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SOFT TISSUE CLOSURE SYSTEMS
This application is a continuation-in-part of U.S., patent 5 application Ser. No. 07/881,213, filed May 11, 1992, now U.S. Pat. No. 5,326,350, the contents of which are incorporated herein by reference.
BRIEF SUMMARY OF THE INVENTION 10
1. Field of Invention
This invention relates generally to the closure of soft tissue sites with self-expandable, bioresorbable, polymer implants, particularly to the closure of percutaneous punc- 15 ture sites. The present invention is also directed to the delivery of such implants with tubular delivery devices which penetrate the soft tissue sites to a defined depth for hemostasis and wound closure. Methods of preparing the implants are also disclosed. 20
2. Background of the Invention
It has been routine practice to insert a catheter through a puncture site into a blood vessel to either treat a diseased blood vessel by a procedure, known in the art as percuta- 25 neous transluminal angioplasty (PTA), or to deliver systemic drugs to the blood stream for chemotherapeutic applications. In the case of a PTA procedure, an introducer sheath is inserted into an artery through the puncture site such that a balloon or other type of catheter can then be inserted into the 3Q vessel to carry out the procedure within a vessel. Depending upon the nature of the disease and the site of arterial insertion, the size of an introducer sheath can vary from 1 mm to as large a 5 mm. One of the complications of these procedures is hemorrhaging at the percutaneous puncture 35 site after removal of the catheter and the introducer sheath. In order to stop the bleeding, pressure is applied at the puncture site until hemostasis occurs. Since the angioplasty and related procedures often require the use of an anticoagulant, the pressure approach is not always effective and 4Q may require a long period of pressurization and occasional surgical treatment and hospital stay.
A variety of commercial hemostatic products are available such as those disclosed in U.S. Pat. Nos. 2,465,357; 3,742, 955; and 3,364,200. A felt or fleece like collagen hemostat 45 is disclosed in U.S. Pat. No. 4,066,083. A hemostatic collagen paste comprising a mixture of collagen powder and saline is disclosed in U.S. Pat. No. 4,891,359. A number of other collagen based hemostatic materials are disclosed in U.S. Pat. Nos. 4,412,947; 4,578,067; 4,515,637; 4,271,070; 50 4,891,359; 4,066,083; 4,016,877 and 4,215,200. None of these patents teaches the art of hemostasis at a vessel puncture site.
The use of a collagen based device to close an arterial puncture site of a blood vessel is disclosed in Ernst, S., 55 Tjonjoegin, R, Schrader, R, et al. Immediate Sealing of Arterial Puncture Sites After Cardiac Catheterization and Coronary Angioplasty Using a Biodegradable Collagen Plug: Results of an International Registry, J. Am. Coll. Cardiology, 15:851-855, 1993). In order to deliver the 60 collagen material into the percutaneous puncture site, the puncture site must be significantly dilated with an oversized applicator sheath. The delivery cartridge is then inserted through the expanded puncture site to deliver the collagen material. The collagen is delivered twice in order to fill the 65 void and secure the hemostasis. This elaborate procedure with additional wound site expansion has resulted in sig
nificant cases of hematoma in the patients treated with this device.
Another device to close an arterial puncture site of a blood vessel is disclosed in U.S. Pat. No. 4,744,364 to Kensey. This device involves the insertion of an expandable, resorbable material inside the lumen of a blood vessel via a tubular member which fits inside an introducer sheath. A retraction filament is secured to the resorbable material for pulling it to the puncture site so that the resorbable material engages the inner surface of the blood vessel contiguous with the puncture. The filament is held taut and taped or otherwise secured to patients' skin to hold the resorbable material in position.
The Kensey device introduces several potential risks to the patient. The device may induce an acute thrombosis due to imperfect alignment of the sealing material or to nonhemocompatibility of the material. The premature degradation of the filament may leave the sealing material unsecured, leading to embolization distal to the puncture site. The migration of the sealing material may not only cause rebleeding, but potential thrombosis which requires surgical intervention. The potential risks involved in such a device may outweigh the benefits such a device can offer. Thus, a safe, effective and user friendly method to close a puncture site and stop the bleeding is still highly desirable and welcome.
It has become apparent to Applicant that the key element in solving puncture site closure complications lies in the design of a resorbable matrix having unique characteristics and properties for such an application.
Accordingly, it is the primary object of the present invention to provide a device which will close a puncture site and stop the bleeding while substantially reducing the disadvantages and risks associated with the prior art.
It is a further object of the present invention to provide an implant which self-expands in vivo to fill the voids or defects of a tissue or organ with a biocompatible, resorbable material.
It is still a further object of the present invention to provide a method to deliver the biocompatible, resorbable implant material to tissues or organs of interest by a tubular delivery device.
It is another object of the present invention to provide a means to deliver medicaments, antibiotics, growth factors and other biologically active molecules to selected tissues or organs.
Its yet another object of the present invention to provide a method of manufacturing the implant.
SUMMARY OF THE INVENTION
By means of the present invention, a self expandable, resorbable, hemostatic implant has been discovered which eliminates or substantially reduces many of the disadvantages and problems associated with the prior art attempts at closing punctured wound sites in vessel catheterization and other soft tissue repair procedures. In addition, by means of the present invention, a method is provided to deliver medicaments to the selected site of a soft tissue. More specifically, by means of the present invention, a resorbable, self-expandable, hemostatic implant is delivered to the specific vessel puncture site to stop the bleeding in post angioplasty and related procedures.
The resorbable, self-expandable tissue closure implant of the present invention is generally a dry, compressed porous matrix comprised of biological fibers. As used herein "bio4
logical fibers" include collagen, elastin, fibrin and polysaccharides. In a preferred form of the invention, the matrix is comprised of collagen fibers of animal or humans.
In particular, the implant of the present invention comprises a compressed matrix having a density of from about 5 0.10 g/cm3 to about 1.30 g/cm3 and pores having an average diameter of from about 0.5 urn to about 50 um. This compressed matrix self expands when in contact with an aqueous medium resulting in pores with an average diameter of from about 100 um to about 3,000 um in its fully 10 expanded configuration, and a corresponding expansion of volume of from about 3 cm3/cm3 to about 100 cm /cm3; and a reduction of density of from about 0.10 to about 1.30 g/cm3 in the compressed configuration to a density of from about 0.01 to about 0.50 g/cm3 in the fully expanded 15 configuration.
The matrix may also include selected medicaments for local therapeutic applications. Therapeutic medicaments include, but are not limited to, hemostatic agents such as thrombin, Ca""" and the like, wound healing agents such as epidermal growth factor (EGF), acidic and basic fibroblast growth factors (FGFs), transforming growth factors alpha and beta (TGF alpha and beta) and the like, glycoproteins such as laminin, fibronectin and the like, various types of collagens.
The method for fabricating the resorbable, self-expandable soft tissue closure implant, in its broadest embodiment, comprises:
a) forming an aqueous dispersion containing biological fibers;
b) pouring the aqueous dispersion into molds;
c) freeze-drying the aqueous dispersion to form a collagen matrix;
d) crosslinking the freeze-dried matrix by treatment with 35 crosslinking agent;
e) spraying the crosslinked matrix with water mist; and then
f) compressing the water mist treated matrix. Still further, the invention includes a method for closing
a soft tissue puncture site with the resorbable, self-expandable implant. The method comprises delivering the resorbable, self-expandable polymer implant in its compressed configuration to the selected site by a delivery means, particularly a tubular delivery device, and releasing the resorbable implant at the selected soft tissue site where the resorbable implant self-expands to conform to the soft tissue site to close the defect. In particular, the method comprises:
a) inserting a delivery means having a longitudinal axis and having an outlet at its distal end into the void of the soft tissue to a depth controlled by a depth insertion guide provided on said delivery means;
b) ejecting an implant, having a length, from said delivery means into the void a controlled distance and in a controlled 55 position, said implant formed of a material capable of being resorbed in the living being characterized by being in a compressed configuration having an average pore size of from about 0.5 um to about 50 um, and being self expandable when wetted to have an average pore size of from about go 100 um to about 3,000 um in the expanded configurtion, wherein (i) the depth insertion guide, (ii) the length of the implant, and (iii) the ejection step, in combination, control the positioning of the implant within the void; and then
c) removing the delivery means to allow the implant to self-expand and form a hydrated matrix conforming to and sealing the soft tissue void.
The invention also includes a device for sealing a void in a soft tissue of a living being comprising:
a) an implant, having a length, formed of a material capable of being resorbed in the living being characterized by being in a compressed configuration having an average pore size of from about 0.5 um to about 50 um, and self-expandable when wetted having an average pore size of from about 100 um to about 3,000 um in the expanded configuration;
b) a delivery means having an outlet at its distal end and a depth insertion guide, said delivery means being adapted to be inserted into the void to a depth which is controlled by the depth insertion guide, said implant being disposed within said delivery means in a compressed configuration; and
c) a retractable ejection means capable of ejecting the compressed implant out of the said outlet a controlled distance into the void of the soft tissue to form an expanded, hydrated matrix which conforms to seal the soft tissue void, wherein the (i) the depth insertion guide, (ii) the length of the implant, and (iii) the retractable ejection means, in combination, control the positioning of the implant within the void.
The resorbable, self-expandable, soft tissue closure implant of the present invention is constructed such that the matrix is highly compressed to provide maximal volume expansion capacity and surface area for fluid absorption, platelet adhesion and hemostasis while maintaining minimal volume for insertion. The highly porous matrix upon expansion also provides maximal surface area for cell infiltration and adhesion for wound healing. Thus, in a preferred embodiment of the present invention, the self-expandable implant of the present invention has the following physical characteristics and physico-chemical properties. It is to be understood that the properties and characteristics given for the self-expandable implant in the "expanded" state are generally the same as and are also descriptive of the collagen matrix prior to being compressed during the formation of the implant.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is the longitudinal cross-sectional view of one embodiment of the present invention showing a soft tissue 15 closure system comprising an implant delivery means and an implant positioned therein.
FIG. 2a depicts the use of the system at a percutaneous puncture site delivering the resorbable implant in crosssectional view. 20
FIG. lb is identical to FIG. la with the only exception being the use of an introducer sheath, which is well known to those skilled in the art, which introducer sheath is inserted into the percutaneous puncture site first into which the 25 implant delivery means of the present invention is subsequently then inserted.
FIG. 3 depicts the resorbable implant in place in crosssection.
DETAILED DESCRIPTION OF THE
Referring now to the figures wherein like reference characters refer to the same elements, FIG. 1 depicts a soft tissue 35 closure system shown generally as 10 comprising an implant delivery means 12 and an implant member 13 disposed within delivery means 12. The primary function of delivery means 12 is to deliver implant member 13 at a desired site in situ to effect the filling and closure of a void in the soft 4Q tissue of a living being. In a preferred embodiment, the soft tissue closure system of the present invention is utilized to effect the closure of a puncture or other opening in a blood vessel, duct or lumen. However, closure system 10 may also be utilized for the treatment of wounds resulting from other 45 voids created to soft tissue in a living being, typically surgeries. Such applications include the filling of voids after removal of malignant tumors, necrotic tissues, degenerative tissues, deep bullet wounds, knife stabbing, and the like. Voids created by plastic or cosmetic surgery, and the like, are 5Q also able to be filled using the closure system of the present invention. Still further, the closure system of the present invention may also be used to stop the bleeding and fill the voids in diagnostic applications, such as tissue biopsy where a biopsy needle or other biopsy device is utilized. 55
While the following description and the Figures are directed to the closure of percutaneous punctures in arteries, it should be understood from the above discussion that the present invention has greater applicability than this preferred embodiment. 60
Delivery means 12 is made from any biocompatible material, such as, stainless steel; synthetic polymeric materials such as polyethylene, polypropylene, polyvinyl chloride, polystyrene, polytetrafiuoroethylene, polyurethane, or the like; natural polymers such as collagen, elastin, or the 65 like; and other such biocompatible materials which are well known to those skilled in the art. Desirably, the delivery
means is made from inexpensive, disposable materials, such that it is simply discarded after use. For ease of manufacture and disposability, synthetic polymers are preferred.
The delivery means shown in the figures comprises a tubular member 11 having an outlet 20 at its distal end and an ejector means 22 slidably mounted at the proximal end 28 of tubular member 11. The tubular member is an elongated body having a depth insertion guide 15, an insertable front portion 32, and flanged projection 30.
Insertable front portion 32 has a fixed length "y" which is selected dependent upon the particular soft tissue site that is being repaired and will generally vary from about 0.2 cm to about 10 cm. It is only this insertable front portion 32 of tubular member 11 which actually is inserted into the patient's skin or the introducer sheath. The depth of insertion is easily controlled by the depth insertion guide 15 which is positioned on tubular member 11 at the length "y" such that the tubular member cannot be inserted past this guide. Guide 15 may simply comprise a partial or full circumferential projection or ledge which will cause the insertion of the delivery means to stop once the insertable front portion has been inserted, said ledge then simply resting upon the outermost surface of the patient's skin or on ledge 62 of introducer sheath 60, as shown in FIG. lb, the use of which is well known to those skilled in the art. The shape or design of the guide is not critical as long as it is capable of controlling the depth of the insertion.
The insertable front portion 32 is preferably constructed of an outside diameter which is less than the introducer sheath that is used for a particular intraluminal procedure so as to enable the insertable front portion 32 to be easily inserted through the skin or the introducer sheath and be juxtaposed to the percutaneous puncture site. Depending upon the particular intraluminal procedure, the outside diameter may vary from about 1 mm to about 6 mm. Except for the insertable front portion 32, the rest of tubular member 11 may have any outside diameter inasmuch as it does not enter the repair site. Desirably, however, for each of construction, the entire tubular member is typically made having the same inside and outside diameters.
Flanged projection 30 is arranged to be grasped by the fingers of the user as the implant member 13 is ejected by ejector means 22. The ranged projection 30 may completely or partially circumscribe tubular body 11 at its proximal end 28.
The ejector means 22 comprises an elongated, cylindrical rod-like member 24 having a push plate 14 attached to its distal end being in a plane which is perpendicular to its longitudinal axis and a thumb rest 26 attached to its proximal end also being in a plane which is perpendicular to the longitudinal axis of rod-like member 24. Push plate 14 is disposed inside of tubular member 11, in insertable portion 32, and has an outside diameter which is slightly less than the inside diameter of insertable portion 32 to enable the push plate 14 to travel down the longitudinal axis of insertable portion 32, to push or force implant member 13 out of the outlet 20. Rod-like member 24 is able to be retracted to a distance of "d", as shown in FIG. 1, which distance is only slightly longer than the length of the implant member 13, so as to ensure complete release of the implant and, most importantly, not push the implant a distance beyond that which is desired. Thus by controlling the length "y" of insertable portion 32, the length of the implant member 13, and distance "d", the implant member 13 is precisely positioned at the repair site.
In use, the closure system of the present invention is desirably utilized as soon as possible after the removal of the
introducer sheath or while the introducer sheath is partially removed from the puncture site. As shown in FIG. 2a, insertable portion 32 is inserted at the repair site through the puncture 42 in skin 40. Depth insertion guide 15 controls the depth of insertion, stopping the travel of the insertable 5 portion 32 once the guide rests upon skin 40. To effect the delivery of the implant member to the repair site, the user grasps projection 30 with his fingers and places his thumb on rest 26. By applying pressure to the thumb rest, the ejector means travels a distance "d" thereby ejecting implant member 13 and delivering it directly over the percutaneous puncture site 42 of vessel 44.
As more clearly shown in FIG. 3, implant member 13 is not positioned inside of the lumen vessel 44, but rather, by the controlled insertion depth provided by the present inven- 15 tion, is delivered extravascularly such that end 46 of the implant member rests outside and directly on top of the puncture vessel. The ejected implant member 13 expands quickly in situ to completely close the puncture site as the delivery device is slowly being removed. 20
FIG. 3 is a schematic representation of a closed puncture site. The implant member 13 is shown as having considerably swelled and the blood around the implant member has been absorbed and clotted through a collagen induced hemostatic mechanism forming blood clot 50. A wound bandage 25 is shown as 52.
The implantable, resorbable member 13 is made primarily from biopolymers, such as proteins, polysaccharides or the like. Preferably, a collagen based material is used due to its intrinsic hemostatic properties. 30
Type I to type XIV collagens may be used either singularly or in combination for the manufacture of the implantable member 13. Preferably, type I collagen is used due to the availability of this material in large quantity, the ease of its isolation and purification, and proven hemostatic prop- 35 erties. The primary source of type I collagen is tendon, skin, bone, and ligament. Both human and animal tissues may be used to isolate the collagen. In general, animal tissues are preferred due to easy availability in fresh forms from local slaughter houses. 40
In preparing the implantable member 13, type I collagen is first isolated and purified. A review of the preparation of collagen can be found in "Methods in Enzymology," vol. 82, pp. 33-64, 1982. In particular the collagen of the present invention may be prepared by the following method. 45
First, a native source of type I collagen, such as skin, tendon, ligament or bone is first cleaned of fat, fascia and other extraneous matter and washed. The clean and washed collagen containing material is then comminuted by slicing 5Q or grinding. Bone material is subsequently subjected to a demineralization procedure. This is achieved either with an acid solution such as hydrochloric acid or a solution of chelating agent such as ethylenediaminetetraacetic acid (EDTA). 55
The material is then subjected to a defatting treatment using fat solubilizing agents such as ethanol, propanols, ethers or a mixture of ether and alcohol. The defatted collagen containing material is then extracted in a neutral salt solution to remove neutral salt soluble material. Typi- go cally, 1 M NaCl solution is used for this purpose. The high ionic strength salt solution weakens the non-specifically bound non-collagenous materials which are solubilized and removed. The salt extracted collagen containing material is then washed with deionized, distilled water. 65
The neutral salt extracted collagen containing material is then subjected to an acid extraction in the presence of a
structure stabilizing salt to further remove acid soluble non-collagenous materials. Applicable acids include acetic acid, lactic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and the like. Regardless of which acid is used, the pH of the acid solution is adjusted to be below 3. The salt used include sodium chloride, ammonium sulfate, sodium sulfate, or the like. Acid extraction weakens the interaction between the collagen and the acidic non-collagenous impurities which are solubilized and removed.
The acid extracted collagen is then neutralized by adjusting the pH to its isoelectric point at pH of from about 6 to about 7 by adding a base. Applicable bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, and the like. By adding a base, the collagen coacervates. The coacervated collagen is then filtered by means well known in the art such as using a stainless steel mesh filter under vacuum.
The acid extracted, base neutralized collagen is then washed with deionized, distilled water to remove the residual salt formed by the neutralization procedure. The washed collagen is then subjected to a base extraction in the presence of a structure stabilizing salt. Such bases are well known in the art such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. Regardless of which base is used, the pH of the solution is adjusted to be above 13. Base extraction weakens the interaction between collagen and the basic non-collagenous impurities. By adding the base, non-collagenous materials are solubilized and removed. The base also lowers the isoelectric point due to a partial deamidation of glutamines and asparagines in collagen which produce additional carboxyl groups. The base extracted collagen is then coacervated by adjusting the pH to its isoelectric point at a pH of from about 4.5 to 5.5 by adding an acid to the collagen dispersion so as to fully separate the fibers from the solution for ease of filtration. Such acids include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, phosphoric acid and the like. The coacervated collagen is then filtered. After discarding the extraction solution, the fibers are washed with deionized, distilled water to remove the residual salts resulting from neutralization of the extraction solutions. The thusly purified collagen is stored in a freezer or stored in freeze-dried form for the preparation of collagen implantable member 13.
To fabricate a collagen implantable member 13, a collagen dispersion is first prepared in a manner well known in the art. One such preparation is taught in U.S. Pat. No. 3,157,524, which is incorporated herein by reference as if set out in full. Another preparation of collagen dispersion is taught in U.S. Pat. No. 3,520,402 which is also incorporated as if set out in full.
In particular, the collagen dispersion of the present invention may be prepared by the following method.
The purified collagen material is first dispersed in 1x10"^ M NaOH solution to swell the collagen fibers. The collagen material is then homogenized by any conventional means such as with a blender or homogenizer so as to fully disperse the fibers. The homogenized collagen is then filtered to remove any unswollen aggregates by means well known in the art such as by passing the dispersion through a stainless steel mesh screen. The pH of the dispersion is adjusted to about 7.4 by adding 0.01 M HC1. The initial dispersion in a base allows the neutralization step to be carried out without passing the isoelectric point so as to not cause coacervation of the collagen and obtain a more uniform dispersion at pH 7.4. The dispersion is then de-aired by vacuum. The resulting collagen dispersion may then be used to prepare the self-expandable, implantable soft tissue closure device.