HK1113325A - Injection of fibrin sealant using reconstituted components in spinal applications - Google Patents

Description

Injection of fibrin sealant using reconstituted components in spinal applications

The authors: brian d. burkinshaw, Steven i. whitlock, Kevin Pauza,

Mark I.Richards，Jim Rogan

[0001] this application claims priority from U.S. provisional application No. 60/623,600 filed on 29/10/2004, which is incorporated herein by reference.

Background

[0002] The present invention relates generally to the use of fibrin sealant, whereby the sealant is delivered to the spinal area, e.g., by injection, and fibrinogen and/or thrombin is reconstituted with a solution containing additives.

[0003] Fibrin sealants and fibrin glues are well known and widely used in a variety of clinical situations. In surgery, such sealants are indicated as an adjunct to bleeding when control of bleeding by conventional surgical methods, including suturing, ligation, and cauterization, is ineffective or impractical. In these cases, the blocking agent is applied topically.

[0004] Recently, fibrin sealants comprising corticosteroids have been used to treat disc problems, such as fissures in the annulus fibrosus. In this regard, U.S. Pat. No. 6,468,527 discloses that compositions are injected into the disc (intradiscal injection) to treat disc problems.

Summary of The Invention

[0005] In practicing the present invention, a fibrin sealant is injected into the spinal region of a human. The blocking agent comprises fibrinogen and an activating compound such as thrombin, which when mixed form fibrin. It has been found that this composition provides surprisingly superior results relative to fibrin sealant compositions containing corticosteroids. Calcium ions, such as provided by calcium chloride, may be included in the fibrin sealant. The fibrinogen and/or thrombin may be obtained from lyophilized components reconstituted with a solution comprising one or more additives, such as various biological and non-biological agents. The use of the one or more additives provides excellent results. However, corticosteroids are not included in the fibrin sealant.

[0006] In one broad aspect, the invention is a method of treating a disc that is leaking nucleus pulposus through at least one defect in the annulus fibrosus, the method comprising: injecting a fibrin sealant into the disc to reduce at least a portion of the at least one defect, wherein the fibrin sealant injected into the disc comprises fibrinogen and an activating compound such as thrombin, wherein at least a portion of the fibrin forms after injection, wherein the fibrinogen, the activating compound, or both has been reconstituted with a solution containing at least one additive, with the proviso that the fibrin sealant injected into the disc lacks a corticosteroid. This treatment can reduce the amount of nucleus pulposus material that leaks out due to a defect in the annulus fibrosus. The defect may be a tear in the annulus fibrosus, a fissure in the annulus fibrosus, or the like. Advantageously, injection of the fibrin sealant may also help restore normal disc height and hydrostatic pressure, which are key elements. It should be understood that normal physiologic hydrostatic pressure may vary from person to person, and that the treatment may produce near normal hydrostatic pressure. As used herein, normal physiological pressure includes this range of pressure. In one embodiment, neither the nucleus pulposus nor the annulus fibrosus has been heated in the body to stiffen the disc prior to or concurrent with the injection, such as discussed in, for example, U.S. Pat. No. 6,095,149. In one embodiment, in practicing the present invention, the nucleus pulposus is not removed surgically, for example in the case of a total or partial discectomy, or by nuclectomy for a herniated disc.

[0007] In another broad aspect, the invention is a method of treating a human back, the method comprising injecting a fibrin sealant into a disc to seal at least one defect of an annulus fibrosus, wherein the fibrin sealant comprises fibrinogen and an activating compound such as thrombin, wherein the fibrinogen and thrombin forms at least a portion of the fibrin after injection, wherein the fibrinogen, the thrombin, or both has been reconstituted with a solution containing at least one additive, and wherein the fibrin sealant does not include a corticosteroid.

[0008] In another broad aspect, the invention is a method of treating a human back, the method comprising providing a mixture of fibrinogen and thrombin within a human disc to treat at least one defect of an annulus fibrosus, wherein the fibrinogen, the thrombin, or both has been reconstituted with a solution comprising at least one additive, and wherein a corticosteroid is absent from the mixture. The mixture may be provided to the disc by injection or other means.

[0009] The invention also includes kits comprising components for injecting the fibrin sealant. The kit may include fibrinogen, such as lyophilized fibrinogen, thrombin, such as lyophilized thrombin, at least one additive, and a needle for injecting the sealant, such as a spinal needle, including, for example, a curved spinal needle. Alternatively, a spinal cannula (spinal canal) may be used. The kit does not include a corticosteroid. The kit may exclude a device that provides thermal energy to the disc. The kit may optionally include contrast agents and other additives. The kit may include a single, dual or multi-barrel syringe or other fibrin sealant delivery device. The fibrin sealant may be delivered using a conventional single lumen needle or through a double or multi-lumen needle. If a dual lumen needle is used, the components may be delivered through separate lumens. In one embodiment, a double lumen or multilumen needle may be used that allows the fibrinogen component and the thrombin component to contact at the tip of the needle. Alternatively, sequential addition of the fibrinogen component followed by injection of the thrombin or other enzyme component may be used, and these injections may occur in the same needle, multiple needles, or in a bilumen or multilumen needle.

[0010] In another broad aspect, the invention is a method for making a kit comprising: providing a fibrinogen component, a thrombin component, at least one additive, and a spinal needle or a polymer catheter or both, wherein the kit does not include a corticosteroid, and wherein the kit does not include a means for providing thermal energy to the disc.

[0011] Advantageously, the methods and kits of the present invention facilitate long-lasting pain relief in patients with leaky disc syndrome, where, for example, the nucleus pulposus leaks out of the disc through a defect (e.g., tear or fissure) in the annulus fibrosus. Surprisingly, it has been found that the use of fibrin without corticosteroid provides unexpectedly superior results relative to the injection of fibrin sealant comprising a corticosteroid. The present invention provides unexpectedly superior results over the method described in U.S. Pat. No. 6,468,527, which discloses the injection of fibrin sealant containing a corticosteroid.

Drawings

[0012] Fig. 1 is a cross-sectional view of a vertebral body at an intervertebral space exhibiting an annular fissure, which may be treated in accordance with an embodiment of the present invention.

[0013] Fig. 2 is a schematic illustration of a trans-foraminal (trans-foraminal) space into which an improved sealant may be injected according to one embodiment of the invention.

[0014] Figures 3 and 4 show graphs of VAS scores from example 3.

Detailed Description

[0015] The fibrin sealant of the present invention comprises a fibrinogen component and an activating compound such as thrombin which converts fibrinogen to fibrin. The sealant contains one or more other additives. The fibrinogen, thrombin, or both is reconstituted with a solution containing at least one of the additives, wherein the additive is not a corticosteroid. The fibrin sealant is injected, for example, into the intervertebral disc to seal fissures and tears in the annulus fibrosus. Defects in the annulus fibrosus are currently commonly diagnosed using MRI scans and discograms. When injected into the lumbar disc, this can treat discogenic low back pain and radiculopathy leg pain.

[0016]Fibrinogen used in the practice of the present invention includes any fibrinogen that will form fibrin in the human body. FiberThe proprotein is often available in lyophilized form and must be reconstituted prior to use. If the thrombin is reconstituted with a solution containing additives, the fibrinogen may also be frozen or fresh, autologous (from the patient receiving the treatment), human including pooled human fibrinogen, recombinant, and bovine or other non-human sources such as fish (e.g., salmon and sea trout). Fibrinogen is used in amounts appropriate for the particular treatment, patient, etc. Lyophilized fibrinogen is reconstituted with a solution, typically containing aprotinin and calcium chloride. As discussed herein, fibrinogen or thrombin or both are reconstituted with a solution containing at least one additive. For example, lyophilized fibrinogen may be reconstituted using: for example, saline water containing additives, saline solution containing aprotinin and additives, saline solution containing additives and calcium ion (Ca)⁺²) For example, a brine solution of calcium ions, which may be provided by calcium chloride, or a solution containing a combination of additives.

[0017] Typically, thrombin is the enzyme used to convert fibrinogen to fibrin. However, other enzymes may be used, such as those obtained from snake venom (e.g., batroxobin), or spider venom as is known in the art. As used herein, "activating compound" refers to a compound that causes fibrinogen to form fibrin, and this term includes thrombin, batroxobin, and the like. Thrombin is commercially available, usually in lyophilized form. The lyophilized thrombin must be reconstituted prior to use. The thrombin may also be frozen or fresh. Thrombin may be autologous, derived from a human or a herd of humans, cattle, fish (e.g. salmon) or other non-human fibrinogen-cleaving enzyme source, such as various arachnids or other toxic species. The thrombin or enzyme is used in any amount that facilitates the conversion of fibrinogen to fibrin, as will be appreciated by those skilled in the art. Thrombin can be reconstituted using the following: brine and one or more additives, or a brine solution containing an additive and calcium ions.

[0018] As used herein, the term "additive" refers to an antibiotic; antiproliferative drugs, cytotoxic drugs, and antineoplastic drugs, including chemotherapeutic drugs; analgesics (analgesic); anti-angiogenic agents (anti-angiogenic agents); an antibody; an antiviral agent; a cytokine; a colony stimulating factor; a protein; a chemoattractant; EDTA; histamine; an antihistamine; erythropoietin; an antifungal agent; an antiparasitic agent; non-corticosteroid anti-inflammatory agents; an anticoagulant; anesthetics, including local anesthetics such as lidocaine and bupivacaine; analgesics (analgesics); an oncology agent; a cardiovascular agent; vitamins and other nutritional supplements; a hormone; a glycoprotein; fibronectin; peptides, including polypeptides and proteins; an interferon; a cartilage-inducing factor; a protease inhibitor; a vasoconstrictor, vasodilator, demineralized bone, or bone morphogenic protein; hormones; a lipid; a carbohydrate; proteoglycans, such as aggrecan (chondroitin sulfate and dermatan sulfate), pluripotent proteoglycan (versican), decorin (decorin), and biglycan; anti-angiogenin (antiangiogenins); an antigen; a DBM; hyaluronic acid and salts and derivatives thereof; a polysaccharide; cellulose compounds such as methyl cellulose, carboxymethyl cellulose and hydroxy-propyl methyl cellulose and derivatives thereof; a plurality of antibodies; a gene therapy agent; genetically engineered cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; cell growth factors that promote the recovery of damaged tissue and/or the growth of new healthy tissue, such as BMP7 and BMP 2; type I and type II collagen; elastin; sulfated glycosaminoglycan (sGAG), glucosamine sulfate; a pH modifier; methylsulfonylmethane (MSM); an osteogenic compound; osteoconductive compounds (osteocondutive compositions); plasminogen; a nucleotide; an oligonucleotide; a polynucleotide; a polymer; osteogenic protein 1(OP-1, including recombinant OP-1); LMP-1(Lim mineralization protein 1); cartilage, including autologous cartilage; an oxygen-containing component; enzymes such as, for example, peroxidases, which mediate the release of oxygen from such components; melatonin; vitamins; and nutritional agents such as, for example, glucose or other sugars. However, it is envisioned that any of these additives may be added to the fibrin sealant, either alone or in combination. One or more of these additives may be injected with the fibrinogen and thrombin, or, alternatively, one or more of these components may be injected separately, either before or after the fibrin sealant is injected. Combinations of these additives may be used, and different additives may be used in the solutions used to reconstitute the fibrinogen and thrombin (e.g., a solution containing a local anesthetic is used to reconstitute the fibrinogen and a solution containing type II collagen is used to reconstitute the thrombin). In addition, one or more other additives may be added to the reconstituted solution of thrombin or fibrinogen. Likewise, one or more of these additives may be injected with the fibrinogen and activating compound, or, alternatively, one or more of these additives may be injected separately, either before or after the fibrin sealant is injected.

[0019] For solutions containing additives that are not completely water soluble, an anti-caking agent, such as, for example, polysorbate, may be added to facilitate suspension of this component. Ethylene glycol may not be suitable for use as an anti-caking agent in the present invention.

[0020] It will be appreciated that fibrin formation begins immediately upon contact between fibrinogen and thrombin, for example in the Y-connector of a double syringe. Thus, the term "injection" of a fibrin sealant, as used herein, encompasses any injection of components that form fibrin in an intervertebral disc, including situations in which portions of the components react to form fibrin due to mixing prior to contact with or actual introduction into the intervertebral disc. It is also within the scope of the invention to inject the components of the fibrin sealant sequentially into the disc, such as injecting the thrombin component followed by the fibrinogen component, or injecting the fibrinogen component followed by the thrombin component. Likewise, the fibrinogen component and the thrombin component may be intermittently injected into the disc separately.

[0021] It should also be understood that the injection site or sites (e.g., at the needle tip of a spinal needle) may be within the annulus fibrosus or in the nucleus pulposus. If the injection occurs in the nucleus pulposus, the injected components can form a plaque at the interface between the nucleus pulposus and the annulus fibrosus, or, more commonly, the components flow into defects (e.g., fissures) in the annulus fibrosus and are likely to "overflow" into the interdiscal space. In practice, over-stressing of the intervertebral disc due to injection of the components into the disc should be avoided.

[0022] It will be apparent to those skilled in the art that the amount of fibrinogen and activating compound injected is an amount effective to seal a given disc defect. The amount of activating compound, such as thrombin, can be varied to shorten or lengthen the time to complete fibrin formation. Generally, the higher the level of thrombin per unit amount of fibrinogen, the faster the formation of fibrin. If slower fibrin formation is desired, a lower amount of thrombin per unit of fibrinogen is used. The use of calcium ions (e.g. from calcium chloride) in one or both component solutions will affect the strength of the fibrin so formed, with the greater the amount of calcium ions, the greater the strength of the fibrin clot. Generally, for aqueous fibrinogen-containing compositions, it is believed that from about 3mL to about 5mL of such compositions are sufficient to be effective fibrin sealants. However, depending on the use of the composition, the dosage may be in the range of about 0.05mL to about 40 mL.

[0023] Fibrin sealant mimics the final stages of the natural coagulation mechanism. Typically, such blocking agents require mixing of the fibrinogen component with an activating enzyme such as thrombin. Thrombin is an enzyme present in plasma that causes blood to clot by converting fibrinogen to fibrin. In common practice, the components of the fibrin sealant are separately reconstituted from a lyophilized state prior to use. However, it is also acceptable to use samples prepared from either a frozen state or a fresh state. To increase the biocompatibility of the sealant with host tissues, the components may be supplied endogenously from host body fluids. The reconstituted components are combined to produce a viscous solution that rapidly becomes an elastic clot. Methods for preparing conventional fibrin sealants are described by J.Rousou et al in Journal of Thoracic and Cardiovascular Surgery, vol.97, No.2, pp194-203, month 2 1989. Cryoprecipitate from the source plasma was washed, dissolved in buffer solution, filtered and freeze-dried. The lyophilized fibrinogen is reconstituted in a fibrinolysis inhibitor solution containing, for example, 3000 KIU/ml of aprotinin (a polyvalent protease inhibitor that prevents premature degradation of the formed fibrin). The solution was stirred and heated to a temperature of about 37 ℃. Each solution (thrombin and fibrinogen solutions) was drawn up with a double syringe and mounted on a Y-connector to which a needle was connected to deliver the combined solution. (see, e.g., Duploject ® device, from ImmunoAG, Vienna, Austria). Thus, mixing of the components occurs only during delivery, which facilitates clot formation only at the desired site of application. The components should be injected sufficiently rapidly to avoid the passage in the needle and/or Y-connector being blocked by fibrin formation.

[0024] In one embodiment, mixing of the fibrin sealant components occurs at least in part in the Y-connector and the needle mounted on the Y-connector to equalize clots that occur in the disc. This method of preparation facilitates the formation of a fibrin clot at the desired location of the disc during or immediately after delivery. Calcium chloride may be included in the fibrin sealant to be injected to modify the composition of the fibrin so formed and the strength of the clot obtained.

[0025] In one embodiment, about 75-105 mg/ml of the lyophilized fibrinogen is reconstituted according to conventional methods, and about 45-55 mg/ml of the thrombin component is independently reconstituted from the lyophilized state according to the methods and compositions of the present invention. Lyophilized fibrinogen and lyophilized thrombin are available in kit form from manufacturers such as Baxter under trade names such as tisel ®. These two fibrin sealant components can be prepared separately, for example, as approximately 2ml samples, resulting in approximately 4ml of total sealant (reconstituted fibrinogen + reconstituted thrombin). At least one of the reconstituted fibrinogen and the reconstituted thrombin is reconstituted with a solution containing at least one additive.

[0026] While several methods and components can be used to prepare the lyophilized thrombin for use in the fibrin sealant of the invention, one method is to provide about 45-55 mg/ml of lyophilized thrombin and mix it with the reconstitution solution. The reconstitution solution for reconstituting thrombin or fibrinogen or both components may further include about 0.1-100 mg of other additives described herein (e.g., local anesthetic) and/or calcium chloride. The concentration of calcium chloride may be, for example, 1 to 100mmol/mL, and in one embodiment, 4 to 40 mmol/mL. If used, the calcium chloride concentration should be sufficient to promote polymerization to form a durable fibrin sealant clot. A preservative-free reconstituting solution may be desirable, but is not required.

[0027] The contrast agent may be used together in the injection of the fibrin sealant. The contrast agent may be injected prior to the fibrin sealant. Alternatively, the contrast agent is contained in the fibrinogen component or the thrombin component that is injected into the disc. Contrast agents and their use are well known to those skilled in the art.

[0028] Alternative amounts and concentrations of fibrinogen and thrombin may be used to form the desired fibrin sealant clot in vivo. For example, as described above, the amount/concentration of fibrinogen and/or thrombin can be varied to vary the viscosity and "setting time" of the combined fibrinogen and thrombin components. Also, varying fibrinogen may alter the density of the combined components, which may be important for controlling flow through long conduits, such as catheters, into the body. Varying thrombin, the polymerization time of the components can be varied, which may be important to control the time of clot formation to ensure that the components function at the correct site and time in vivo rather than prematurely.

[0029] When obtained in lyophilized form, the thrombin and fibrinogen need to be reconstituted for use. The thrombin reconstituting solution (e.g., saline-based solution), optionally containing one or more additives, may be prepared in a vial prior to mixing with the lyophilized thrombin. This component of the fibrin sealant can then be provided to the user in a reconstituted state, or alternatively, in two uncombined vials containing the lyophilized thrombin and the premixed reconstitution solution, respectively. The contents of the two vials may be mixed at any time prior to the fibrin sealant (or its components) being injected into a patient, including at the time of injection into a patient. Reconstitution of the fibrinogen solution can be accomplished according to conventional methods. For example, the fibrinogen component may be reconstituted in an aprotinin saline solution, optionally containing additives such as, for example, a local anesthetic. If desired, the thrombin or fibrinogen or both may be reconstituted with a saline solution containing one or more additives. The temperature of all solutions was brought to about 37 ℃. Preferably, the thrombin is combined with the fibrinogen solution using a dual syringe injection procedure, as described herein, to form a single sealant composition that is injected into the patient. The present invention provides a means for delivering the sealant, which delivers the sealant to a precise area of the back, seals all of the annular fissures, and holds the fibrin in place by elastic clotting. In addition, the biodegradable nature of the formed fibrin clot minimizes or eliminates the need for invasive surgical removal after the effective period of use. Thus, the sealant and method of application have the advantage of providing an excellent minimally invasive means of accomplishing localized, prolonged sealing of defects (e.g., fissures) in the annulus fibrosus, and, if present in the sealant, sustained release delivery of the additive.

[0030] The fibrin sealant may be injected into an intervertebral disc or other body region using procedures well known to those skilled in the art. Typically, a trocar is inserted into the intradiscal space with the tip of the needle positioned adjacent to the defect in the annulus fibrosus. A finer gauge needle (made of, for example, stainless steel, capable of puncturing the annulus fibrosus) is then inserted into the trocar. The fibrin sealant is injected through the finer gauge needle. Alternatively, a catheter made of a synthetic polymer may be used. For a finer gauge needle or a catheter made of a synthetic polymer, the needle or catheter can be advanced through the trocar and into the nucleus pulposus. Alternatively, the needle or catheter may be advanced until the tip of the trocar is reached, but not beyond the tip of the trocar. This may have the advantage of accurately locating the injection site, especially since the polymer catheter may bend in the nucleus pulposus, resulting in a wrong location. Also, by first positioning the trocar at the desired injection site, the fibrin sealant can be injected quickly to speed up the procedure, which is beneficial to the patient. Generally, the fibrin sealant of the present invention is injected into the intervertebral disc, epidural space, zygapophyseal joint (2-joint), spinal canal and/or dural sac. With respect to the injection of a fibrin sealant into an intervertebral disc, an intra-discal injection may create a fibrin matrix that seals the disc, preventing the material in the nucleus pulposus from leaking into the area outside the disc. For example, fibrin sealant can be delivered by fluoroscopy via epidural or intradiscal injection through the lumbar spine of the foramina, such as described in U.S. Pat. No. 6,468,527. To treat a back injury such as this, a fibrin sealant is injected into the nucleus pulposus, as shown in fig. 1, to fill any fissures or voids in the annulus fibrosus, seal the bony endplates of the disc, increase the pressure of the disc, and increase the height of the intervertebral space. Generally, a fibrin sealant is injected at a location near the annulus fibrosus defect. Typically, the fibrin sealant will flow into the fissures of the annulus fibrosus, and some fibrin sealant may thus flow out of the intradiscal space. The injection may also cover the area adjacent to the disc, directly into the nerve roots and surrounding areas, which may protect these areas from the leaking nucleus material. Sealing the fissures and bone endplates prevents the leakage of harmful chemicals into the disc environment and prevents the immune system from initiating foreign body reactions against the damaged disc. Increasing the intervertebral space and relieving pressure on the nerve roots. That is, due to the injection, the disc height increases, which increases the gap between the laminae, which in turn relieves pressure on the nerve roots on the lamina. For the present application, supplementation of the fibrin sealant with growth factors may promote repair of damaged tissues or gradual replacement of the fibrin sealant with healthy tissues.

[0031] The use of the improved fibrin sealant composition may be better understood by reference to the following examples. These examples are representative and should not be construed as limiting the scope of the invention or its claims. Unless otherwise indicated (example 3), the fibrin sealant used in these examples did not contain a corticosteroid and the procedure was performed in the absence of a heating step to the nucleus pulposus and annulus fibrosus and without a partial or total discectomy.

Example 1

Fluoroscopy transintervertebral foramen epidural injection

[0032] The patient lies in a prone position on the imaging table, and the fluoroscope is positioned and adjusted to locate the intervertebral foramen of the affected nerve root. After anesthetizing the skin and deep tissues, a bent 22 gauge (22ga.) x 3.5 "needle was introduced. The needle is advanced to a position in the anterior epidural space under direct fluoroscopy. The positioning of the needle is verified by a lateral X-ray view and by injecting a contrast medium through the needle. Such positioning may or may not require further adjustment. If adjusted, the position of the needle is verified again. The needle is advanced into the correct area, possibly stimulating pain in a manner consistent with the original affliction. Thus, the placement of the needle may also be verified by the pain sensation of the patient. The epidural space is anesthetized with an injectable anesthetic. The fibrin sealant containing fibrinogen and thrombin (prior to clotting) is then introduced through the needle by continuous gentle pressure until the contents of the dual syringe system are completely exhausted. The thrombin or fibrinogen or both has been reconstituted with a solution containing at least one additive. The fibrin sealant then coats the nerve roots and annulus, and the needle is withdrawn. Following this procedure, the patient is observed, monitored for vital signs, and performed for approximately 20-30 minutes.

[0033] For this procedure, a sufficient volume of fibrin sealant is injected to effectively hydro-dissect the area around the targeted nerve root. It is believed that due to the avascular nature of the epidural space, the absorption/degradation period is generally longer than that observed in open applications in areas with more vascularity and exposure to room air upon administration.

[0034] The ability of the fibrin sealant to seal the annular fissures associated with disc herniation provides a therapeutic benefit to the patient. Chemical radiculitis or radiculitis is known to be rather painful in some cases. It is believed that the use of fibrin sealant in the manner described above not only coats the nerve roots, but also seals the annular fissures surrounding the herniated disc. (see FIG. 1). The sealant also seals the annulus fissures from the outside of the annulus fibrosus due to hydrodynamic segmentation of the area around the affected nerve root.

Example 2

Fluoroscopic guided intra-discal injection

[0035] After sterile preparation, the trocar was delivered to the superior articular process in an oblique projection. A curved spinal needle is delivered through the trocar to the disc. Anteroposterior and lateral X-ray projections are used to confirm correct needle position. If the needle position needs to be adjusted, its placement is again confirmed by fluoroscopy. Contrast is injected to verify the needle position. In patients with chemical radiculitis, leakage of contrast agent through the annulus may be observed and/or intradiscal pathology may be identified. Once the needle is properly positioned in the intradiscal space, the fibrin sealant (or component thereof) is injected. Either thrombin or fibrinogen or both has been reconstituted with a solution containing at least one additive. When the fibrin sealant sealed the annular fissures, it was observed that the fibrin sealant exerted force on the contrast agent in the intradiscal space. Alternatively, the contrast agent is injected with the blocking agent. Alternatively, no contrast agent is used. This procedure seals the defect/fissure of the annulus fibrosus and prevents chemical leakage and facilitates healing within the disc.

Example 3

Comparison of injection of fibrin sealant with fibrin sealant containing corticosteroid

[0036] The 20 patients were divided into two groups of 10 patients each. All patients had pain due to disc degeneration caused by defects (fissures) in the annulus fibrosus. All patients had previously experienced at least 6 months of conventional conservative treatment with no effect. Using the procedure in example 2, the first group of patients was injected intradiscally with a fibrin sealant containing fibrinogen and thrombin. Using the procedure in example 2, a second group of patients was injected intradiscally with a fibrin sealant containing fibrinogen, thrombin and betamethasone (a corticosteroid). The corticosteroid is in the thrombin component. The back pain and leg pain for each patient were rated on a scale of 0-10 at predetermined time intervals before and after surgery. The results (VAS scores) are shown in fig. 3 and 4. As can be seen, patients injected with fibrin sealant alone (without betamethasone) experienced superior pain relief relative to patients injected with fibrin sealant containing betamethasone. It was thought that patients receiving injections containing betamethasone would have superior efficacy due to the inflammation reducing effect of betamethasone. However, the opposite was observed. In fact, patients injected with fibrin sealant alone experienced significantly improved pain relief, not only 1 week after surgery, but especially 12 weeks after surgery. These results are surprising and unexpected.

Example 4

Fibrin sealant reconstituted with local anesthetic

[0037] The patient is treated with a fibrin sealant containing a local anesthetic. The local anesthetic is used to reconstitute the thrombin. The patient suffers from pain resulting from disc degeneration due to defects (fissures) in the annulus fibrosus. Using the method in example 2, the patient was intradiscally injected with a fibrin sealant containing fibrinogen, thrombin, and a local anesthetic (3cc of 75% bupivacaine). Local anesthetics are used to reconstitute thrombin. Fibrinogen, thrombin and local anesthetic were injected for a total of 5 cc. At predetermined time intervals before and after surgery, patients were rated on a scale of 0-10 for back and leg pain. For back pain, the results are as follows: before treatment, 4; one week after treatment, 4; three weeks after treatment, 1; six weeks after treatment, 1. Leg pain was 0 both before and after treatment. These results are surprising and unexpected due to the significant reduction in pain after six weeks.

******

[0038] It is envisaged that the present invention may be used to address a variety of conditions by using fibrin sealant in a manner similar to that described in the above examples. The discussion of the invention refers to particular means, materials and embodiments which elaborate limited applications of the claimed invention. The invention is not limited to these specific cases but applies to all equivalents. Although the invention has been described with reference to particular means, materials and embodiments, it is to be understood that the invention is not limited to the particulars disclosed, but extends to all equivalents within the scope of the claims.

Claims (79)

1. A method of treating a disc that leaks through the nucleus pulposus through at least one defect in the annulus fibrosus, comprising: injecting a fibrin sealant into the disc to reduce at least a portion of the at least one defect, wherein the fibrin sealant injected into the disc comprises fibrinogen and an activating compound, wherein at least a portion of the fibrin forms after injection, wherein the fibrinogen, the activating compound, or both has been reconstituted with a solution containing at least one additive, with the proviso that the fibrin sealant injected into the disc lacks a corticosteroid.

2. The method of claim 1, with the proviso that neither the nucleus pulposus nor the annulus fibrosus has been heated.

3. The method of claim 1, wherein the fibrin sealant consists essentially of fibrinogen, an activating compound, and at least one additive and optionally calcium chloride.

4. The method of claim 1, wherein the fibrin sealant consists of fibrinogen, an activating compound, and at least one additive, and optionally contains calcium chloride.

5. The method of claim 1, wherein calcium chloride is injected with the fibrinogen and the activating compound.

6. The method of claim 1, wherein the activating compound is thrombin.

7. The method of claim 1, wherein the method consists of the injecting step.

8. The method of claim 1, wherein the additive is selected from the group consisting of: (ii) an antibiotic; antiproliferative drugs, cytotoxic drugs, and antineoplastic drugs, including chemotherapeutic drugs; an analgesic; an anti-angiogenic agent; an antibody; an antiviral agent; a cytokine; a colony stimulating factor; a protein; a chemoattractant; EDTA; histamine; an antihistamine; erythropoietin; an antifungal agent; an antiparasitic agent; non-corticosteroid anti-inflammatory agents; an anticoagulant; an anesthetic; an analgesic; an oncology agent; a cardiovascular agent; vitamins and other nutritional supplements; a hormone; a glycoprotein; fibronectin; peptides, including polypeptides and proteins; an interferon; a cartilage-inducing factor; a protease inhibitor; a vasoconstrictor, vasodilator, demineralized bone, or bone morphogenic protein; hormones; a lipid; a carbohydrate; proteoglycan; anti-angiogenin; an antigen; a DBM; hyaluronic acid and salts and derivatives thereof; a polysaccharide; cellulose compounds and derivatives thereof; a plurality of antibodies; a gene therapy agent; genetically engineered cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; a cell growth factor; type II collagen; elastin; glycosaminoglycans sulfate (sGAG), glucosamine sulfate; a pH modifier; methylsulfonylmethane (MSM); an osteogenic compound; a bone conduction compound; plasminogen; a nucleotide; an oligonucleotide; a polynucleotide; a polymer; osteogenic protein 1(OP-1, including recombinant OP-1); LMP-1(Lim mineralization protein 1); cartilage; an oxygen-containing component; an enzyme; melatonin; a vitamin; and a nutritional agent.

9. The method of claim 1, wherein at least one additive is a local anesthetic.

10. The method of claim 1, wherein no portion of the nucleus pulposus has been removed by surgery.

11. The method of claim 1, wherein said at least one defect is a tear or fissure in said annulus fibrosus.

12. The method of claim 1, wherein normal hydrostatic pressure of the disc is restored, or normal disc height is restored, or both.

13. The method of claim 1, wherein the fibrinogen is autologous.

14. The method of claim 1, wherein the injection is performed using a dual barrel syringe.

15. The method of claim 1, wherein the activating compound is thrombin, and wherein a mixture of fibrinogen and thrombin is injected.

16. The method of claim 1, wherein the activating compound is thrombin, and wherein the fibrinogen and thrombin are injected sequentially and at least partially mixed in the disc.

17. The method of claim 1, wherein the additives are injected sequentially before, simultaneously with, or after the fibrinogen and thrombin, and at least partially mixed in the disc.

18. The method of claim 1, wherein the disc is injected with the fibrin sealant at multiple sites.

19. The method of claim 1, wherein the injecting occurs by the following procedure: inserting a trocar having a needle tip into the intervertebral disc space to a location adjacent the at least one defect; inserting a second needle or a polymeric catheter through the trocar up to, but not beyond, the needle tip of the trocar; and injecting the fibrin sealant through the second needle or polymer catheter.

20. The method of claim 1, wherein the disc is a lumbar disc.

21. The method of claim 1, wherein the disc is a cervical disc.

22. The method of claim 1, wherein the disc is a thoracic disc.

23. The method of claim 1, wherein a contrast agent is injected before the fibrin sealant, at the same time the fibrin sealant is injected, or after the fibrin sealant has been injected.

24. A method of treating a human back comprising injecting a fibrin sealant into a disc to seal at least one defect of an annulus fibrosus, wherein the fibrin sealant comprises fibrinogen and thrombin, wherein the fibrinogen and thrombin forms at least a portion of the fibrin after injection, wherein the fibrinogen, the thrombin, or both has been reconstituted with a solution comprising at least one additive, and wherein the fibrin sealant does not comprise a corticosteroid.

25. The method of claim 24, with the proviso that neither the nucleus pulposus nor the annulus fibrosus has been heated.

26. The method of claim 24, wherein the fibrin sealant consists essentially of fibrinogen, an activating compound, and at least one additive.

27. The method of claim 24, wherein the fibrin sealant consists of fibrinogen, an activating compound, at least one additive, and calcium chloride.

28. The method of claim 24, wherein calcium chloride is injected with the fibrinogen and the thrombin.

29. The method of claim 24, wherein the method consists of the injecting step.

30. The method of claim 24, wherein the activating compound is thrombin.

31. The method of claim 24, wherein the additive is selected from the group consisting of: (ii) an antibiotic; antiproliferative drugs, cytotoxic drugs, and antineoplastic drugs, including chemotherapeutic drugs; an analgesic; an anti-angiogenic agent; an antibody; an antiviral agent; a cytokine; a colony stimulating factor; a protein; a chemoattractant; EDTA; histamine; an antihistamine; erythropoietin; an antifungal agent; an antiparasitic agent; non-corticosteroid anti-inflammatory agents; an anticoagulant; an anesthetic; an analgesic; an oncology agent; a cardiovascular agent; vitamins and other nutritional supplements; a hormone; a glycoprotein; fibronectin; peptides, including polypeptides and proteins; an interferon; a cartilage-inducing factor; a protease inhibitor; a vasoconstrictor, vasodilator, demineralized bone, or bone morphogenic protein; hormones; a lipid; a carbohydrate; proteoglycan; anti-angiogenin; an antigen; a DBM; hyaluronic acid and salts and derivatives thereof; a polysaccharide; cellulose compounds and derivatives thereof; a plurality of antibodies; a gene therapy agent; genetically engineered cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; a cell growth factor; type II collagen; elastin; glycosaminoglycans sulfate (sGAG), glucosamine sulfate; a pH modifier; methylsulfonylmethane (MSM); an osteogenic compound; a bone conduction compound; plasminogen; a nucleotide; an oligonucleotide; a polynucleotide; a polymer; osteogenic protein 1(OP-1, including recombinant OP-1); LMP-1(Lim mineralization protein 1); cartilage; an oxygen-containing component; an enzyme; melatonin; a vitamin; and a nutritional agent.

32. The method of claim 24, wherein at least one additive is a local anesthetic.

33. The method of claim 24, wherein no portion of the nucleus pulposus has been removed by surgery.

34. The method of claim 24, wherein said at least one defect is a tear or fissure in said annulus fibrosus.

35. The method of claim 24, wherein normal hydrostatic pressure of the disc is restored, or normal disc height is restored, or both.

36. The method of claim 24, wherein the fibrinogen is autologous.

37. The method of claim 24, wherein the injection is performed using a dual barrel syringe.

38. The method of claim 24, wherein the activating compound is thrombin, and wherein a mixture of fibrinogen and thrombin is injected.

39. The method of claim 24, wherein the activating compound is thrombin, and wherein the fibrinogen and thrombin are injected sequentially and at least partially mixed in the disc.

40. The method of claim 24, wherein the disc is injected with the fibrin sealant at multiple locations in the disc.

41. The method of claim 24, wherein the injecting occurs by the following procedure: inserting a trocar having a needle tip into the intervertebral disc space to a location adjacent the at least one defect; inserting a second needle or a polymeric catheter through the trocar up to, but not beyond, the needle tip of the trocar; and injecting the fibrin sealant through the second needle or polymer catheter.

42. The method of claim 24, wherein the disc is a lumbar disc.

43. The method of claim 24, wherein the disc is a cervical disc.

44. The method of claim 24, wherein the disc is a thoracic disc.

45. The method of claim 24, wherein a contrast agent is injected before the fibrin sealant, at the same time the fibrin sealant is injected, or after the fibrin sealant has been injected.

46. The method of claim 24, wherein the additives are injected sequentially before, simultaneously with, or after the fibrinogen and thrombin, and at least partially mixed in the disc.

47. A method of treating a human back comprising providing a mixture of fibrinogen and thrombin within a human disc to treat at least one defect of an annulus fibrosus, wherein the fibrinogen, the thrombin, or both has been reconstituted with a solution containing at least one additive, and wherein the mixture does not include a corticosteroid.

48. The method of claim 47, with the proviso that neither the nucleus pulposus nor the annulus fibrosus has been heated.

49. The method of claim 47, wherein the fibrin sealant consists essentially of fibrinogen, thrombin, and at least one additive.

50. The method of claim 47, wherein the fibrin sealant consists of fibrinogen, thrombin, at least one additive, and calcium chloride.

51. The method of claim 47, wherein calcium chloride is provided with said fibrinogen and said thrombin.

52. The method of claim 47, wherein said method consists of said providing step.

53. The method of claim 47, wherein the additive is selected from the group consisting of: (ii) an antibiotic; antiproliferative drugs, cytotoxic drugs, and antineoplastic drugs, including chemotherapeutic drugs; an analgesic; an anti-angiogenic agent; an antibody; an antiviral agent; a cytokine; a colony stimulating factor; a protein; a chemoattractant; EDTA; histamine; an antihistamine; erythropoietin; an antifungal agent; an antiparasitic agent; non-corticosteroid anti-inflammatory agents; an anticoagulant; an anesthetic; an analgesic; an oncology agent; a cardiovascular agent; vitamins and other nutritional supplements; a hormone; a glycoprotein; fibronectin; peptides, including polypeptides and proteins; an interferon; a cartilage-inducing factor; a protease inhibitor; a vasoconstrictor, vasodilator, demineralized bone, or bone morphogenic protein; hormones; a lipid; a carbohydrate; proteoglycan; anti-angiogenin; an antigen; a DBM; hyaluronic acid and salts and derivatives thereof; a polysaccharide; cellulose compounds and derivatives thereof; a plurality of antibodies; a gene therapy agent; genetically engineered cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; a cell growth factor; type II collagen; elastin; glycosaminoglycans sulfate (sGAG), glucosamine sulfate; a pH modifier; methylsulfonylmethane (MSM); an osteogenic compound; a bone conduction compound; plasminogen; a nucleotide; an oligonucleotide; a polynucleotide; a polymer; osteogenic protein 1(OP-1, including recombinant OP-1); LMP-1(Lim mineralization protein 1); cartilage; an oxygen-containing component; an enzyme; melatonin; a vitamin; and a nutritional agent.

53. The method of claim 47, wherein at least one additive is a local anesthetic.

54. The method of claim 47, wherein no portion of the nucleus pulposus has been removed by surgery.

55. The method of claim 47, wherein said at least one defect is a tear or fissure in said annulus fibrosus.

56. The method of claim 47, wherein normal hydrostatic pressure of the disc is restored, or normal disc height is restored, or both.

57. The method of claim 47, wherein the fibrinogen is autologous.

58. The method of claim 47, wherein the providing is performed by using a dual barrel syringe.

59. The method of claim 47, wherein a mixture of fibrinogen, thrombin and the at least one additive is provided.

60. The method of claim 47, wherein the fibrinogen and thrombin are provided sequentially and at least partially mixed in the disc.

61. The method of claim 47, wherein the disc is provided with the fibrin sealant at a plurality of locations in the disc.

62. The method of claim 47, wherein the injection occurs by the following procedure: inserting a trocar having a needle tip into the intervertebral disc space to a location adjacent the at least one defect; inserting a second needle or a polymeric catheter through the trocar up to, but not beyond, the needle tip of the trocar; and injecting the fibrin sealant through the second needle or polymer catheter.

63. The method of claim 47, wherein the disc is a lumbar disc.

64. The method of claim 47, wherein the disc is a cervical disc.

65. The method of claim 47, wherein the disc is a thoracic disc.

66. The method of claim 47, wherein a contrast agent is injected before the fibrin sealant, at the same time the fibrin sealant is injected, or after the fibrin sealant has been injected.

67. The method of claim 47, wherein the additive is injected sequentially before, simultaneously with, or after the fibrinogen and thrombin, and at least partially mixed in the disc.

68. A kit, comprising:

the amount of fibrinogen is such that it is,

the thrombin is a compound of the formula (I),

at least one additive selected from the group consisting of,

a spinal needle, or a polymer catheter, or both,

wherein the kit does not include a corticosteroid and the kit does not include a means for providing thermal energy to the disc.

69. The kit of claim 68, wherein at least one additive is a local anesthetic.

70. The kit of claim 68, further comprising calcium chloride.

71. The kit of claim 68, wherein the additive is selected from the group consisting of: (ii) an antibiotic; antiproliferative drugs, cytotoxic drugs, and antineoplastic drugs, including chemotherapeutic drugs; an analgesic; an anti-angiogenic agent; an antibody; an antiviral agent; a cytokine; a colony stimulating factor; a protein; a chemoattractant; EDTA; histamine; an antihistamine; erythropoietin; an antifungal agent; an antiparasitic agent; non-corticosteroid anti-inflammatory agents; an anticoagulant; an anesthetic; an analgesic; an oncology agent; a cardiovascular agent; vitamins and other nutritional supplements; a hormone; a glycoprotein; fibronectin; peptides, including polypeptides and proteins; an interferon; a cartilage-inducing factor; a protease inhibitor; a vasoconstrictor, vasodilator, demineralized bone, or bone morphogenic protein; hormones; a lipid; a carbohydrate; proteoglycan; anti-angiogenin; an antigen; a DBM; hyaluronic acid and salts and derivatives thereof; a polysaccharide; cellulose compounds and derivatives thereof; a plurality of antibodies; a gene therapy agent; genetically engineered cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; a cell growth factor; type II collagen; elastin; glycosaminoglycans sulfate (sGAG), glucosamine sulfate; a pH modifier; methylsulfonylmethane (MSM); an osteogenic compound; a bone conduction compound; plasminogen; a nucleotide; an oligonucleotide; a polynucleotide; a polymer; osteogenic protein 1(OP-1, including recombinant OP-1); LMP-1(Lim mineralization protein 1); cartilage; an oxygen-containing component; an enzyme; melatonin; a vitamin; and a nutritional agent.

72. The kit of claim 68, wherein the fibrinogen and thrombin are in a lyophilized state.

73. The kit of claim 69, further comprising a trocar.

74. The kit of claim 69, wherein the polymeric catheter is sized such that it does not extend beyond the needle tip of the trocar during use.

75. A method of producing a kit comprising: provide for

A fibrinogen component comprising a mixture of a fibrinogen component,

the components of the thrombin are mixed and then mixed,

at least one additive selected from the group consisting of,

and a spinal needle, or a polymer catheter, or both,

wherein the kit does not include a corticosteroid and the kit does not include a means for providing thermal energy to the disc.

76. The method of claim 75, wherein the polymer catheter is sized such that it does not extend beyond the needle tip of the trocar during use.

77. The method of claim 75, wherein the spinal needle is sized so that it does not extend beyond the tip of the trocar during use.

78. Use of a first solution comprising fibrinogen and a second solution comprising thrombin for the preparation of a pharmaceutical composition for the treatment of a mammalian disc that is leaking nucleus pulposus due to at least one defect in the annulus fibrosus, wherein a solution comprising an additive is used to reconstitute the fibrinogen, the thrombin, or both, wherein neither the first solution nor the second solution comprises a corticosteroid.