Surgery – Instruments – Sutureless closure
Reexamination Certificate
1998-12-11
2002-09-24
Jackson, Gary (Department: 3731)
Surgery
Instruments
Sutureless closure
C128SDIG008, C106S122000, C514S801000, C424S423000
Reexamination Certificate
active
06454787
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of hemostatic devices for controlling bleeding.
BACKGROUND OF THE INVENTION
Uncontrolled bleeding can result in shock and death. In surgical patients and patients receiving anticoagulant medication, the problem of rapid blood loss arising from, for example, a hemorrhage of a blood vessel, body tissue, organ or bone can give rise to a life threatening situation.
Biodegradable devices for controlling bleeding are commercially available. However, many of these devices require the impregnation of protein agents such as thrombin or fibrinogen to be effective. Unfortunately, special storage conditions are required to preserve the hemostatic activity of these protein agents. For example, many of these devices must be stored under refrigeration conditions to maintain the bioactivity of the hemostatic devices into which the protein agents have been impregnated. Such requirements prohibit certain field applications of the patch, where refrigeration facilities are unavailable. Another problem with certain commercially available hemostatic devices is their lack of flexibility in the dry state. Many hemostatic devices do not conform easily to the shape of the body surface to which it is applied. In addition, hemostatic devices which further include hemostatic agents, such as thrombin, typically require that the thrombin be reconstituted and added to the dry devices immediately before use to provide a flexible hemostatic device having sufficient hemostatic activity to control bleeding.
SUMMARY OF THE INVENTION
The invention provides a hemostatic device which solves the above-described and other problems of the prior art devices. Methods for preparing the hemostatic devices of the invention also are provided. The hemostatic devices of the invention do not require exogenously added protein agents to be effective. Accordingly, the hemostatic devices of the invention can withstand elevated temperatures and do not require refrigeration to retain hemostatic efficacy. In addition, the hemostatic devices disclosed herein are easy to use and mold easily to body contours. Accordingly, the hemostatic devices of the invention are particularly useful for treating the problematic hemorrhages of parenchymal organs, spine, and brain. Such hemostatic devices can be sterilized and packaged in a sterile package for pharmaceutical applications.
According to one aspect of the invention, a process for preparing a hemostatic device of the invention is provided. The process involves: (a) suspending a plurality of collagen particles in water to form a collagen slurry, wherein the collagen particles have a bulk density sufficient to form a suspension in water and wherein the collagen slurry has a concentration in the range of about 1% to about 2% (weight/volume); and (b) lyophilizing (freeze-drying) the collagen slurry to form a hemostatic device. The hemostatic devices that are formed in accordance with this method are foams, preferably reticulated open cell foams. Foams also are referred to in the art as “sponges”. Preferably, the collagen particles of the hemostatic device have a hemostatic activity that is equivalent to the hemostatic activity of the collagen particles from which the hemostatic device is formed. More preferably, the hemostatic devices are formed of Avitene® flour and the collagen particles of the hemostatic devices of the invention have a hemostatic activity equivalent to the hemostatic activity of Avitene® flour.
Hemostasis is a term of art which refers to cessation of bleeding. Although not wishing to be bound to any particular theory or mechanism, it is believed that avoiding contact between the collagen particles and an acid solution and minimizing exposure of the collagen to denaturing conditions, such as excessive mechanical shear, high temperature, or long H
2
O residence times, during the fabrication process results in a greater retention of hemostatic activity by the collagen particles compared to particles which are subjected to such denaturing conditions. Accordingly, the hemostatic devices of the invention have a greater hemostatic activity compared to conventional collagen hemostatic devices in which the fabrication process has involved dissolution of collagen in acid solution.
In one embodiment of the invention, the method for forming a hemostatic device of the invention involves suspending a plurality of collagen particles (preferably, collagen fibrils) in water to form a collagen slurry and subjecting the collagen slurry to lyophilization (freeze-drying) to form the hemostatic device. The collagen particles have a bulk density sufficient to form a suspension in water. In general, the bulk density of the collagen particles is in the range of about 1.5 to about 3.5 lbs/ft
3
and, more preferably, from about 2 to about 3 lbs/ft
3
. The particles are suspended in water to obtain a collagen concentration in the range of about 1% to about 2% (weight/volume), and, more preferably, in the range of about 1.1% to about 1.64% (weight/volume). In the preferred embodiments, the hemostatic devices are formed of collagen particles that have not been subjected to acid dissolution or other denaturing conditions.
According to yet another aspect of the invention, a product prepared by the above-described process is provided. A particular embodiment of this process in provided in the Examples. The process, optionally, further includes the step of cross linking the collagen within the hemostatic devices of the invention, e.g., by heating the collagen fibers of the invention at a temperature and for a period of time sufficient to form crosslinks, preferably, without substantially reducing the hemostatic activity of the collagen fiber. Preferably, the crosslinked hemostatic devices retain at least about 80%, more preferably, at least about 90% and, most preferably, at least about 95% hemostatic activity compared to the hemostatic activity of the hemostatic device prior to crosslinking.
In certain preferred embodiments, the hemostatic device is formed of collagen particles that have a hemostatic activity equivalent to the hemostatic activity of the collagen particles from which the device is formed. In the preferred embodiments, the hemostatic device is formed of collagen flour, preferably Avitene® flour, that has not been subjected to acid dissolution. In these and other embodiments, the hemostatic device preferably has a density of from about 0.015 to about 0.023 gm/cc; and/or a weight percent solids ranging from about 1.10 to about 1.64 weight percent.
In yet other embodiments, the hemostatic device of the invention is formed of collagen and has a hemostatic activity in a pig spleen animal model of hemostasis that corresponds to one tamponade for a hemostatic device having a thickness of ⅜ inch, a length of ½ inch, and a width of ½ inch. An exemplary pig spleen animal model of hemostasis is provided in the Examples.
In certain embodiments, the hemostatic devices of the invention further include a hemostasis-promoting amount of at least one hemostatic agent. As used herein, a “hemostasis-promoting amount” is the amount effective to accelerate clot formation at an interface between a surface (e.g., of a wound or lesion) and the hemostatic device. Exemplary hemostatic agents include a thrombin molecule, a fibrinogen molecule, a source of calcium ions, an RGD peptide, protamine sulfate, an epsilon amino caproic acid, and chitin. In the preferred embodiments, the hemostatic agent is thrombin. The hemostatic agents can be introduced into the hemostatic devices at any stage during the preparation of these devices, including adding the hemostatic agent to the collagen slurry, lyophilizing the agents into the hemostatic device during its preparation or applying the agents to the device post-processing.
In certain embodiments, the hemostatic devices of the invention further include a therapeutically effective amount of at least one therapeutic agent, such as agents which promote wound-healing and or reduce pain (e.g., vascular pai
Eldridge Stephen N.
Iampietro Mark V.
Maddalo Francis B.
Torgerson Robert D.
C. R. Bard Inc.
Jackson Gary
Wolf Greenfield & Sacks P.C.
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