US20020128683A1 - Method and apparatus for preparing fibrinogen adhesive from whole blood - Google Patents
Method and apparatus for preparing fibrinogen adhesive from whole blood Download PDFInfo
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- US20020128683A1 US20020128683A1 US10/072,509 US7250902A US2002128683A1 US 20020128683 A1 US20020128683 A1 US 20020128683A1 US 7250902 A US7250902 A US 7250902A US 2002128683 A1 US2002128683 A1 US 2002128683A1
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- fibrinogen
- chamber
- plasma
- adhesive
- dispensing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00491—Surgical glue applicators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/75—Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00491—Surgical glue applicators
- A61B2017/00495—Surgical glue applicators for two-component glue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/81—Packaged device or kit
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S604/00—Surgery
- Y10S604/902—Suction wands
Definitions
- the invention is related to medical and veterinary technology and procedures. More specifically, it concerns a convenient method for preparation of a fibrinogen adhesive directly from withdrawn blood.
- These authors adapted the method of Masri, M. A., et al., Thromb Hemeostas (1983) 49:116-119, which involved incubation of the harvested plasma with barium sulfate and magnesium sulfate in order to remove thrombin (and thus prevent premature fibrin formation) followed by treatment of the supernatant from the resulting precipitation with a 30% solution of polyethylene glycol (PEG) of MW approximately 1000.
- PEG polyethylene glycol
- the product was found to contain about 13-50 mg/ml of fibrinogen when the material precipitated from 50 ml blood was brought to a volume of 1 ml, wherein this concentration varies with the concentration of PEG.
- the percent of total protein attributable to fibrinogen ranged from 42-92 percent; the lower the PEG concentration, the higher the percentage of fibrinogen.
- the concentrations of kallikrein and pre-kallikrein were shown to be reduced to 1-2% of their levels in plasma in the presence of 10% PEG, and Factor XIII activity was shown to be present.
- the present invention by providing a surprisingly simple method and apparatus for the preparation of autologous adhesive, permits the autologous composition to be prepared in the operating room and administered at the time of preparation.
- the adhesive is administered as a two-component system—the fibrinogen preparation as one component and a thrombin/Ca +2 composition as another.
- the TissucolTM system uses a double-syringe arrangement wherein the two components are mixed in the injector immediately prior to dispensing. No means to remove debris or excess adhesive from the site of application is provided, and the potential for premature adhesion also exists.
- the present invention also provides an applicator with a premix immediately upstream of the application outlet means and a means to apply suction at the outlet to maintain the application area in condition for successful adhesion.
- the invention provides effective means to prepare and administer autologous plasma-derived adhesive during the course of a surgical procedure.
- the method of the invention can also be used to prepare the adhesive under less constrained conditions, but the simplicity and ease with which the invention method results in the desired adhesive makes it adaptable to this important use.
- the invention process provides the desired adhesive composition in a one-step treatment directly applicable to separated plasma using a recognized, nontoxic precipitant, such as suitable concentrations of amino acids, but preferably a nontoxic polymer such as polyvinyl alcohol (PVA) or polyethylene glycol (PEG).
- a nontoxic polymer such as polyvinyl alcohol (PVA) or polyethylene glycol (PEG).
- PVA polyvinyl alcohol
- PEG polyethylene glycol
- the invention is directed to a process for preparing a fibrinogen adhesive composition from whole blood, which process comprises directly contacting plasma with an amount of polyethylene glycol of molecular weight 200-8000, or other precipitant selected from the group consisting of amino acids and nontoxic hydrophilic polymers, which is effective to precipitate the fibrinogen-containing fraction. Then the precipitated fibrinogen fraction is recovered for use, either by mechanical disruption of the precipitate or pellet or by suspension in an aqueous medium.
- the invention is directed to the fibrinogen-containing preparation obtained by the method of the invention.
- the invention is directed to an apparatus for preparing the fibrinogen composition consisting essentially of a device with dual separation chambers with a means for fluid communication between the chambers.
- the invention is directed to an applicator for injecting this or any other two-component system into a human or other animal subject which provides for simultaneous application of suction at the outlet for the components, and to a method to administer the fibrinogen composition using this apparatus.
- FIG. 1 is a perspective view of one embodiment of the apparatus of the invention for preparing the plasma-derived adhesive.
- FIG. 2 is an alternative embodiment of the isolation apparatus of the invention.
- FIG. 3 is an additional alternative embodiment of the isolation apparatus of the invention.
- FIG. 4 is a longitudinal sectional view of an apparatus for administering a two-component composition to an animal subject.
- FIG. 5 is a perspective view of the apparatus of FIG. 3.
- FIGS. 6A and 6B are perspective views of the mixing head of the apparatus of FIGS. 4 and 5.
- FIG. 7 is a perspective view of the filler tray and reservoir tip of the apparatus of FIGS. 4 and 5.
- the adhesive composition of the invention contains substantial amounts of fibrinogen and sufficient Factor XIII to effect fibrin formation and cross-linking in the presence of added thrombin and calcium ion.
- fibrinogen adhesive composition refers to a fraction of blood plasma which contains substantial amounts of fibrinogen and sufficient amounts of other factors required for fibrin formation that, when combined with a preparation of thrombin and calcium ion, fibrin formation and cross-linking takes place conferring on the composition the properties of a tissue adhesive.
- the necessary components of the fibrinogen adhesive composition are fibrinogen itself and Factor XIII.
- Other components may also be present or may be added to modify and improve the effect of the adhesive.
- a fibrinolysis inhibitor such as aprotinin or aminocaproic acid can also be added.
- the levels of kallikrein and prekallikrein are greatly reduced from those present in plasma; these factors are also fibrinolytic.
- Other additives useful for purposes not directly related to the adhesive properties of the composition may also be included, such as various protein factors which are useful in wound healing, for example, fibroblast growth factor, platelet-derived growth factor, various angiogenic factors and the like.
- compositions may be prepared sufficiently efficiently to permit the use of an autologous fraction, other factors from plasma which aid in clotting, such as Factor VIII and immunoglobulins, are beneficial rather than detrimental when brought down with the fibrinogen precipitate.
- concentration of the precipitant and/or, in this case of a polymeric precipitant, its molecular weight variable amounts of these factors may be included in the composition.
- the method of the invention which provides the fibrinogen adhesive composition is straightforward and sufficiently simple that it can be used in the operating room to provide an autologous adhesive preparation.
- the appropriateness of the process for this application does not mean, of course, that its application is thus limited.
- This straightforward process can be used as well in the preparation of fibrinogen adhesive compositions in advance of surgery from autologous, designated donor, or pooled plasma sources, if desired.
- the process results in a composition which has 50-80 mg/ml of fibrinogen, in general, as compared to the 2-6 mg/ml concentration in plasma or whole blood. This is a range comparable to the commercially available TisseelTM composition which contains 70-110 mg/ml. Also, like the commercial TisseelTM composition, the fibrinogen adhesives of the present invention contain sufficient Factor XIII to provide cross-linking of the fibrin obtained. There may also be present varying amounts of plasma components which are not absolutely necessary for fibrin formation but may be helpful, such as, e.g., Factor VIII, prostaglandins, and platelets.
- the process begins with the withdrawal of whole blood from an autologous, or other, or multiple donors in the presence of an anticoagulant, and separation of plasma from the red blood cell fraction.
- Typical anticoagulants include heparin and sodium citrate; others generally known in the art may also be used. If sodium citrate is used, it is generally supplied as a buffer at physiological pH with citrate ion present at 3-5%. The sodium salt is preferred.
- the range of means to prepare citrate and other anticoagulants suitable for primary separation of blood into red blood cells and plasma is well understood in the art.
- the separation can be effected by centrifugation; a suitable protocol involves spinning at about 2000-5000 g for about 5-10 minutes.
- the plasma is separated from the red blood cells, it is treated directly, at ambient temperature, without prior treatment to remove thrombin, with a physiologically acceptable nontoxic precipitant.
- the precipitants of the invention include the natural amino acids and nontoxic polymers, especially polyvinyl alcohol and, most preferably, polyethylene glycol.
- Preferred amino acids are small neutral amino acids such as glycine, serine and alanine, most preferably glycine.
- Most preferred among the polymer precipitants is polyethylene glycol in a molecular range of 200-8000 supplied as a concentrated solution.
- the precipitant is preferably supplied as a concentrated solution which, when mixed with plasma, will yield a concentration effective in precipitating the adhesive composition.
- Optimal concentration of the precipitant can readily be determined by routine experimentation; simple in vitro assays for fibrin formation, such as those described by Epstein, G. H., et al., Anals Otol Rhinol and Laryngol (1986) 287:999-1005, can be used, and fibrinogen content measured as described.
- the concentrated solution or, in some instances, undiluted precipitant is added to the plasma in an amount effective to precipitate the fibrinogen adhesive composition of the invention.
- the final concentration of PEG depends on the concentration of plasma in the precipitating solution and on the molecular weight of the PEG.
- a suitable and typical set of parameters utilizes an approximately 60% solution of PEG of molecular weight 1000 in saline at pH 7.4, and the plasma is added in sufficient volume (typically 10% w/v of precipitant solution/final volume) to obtain a resulting concentration of 8-15% w/v PEG in the volume of the final mixture.
- the plasma itself is, therefore, only slightly diluted.
- the precipitation takes place at room temperature and is complete essentially instantaneously, although generally it is advantageous to cure the precipitate for 5-10 min.
- the precipitate containing the fibrinogen adhesive is then recovered, typically by centrifugation.
- the pellet may be recovered by mechanical disruption or resuspended in normal saline for use at a concentration of about 50 mg/ml-80 mg/ml of fibrinogen.
- a fibrinogen adhesive composition which would contain 30-50 mg fibrinogen when resuspended to 1.5 ml is obtained.
- the use of the amino acids and biocompatible polymers as precipitant has considerable advantage over the prior art use of ethanol and cryoprecipitation.
- the resulting concentration of fibrinogen is markedly higher, and the precipitants are recognized material safe for internal use.
- PEG has been used as a lubricant or conditioner in ointments and in pharmaceutical and cosmetic preparations, including injectables. It is a water-soluble, nonvolatile material of no known clinical toxicity.
- the amino acids are, of course, nontoxic metabolites and are common components of pharmaceutical compositions.
- the remaining supernatant plasma fraction which contains platelets and white blood cells, can be reused for other purposes; similarly, the red blood cells removed could, if desired, be returned to the patient.
- the process of the invention can be conducted using standard laboratory and medical equipment.
- the blood may simply be withdrawn into a syringe containing anticoagulant and emptied into a centrifuge tube for separation.
- the supernatant plasma can then be removed by a syringe containing the precipitant or can be pipetted into a separate vessel and the precipitant added.
- the suspension can then be centrifuged using standard equipment and the precipitated material disrupted or resuspended by addition of saline after removal of the supernatant.
- the invention apparatus contains two chambers, both of which can be used directly in a laboratory or medical centrifuge.
- the first chamber is designed to effect the separation of plasma and red blood cells; the second chamber provides a method to separate the fibrinogen adhesive composition from the supernatant plasma fraction. Because a means of fluid communication is provided between the first and second chamber, the plasma obtained in the first chamber can be made the subject of fibrinogen adhesive separation in the second, and the supernatant from the precipitate can be returned to the first chamber.
- the first chamber generally contains an effective amount of anticoagulant; the second chamber contains an effective amount of precipitant such as polyethylene glycol solution to effect precipitation of the fibrinogen adhesive.
- the apparatus then, comprises a first and second chamber, a means of fluid communication between the first and second chambers and a means to interrupt this communication, wherein the first chamber contains anticoagulant and the second chamber contains the precipitant and permits the removal of the precipitate.
- FIG. 1 One convenient embodiment of the apparatus of the invention is shown in FIG. 1.
- the apparatus consists of two especially adapted syringe bodies 10 and 11 interconnected by a supported tube 12 .
- the tube is provided with a valve 13 which is capable of turning on and off the flow of fluid between chambers 10 and 11 .
- Both of the chambers are fitted onto the frame and locked onto a tube having a T-joint at 10 t and 11 t .
- Both syringe cylinders are provided with a modified plunger 10 p and 11 p which may be withdrawn by a pulling means such as a plastic cord 10 c and 11 c causing the withdrawal of the plunger to a position flush with the ends of the cylinders where the top of the plunger is sealed by a flange ( 10 f and 11 f ) when withdrawn to a fully extended position.
- a pulling means such as a plastic cord 10 c and 11 c causing the withdrawal of the plunger to a position flush with the ends of the cylinders where the top of the plunger is sealed by a flange ( 10 f and 11 f ) when withdrawn to a fully extended position.
- the plasma separation chamber 10 is fitted with a needle 10 n which is inserted into the subject for withdrawal of blood.
- the valve 13 is closed during this step, thus preventing the formation of a vacuum in the connecting tube 12 and confining the flow of blood to the chamber 10 when the plunger 10 p is withdrawn by pulling the cord 10 c .
- the size of the plunger is adjusted to permit withdrawal of a predetermined amount of blood, typically 60 cc.
- the chamber 10 is previously supplied with sufficient citrate buffer to obtain a concentration of about 4% citrate ion when the predetermined amount of blood is withdrawn.
- valve 13 After centrifugation, the valve 13 is opened and the plunger 11 p is withdrawn and sealed at flange 11 f , thus transferring the plasma into chamber 11 .
- Chamber 11 is presupplied with an approximately 60% PEG solution of molecular weight 1000, or a comparable concentration of an alternate molecular weight sufficient to effect precipitation of the fibrinogen adhesive.
- the motion of the plungers is stopped when the red blood cells reach the upper portion of the chamber 10 .
- the valve 13 is then closed.
- the red blood cells remaining in chamber 10 can be withdrawn or expelled and returned to the patient.
- the apparatus is then agitated, if necessary, to intermix the PEG with the plasma. Outlet 11 o remains sealed.
- the chamber 11 is then centrifuged either within the device or after removal therefrom to separate the precipitate from the supernatant plasma.
- the apparatus is, of course, inverted from the position shown in FIG. 1. After about 15-20 minutes at 6000-10,000 g sufficient separation of precipitate has occurred.
- the chamber 11 is replaced in the apparatus if it has been removed, and the valve 13 again opened while the outlet 11 o remains sealed.
- the supernatant is then withdrawn into chamber 10 by withdrawal of plunger 10 p ( 10 o remains closed) until the fibrinogen precipitate begins to enter the connecting tube 12 ; valve 13 is then closed.
- the fibrinogen adhesive is removed for use from chamber 11 by further reinsertion of the plunger 11 p , or preferably by withdrawal into the syringe attached at the outlet 11 o . If desired, the fibrinogen adhesive can be diluted in saline and the composition quantitatively removed from chamber 11 by washing.
- chamber 10 now contains all blood components except the fibrinogen adhesive composition and contains as added components only anticoagulant and the clearly nontoxic PEG. Therefore, the modified blood in chamber 10 could, if necessary, be used for other purposes or returned to the patient.
- FIG. 2 shows an alternative embodiment of the apparatus of the invention which dispenses with the need for the frame 14 .
- This apparatus consists essentially of two syringes with detachable plungers and a Luer-locked connector.
- This embodiment has the advantage of utilizing standard medical equipment but the disadvantage of utilization of several separate parts.
- the blood separation syringe 20 is fitted with a needle for the withdrawal of blood.
- chamber 20 is supplied with a premeasured quantity of citrate which, when mixed with the withdrawn blood will result in a citrate buffer of about 4% citrate ion.
- the plunger is retracted and chamber 20 contains whole blood, the needle and the extended portion of the plunger are detached to permit the syringe body and sealed end to be placed in a centrifuge, with the Luer lock outlet 20 o sealed.
- Suitable syringes with plungers which can be detached and the body sealed for centrifugation of the syringe body are available commercially.
- the syringe barrel 20 is then centrifuged as described above, and Luer lock at 20 o is engaged by the interconnecting tube 24 , and the plunger is replaced. With the syringe in the inverted position, the interconnector 24 is attached to a second similarly constructed syringe 21 at Luer lock 21 o .
- Syringe 21 contains a premeasured quantity of PEG. Plasma is transferred from chamber 20 to chamber 21 through retraction of the plunger 21 p which causes effective reinsertion of plunger 20 p . When red blood cells begin to enter the interconnector, an event which is readily observable, the interconnector 24 is detached from chamber 21 and the mixture of plasma and PEG in chamber 21 agitated if necessary.
- Syringe 21 is then prepared for centrifugation by removal of the extended portion of the plunger and sealing of the body of the syringe, and closure at 21 o , and the fibrinogen adhesive and plasma are separated under the centrifugation conditions described above.
- the interconnector 24 and plunger 21 p are then put back in place and the plasma supernatant withdrawn into chamber 20 by retraction of plunger 20 p .
- fibrinogen adhesive precipitate begins to enter the interconnector, the interconnector is detached and the fibrinogen adhesive expelled into diluent, or diluent is withdrawn into chamber 21 through 21 o.
- the resuspended fibrinogen adhesive is placed in a suitable applicator for use.
- FIG. 3 shows a third embodiment of the apparatus for isolation of the fibrinogen adhesive.
- Chambers 30 and 31 are connected through the tubing 32 , which is regulated by a valve 33 .
- Any suitable type of valve can be used; as shown in FIG. 3, valve 33 operates by sliding the roller so as to pinch off the tubing 32 .
- Chambers 30 and 31 are attached to each other by sealing or by forming the chambers using the same mold; the chambers are, as before, preloaded with suitable amounts of anticoagulant (chamber 30 ) and precipitant (chamber 31 ).
- Chambers 30 and 31 are provided with outlets 30 o and 31 o at the sides of the chambers, as shown.
- Outlet 30 o is a Luer lock designed to accommodate a needle as ordinarily attached to a syringe.
- Outlet 31 is a Luer lock designed to accommodate an externally attached syringe body. Both outlets 30 and 31 have detachable sealing caps 30 s and 31 s.
- the chambers 30 and 31 have plungers 30 p and 31 p which are sealed with gaskets 30 g and 31 g to the sides of the chambers. When fully withdrawn, the plungers are snug against the end plates 30 e and 31 e at the bases of the chambers.
- the plungers are withdrawn by a flexible plastic cord 30 c and 31 c , which are provided with disks 30 d and 31 d to aid in the withdrawal. Additional apertures 30 a and 31 a permit insertion of rigid rods to push the plungers forward, if required; however, the movement of the plungers is generally effected by application of a vacuum either by withdrawal of the plunger in the adjacent chamber or by an externally attached syringe.
- FIG. 3 The operation of the apparatus as shown in FIG. 3 is substantially analogous to that shown in FIG. 1.
- the patient's blood about 60 cc
- Outlet 30 o is then sealed, the apparatus is placed in a centrifuge, and the plasma and red blood cells in chamber 30 are separated.
- Valve 33 is then opened and plunger 31 p is withdrawn until the red blood cells are seen entering the tubing 32 .
- Valve 33 is closed, and the apparatus is agitated, if necessary, and inverted and centrifuged to separate the fibrinogen adhesives from the supernatant plasma.
- the red blood cells in chamber 30 may be returned to the patient by an attached needle and pushing the plunger 30 p prior to centrifugation, if desired.
- valve 33 is again opened and plunger 30 p withdrawn to draw the supernatant into chamber 30 . Withdrawal of the plunger is stopped as soon as the supernatant has left chamber 31 .
- Outlet 31 o is opened and a syringe body attached.
- the fibrinogen adhesive pellet is disrupted, for example, by repeated motion of the syringe plunger, and, if desired, saline may be included in the attached syringe to achieve quantitative transfer of the fibrinogen adhesive.
- the adhesive composition is then placed in a suitable applicator for administration to the subject.
- the fibrinogen adhesive composition of the invention is useful in medical and veterinary applications generally comparable to those known in the art for the commercially available product TissucolTM.
- Commercial preparations of thrombin and calcium ion for admixture with the fibrinogen adhesive of the invention are commercially available and are used as is generally known in the art.
- a dual-barreled applicator with one barrel for supply of the fibrinogen adhesive and the other for the thrombin/calcium ion mixture is employed wherein the outlet of each barrel is proximal to a suction device so that the surface prior to application can be instantly cleaned and excess components immediately removed.
- the provision of suction at the site of sealant application permits the withdrawal of interfering substances as well as control of the quantity of sealant applied.
- the modified adhesive applicator described hereinbelow is highly advantageous. This device is designed to permit controlled application of both fibrinogen adhesive and thrombin/calcium mixture with premixing of these components immediately prior to injection along with a means to produce suction for surface cleaning and excess sealant removal.
- FIGS. 4 - 7 A particularly advantageous design of such an applicator is shown in FIGS. 4 - 7 herein, and was described in U.S. Ser. No. 06/683,621 filed Dec. 19, 1984 by the applicant, and now abandoned.
- FIGS. 4 and 5 show a housing 2 which resembles a pen in both size and shape, and which is held in a similar fashion.
- the interior of the housing 2 includes a chamber 4 having walls that are sufficiently flexible so that the chamber 4 may be compressed by a relatively slight amount of external pressure.
- the walls of the chamber 4 are sufficiently resilient so that, in the absence of external pressure, the chamber 4 will return to its original volume and configuration.
- the chamber 4 is divided into a first compartment 6 and a separate but identical second compartment 8 .
- one chamber ( 6 ) contains the fibrinogen adhesive composition and the other ( 8 ) contains the thrombin/Ca +2 preparation.
- the chamber 4 consists of a rubber bulb, although it is recognized that any chamber whose volume may be easily reduced and expanded may serve as the chamber 4 .
- the first compartment 6 of the chamber 4 is connected to a first liquid channel 10 which runs lengthwise through the interior of the housing 2 and which terminates at the housing end piece 12 .
- the second compartment 8 of the chamber 4 is likewise connected to a second liquid channel 14 which runs parallel to the first liquid channel 91 and which similarly terminates at the housing end piece 92 .
- the housing end piece 92 is fitted with an adaptor 22 which is configured to receive a connector 24 or 93 of a detachable channel extension 25 .
- the channel extension 25 includes two liquid channels 26 and 28 (and a suction channel 97 to be described below).
- the liquid channels 28 and 26 serve as extensions, respectively, of the fluid channels 91 and 95 and as reservoirs for the fibrinogen adhesive and the Ca +2 /thrombin preparation.
- the channel extension 25 may be configured in a variety of lengths and shapes, depending upon the particular requirements of the applicator.
- the use of a detachable channel extension 25 allows a single applicator housing 2 to be used in conjunction with a variety of differently configured channel extensions 25 .
- the present invention also includes a mixing head 94 (see FIGS. 6A and 6B)
- the mixing head 94 includes three entry ports of which two, 34 and 36 , are configured to be attached respectively to the distal ends 40 and 42 of the liquid channels 26 and 28 .
- the interior of the mixing head 94 includes a Y-shaped channel 46 which connects the entry ports 34 and 36 with the exit port 48 .
- the liquid adhesive components dispensed through the entry ports 34 and 36 are thereby combined in the channel 46 before being ejected through the single exit port 48 .
- a single adhesive channel tube 50 is connected to the exit port 48 , thus permitting the premixed adhesive to be applied.
- the apparatus as shown in FIGS. 4 and 5 includes a suction channel 16 which is incorporated into the wall of the housing 2 and which runs parallel to the first and second liquid channels 91 and 95 .
- Suction channel 16 also terminates at the housing end piece 92 .
- the proximal end of the suction channel 16 is surrounded by an adaptor 18 which is configured to connect the suction channel 16 to a remote vacuum source (not shown).
- Operation of the suction channel 16 is controlled by means of a venturi opening 96 which is located on the exterior of the housing 2 . Obstruction of the venturi opening 96 permits the suction force which originates at the remote vacuum source to be conducted through the length of the section channel 16 .
- the interior of the mixing head 94 also includes a channel 52 which connects the entry port 38 with an exit port 54 .
- the channel 52 serves to conduct the suction force from the distal end 44 of the suction channel 97 to the exit port 54 .
- a single suction channel tube 56 is connected to the exit port 54 .
- the suction channel tube 56 is shorter than the adhesive channel tube 50 so that the suction channel tube 56 does not interfere visually or functionally with the application of the adhesive. Materials from the site of application, when suctioned, are drawn along the exterior surface of the adhesive channel tube 50 to the orifice of the suction channel tube 56 . This provides gentle, atraumatic suction required in microsurgery.
- the leverage mechanisms 58 includes an outer lever arm 60 and an inner lever arm 62 . Both lever arm 60 and lever arm 62 turn about a fulcrum 64 .
- the free end 66 of the outer lever arm 60 is positioned adjacent the venturi opening 96 of the suction channel 16 . This placement allows the operator to switch rapidly and with a minimum amount of movement from the control of the venturi opening 96 to the control of the lever arm 60 .
- the free end 68 of the inner lever arm 62 rests against the exterior of the flexible bulb 4 . Movement of the free end 68 of the inner lever arm 62 toward the bulb 4 will cause both compartments 6 and 8 of the bulb 4 to be compressed in equal amounts, thereby causing a small quantity of air to be displace from each of the compartments 6 and 8 through the liquid channels 91 and 95 , respectively. Movement of the free end 68 of the inner lever arm 62 away from the bulb 4 will allow the resilient bulb material to return to its original dimensions.
- the lateral motion of the free end 66 of the outer lever arm 60 that is transferred to the free end 68 of the inner lever arm 62 is proportional to the relative lengths of the outer lever arm 60 and inner lever arm 62 . If the inner lever arm 62 is shorter than the outer lever arm 60 , as shown in FIGS. 4 and 5, then a relatively large lateral motion of the free end 66 will be translated into a relatively short lateral motion of the free end 68 . In this manner, a relatively broad finger-controlled lateral movement of the lever arm 60 may be used to control a relatively small displacement of air through each of the liquid channels 91 and 95 .
- ratchet wheel 70 The pivot ends of both the outer lever arm 60 and the inner lever arm 62 are fixed to a ratchet wheel 70 .
- the rotational axis of the ratchet wheel 70 is concentric with the fulcrum 64 .
- Disposed about a portion of the circumference of the ratchet wheel 70 is a set of spaced ratchet teeth 72 .
- a pawl 74 is positioned to engage the ratchet teeth 72 , and to thereby prevent movement of the ratchet wheel 70 in a clockwise direction as shown in FIG. 4.
- a finger-operable pawl release 76 is attached to the pawl 74 .
- the pawl release 76 provides a mechanism for disengaging the pawl 74 from the ratchet teeth 72 , thereby allowing unrestricted movement of the ratchet wheel 70 .
- the combination of the ratchet wheel 70 and pawl 74 thereby provides a mechanism for stopping movement of the lever arms 60 and 62 (as well as compression or expansion of the bulb 4 ) at a plurality of fixed intervals.
- the size of these intervals is dependent on the spacing between the teeth 72 and the circumference of the ratchet wheel 70 .
- the two components of the dual-component adhesive are drawn into the channels 26 and 28 from a filler tray 78 shown in FIG. 7.
- the filler tray 78 is designed to orient the operator so that the possibility of drawing a liquid component into the incorrect channel is minimized.
- the filler tray 78 is generally of rectangular configuration and divided by a septum 80 along the center of its longer axis into a first container 82 and second container 84 .
- the floor of the first container 82 has a trough 86 which is perpendicular to the septum 80 .
- the floor of the second container 84 has a similar trough 88 which is also perpendicular to the septum 80 .
- Both troughs 86 and 88 are located closer to one end of the filler tray 78 than the other.
- the resulting asymmetry of the filler tray 78 provides a useful visual orientation for the operator.
- Both troughs 86 and 88 slant downward toward the septum 80 , so that even a small amount of liquid placed in either container 82 or 84 will pool towards the septum 80 .
- the height and width of the septum 80 are selected so that the distal end 40 of the channel 26 will rest in the lowest part of the trough 88 at the same time that the distal end 42 of the channel 28 will rest in the lowest end of the trough 86 . In this way, even small amounts of liquid in the containers 82 and 84 will be directed to the distal ends 40 and 42 of the channels 26 and 28 .
- the height of the septum 80 is selected so that the distal end 44 of the suction channel 97 rests above the septum 80 when fluid is drawn from the filler tray 78 .
- the points at which the distal ends 40 and 42 of the channels 26 and 28 rest adjacent to the septum 80 are the lowest of all points in the filler tray 78 . In this way any fluid placed in either container 82 or 84 of the tray 78 will pool towards the distal ends 40 and 42 during the filling of channels 26 and 28 .
- the filler tray 78 is anchored to a heavyweight base 90 to help prevent the liquid contents of the filler tray from being spilled.
- the outer lever arm 60 is first pressed toward the housing 2 so that the fulcrum 64 rotates in a counterclockwise direction as shown in FIG. 4.
- the free end 68 of the inner lever arm 62 is thereby forced against the exterior of the bulb 4 , compressing the bulb.
- the free end 68 of the lever arm 62 will be held in place against the bulb 4 by means of the pawl 74 engaging the ratchet teeth 72 of the ratchet wheel 70 .
- the distal ends 40 and 42 of the fluid channels 26 and 28 are then removed from the containers 82 and 84 of the filler tray 78 .
- the mixing tip 94 is then attached to the fluid channels 26 and 28 and the suction channel 97 .
- the mixing tip 94 is brought to the work surface. If cleaning of the surface is desired immediately before application of the adhesive, then the venturi opening 96 of the suction channel 16 is closed off by the operator's finger.
- the suction force created by a remote vacuum attached to the proximal end of the suction channel is transmitted via suction channel 16 to the work surface. Fluid and debris on the work surface is thereby removed through the suction channel 16 .
- the ratchet teeth 72 may be positioned so that each “click” represents the deposit of a predefined amount of adhesive. For example, if the ratchet teeth 72 are positioned so that each “click” corresponds to the deposit of one microliter of adhesive, then an operator wishing to apply precisely three microliters of adhesive will press the outer lever arm 60 until three “clicks” are heard. The operator's visual attention to the work area thereby remains uninterrupted.
- the fibrinogen adhesive of the invention is applied along with a calcium/thrombin composition as understood by the art by any suitable application means.
Abstract
A process and apparatus for one-step preparation of fibrinogen adhesive by polyethylene glycol-mediated precipitation from plasma are disclosed. The methods and apparatus of the invention permit preparation of autologous fibrinogen adhesive composition from the patient during surgery, and can be applied generally to provide such compositions. Also disclosed are an apparatus and method for application of sealant comprising this fibrinogen adhesive composition.
Description
- The invention is related to medical and veterinary technology and procedures. More specifically, it concerns a convenient method for preparation of a fibrinogen adhesive directly from withdrawn blood.
- The need for a suitable tissue adhesive for use in surgical procedures in human and animal medicine is well understood, and has been for nearly a century. Various substances have been tried, including completely synthetic materials such as cyanoacrylate. Because, however, the ability of the natural material fibrin to behave as an adhesive is known, fibrin powders were used for this purpose early in the development of this technology.
- It has also long been recognized that the in situ formation of fibrin from fibrinogen is a preferable approach. In a relatively recent article, Staindl, O., in Ann. Otol. (1979) 88:413-418, described the use of a combination of three separately prepared substances, human fibrinogen cryoprecipitate, thrombin in the presence of calcium ion, and Factor XIII concentrate, to obtain a glue that was applied in skin graft applications, myringoplasty, repair of dural defects, hemeostatis after tonsillectomy, and tracheoplasty. Around this time, Immuno-AG, Vienna, Austria, began producing and commercializing a two-component “fibrin seal” system, wherein one component contains highly concentrated human fibrinogen, Factor XIII, and other human plasma proteins, prepared from pooled blood, and the other component supplies thrombin and calcium ion. The two components are added together in the presence of a fibrinolysis inhibitor. After application, the processes of coagulation and fibrin cross-linking occur. Eventually, the seal may lyse in the process of healing of the wound or trauma which accompanies the reconstruction of the tissue. Redl, H., et al., “Biomaterials 1980,” Winter, G. D., et al., eds. (1982), John Wiley & Sons, Ltd., at page 669-675, describe the development of an applicator device for this system which mixes and applies the two components of the system simultaneously.
- This two-component system has been marketed over the last ten years under the trade name Tissucol™ or Tisseel™, and a number of publications have appeared describing the use of this preparation in surgical procedures. See, for example, Seelich, T., J Head and Neck Pathol. (1982) 3:65-69; O'Connor, A. F., et al., Otolaryngol Head Neck Surg. (1982) 90:347-348; Marquet, J., J Head and Neck Pathol. (1982) 3:71-72; Thorson, G. K., et al., J Surg. Oncol. (1983) 24:221-223. McCarthy, P. M., et al., Mayo Clin. Pros. (1987) 62:317-319, reported the addition of barium ion to this fibrin glue system in the treatment of a bleeding duodenal sinus in order to facilitate follow-up surveillance. See also Portman, M., J Head and Neck Pathol. (1982) 3:96; Panis, R., ibid., 94-95.
- It has been recognized, of course, that the use of the commercial product, which is prepared from pooled human blood, poses at least a theoretical risk of contamination by disease-producing organisms, especially viruses. The earlier concerns were directed to transmission of hepatitis B, but more recently the focus has shifted to concern about inadvertent transfer of the AIDS virus. Therefore, attention has been given to methods to isolate an autologous counterpart of the fibrinogen-containing component in the Tissucol™. system in a practical manner for use in surgery. For example, Siedentop, K. H., et al., Laryngoscope (1985) 95:1074-1076, describes a number of approaches to the precipitation of fibrinogen from plasma in the context of the proposed use of this material as the fibrinogen-furnishing component of a fibrin glue. Four methods were suggested: Precipitation with ethanol, use of unfractionated plasma, cryoprecipitation, and precipitation with ammonium sulfate. The first three methods were considered by the authors to be unsatisfactory; the fourth, which was the method described by Harker, L. A., et al., New Eng J Med (1972) 287:999-1005, was considered to have some promise.
- Epstein, G. H., et al., Anals Otol Rhinol and Laryngol (1986) 95:4045, suggest the use of a fibrinogen preparation from autologous plasma obtained using polyethylene glycol precipitation. These authors adapted the method of Masri, M. A., et al., Thromb Hemeostas (1983) 49:116-119, which involved incubation of the harvested plasma with barium sulfate and magnesium sulfate in order to remove thrombin (and thus prevent premature fibrin formation) followed by treatment of the supernatant from the resulting precipitation with a 30% solution of polyethylene glycol (PEG) of MW approximately 1000. This purified fraction was then mixed with thrombin containing calcium ion in order to form the glue. The isolation process required approximately two-three hours, but the PEG-precipitated fraction could be stored for as much as several weeks, and therefore the preparation could be made in advance of surgery. Autologous fibrinogen preparations obtained following this procedure were shown to be adhesive with implant materials by Feldman, M. C., et al., Arch Otolaryngol—Head and Neck Surg (1988) 114:182-185; additional applications of this approach to other surgical indications were also reported by Feldman, M. C., et al., Arch Ophthalmol (1987) 105:963-967; Feldman, M. C., et al., M J Otolog (1988) 9:302-305; Silberstein, L. E., et al., Transfusion (1988) 28:319-321.
- In addition, the material prepared as described by Epstein et al., by barium sulfate/magnesium sulfate precipitation followed by treatment of the supernatant with polyethylene glycol, was characterized to as to its components by Weisman, R. A., et al., Laryngoscope (1987) 97:1186-1190. The product was found to contain about 13-50 mg/ml of fibrinogen when the material precipitated from 50 ml blood was brought to a volume of 1 ml, wherein this concentration varies with the concentration of PEG. The percent of total protein attributable to fibrinogen ranged from 42-92 percent; the lower the PEG concentration, the higher the percentage of fibrinogen. The concentrations of kallikrein and pre-kallikrein were shown to be reduced to 1-2% of their levels in plasma in the presence of 10% PEG, and Factor XIII activity was shown to be present.
- A system for preparing autologous tissue adhesive was also described by WeisFogh in PCT Application ______, which discloses a reasonably complex system based on ethanol precipitation.
- General methods for preparing plasma adhesives have also been described in a series of related U.S. patents by Schwarz et al. assigned to Immuno-AG: U.S. Pat. Nos. 4,414,976; 4,298,598; 4,362,567; and 4,377,572. These methods involve cryoprecipitation of the adhesive material from plasma and various work-up procedures to obtain a mixture of defined composition. In addition, U.S. Pat. No. 4,427,650 to Stroetmann describes a preparation method involving the formation of a cryoprecipitate.
- Very early studies on blood fibrinogen, unrelated to the preparation of adhesive compositions, experimented with the use of glycine as a precipitant. A 1963 paper by Kazal, L. A., et al., Proc Sec Exp Biol Med (1963) 10:989-994, described the use of glycine at about 2.2M at room temperature to precipitate fibrinogen after removal of the thrombin with BaSO4/MgSO4 precipitation. Moesson, M. W., et al., Biochemistry (1966) 5:2829-2835, recognized that fibrinogen can be directly precipitated in this manner, but did not assess the suitability of the precipitated material to behave as a controlled adhesive.
- None of the foregoing methods is readily adaptable for convenient use of an autologous plasma fraction as an adhesive which can be prepared quickly in the course of the surgical procedure. All of the approaches suggested for preparation of the fibrinogen-containing fraction for this purpose are too time-consuming and complex to be finished in a short enough time period to be accomplished during the course of the surgery. Also, in some procedures, such as cryoprecipitation, special equipment, such as refrigerated centrifuges, is required. While the prior art approach is to prepare the composition in advance, this immediately imposes the necessity for additional procedures for identification and retrieval of the samples matched with the patient, and the concomitant opportunity for error, in addition to the inconvenience to the patient, who must then arrange time for an additional medical appointment. And, of course, this practice is not possible when the surgery is conducted on an emergency basis.
- The present invention, by providing a surprisingly simple method and apparatus for the preparation of autologous adhesive, permits the autologous composition to be prepared in the operating room and administered at the time of preparation.
- In addition to the problem of preparation, methods to administer the adhesive have not provided sufficient controls to permit clean fusions of tissue to be made. The adhesive is administered as a two-component system—the fibrinogen preparation as one component and a thrombin/Ca+2 composition as another. The Tissucol™ system uses a double-syringe arrangement wherein the two components are mixed in the injector immediately prior to dispensing. No means to remove debris or excess adhesive from the site of application is provided, and the potential for premature adhesion also exists. The present invention also provides an applicator with a premix immediately upstream of the application outlet means and a means to apply suction at the outlet to maintain the application area in condition for successful adhesion.
- The invention provides effective means to prepare and administer autologous plasma-derived adhesive during the course of a surgical procedure. The method of the invention can also be used to prepare the adhesive under less constrained conditions, but the simplicity and ease with which the invention method results in the desired adhesive makes it adaptable to this important use.
- The invention process provides the desired adhesive composition in a one-step treatment directly applicable to separated plasma using a recognized, nontoxic precipitant, such as suitable concentrations of amino acids, but preferably a nontoxic polymer such as polyvinyl alcohol (PVA) or polyethylene glycol (PEG). The fraction precipitated by these pharmaceutically acceptable reagents results in a high concentration of fibrinogen in the precipitate, along with other factors necessary for fibrin formation, as well as permitting the use of a simple, disposable apparatus to carry out the manipulations.
- Thus, in one aspect, the invention is directed to a process for preparing a fibrinogen adhesive composition from whole blood, which process comprises directly contacting plasma with an amount of polyethylene glycol of molecular weight 200-8000, or other precipitant selected from the group consisting of amino acids and nontoxic hydrophilic polymers, which is effective to precipitate the fibrinogen-containing fraction. Then the precipitated fibrinogen fraction is recovered for use, either by mechanical disruption of the precipitate or pellet or by suspension in an aqueous medium.
- In another aspect, the invention is directed to the fibrinogen-containing preparation obtained by the method of the invention.
- In still another aspect, the invention is directed to an apparatus for preparing the fibrinogen composition consisting essentially of a device with dual separation chambers with a means for fluid communication between the chambers.
- In still another aspect, the invention is directed to an applicator for injecting this or any other two-component system into a human or other animal subject which provides for simultaneous application of suction at the outlet for the components, and to a method to administer the fibrinogen composition using this apparatus.
- FIG. 1 is a perspective view of one embodiment of the apparatus of the invention for preparing the plasma-derived adhesive.
- FIG. 2 is an alternative embodiment of the isolation apparatus of the invention.
- FIG. 3 is an additional alternative embodiment of the isolation apparatus of the invention.
- FIG. 4 is a longitudinal sectional view of an apparatus for administering a two-component composition to an animal subject.
- FIG. 5 is a perspective view of the apparatus of FIG. 3.
- FIGS. 6A and 6B are perspective views of the mixing head of the apparatus of FIGS. 4 and 5.
- FIG. 7 is a perspective view of the filler tray and reservoir tip of the apparatus of FIGS. 4 and 5.
- The Adhesive Composition
- The adhesive composition of the invention contains substantial amounts of fibrinogen and sufficient Factor XIII to effect fibrin formation and cross-linking in the presence of added thrombin and calcium ion. Thus, as used herein, “fibrinogen adhesive composition” refers to a fraction of blood plasma which contains substantial amounts of fibrinogen and sufficient amounts of other factors required for fibrin formation that, when combined with a preparation of thrombin and calcium ion, fibrin formation and cross-linking takes place conferring on the composition the properties of a tissue adhesive.
- It is believed that the formation of the adhesive occurs through the conversion of fibrinogen into fibrin monomers, which conversion is mediated by thrombin; these monomers aggregate and form a gel. Thrombin also catalyzes the transformation of Factor XIII to Factor XIII* which is activated in the presence of calcium ions to Factor XIIIa. Factor XIIIa cross-links the fibrin monomers of the gel aggregation into a polymeric state. The polymeric material adheres to tissue or bone, and continued cross-linking can occur as Factor XIIIa also cross-links fibronectin.
- Therefore, the necessary components of the fibrinogen adhesive composition are fibrinogen itself and Factor XIII. Other components may also be present or may be added to modify and improve the effect of the adhesive. For example, a fibrinolysis inhibitor, such as aprotinin or aminocaproic acid can also be added. In the compositions of the invention, the levels of kallikrein and prekallikrein are greatly reduced from those present in plasma; these factors are also fibrinolytic. Other additives useful for purposes not directly related to the adhesive properties of the composition may also be included, such as various protein factors which are useful in wound healing, for example, fibroblast growth factor, platelet-derived growth factor, various angiogenic factors and the like. Other hormones, such as insulin, glucagon, steroids, and prostaglandins can also be included, resulting in a slow release system for these drugs. Also because the invention compositions may be prepared sufficiently efficiently to permit the use of an autologous fraction, other factors from plasma which aid in clotting, such as Factor VIII and immunoglobulins, are beneficial rather than detrimental when brought down with the fibrinogen precipitate. By adjusting the concentration of the precipitant and/or, in this case of a polymeric precipitant, its molecular weight, variable amounts of these factors may be included in the composition.
- Preparation of the Composition
- The method of the invention which provides the fibrinogen adhesive composition is straightforward and sufficiently simple that it can be used in the operating room to provide an autologous adhesive preparation. The appropriateness of the process for this application does not mean, of course, that its application is thus limited. This straightforward process can be used as well in the preparation of fibrinogen adhesive compositions in advance of surgery from autologous, designated donor, or pooled plasma sources, if desired. Furthermore, while its use is envisioned as most dramatically associated with surgery in humans, it is also suitable for veterinary uses.
- The process results in a composition which has 50-80 mg/ml of fibrinogen, in general, as compared to the 2-6 mg/ml concentration in plasma or whole blood. This is a range comparable to the commercially available Tisseel™ composition which contains 70-110 mg/ml. Also, like the commercial Tisseel™ composition, the fibrinogen adhesives of the present invention contain sufficient Factor XIII to provide cross-linking of the fibrin obtained. There may also be present varying amounts of plasma components which are not absolutely necessary for fibrin formation but may be helpful, such as, e.g., Factor VIII, prostaglandins, and platelets.
- In general, the process begins with the withdrawal of whole blood from an autologous, or other, or multiple donors in the presence of an anticoagulant, and separation of plasma from the red blood cell fraction. Typical anticoagulants include heparin and sodium citrate; others generally known in the art may also be used. If sodium citrate is used, it is generally supplied as a buffer at physiological pH with citrate ion present at 3-5%. The sodium salt is preferred. The range of means to prepare citrate and other anticoagulants suitable for primary separation of blood into red blood cells and plasma is well understood in the art. Typically, the separation can be effected by centrifugation; a suitable protocol involves spinning at about 2000-5000 g for about 5-10 minutes.
- In the method of the invention, after the plasma is separated from the red blood cells, it is treated directly, at ambient temperature, without prior treatment to remove thrombin, with a physiologically acceptable nontoxic precipitant. The precipitants of the invention include the natural amino acids and nontoxic polymers, especially polyvinyl alcohol and, most preferably, polyethylene glycol. Preferred amino acids are small neutral amino acids such as glycine, serine and alanine, most preferably glycine. Most preferred among the polymer precipitants is polyethylene glycol in a molecular range of 200-8000 supplied as a concentrated solution. The precipitant is preferably supplied as a concentrated solution which, when mixed with plasma, will yield a concentration effective in precipitating the adhesive composition. Optimal concentration of the precipitant can readily be determined by routine experimentation; simple in vitro assays for fibrin formation, such as those described by Epstein, G. H., et al., Anals Otol Rhinol and Laryngol (1986) 287:999-1005, can be used, and fibrinogen content measured as described.
- The concentrated solution or, in some instances, undiluted precipitant is added to the plasma in an amount effective to precipitate the fibrinogen adhesive composition of the invention. If PEG is used, the final concentration of PEG depends on the concentration of plasma in the precipitating solution and on the molecular weight of the PEG. A suitable and typical set of parameters utilizes an approximately 60% solution of PEG of molecular weight 1000 in saline at pH 7.4, and the plasma is added in sufficient volume (typically 10% w/v of precipitant solution/final volume) to obtain a resulting concentration of 8-15% w/v PEG in the volume of the final mixture. The plasma itself is, therefore, only slightly diluted. The precipitation takes place at room temperature and is complete essentially instantaneously, although generally it is advantageous to cure the precipitate for 5-10 min.
- The precipitate containing the fibrinogen adhesive is then recovered, typically by centrifugation. The pellet may be recovered by mechanical disruption or resuspended in normal saline for use at a concentration of about 50 mg/ml-80 mg/ml of fibrinogen. Typically from about 60 cc of whole blood a fibrinogen adhesive composition which would contain 30-50 mg fibrinogen when resuspended to 1.5 ml is obtained.
- The use of the amino acids and biocompatible polymers as precipitant has considerable advantage over the prior art use of ethanol and cryoprecipitation. The resulting concentration of fibrinogen is markedly higher, and the precipitants are recognized material safe for internal use. For example, PEG has been used as a lubricant or conditioner in ointments and in pharmaceutical and cosmetic preparations, including injectables. It is a water-soluble, nonvolatile material of no known clinical toxicity. The amino acids are, of course, nontoxic metabolites and are common components of pharmaceutical compositions.
- Because of the benign nature of the precipitant, the remaining supernatant plasma fraction, which contains platelets and white blood cells, can be reused for other purposes; similarly, the red blood cells removed could, if desired, be returned to the patient.
- Isolation Apparatus
- The process of the invention can be conducted using standard laboratory and medical equipment. For example, the blood may simply be withdrawn into a syringe containing anticoagulant and emptied into a centrifuge tube for separation. The supernatant plasma can then be removed by a syringe containing the precipitant or can be pipetted into a separate vessel and the precipitant added. The suspension can then be centrifuged using standard equipment and the precipitated material disrupted or resuspended by addition of saline after removal of the supernatant.
- It is evident, however, that the use of standard equipment adds complexity to the process and imposes requirements for sterilization of the various pieces of apparatus and maintenance of integrity of the sample. The invention apparatus provides a simple design which eliminates these complexities and streamlines the process.
- The invention apparatus contains two chambers, both of which can be used directly in a laboratory or medical centrifuge. The first chamber is designed to effect the separation of plasma and red blood cells; the second chamber provides a method to separate the fibrinogen adhesive composition from the supernatant plasma fraction. Because a means of fluid communication is provided between the first and second chamber, the plasma obtained in the first chamber can be made the subject of fibrinogen adhesive separation in the second, and the supernatant from the precipitate can be returned to the first chamber. The first chamber generally contains an effective amount of anticoagulant; the second chamber contains an effective amount of precipitant such as polyethylene glycol solution to effect precipitation of the fibrinogen adhesive. The apparatus, then, comprises a first and second chamber, a means of fluid communication between the first and second chambers and a means to interrupt this communication, wherein the first chamber contains anticoagulant and the second chamber contains the precipitant and permits the removal of the precipitate.
- One convenient embodiment of the apparatus of the invention is shown in FIG. 1. In this embodiment, the apparatus consists of two especially adapted
syringe bodies 10 and 11 interconnected by a supportedtube 12. The tube is provided with a valve 13 which is capable of turning on and off the flow of fluid betweenchambers 10 and 11. Both of the chambers are fitted onto the frame and locked onto a tube having a T-joint at 10 t and 11 t. Both syringe cylinders are provided with a modifiedplunger 10 p and 11 p which may be withdrawn by a pulling means such as a plastic cord 10 c and 11 c causing the withdrawal of the plunger to a position flush with the ends of the cylinders where the top of the plunger is sealed by a flange (10 f and 11 f) when withdrawn to a fully extended position. This permits the syringe bodies to be used as centrifuge tubes when the plunger is fully withdrawn to the end of the syringe and sealed at the flange. While the plunger could be returned to the position toward the tip of the syringe by use of a rod inserted at the apertures 10 a and 11 a, this is generally not necessary as the material in the chamber can be removed by suction, provided either by the adjacent chamber or by the application of a vacuum at the chamber outlet. Thus, withdrawal of the plunger in the chamber 11 with valve 13 open and the outlets 10 o and 11 o sealed results in transfer of the liquid fromchamber 10 to chamber 11. Both syringes can be detached from the supportingframe 14 by release of the locks to the T-tube, and can be sealed if appropriate. - In use, the
plasma separation chamber 10 is fitted with a needle 10 n which is inserted into the subject for withdrawal of blood. The valve 13 is closed during this step, thus preventing the formation of a vacuum in the connectingtube 12 and confining the flow of blood to thechamber 10 when theplunger 10 p is withdrawn by pulling the cord 10 c. The size of the plunger is adjusted to permit withdrawal of a predetermined amount of blood, typically 60 cc. Thechamber 10 is previously supplied with sufficient citrate buffer to obtain a concentration of about 4% citrate ion when the predetermined amount of blood is withdrawn. - When the blood is withdrawn into
chamber 10, the needle is detached, the outlet 10 o sealed with a sealing cap, and the device removed to a centrifuge with a head designed to accommodate this device, or, if desired,chamber 10 is detached for centrifugation independently. The application of 4500 g for 5-10 minutes results in a separation of the red blood cells from the plasma. If the device is placed intact into the centrifuge, the plunger of chamber 11 is unaffected as the outlet of 11, shown as 11 o, is sealed and the-PEG contained in this chamber is not compressible. - After centrifugation, the valve13 is opened and the plunger 11 p is withdrawn and sealed at flange 11 f, thus transferring the plasma into chamber 11. Chamber 11 is presupplied with an approximately 60% PEG solution of molecular weight 1000, or a comparable concentration of an alternate molecular weight sufficient to effect precipitation of the fibrinogen adhesive. The motion of the plungers is stopped when the red blood cells reach the upper portion of the
chamber 10. The valve 13 is then closed. - If desired, the red blood cells remaining in
chamber 10 can be withdrawn or expelled and returned to the patient. - The apparatus is then agitated, if necessary, to intermix the PEG with the plasma. Outlet11 o remains sealed. The chamber 11 is then centrifuged either within the device or after removal therefrom to separate the precipitate from the supernatant plasma. The apparatus is, of course, inverted from the position shown in FIG. 1. After about 15-20 minutes at 6000-10,000 g sufficient separation of precipitate has occurred. The chamber 11 is replaced in the apparatus if it has been removed, and the valve 13 again opened while the outlet 11 o remains sealed. The supernatant is then withdrawn into
chamber 10 by withdrawal ofplunger 10 p (10 o remains closed) until the fibrinogen precipitate begins to enter the connectingtube 12; valve 13 is then closed. - The fibrinogen adhesive is removed for use from chamber11 by further reinsertion of the plunger 11 p, or preferably by withdrawal into the syringe attached at the outlet 11 o. If desired, the fibrinogen adhesive can be diluted in saline and the composition quantitatively removed from chamber 11 by washing.
- It should be noted that
chamber 10 now contains all blood components except the fibrinogen adhesive composition and contains as added components only anticoagulant and the clearly nontoxic PEG. Therefore, the modified blood inchamber 10 could, if necessary, be used for other purposes or returned to the patient. - FIG. 2 shows an alternative embodiment of the apparatus of the invention which dispenses with the need for the
frame 14. This apparatus consists essentially of two syringes with detachable plungers and a Luer-locked connector. This embodiment has the advantage of utilizing standard medical equipment but the disadvantage of utilization of several separate parts. - In the apparatus of FIG. 2, the
blood separation syringe 20, is fitted with a needle for the withdrawal of blood. Again,chamber 20 is supplied with a premeasured quantity of citrate which, when mixed with the withdrawn blood will result in a citrate buffer of about 4% citrate ion. When the plunger is retracted andchamber 20 contains whole blood, the needle and the extended portion of the plunger are detached to permit the syringe body and sealed end to be placed in a centrifuge, with the Luer lock outlet 20 o sealed. Suitable syringes with plungers which can be detached and the body sealed for centrifugation of the syringe body are available commercially. Thesyringe barrel 20 is then centrifuged as described above, and Luer lock at 20 o is engaged by the interconnectingtube 24, and the plunger is replaced. With the syringe in the inverted position, theinterconnector 24 is attached to a second similarly constructedsyringe 21 at Luer lock 21 o.Syringe 21 contains a premeasured quantity of PEG. Plasma is transferred fromchamber 20 tochamber 21 through retraction of the plunger 21 p which causes effective reinsertion ofplunger 20 p. When red blood cells begin to enter the interconnector, an event which is readily observable, theinterconnector 24 is detached fromchamber 21 and the mixture of plasma and PEG inchamber 21 agitated if necessary.Syringe 21 is then prepared for centrifugation by removal of the extended portion of the plunger and sealing of the body of the syringe, and closure at 21 o, and the fibrinogen adhesive and plasma are separated under the centrifugation conditions described above. Theinterconnector 24 and plunger 21 p are then put back in place and the plasma supernatant withdrawn intochamber 20 by retraction ofplunger 20 p. When fibrinogen adhesive precipitate begins to enter the interconnector, the interconnector is detached and the fibrinogen adhesive expelled into diluent, or diluent is withdrawn intochamber 21 through 21 o. - In either case, the resuspended fibrinogen adhesive is placed in a suitable applicator for use.
- FIG. 3 shows a third embodiment of the apparatus for isolation of the fibrinogen adhesive.
Chambers tubing 32, which is regulated by avalve 33. Any suitable type of valve can be used; as shown in FIG. 3,valve 33 operates by sliding the roller so as to pinch off thetubing 32. -
Chambers Chambers Outlet 31 is a Luer lock designed to accommodate an externally attached syringe body. Bothoutlets - The
chambers plungers 30 p and 31 p which are sealed with gaskets 30 g and 31 g to the sides of the chambers. When fully withdrawn, the plungers are snug against theend plates disks Additional apertures - The operation of the apparatus as shown in FIG. 3 is substantially analogous to that shown in FIG. 1. In a typical procedure, the patient's blood, about 60 cc, is withdrawn into
chamber 30 withvalve 33 and outlet 31 o both closed. Outlet 30 o is then sealed, the apparatus is placed in a centrifuge, and the plasma and red blood cells inchamber 30 are separated.Valve 33 is then opened andplunger 31 p is withdrawn until the red blood cells are seen entering thetubing 32.Valve 33 is closed, and the apparatus is agitated, if necessary, and inverted and centrifuged to separate the fibrinogen adhesives from the supernatant plasma. The red blood cells inchamber 30 may be returned to the patient by an attached needle and pushing the plunger 30 p prior to centrifugation, if desired. - After centrifugation, the
valve 33 is again opened and plunger 30 p withdrawn to draw the supernatant intochamber 30. Withdrawal of the plunger is stopped as soon as the supernatant has leftchamber 31. - Outlet31 o is opened and a syringe body attached. The fibrinogen adhesive pellet is disrupted, for example, by repeated motion of the syringe plunger, and, if desired, saline may be included in the attached syringe to achieve quantitative transfer of the fibrinogen adhesive. The adhesive composition is then placed in a suitable applicator for administration to the subject.
- Administration and Use
- The fibrinogen adhesive composition of the invention is useful in medical and veterinary applications generally comparable to those known in the art for the commercially available product Tissucol™. Commercial preparations of thrombin and calcium ion for admixture with the fibrinogen adhesive of the invention are commercially available and are used as is generally known in the art.
- In a particularly advantageous way to apply the two components of the sealant to the tissue to be cemented, a dual-barreled applicator with one barrel for supply of the fibrinogen adhesive and the other for the thrombin/calcium ion mixture is employed wherein the outlet of each barrel is proximal to a suction device so that the surface prior to application can be instantly cleaned and excess components immediately removed.
- Although the premixing of the components for this purpose is known in the art, as described in U.S. Pat. No. 4,359,049, incorporated herein by reference, the advantages of simultaneous application of suction for controlling the environment of the application have not been recognized. To applicants' knowledge, the only medical devices which simultaneously permit application of a material and suction are devices designed for irrigation, such as that described in U.S. Pat. No. 4,299,221, where a fluid is applied and then removed from a target tissue, especially in dental applications, for cleansing purposes.
- In the present application, the provision of suction at the site of sealant application permits the withdrawal of interfering substances as well as control of the quantity of sealant applied. Thus, although the commercially available Duploject device can be used for application, the modified adhesive applicator described hereinbelow is highly advantageous. This device is designed to permit controlled application of both fibrinogen adhesive and thrombin/calcium mixture with premixing of these components immediately prior to injection along with a means to produce suction for surface cleaning and excess sealant removal.
- A particularly advantageous design of such an applicator is shown in FIGS.4-7 herein, and was described in U.S. Ser. No. 06/683,621 filed Dec. 19, 1984 by the applicant, and now abandoned.
- In more detail, FIGS. 4 and 5 show a
housing 2 which resembles a pen in both size and shape, and which is held in a similar fashion. The interior of thehousing 2 includes achamber 4 having walls that are sufficiently flexible so that thechamber 4 may be compressed by a relatively slight amount of external pressure. At the same time, the walls of thechamber 4 are sufficiently resilient so that, in the absence of external pressure, thechamber 4 will return to its original volume and configuration. Thechamber 4 is divided into afirst compartment 6 and a separate but identicalsecond compartment 8. In application of the composition of the invention to a subject, one chamber (6) contains the fibrinogen adhesive composition and the other (8) contains the thrombin/Ca+2 preparation. In the preferred embodiment of the present invention, thechamber 4 consists of a rubber bulb, although it is recognized that any chamber whose volume may be easily reduced and expanded may serve as thechamber 4. - The
first compartment 6 of thechamber 4 is connected to a firstliquid channel 10 which runs lengthwise through the interior of thehousing 2 and which terminates at thehousing end piece 12. Thesecond compartment 8 of thechamber 4 is likewise connected to a secondliquid channel 14 which runs parallel to the firstliquid channel 91 and which similarly terminates at thehousing end piece 92. - The
housing end piece 92 is fitted with anadaptor 22 which is configured to receive aconnector detachable channel extension 25. Thechannel extension 25 includes twoliquid channels 26 and 28 (and asuction channel 97 to be described below). When thechannel extension 25 is attached to thehousing end piece 92 by means of theadaptor 22 and the connector 24 (FIG. 5) or 93 (FIG. 4), theliquid channels fluid channels - The
channel extension 25 may be configured in a variety of lengths and shapes, depending upon the particular requirements of the applicator. The use of adetachable channel extension 25 allows asingle applicator housing 2 to be used in conjunction with a variety of differently configuredchannel extensions 25. - The present invention also includes a mixing head94 (see FIGS. 6A and 6B) The mixing
head 94 includes three entry ports of which two, 34 and 36, are configured to be attached respectively to the distal ends 40 and 42 of theliquid channels - The interior of the mixing
head 94 includes a Y-shapedchannel 46 which connects theentry ports exit port 48. The liquid adhesive components dispensed through theentry ports channel 46 before being ejected through thesingle exit port 48. A singleadhesive channel tube 50 is connected to theexit port 48, thus permitting the premixed adhesive to be applied. - The apparatus as shown in FIGS. 4 and 5 includes a
suction channel 16 which is incorporated into the wall of thehousing 2 and which runs parallel to the first and secondliquid channels Suction channel 16 also terminates at thehousing end piece 92. The proximal end of thesuction channel 16 is surrounded by an adaptor 18 which is configured to connect thesuction channel 16 to a remote vacuum source (not shown). - Operation of the
suction channel 16 is controlled by means of aventuri opening 96 which is located on the exterior of thehousing 2. Obstruction of the venturi opening 96 permits the suction force which originates at the remote vacuum source to be conducted through the length of thesection channel 16. - The interior of the mixing
head 94, shown in FIGS. 6A and 6B, also includes achannel 52 which connects theentry port 38 with anexit port 54. Thechannel 52 serves to conduct the suction force from thedistal end 44 of thesuction channel 97 to theexit port 54. A singlesuction channel tube 56 is connected to theexit port 54. - The
suction channel tube 56 is shorter than theadhesive channel tube 50 so that thesuction channel tube 56 does not interfere visually or functionally with the application of the adhesive. Materials from the site of application, when suctioned, are drawn along the exterior surface of theadhesive channel tube 50 to the orifice of thesuction channel tube 56. This provides gentle, atraumatic suction required in microsurgery. - In the apparatus of FIGS. 4 and 5, compression and expansion of the
bulb 4 is controlled by means of aleverage mechanism 58. Theleverage mechanisms 58 includes anouter lever arm 60 and aninner lever arm 62. Bothlever arm 60 andlever arm 62 turn about afulcrum 64. - The
free end 66 of theouter lever arm 60 is positioned adjacent theventuri opening 96 of thesuction channel 16. This placement allows the operator to switch rapidly and with a minimum amount of movement from the control of theventuri opening 96 to the control of thelever arm 60. - The
free end 68 of theinner lever arm 62 rests against the exterior of theflexible bulb 4. Movement of thefree end 68 of theinner lever arm 62 toward thebulb 4 will cause bothcompartments bulb 4 to be compressed in equal amounts, thereby causing a small quantity of air to be displace from each of thecompartments liquid channels free end 68 of theinner lever arm 62 away from thebulb 4 will allow the resilient bulb material to return to its original dimensions. - The lateral motion of the
free end 66 of theouter lever arm 60 that is transferred to thefree end 68 of theinner lever arm 62 is proportional to the relative lengths of theouter lever arm 60 andinner lever arm 62. If theinner lever arm 62 is shorter than theouter lever arm 60, as shown in FIGS. 4 and 5, then a relatively large lateral motion of thefree end 66 will be translated into a relatively short lateral motion of thefree end 68. In this manner, a relatively broad finger-controlled lateral movement of thelever arm 60 may be used to control a relatively small displacement of air through each of theliquid channels - The pivot ends of both the
outer lever arm 60 and theinner lever arm 62 are fixed to aratchet wheel 70. The rotational axis of theratchet wheel 70 is concentric with thefulcrum 64. Disposed about a portion of the circumference of theratchet wheel 70 is a set of spacedratchet teeth 72. - A
pawl 74 is positioned to engage theratchet teeth 72, and to thereby prevent movement of theratchet wheel 70 in a clockwise direction as shown in FIG. 4. A finger-operable pawl release 76 is attached to thepawl 74. The pawl release 76 provides a mechanism for disengaging thepawl 74 from theratchet teeth 72, thereby allowing unrestricted movement of theratchet wheel 70. - The combination of the
ratchet wheel 70 andpawl 74 thereby provides a mechanism for stopping movement of thelever arms 60 and 62 (as well as compression or expansion of the bulb 4) at a plurality of fixed intervals. The size of these intervals is dependent on the spacing between theteeth 72 and the circumference of theratchet wheel 70. - In the apparatus shown, the two components of the dual-component adhesive are drawn into the
channels filler tray 78 shown in FIG. 7. Thefiller tray 78 is designed to orient the operator so that the possibility of drawing a liquid component into the incorrect channel is minimized. - The
filler tray 78 is generally of rectangular configuration and divided by aseptum 80 along the center of its longer axis into afirst container 82 andsecond container 84. The floor of thefirst container 82 has atrough 86 which is perpendicular to theseptum 80. The floor of thesecond container 84 has a similar trough 88 which is also perpendicular to theseptum 80. Bothtroughs 86 and 88 are located closer to one end of thefiller tray 78 than the other. The resulting asymmetry of thefiller tray 78 provides a useful visual orientation for the operator. Bothtroughs 86 and 88 slant downward toward theseptum 80, so that even a small amount of liquid placed in eithercontainer septum 80. - The height and width of the
septum 80 are selected so that thedistal end 40 of thechannel 26 will rest in the lowest part of the trough 88 at the same time that thedistal end 42 of thechannel 28 will rest in the lowest end of thetrough 86. In this way, even small amounts of liquid in thecontainers channels septum 80 is selected so that thedistal end 44 of thesuction channel 97 rests above theseptum 80 when fluid is drawn from thefiller tray 78. The points at which the distal ends 40 and 42 of thechannels septum 80 are the lowest of all points in thefiller tray 78. In this way any fluid placed in eithercontainer tray 78 will pool towards the distal ends 40 and 42 during the filling ofchannels - The
filler tray 78 is anchored to a heavyweight base 90 to help prevent the liquid contents of the filler tray from being spilled. - To operate the device, the
outer lever arm 60 is first pressed toward thehousing 2 so that thefulcrum 64 rotates in a counterclockwise direction as shown in FIG. 4. Thefree end 68 of theinner lever arm 62 is thereby forced against the exterior of thebulb 4, compressing the bulb. Thefree end 68 of thelever arm 62 will be held in place against thebulb 4 by means of thepawl 74 engaging theratchet teeth 72 of theratchet wheel 70. - The distal ends40 and 42 of the
fluid channels containers filler tray 78. The pawl release 76 is operated to disengage thepawl 74 from theratchet teeth 72. Theratchet wheel 70 is thereby allowed to rotate freely about thefulcrum 64. - In the absence of pressure exerted by the
free end 68 of theinner lever arm 62, the resilient flexible material of thebulb 4 will return to its initial configuration, creating a pressure differential between the interior of thebulb 4 and the ambient atmosphere. Atmospheric pressure will force the liquid contents of thefiller tray containers fluid channels bulb 4. - The distal ends40 and 42 of the
fluid channels containers filler tray 78. The mixingtip 94 is then attached to thefluid channels suction channel 97. The mixingtip 94 is brought to the work surface. If cleaning of the surface is desired immediately before application of the adhesive, then theventuri opening 96 of thesuction channel 16 is closed off by the operator's finger. The suction force created by a remote vacuum attached to the proximal end of the suction channel is transmitted viasuction channel 16 to the work surface. Fluid and debris on the work surface is thereby removed through thesuction channel 16. - The precise amount of adhesive deposited on the work surface is accurately controlled via the
leverage mechanism 58. As theouter lever arm 60 is pressed, theratchet teeth 72 will rotate past thepawl 74. As each ratchet tooth passes thepawl 74, an audible “click” will be heard. - The
ratchet teeth 72 may be positioned so that each “click” represents the deposit of a predefined amount of adhesive. For example, if theratchet teeth 72 are positioned so that each “click” corresponds to the deposit of one microliter of adhesive, then an operator wishing to apply precisely three microliters of adhesive will press theouter lever arm 60 until three “clicks” are heard. The operator's visual attention to the work area thereby remains uninterrupted. - At any point during the procedure, application of the adhesive may be halted by merely removing finger pressure from the
outer lever arm 60. Thelever arm 60 will be maintained in position by thepawl 74 engaging theratchet teeth 72. - In any event, the fibrinogen adhesive of the invention is applied along with a calcium/thrombin composition as understood by the art by any suitable application means.
Claims (17)
1. A process for preparing fibrinogen adhesive from whole blood which process comprises:
directly contacting plasma which has been removed from said whole blood with an amount of polyethylene glycol (MW 200-8000) effective to precipitate said fibrinogen;
recovering the precipitated fibrinogen; and
suspending said precipitate in aqueous medium.
2. The process of claim 1 wherein the plasma is prepared by centrifugation of whole blood treated with anticoagulant.
3. The method of claim 2 wherein the anticoagulant is citrate buffer.
4. The method of claim 1 wherein the PEG has a molecular weight of 1,000-1,500.
5. The method of claim 4 wherein said effective amount is 8-15% w/v.
6. The method of claim 1 wherein the fibrinogen precipitate is recovered by centrifugation.
7. A fibrinogen adhesive composition prepared by the method of claim 1 .
8. A pharmaceutical composition effective for cementing tissues which comprises the fibrinogen adhesive composition of claim 7 in admixture with thrombin and calcium ion.
9. A method to cement tissues which method comprises applying to said tissues an effective amount of the fibrinogen adhesive composition of claim 7 and an effective amount of thrombin and calcium ion.
10. An apparatus for preparing a fibrinogen adhesive composition from human blood, which apparatus comprises:
a first chamber in fluid communication with a second chamber,
means for effecting said fluid communication, and means for interrupting said fluid communication;
means for withdrawing a sample of human blood into said first chamber in the presence of anticoagulant;
said first chamber being configured so as to permit separation of plasma and red blood cells in said blood sample;
a means to dispense said separated plasma from said first chamber to said second chamber free of said red blood cells wherein said second chamber contains an amount of polyethylene glycol effective to precipitate fibrinogen from said plasma, said second chamber being configured so as to permit separation of the precipitated fibrinogen from the remaining plasma;
means to dispose of said remaining plasma.
11. The apparatus of claim 10 wherein said each of first and second chambers is a body of a syringe.
12. The apparatus of claims 11 wherein said means for dispensing plasma comprises a plunger fitted to the syringe body.
13. The apparatus of claim 12 wherein said means for interrupting fluid communication includes a valve between said first and second chambers.
14. The apparatus of claim 12 wherein said means for interrupting fluid communication includes a means for detaching said means for effecting fluid communication.
15. An applicator device for injecting a two-component system into an animal subject, which applicator comprises a first and second dispensing means each having an inlet end and an outlet end disposed in parallel so as to permit the two components to be mixed when dispensing pressure is applied to the first and second dispensing means;
a means for applying dispensing pressure to said first and second dispensing means; and
disposed adjacent to said first and second outlet ends, a means to apply suction adjacent to and at said outlet ends.
16. A method to apply sealant to a tissue to be sealed which sealant comprises a fibrinogen adhesive component and a Ca+2/thrombin component, which method comprises dispensing said components into a premixing space adjacent to the tissue to be sealed to form the sealant, and
applying suction to the tissue to be sealed to remove debris and excess sealant.
17. A method to apply sealant to a tissue to be sealed with sealant comprises a fibrinogen adhesive component and a Ca+2/thrombin component,
which method comprises dispensing said components from the apparatus of claim 15.
Priority Applications (1)
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US10/072,509 US7156835B2 (en) | 1989-06-23 | 2002-02-05 | Method of applying composition to a surface |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US07/372,443 US5226877A (en) | 1989-06-23 | 1989-06-23 | Method and apparatus for preparing fibrinogen adhesive from whole blood |
US08/090,587 US5405607A (en) | 1989-06-23 | 1993-07-12 | Method for preparing fibrinogen adhesive from whole blood |
US08/370,793 US5648265A (en) | 1989-06-23 | 1995-01-10 | Apparatus for preparing fibrinogen adhesive from whole blood |
US08/645,464 US5976102A (en) | 1989-06-23 | 1996-05-13 | Applicator system for two component mixture and suction control |
US08/703,148 US5879340A (en) | 1989-06-23 | 1996-08-29 | Applicator system with suction control |
US08/863,883 US6394975B1 (en) | 1989-06-23 | 1997-05-28 | Method to apply compositions to a surface |
US10/072,509 US7156835B2 (en) | 1989-06-23 | 2002-02-05 | Method of applying composition to a surface |
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US08/863,883 Division US6394975B1 (en) | 1989-06-23 | 1997-05-28 | Method to apply compositions to a surface |
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US20050101992A9 US20050101992A9 (en) | 2005-05-12 |
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Application Number | Title | Priority Date | Filing Date |
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US07/372,443 Expired - Fee Related US5226877A (en) | 1989-06-23 | 1989-06-23 | Method and apparatus for preparing fibrinogen adhesive from whole blood |
US08/090,587 Expired - Lifetime US5405607A (en) | 1989-06-23 | 1993-07-12 | Method for preparing fibrinogen adhesive from whole blood |
US08/370,793 Expired - Fee Related US5648265A (en) | 1989-06-23 | 1995-01-10 | Apparatus for preparing fibrinogen adhesive from whole blood |
US08/645,464 Expired - Fee Related US5976102A (en) | 1989-06-23 | 1996-05-13 | Applicator system for two component mixture and suction control |
US08/703,148 Expired - Fee Related US5879340A (en) | 1989-06-23 | 1996-08-29 | Applicator system with suction control |
US08/863,883 Expired - Fee Related US6394975B1 (en) | 1989-06-23 | 1997-05-28 | Method to apply compositions to a surface |
US10/072,509 Expired - Fee Related US7156835B2 (en) | 1989-06-23 | 2002-02-05 | Method of applying composition to a surface |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
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US07/372,443 Expired - Fee Related US5226877A (en) | 1989-06-23 | 1989-06-23 | Method and apparatus for preparing fibrinogen adhesive from whole blood |
US08/090,587 Expired - Lifetime US5405607A (en) | 1989-06-23 | 1993-07-12 | Method for preparing fibrinogen adhesive from whole blood |
US08/370,793 Expired - Fee Related US5648265A (en) | 1989-06-23 | 1995-01-10 | Apparatus for preparing fibrinogen adhesive from whole blood |
US08/645,464 Expired - Fee Related US5976102A (en) | 1989-06-23 | 1996-05-13 | Applicator system for two component mixture and suction control |
US08/703,148 Expired - Fee Related US5879340A (en) | 1989-06-23 | 1996-08-29 | Applicator system with suction control |
US08/863,883 Expired - Fee Related US6394975B1 (en) | 1989-06-23 | 1997-05-28 | Method to apply compositions to a surface |
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US (7) | US5226877A (en) |
AU (1) | AU5853990A (en) |
WO (1) | WO1991000046A2 (en) |
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US20050125033A1 (en) * | 2003-12-04 | 2005-06-09 | Mcnally-Heintzelman Karen M. | Wound closure apparatus |
US20050125015A1 (en) * | 2003-12-04 | 2005-06-09 | Mcnally-Heintzelman Karen M. | Tissue-handling apparatus, system and method |
US8518433B2 (en) | 2003-12-11 | 2013-08-27 | Zimmer, Inc. | Method of treating an osteochondral defect |
US8524268B2 (en) | 2003-12-11 | 2013-09-03 | Zimmer, Inc. | Cadaveric allogenic human juvenile cartilage implant |
US8652507B2 (en) | 2003-12-11 | 2014-02-18 | Zimmer, Inc. | Juvenile cartilage composition |
US8765165B2 (en) | 2003-12-11 | 2014-07-01 | Zimmer, Inc. | Particulate cartilage system |
US8784863B2 (en) | 2003-12-11 | 2014-07-22 | Zimmer, Inc. | Particulate cadaveric allogenic cartilage system |
US8834914B2 (en) | 2003-12-11 | 2014-09-16 | Zimmer, Inc. | Treatment methods using a particulate cadaveric allogenic juvenile cartilage particles |
US8480757B2 (en) | 2005-08-26 | 2013-07-09 | Zimmer, Inc. | Implants and methods for repair, replacement and treatment of disease |
US8497121B2 (en) | 2006-12-20 | 2013-07-30 | Zimmer Orthobiologics, Inc. | Method of obtaining viable small tissue particles and use for tissue repair |
US9138318B2 (en) | 2007-04-12 | 2015-09-22 | Zimmer, Inc. | Apparatus for forming an implant |
US10167447B2 (en) | 2012-12-21 | 2019-01-01 | Zimmer, Inc. | Supports and methods for promoting integration of cartilage tissue explants |
Also Published As
Publication number | Publication date |
---|---|
US5226877A (en) | 1993-07-13 |
US7156835B2 (en) | 2007-01-02 |
US20050101992A9 (en) | 2005-05-12 |
US5879340A (en) | 1999-03-09 |
US5648265A (en) | 1997-07-15 |
AU5853990A (en) | 1991-01-17 |
US5405607A (en) | 1995-04-11 |
WO1991000046A3 (en) | 1996-10-31 |
US5976102A (en) | 1999-11-02 |
US6394975B1 (en) | 2002-05-28 |
WO1991000046A2 (en) | 1991-01-10 |
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