room expenses increase logarithmically with the percent of body surface area burned. Clearly, there is a requirement for advances in technology to mitigate these costs and to reduce the suffering of the patients.
Skin consists of a dermal layer which underlies an epidermal layer. The dermal layer consists mostly of fibroblasts and is about five times the thickness of the epidermal layer. The epidermal layer of intact skin, consisting mainly of keratinocytes and immune cells such as dendritic Langerhans cells, normally prevents water loss and microbial invasion, so that full- and partial-thickness skin injuries can be life-threatening. The rate of wound closure to prevent the escape of essential body fluids and the invasion of bacteria is therefore a vital factor in the recovery of the patient. Accordingly a wide array of wound coverings has been developed to expedite wound closure.
An existing treatment of burns and wounds includes the use of the patient's own skin, or cadaver- or porcine-derived tissue for grafting onto the wound of the patient. Traditional patient-derived skin graft (autograft) techniques are generally very painful to the patient who is already suffering from the burn or other wound. An autograft is comprised of a substantial thickness of both the epidermal and dermal layers of the skin taken from another site on the body. In an attempt to limit the amount of skin taken and therefore the size of the new wound, the autograft is treated to form a lattice pattern across the skin injury. However, the lattice pattern in the dermis layer of the autograft are subsequently filled with permanent scar tissue in vivo. These scars are often very large and can be severely disfiguring or, depending on their location, can cause dysfunction. Furthermore, the patient may not have enough non-burned area in order to salvage a large enough graft for transplant to another location of the body.
Skin grafts derived from cadavers (allograft) or porcine (xenograft) sources have been used in an effort to reduce the suffering of the patient and to encourage wound healing. A major drawback of the allograft is the possibility of disease transmission (for example, HIV, hepatitis B). Moreover, the epidermal layer shows marked antigenicity so that grafts, including allografts, not derived directly from the patient are usually rejected within two weeks of implant. While the xenograft provides a graft when there is a shortage of human donor tissue, it is rejected even more rapidly than the allograft and must be removed on the third day after application before drying and sloughing and before strong adhesion to the wound necessitates surgical excision.
All of these skin grafts, namely the autograft, allograft, and xenograft, are normally very thin and fragile, making transport and handling thereof extremely difficult. Furthermore, the grafts are attached to the wound site with often extensive suturing and/or stapling adding significantly to the discomfort of the patient. Additionally,

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Beumar et al. "Biocompatibility and Characterization of a Polymeric Cell-Seeded Skin Substitute" 17th Ann. Meeting Soc. For Biomaterials, May 1-5 1991, Scottsdale, AZ, p. 263.
Demetriou et al. "Replacement of Liver Function in Rats by Transplantation of Microcarrier-Attached Hepatocytes" Science 233: 1190-1192 (Sep. 12, 1986).
Bagot et al. "Reconstructed human epidermis: absence of Langerhans cells and failure to stimulate allogeneic . . . " Clin. Exp. Immunol. 71: 138 (1988).
van Wezel. "Growth of cell-strains and primary cells in microcarriers in homogenous culture" Nature 216: 64-65 (Oct. 7, 1967).
Bibel et al. "Antimicrobial Activity of Sphingosines" J. Invest Dermatol. 98: 269-273 (1992).
McMillan et al., J. Burn Care Rehab. 6: 444-446 (1985).

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