Surgery – Miscellaneous – Methods
Reexamination Certificate
1999-02-11
2001-06-26
Isabella, David J. (Department: 3738)
Surgery
Miscellaneous
Methods
C623S001150, C623S008000, C600S032000, C434S262000
Reexamination Certificate
active
06250306
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the assessment of ischemic wound therapeutics by characterizing wound healing parameters such as epithelialization, granulation tissue formation and contraction. The present invention is also directed to an animal model for assessing ischemic wound therapeutics.
BACKGROUND OF THE INVENTION
Tissue ischemia is a condition resulting from hypoperfusion which is caused by arterial occlusion, veneous obstruction or impaired microcirculation. Ischemia predisposes individuals to the development of chronic wounds. Chronic ischemic conditions impair the normal wound healing process in the tissue affected. Many components of the normal wound healing process such as epithelialization, contraction and granulation tissue formation are inhibited as a direct result of perfusion disturbances.
Numerous studies have been undertaken in an effort to develop a model of cutaneous ischemia for use in assessing the efficacy of wound healing therapeutics. However, many investigators report that conditions of chronic tissue ischemia are difficult to create in animal models. Several factors alone or in combination render current methods and models unacceptable for tissue ischemia research. For example, surgical creation of a cutaneous flap on an animal results in an abrupt reduction of blood flow through the flap, which is not characteristic of the chronic ischemia. Furthermore, rapid revascularization of the flap from contact with underlying tissue renders the flap non-ischemic. Moreover, prior art ischemia models are prone to infection, drying and necrosis because they lack a closed structure.
Schwartz, et al. employed an ischemia bipedicle flap rat model (1995)
Wound Repair and Regeneration
3:204-212. The bipedicle flap was prepared by making two longitudinal incisions on both sides of the spine. The flap, thus created was bluntly lifted and then sutured back to the animal. Subsequently, wounds were made in the flap. However, the flap rapidly revascularized, causing a cessation of ischemia.
Pittet, et al. (1996)
Plast. Reconstr. Surg.
97:621-629 prepared an “H-shaped” flap model. Two parallel incisions (one on each side of the rats spine). The flap was subsequently separated from the underlying tissue followed by a transverse full thickness incision in the center of the flap. The flap was separated into two pieces, cranial and caudal, resembling an “H” structure. The transverse incision was immediately closed and the flap was sutured back to the underlying structures. Wounds were created in the flap on both sides of the transverse incision. This model suffers from unpredictable reproducibility of the healing process of the wounds due to necrosis and/or revascularization of the flap.
McFarlane, et al. (1965)
Reconstructive Surgery
35(3):245-262 prepared a monopedicle flap on the back of rats. Two parallel longitudinal incisions and one transverse incision connecting the origins of the parallel incisions were made. The flap, thus formed was raised and remained attached to the animal only at the caudal end. This model produced severe necrosis at the cranial end of the flap, rapid revascularization at the caudal end and subsequent reversal of ischemia.
Hammond, et al. (1993)
Plast. Reconstr. Surg.
91:316-321 developed another model based on the monopedicle flap of McFarlane, et al. Hammond, et al. sutured the monopedicle flap atop the closed normal skin on the back of the animal. This technique inhibited revascularization of the flap from the underlying tissue but the flap lacked a closed structure. The Hammond, et al. model was thus prone to infection, drying and necrosis. Moreover, the wounds made in the Hammond, et al. flap model lacked the underlying vasculature and thus failed to simulate the clinical situation.
Shultz, et al. (1998)
Keystone Symposia
, January 10-15 developed a Gortex™ sheet implant model. By this model a Gortex™ sheet was implanted beneath the flap (created as described by Schwartz, et al. infra) and above the underlying structures. Unfortunately, the sheet acted as a barrier to the wound healing process rendering any conclusions regarding the impact of ischemia or tissue repair tenuous at best.
At the present time there are no reproducible models of controlled chronic cutaneous tissue ischemia available for the purpose of assessing wound healing therapeutics. In addition to the recognized difficulty encountered in creating reproducible levels of ischemia in tissue, there is another problem related to the anatomical differences between rodent and human skin which make ischemia models difficult to create—wound contraction.
Skin in lower mammals, like rodents, contains a subcutaneous layer of muscle, called
Panniculus carnosus
. The rodent skin is loosely attached to underlying structures which accounts for its characteristic mobility. The initial mechanism for cutaneous wound repair in these species is contraction. Humans lack the rodents' subcutaneous muscular layer except for some areas in the neck and upper chest. The skin in humans is firmly attached to the underlying structures by means of subcutaneous ligaments and adipose tissue. This is especially true of the areas where ischemic ulcer wounds usually develop such as on the feet. In these areas the skin is attached to the fascia and bone, causing the skin to resist contraction.
The present invention provides the skilled artisan with an animal model of cutaneous ischemia having minimal tissue contraction. Minimal tissue contraction, simulating the human condition, is accomplished for the first time, in connection with the present invention by an implanted stent. Minimal tissue contraction permits granulation tissue formation and epithelialization to be monitored in respect of the healing process of ischemic wounds.
The model employed effectively simulates the frequent clinical situation when ischemic wounds occur i.e. in areas anatomically challenged for skin mobility and contraction, such as feet. The closed structure of the ischemic flap of the present invention resists infection and drying, thus creating a viable zone of suboptimal cutaneous perfusion. With the present invention, the practitioner can now inexpensively and reproducibly create a model of cutaneous ischemia which can provide crucial information about the efficacy of applied wound healing therapeutic agents.
SUMMARY OF THE INVENTION
The present invention is directed to the assessment of ischemic wound therapeutics. By assessment is meant in vivo standardized testing of the effects of wound healing therapeutics applied to an animal model of cutaneous ischemia. Such cutaneous ischemia is inexpensively and reproducibly created for the first time in accordance with the present invention by means of a surgically created cutaneous flap on the back of a laboratory animal. The cutaneous flap has a mechanical framework implanted thereunder for stability. In a preferred embodiment the framework is a stent.
In one embodiment of the present invention chronic cutaneous ischemia is created by surgically constructing a tissue flap on the back of an animal. In a preferred embodiment the animal is a rodent. In a most preferred embodiment the rodent is a rat.
In another embodiment the cutaneous flap has a length to width ratio of about 2.5 to 1. In a preferred embodiment the length to width ratio is 2.5 to 1.
In another embodiment a mechanical framework is implanted under the cutaneous flap and the edges of the flap are brought together and closed around the framework.
In still another embodiment one or more wounds are inflicted on the cutaneous flap.
In a further embodiment wound therapeutic agents are applied to the wound. In a preferred embodiment the wound therapeutic agent is applied from zero to about sixty days post-wounding.
In yet another embodiment the effects of the wound healing therapeutics are conventionally assessed.
Still another embodiment of the present invention is directed to an animal model for assessing ischemic wound healing therapeutics which contains a mechanical framework impla
Gritsus Vadim
Iarkowski Laura
Niciporciukas Maria Cristina
Ward James
Ethicon Inc.
Isabella David J.
Koh Choon P.
Scully Scott Murphy & Presser
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