CN101048190A - Injection of fibrin sealant using reconstituted components in spinal applications - Google Patents

Abstract

A method of treating a disc that is leaking nucleus pulposus through at least one defect in the annulus fibrosus. The method comprises 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.

Description

Injectable Fibrin Sealant Using Reconstituted Components in Spinal Applications

By Brian D. Burkinshaw, Steven I. Whitlock, Kevin Pauza,

  Mark I. Richards, Jim Rogan

[0001] This application claims priority to U.S. Provisional Application No. 60/623,600, filed October 29, 2004, which is incorporated herein by reference.

Background of the invention

[0002] In general, the present invention relates to the application of a fibrin sealant, whereby the sealant is delivered to the spinal region, for example by injection, and the fibrinogen and/or thrombin are reconstituted with a solution containing additives. structure.

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

[0004] More recently, fibrin sealants containing corticosteroids have been used to treat intervertebral disc problems, such as fissures in the annulus fibrosus. In this regard, US 6,468,527 discloses that compositions are injected into the intervertebral disc (intradiscal injection) to treat intervertebral disc problems.

Summary of the invention

[0005] In practicing the present invention, a fibrin sealant is injected into the spinal region of a person. The sealant includes fibrinogen and an activating compound such as thrombin, which when mixed form fibrin. It has been found that this composition provides surprisingly superior results over corticosteroid containing fibrin sealant compositions. Calcium ions, such as provided by calcium chloride, may be included in the fibrin sealant. Fibrinogen and/or thrombin can be obtained from lyophilized components reconstituted with a solution containing 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 excluded from this fibrin sealant.

[0006] In one broad aspect, the present invention is a method of treating an intervertebral disc that leaks a nucleus pulposus due to at least one defect in the annulus fibrosus, the method comprising: injecting a fibrin sealant into the intervertebral disc to reduce the At least a partial defect of at least one defect wherein the fibrin sealant injected into the intervertebral disc comprises fibrinogen and an activating compound such as thrombin, wherein at least part of the fibrin is formed after injection, wherein said fibrinogen, said activating compound Or both have been reconstituted with a solution containing at least one additive, provided that the fibrin sealant injected into the disc lacks corticosteroids. This treatment can reduce the amount of nucleus pulposus material that leaks due to the defect in the annulus fibrosus. The defect may be a tear in the annulus, a fissure in the annulus, or the like. Advantageously, injecting a fibrin sealant can also help restore normal disc height and hydrostatic pressure, which are key elements. It should be understood that normal physiological hydrostatic pressure can vary from person to person, and that the therapy can produce near normal hydrostatic pressure. As used herein, normal physiological stress includes this range of stress. In one embodiment, neither the nucleus pulposus nor the annulus fibrosus is heated in vivo to stiffen the disc, such as discussed in, eg, US 6,095,149, prior to or concurrently with said injection. In one embodiment, in practicing the invention, the nucleus pulposus is not surgically removed, such as in the case of a total or partial discectomy, or by nucleoplasty for a herniated disc.

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

[0008] In another broad aspect, the invention is a method of treating a human back comprising providing a mixture of fibrinogen and thrombin in a human intervertebral disc to treat at least one defect of the annulus fibrosus, wherein said Fibrinogen, said thrombin, or both have been reconstituted with a solution containing at least one additive, and wherein said mixture is free of corticosteroids. The mixture may be delivered to the disc by injection or otherwise.

[0009] The invention also includes a kit comprising components for injecting a fibrin sealant. The kit may comprise fibrinogen such as lyophilized fibrinogen, thrombin such as lyophilized thrombin, at least one additive, and a needle such as a spinal needle for injecting the sealant, including An example is a curved spinal needle. Alternatively, a spinal canula may be used. This kit does not include corticosteroids. The kit can exclude devices that provide thermal energy to the intervertebral disc. The kit may optionally include contrast media and other additives. The kit may include a single, double or multiple syringe or other fibrin sealant delivery device. Fibrin sealants can be delivered using conventional single-lumen needles or via double- or multi-lumen needles. If a dual lumen needle is used, the components can be delivered through separate lumens. In one embodiment, a double-lumen or multi-lumen needle may be used that allows the fibrinogen component and the thrombin component to contact at the needle tip. 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, in multiple needles, or in a double or multi-lumen needle.

[0010] In another broad aspect, the invention is a method for the manufacture of a kit comprising: providing a fibrinogen component, a thrombin component, at least one additive, and a spinal needle or polymer catheter or spinal cord A puncture needle and a polymeric catheter, wherein the kit does not include a corticosteroid, and wherein the kit does not include a device for providing thermal energy to an intervertebral disc.

[0011] Advantageously, the methods and kits of the present invention contribute to durable pain relief in patients suffering from leaky disc syndrome in which, for example, the nucleus pulposus passes through the annulus fibrosus A defect (such as a tear or fissure) in the spine leaks from the disc. Surprisingly, it has been found that the use of corticosteroid-free fibrin provides unexpectedly superior results relative to injection of a fibrin sealant comprising corticosteroid. The present invention provides unexpectedly superior results over the method described in US 6,468,527, which discloses the injection of a corticosteroid-containing fibrin sealant.

Description of drawings

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

[0013] FIG. 2 is a schematic illustration of a trans-foraminal space into which a modified sealant may be injected according to one embodiment of the present invention.

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

Detailed description of the invention

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

[0016] Fibrinogen useful in the practice of the present invention includes any fibrinogen that will form fibrin in the human body. Fibrinogen is often available in lyophilized form and must be reconstituted prior to use. If thrombin is reconstituted with a solution containing additives, fibrinogen can also be frozen or fresh, autologous (from a patient undergoing treatment), human including pooled human fibrinogen, recombinant, and bovine or other non- Human sources such as fish (eg salmon and sea trout). Fibrinogen is used in an amount suitable for a particular treatment, patient, or the like. Lyophilized fibrinogen is reconstituted with a solution, usually a solution containing aprotinin and calcium chloride. As discussed herein, either fibrinogen or thrombin or both are reconstituted with a solution containing at least one additive. For example, lyophilized fibrinogen can be reconstituted using, for example, saline with supplements, saline solution with aprotinin and supplements, saline solution with supplements and calcium ions (Ca ⁺² ) such as may be provided by calcium chloride A salt solution of calcium ions, 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 enzymes obtained from snake venoms (eg batroxobin), or from spider venoms 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. Lyophilized thrombin must be reconstituted before use. Thrombin can also be frozen or made fresh. Thrombin may be autologous, from a human or herd of humans, cattle, fish (eg salmon) or other non-human sources of fibrinogen cutting enzymes, such as various spiders or other venomous species. The thrombin or enzyme is used in any amount that facilitates conversion of fibrinogen to fibrin, as known to those skilled in the art. Thrombin can be reconstituted using saline and one or more additives, or a saline solution containing additives and calcium ions.

[0018] As used herein, the term "additive" refers to antibiotics; antiproliferative, cytotoxic and antineoplastic agents, including chemotherapeutics; analgesic; antiangiogen; an antibody; Virals; Cytokines; Colony Stimulating Factors; Proteins; Chemoattractants; EDTA; Histamines; Antihistamines; Erythropoietin; Antifungals; Antiparasitic Agents; Noncorticosteroid Anti-inflammatory Drugs; Anticoagulants; Anesthetics, including local anesthetics such as lidocaine and bupivacaine; analgesics; oncology agents; cardiovascular drugs; vitamins and other nutritional supplements; hormones; glycoproteins; fibronectin; peptides, including polypeptides and Proteins; interferons; chondroinductive factors; protease inhibitors; vasoconstrictors, vasodilators, demineralized bone or bone morphogenetic proteins; hormones; lipids; carbohydrates; proteoglycans such as aggrecan (chondrosulfate and deratin sulfate), versican, decorin, and biglycan; antiangiogenins; antigens; DBM; Hyaluronic acid and its salts and derivatives; polysaccharides; cellulosic compounds such as methylcellulose, carboxymethylcellulose, and hydroxy-propylmethylcellulose and their derivatives; various antibodies; gene therapy agents; genetic modification cells, stem cells including mesenchymal stem cells with transforming growth factors, and/or other cells; cell growth factors that promote restoration of damaged tissue and/or growth of new healthy tissue, such as BMP7 and BMP2; type I and Type II collagen; elastin; sulfated glycosaminoglycan (sGAG), glucosamine sulfate; pH modifiers; methylsulfonylmethane (MSM); osteogenic compounds; osteoconductive compounds; plasmin Pro; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; Osteogenic protein 1 (OP-1, including recombinant OP-1); LMP-1 (Lim mineralization protein 1); Cartilage, including autologous cartilage ; oxygen-containing components; enzymes, such as, for example, peroxidase, which mediate the release of oxygen from such components; melatonin; vitamins; and nutrients, 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 together with the fibrinogen and thrombin, or, alternatively, one or more of these components may be injected separately, at the time of injection. before or after the fibrin sealant described above. Combinations of these additives can be used, and different additives can be used in solutions used to reconstitute fibrinogen and thrombin (for example, solutions containing local anesthetic are used to reconstitute fibrinogen, solutions containing type II collagen solution was used to reconstitute thrombin). Additionally, 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 together with the fibrinogen and activating compound, or, alternatively, one or more of these additives may be injected either before or after the injection of the fibrin sealant. Injected separately.

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

[0020] It will be appreciated that as soon as the fibrinogen and thrombin come into contact, for example in the Y-connector of a double barreled syringe, fibrin formation begins immediately. Thus, the term "injection" of a fibrin sealant, as used herein, encompasses any injection of a fibrin-forming component in an intervertebral disc, including cases where some of the components are in contact with the disc or Fibrin is formed by reacting with mixing prior to 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, for example injecting the thrombin component followed by the fibrinogen component, or injecting the fibrinogen component followed by the injection of the fibrinogen component Thrombin component. Likewise, the fibrinogen component and the thrombin component can be injected separately into the intervertebral disc intermittently.

[0021] It should also be understood that the site or sites of injection (eg, at the tip of a spinal needle), may be within the annulus fibrosus or within the nucleus pulposus. If the injection occurs in the nucleus pulposus, the injected component can form a plaque at the interface between the nucleus pulposus and the annulus or, more commonly, the component flows into a defect (such as a fissure) in the annulus , and will likely "overflow" into the interdisk gap. In practice, excessive stress on the intervertebral disc due to injection of the components into the intervertebral disc should be avoided.

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

[0023] Fibrin sealants mimic the final stages of the natural coagulation mechanism. Typically, such sealants require admixture of a 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 a fibrin sealant are reconstituted separately from a lyophilized state prior to use. However, it is also acceptable to use samples prepared from the frozen or fresh state. To increase the biocompatibility of the sealant with host tissues, the components can be supplied endogenously from host body fluids. Combining the reconstituted components produces a viscous solution that quickly becomes an elastic clot. The method for preparing a conventional fibrin sealant is described by J.Rousou et al. in Journal of Thoracic and Cardiovascular Surgery, vol.97, no.2, pp194-203, February 1989. The cryoprecipitate from the source plasma was washed, dissolved in buffer solution, filtered and lyophilized. 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 formed fibrin). The solution was stirred and heated to a temperature of approximately 37°C. Each solution (thrombin and fibrinogen solution) was drawn up with a double barreled syringe and placed on a Y-connector to which a needle was attached for delivery of the combined solutions. (See, eg, Duploject(R) 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 quickly enough to avoid obstruction of the needle and/or channel in the Y-connector due to fibrin formation.

[0024] In one embodiment, the 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 the clot that occurs in the disc. This method of preparation facilitates the formation of a fibrin clot at the desired site of the intervertebral disc during or immediately after delivery. Calcium chloride may be included in the fibrin sealant to be injected in order to modify the composition of the fibrin thus formed and the strength of the clot obtained.

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

[0026] While several methods and ingredients are available for preparing the lyophilized thrombin used in the inventive fibrin sealant, one method is to provide approximately 45-55 mg/ml of lyophilized thrombin and combine it with Reconstitute solution to mix. The reconstitution solution for reconstituting thrombin or fibrinogen or both components may further include about 0.1-100 mg of other additives described herein (eg local anesthetic) and/or calcium chloride. The concentration of calcium chloride may be, for example, 1-100 mmol/mL, in one embodiment, 4-40 mmol/mL. If used, calcium chloride concentrations should be sufficient to promote polymerization to form durable fibrin sealant clots. A preservative-free reconstitution solution may be desired, but is not required.

[0027] A contrast agent may be used with the injection of the fibrin sealant. The contrast medium can be injected before the fibrin sealant. Alternatively, the contrast agent is included in the fibrinogen or thrombin components 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 can 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 "set time" of the combined fibrinogen and thrombin components. Likewise, varying the fibrinogen, can alter the density of the combined components, which may be important for controlling flow into the body through long conduits such as catheters. By altering thrombin, the polymerization time of the components can be changed, which may be important in controlling the timing of clot formation to ensure that the components act at the right place and time in the body and not prematurely.

[0029] When obtained in lyophilized form, thrombin and fibrinogen need to be reconstituted for use. A thrombin reconstitution solution (eg, a saline-based solution), optionally containing one or more additives, can be prepared in a vial prior to mixing with lyophilized thrombin. This component of the fibrin sealant can then be provided to the user in a reconstituted state, or in two uncombined vials containing lyophilized thrombin and pre- mixed reconstitution solution. The contents of the two vials can be mixed at any time before, including when the fibrin sealant (or its components) is injected into the patient. Reconstitution of the fibrinogen solution can be accomplished according to conventional methods. For example, the fibrinogen component can be reconstituted in aprotinin saline solution, optionally containing additives such as, for example, a local anesthetic. If desired, thrombin or fibrinogen or both can be reconstituted with saline solution containing one or more additives. All solutions were brought to a temperature of approximately 37°C. Preferably, thrombin is combined with the fibrinogen solution using a double-barrelled syringe injection procedure, as described herein, to form a single sealant composition that is injected into the patient. The present invention provides means for delivering the sealant that delivers the sealant to precise areas of the back, seals all annular fissures, and holds fibrin in place through the elastic clot. Furthermore, the biodegradable nature of the formed fibrin clot minimizes or eliminates the need for invasive surgical removal after the expiration date. Thus, the advantages of the sealant and method of application are that it provides an excellent minimally invasive means of achieving localized durable closure of defects (e.g. fissures) in the annulus fibrosus and, if additives are present in the sealant, , can also provide sustained release delivery of additives.

[0030] The fibrin sealant can be injected into a disc or other body area using procedures well known to those skilled in the art. Typically, the trocar is inserted into the intradiscal space with the tip positioned adjacent to the defect in the annulus. A finer gauge needle (made of, for example, stainless steel, capable of piercing the annulus fibrosus) is then inserted into the trocar. Fibrin sealant is injected through this finer gauge needle. Alternatively, catheters made of synthetic polymers can be used. For finer gauge needles or catheters made of synthetic polymers, the needle or catheter can be advanced through the trocar and into the nucleus pulposus. Alternatively, the needle or catheter can be advanced up to but not beyond the tip of the trocar. This may have the advantage of accurately locating the injection point, especially since the polymer catheter may bend in the nucleus leading to incorrect positioning. Also, by first positioning the trocar at the desired injection site, the fibrin sealant can be injected quickly thereby speeding up the procedure, which is beneficial to the patient. Generally, the fibrin sealants of the invention are injected into the intervertebral disc, epidural space, facet (2-joint) joint (zygaphysical joint), spinal canal and/or dural sac. With regard to the injection of fibrin sealant into the disc, intradiscal injections create a fibrin matrix that seals the disc, preventing leakage of material from the nucleus pulposus into the extradiscal area. For example, a fibrin sealant may be delivered by fluoroscopic transforaminal lumbar epidural injection or intradiscal injection, such as described in US 6,468,527. To treat back injuries such as these, a fibrin sealant is injected into the nucleus pulposus, as shown in Figure 1, to fill any fissures or holes in the annulus, seal off the bony endplates of the disc, increase disc compression, and increase intervertebral space space. high. Generally, fibrin sealant is injected close to the annular defect. Typically, the fibrin sealant will flow into the fissures of the annulus, and some fibrin sealant may thus flow out of the intradiscal space. Injections can also cover the area adjacent to the disc, injecting directly into the nerve root as well as the surrounding area, which protects these areas from leaking nucleus pulposus material. Seals the fissures and bone endplates, stops harmful chemicals from leaking into the disc environment, and prevents the immune system from triggering a foreign body response to the damaged disc. Increased intervertebral space reduces pressure on nerve roots. That is, as a result of the injection, the disc height increases, which increases the space between the lamina, which in turn reduces pressure on the nerve roots on the lamina. For the present application, supplementation of the fibrin sealant with growth factors can promote the repair of damaged tissue or the gradual replacement of the fibrin sealant by healthy tissue.

[0031] The use of the improved fibrin sealant composition can 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 stated (Example 3), the fibrin sealants used in these examples did not contain corticosteroids, and the procedure described was performed in the absence of a heating step to the nucleus pulposus and annulus fibrosus and without partial or total performed in the case of discectomy.

Example 1

            Transforaminal epidural injection under fluoroscopy

[0032] With the patient lying prone on the imaging table, the fluoroscopic screen is placed and adjusted to locate the foramina of the affected nerve root. After anesthetizing the skin and deep tissue, a curved 22 gauge (22 ga.) x 3.5" needle was introduced. Under direct fluoroscopy, the needle was advanced to a position in the anterior epidural space. Positioning of the needle Verify by lateral x-ray view and by injecting contrast media through the needle. Such positioning may or may not require further adjustment. If adjusted, the needle position is verified again. The needle is advanced into the correct area, may stimulate pain in a manner consistent with the original ailment. Needle placement can therefore also be verified by the patient's pain sensation. The epidural space is anesthetized with an injectable anesthetic. Then, a fibrinogen-containing and coagulation An enzymatic fibrin sealant (prior to clotting) is introduced through the needle by continuous gentle pressure until the volume in the dual barrel syringe system is completely exhausted. The thrombin or fibrinogen or both It has been reconstituted with a solution containing at least one additive. The fibrin sealant then coats the nerve root and annulus while the needle is withdrawn. Following this procedure, the patient is observed and vital signs are monitored for approximately 20-30 minutes.

[0033] For this procedure, a sufficient volume of fibrin sealant is injected to effectively hydro-dissect the area surrounding 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 that have a more vascular distribution and are exposed to room air at the time of application.

[0034] The ability of a fibrin sealant to seal an annular fissure associated with a herniated disc provides a therapeutic benefit to the patient. Chemical radiculitis or nerve root inflammation is known to be quite painful in some cases. It is believed that the use of a fibrin sealant in the manner described above not only encapsulates the nerve root, but also seals the annular fissure around the herniated disc. (See Figure 1). The sealant also seals the annulus fissure from the outside of the annulus fibrosus due to hydrodynamic division of the area around the affected nerve root.

Example 2

Intradiscal injection under fluoroscopy guidance

[0035] After aseptic 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 were used to confirm correct needle placement. If the needle position needs to be adjusted, its placement is again confirmed by fluoroscopy. A contrast agent is injected to confirm the needle's position. In patients with chemical radiculitis, leakage of contrast medium through annular fissures may be observed and/or intradiscal pathology may be identified. Once the needle is properly positioned in the intradiscal space, fibrin sealant (or components thereof) is injected. Thrombin or fibrinogen or both have been reconstituted with a solution containing at least one additive. As the fibrin sealant seals the annular fissure, it is observed that the fibrin sealant exerts a force on the contrast agent in the intradiscal space. Alternatively, a contrast medium is injected along with the sealant. Alternatively, no contrast agent is used. This method seals the defect/fissure of the annulus and prevents chemical leakage and facilitates intradiscal restoration.

Example 3

Injectable fibrin sealant compared with injectable fibrin sealant containing corticosteroids

[0036] 20 patients were divided into two groups, 10 in each group. All patients had pain from degeneration of the intervertebral disc caused by a defect (crack) in the annulus fibrosus. All patients had previously experienced at least 6 months of conventional conservative treatment without effect. Using the procedure in Example 2, a 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. Each patient was rated on a scale of 0-10 for back pain and leg pain before surgery and at predetermined intervals after surgery. The results (VAS scores) are shown in Figures 3 and 4. As can be seen, patients injected with the fibrin sealant alone (without betamethasone) experienced superior pain relief relative to patients injected with the fibrin sealant containing betamethasone. It was thought that patients who received injections containing betamethasone would have excellent results due to the inflammation-reducing effects of betamethasone. However, the opposite was observed. In fact, patients who received only fibrin sealant injections experienced significantly improved pain relief, not just at 1 week post-surgery, but especially at 12 weeks post-surgery. These results were 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 thrombin. Patients suffer from pain resulting from degeneration of the intervertebral disc due to a defect (crack) in the annulus fibrosus. Using the method in Example 2, patients were injected intradiscally with a fibrin sealant containing fibrinogen, thrombin, and local anesthetic (3 cc of 75% bupivacaine). Local anesthetics are used to reconstitute thrombin. A total of 5cc of fibrinogen, thrombin, and local anesthetic were injected. Patients were rated on a scale of 0-10 for back pain and leg pain before surgery and at predetermined time intervals after surgery. For back pain, the results were as follows: before treatment, 4; one week after treatment, 4; three weeks after treatment, 1; six weeks after treatment, 1. Leg pain was 0 before and after treatment. These results were surprising and unexpected due to the significant reduction in pain after six weeks.

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

Claims (79)

1. method for the treatment of intervertebral disc, described intervertebral disc is by at least one the damaged seepage vertebral pulp in the fibrous ring, described method comprises: inject fibrin sealant to reduce described at least one damaged segmental defect at least to described intervertebral disc, the described fibrin sealant that wherein is injected into described intervertebral disc comprises Fibrinogen and activating compounds, wherein after injection, be formed up to the described fibrin of small part, wherein said Fibrinogen, with the solution reconstruct that contains at least a additive, condition is that the described fibrin sealant that is injected into described intervertebral disc lacks corticosteroid for described activating compounds or both.

2. the method for claim 1, condition is that described vertebral pulp and described fibrous ring all are not heated.

3. the process of claim 1 wherein described fibrin sealant basically by Fibrinogen, activating compounds, and at least a additive and optional calcium chloride composition.

4. the process of claim 1 wherein that described fibrin sealant is made up of Fibrinogen, activating compounds and at least a additive, and randomly contain calcium chloride.

5. the process of claim 1 wherein that calcium chloride and described Fibrinogen and described activating compounds are injected together.

6. the process of claim 1 wherein that described activating compounds is a thrombin.

7. the process of claim 1 wherein that described method is made of described injecting step.

8. the process of claim 1 wherein that described additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Anesthetis; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Multiple antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.

9. the process of claim 1 wherein that at least a additive is a local anesthetic.

10. the process of claim 1 wherein and be removed by operation without any described vertebral pulp partly.

11. the process of claim 1 wherein described at least one damaged be tearing or the crack in the described fibrous ring.

12. the process of claim 1 wherein that the normal fluid static pressure of described intervertebral disc is resumed, perhaps normal disc height is resumed, perhaps both all are resumed.

13. the process of claim 1 wherein that described Fibrinogen is from body.

14. the process of claim 1 wherein that described injection is by using dual barrel syringe to implement.

15. the process of claim 1 wherein that described activating compounds is a thrombin, and wherein the mixture of Fibrinogen and thrombin is injected.

16. the process of claim 1 wherein that described activating compounds is a thrombin, and wherein said Fibrinogen and thrombin injected successively, and in described intervertebral disc, mixed at least in part.

17. the process of claim 1 wherein described additive before described Fibrinogen and thrombin, simultaneously or sequentially injected afterwards, and in described intervertebral disc, mix at least in part.

18. the process of claim 1 wherein that described intervertebral disc injects in a plurality of sites with described fibrin sealant.

19. the process of claim 1 wherein that described injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.

20. the process of claim 1 wherein that described intervertebral disc is a lumbar intervertebral disc.

21. the process of claim 1 wherein that described intervertebral disc is a cervical intervertebral disk.

22. the process of claim 1 wherein that described intervertebral disc is a thoracic disc.

23. the process of claim 1 wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.

24. method for the treatment of the people back, comprise that fibrin sealant is injected intervertebral disc is damaged to seal at least one of fibrous ring, wherein said fibrin sealant comprises Fibrinogen and thrombin, wherein said Fibrinogen and thrombin are formed up to the described fibrin of small part after injection, wherein said Fibrinogen, described thrombin or both are with the solution reconstruct that contains at least a additive, and wherein said fibrin sealant does not comprise corticosteroid.

25. being described vertebral pulp and described fibrous ring, the method for claim 24, condition all be not heated.

26. the method for claim 24, wherein said fibrin sealant are made up of Fibrinogen, activating compounds and at least a additive basically.

27. the method for claim 24, wherein said fibrin sealant is made up of Fibrinogen, activating compounds, at least a additive and calcium chloride.

28. the method for claim 24, wherein calcium chloride and described Fibrinogen and described thrombin are injected together.

29. the method for claim 24, wherein said method is made of described injecting step.

30. the method for claim 24, wherein said activating compounds is a thrombin.

31. the method for claim 24, wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Anesthetis; Analgesic; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Multiple antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.

32. the method for claim 24, wherein at least a additive is a local anesthetic.

33. the method for claim 24, wherein the described vertebral pulp without any part is removed by operation.

34. the method for claim 24, wherein said at least one damaged be tearing or the crack in the described fibrous ring.

35. the method for claim 24, the normal fluid static pressure of wherein said intervertebral disc is resumed, and perhaps normal disc height is resumed, and perhaps both all are resumed.

36. the method for claim 24, wherein said Fibrinogen is from body.

37. the method for claim 24, wherein said injection are by using dual barrel syringe to implement.

38. the method for claim 24, wherein said activating compounds is a thrombin, and wherein the mixture of Fibrinogen and thrombin is injected.

39. the method for claim 24, wherein said activating compounds is a thrombin, and wherein said Fibrinogen and thrombin successively injected, and mixes in described intervertebral disc at least in part.

40. the method for claim 24, wherein said intervertebral disc is injected with a plurality of positions of described fibrin sealant in described intervertebral disc.

41. the method for claim 24, wherein said injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.

42. the method for claim 24, wherein said intervertebral disc is a lumbar intervertebral disc.

43. the method for claim 24, wherein said intervertebral disc is a cervical intervertebral disk.

44. the method for claim 24, wherein said intervertebral disc is a thoracic disc.

45. the method for claim 24, wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.

46. the method for claim 24, wherein said additive before described Fibrinogen and thrombin, simultaneously or sequentially injected afterwards, and in described intervertebral disc, mix at least in part.

47. method for the treatment of the people back, it is damaged with at least one of treatment fibrous ring to be included in mixture that Fibrinogen and thrombin are provided in the human disc, wherein said Fibrinogen, described thrombin or both are with the solution reconstruct that contains at least a additive, and wherein said mixture does not comprise corticosteroid.

48. being described vertebral pulp and described fibrous ring, the method for claim 47, condition all be not heated.

49. the method for claim 47, wherein said fibrin sealant are made up of Fibrinogen, thrombin and at least a additive basically.

50. the method for claim 47, wherein said fibrin sealant is made up of Fibrinogen, thrombin, at least a additive and calcium chloride.

51. the method for claim 47, wherein calcium chloride and described Fibrinogen and described thrombin are provided together.

52. the method for claim 47, wherein said method is made of the described step that provides.

53. the method for claim 47, wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Anesthetis; Analgesics; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Multiple antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.

53. the method for claim 47, wherein at least a additive is a local anesthetic.

54. the method for claim 47, wherein the described vertebral pulp without any part is removed by operation.

55. the method for claim 47, wherein said at least one damaged be tearing or the crack in the described fibrous ring.

56. the method for claim 47, the normal fluid static pressure of wherein said intervertebral disc is resumed, and perhaps normal disc height is resumed, and perhaps both all are resumed.

57. the method for claim 47, wherein said Fibrinogen is from body.

58. the method for claim 47, wherein said providing is by using dual barrel syringe to implement.

59. the method for claim 47, wherein the mixture of Fibrinogen, thrombin and described at least a additive is provided.

60. the method for claim 47, wherein said Fibrinogen and thrombin are successively provided, and mix in described intervertebral disc at least in part.

61. the method for claim 47, the wherein said intervertebral disc a plurality of positions in this intervertebral disc are provided to described fibrin sealant.

62. the method for claim 47, wherein said injection takes place by follow procedure: the trocar that will have needle point is inserted into the intervertebral disc internal clearance, arrives contiguous described at least one damaged position; Second pin or polymeric catheter are passed through the needle point of described trocar insertion until the described trocar, but be no more than the needle point of the described trocar; With inject described fibrin sealant by described second pin or polymeric catheter.

63. the method for claim 47, wherein said intervertebral disc is a lumbar intervertebral disc.

64. the method for claim 47, wherein said intervertebral disc is a cervical intervertebral disk.

65. the method for claim 47, wherein said intervertebral disc is a thoracic disc.

66. the method for claim 47, wherein before the described fibrin sealant of injection, in the described fibrin sealant of injection, perhaps after injecting described fibrin sealant, injection of contrast medium.

67. the method for claim 47, wherein said additive before described Fibrinogen and thrombin, simultaneously or sequentially injected afterwards, and in described intervertebral disc, mix at least in part.

68. test kit comprises:

Fibrinogen,

Thrombin,

At least a additive,

Spinal needle or polymeric catheter or spinal needle and polymeric catheter,

Wherein said test kit does not comprise corticosteroid, and described test kit does not comprise the device that heat energy is provided to intervertebral disc.

69. the test kit of claim 68, wherein at least a additive is a local anesthetic.

70. the test kit of claim 68 also comprises calcium chloride.

71. the test kit of claim 68, wherein said additive is selected from: antibiotic; Anti-proliferative drugs, cytotoxic drug and antitumor drug comprise chemotherapeutic; Analgesic; Anti-angiogenic agent; Antibody; Antiviral agents; Cytokine; Colony stimulating factor; Protein; Chemoattractant; EDTA; Histamine; Antihistaminic; Erythropoietin; Antifungal agent; Antiparasitic; Non-corticosteroid antibiotic medicine; Anticoagulant; Anesthetis; Analgesics; Oncology's medicament; Cardiovascular drugs; Vitamin and other supplementarys; Hormone; Glycoprotein; Fibronectin; Peptide comprises polypeptide and protein; Interferon; Cartilage-inducing factor; Protease inhibitor; Vasoconstrictor, vasodilation, demineralized bone or bone morphogenetic protein; Hormone; Lipid; Carbohydrate; Dan Baijutang; The angiogenesis inhibitor element; Antigen; DBM; Hyaluronic acid and salt thereof and derivant; Polysaccharide; Cellulosic cpd and derivant thereof; Multiple antibody; Gene therapeutic agents; Genetically modified cell, stem cell comprise the interstital stem cell that has transforming growth factor, and/or other cell; Cell growth factor; The II Collagen Type VI; Elastin laminin; Sulphuric acid glycosaminoglycan (sGAG), glucosamine sulfate; The pH dressing agent; Methylsulfonyl methane (MSM); The skeletonization chemical compound; The bone conduction chemical compound; Plasminogen; Nucleotide; Oligonucleotide; Polynucleotide; Polymer; BMP 1 (OP-1 comprises reorganization OP-1); LMP-1 (Lim mineralization protein 1); Cartilage; Oxygen-containing component; Enzyme; Melatonin; Vitamin; And nutrient.

72. the test kit of claim 68, wherein said Fibrinogen and thrombin are lyophilised states.

73. the test kit of claim 69 also comprises the trocar.

74. the test kit of claim 69, wherein the size of polymeric catheter makes it can not extend beyond the needle point of the trocar during use.

75. produce the method for test kit, comprising: provide

Fibrinogen component,

Thrombin component,

At least a additive,

And spinal needle or polymeric catheter or spinal needle and polymeric catheter,

Wherein said test kit does not comprise corticosteroid, and described test kit does not comprise the device that heat energy is provided to intervertebral disc.

76. the method for claim 75, the size of wherein said polymeric catheter make it can not extend beyond the needle point of the described trocar during use.

77. the method for claim 75, the size of wherein said spinal needle make it can not extend beyond the needle point of the described trocar during use.

78. second solution that contains fibrinogenic first solution and contain thrombin is used for the treatment of application in the pharmaceutical composition of the mammal intervertebral disc of seepage vertebral pulp because at least one in the fibrous ring is damaged in preparation, the solution that wherein contains additive is used to the described Fibrinogen of reconstruct, described thrombin or both, and wherein said first solution and second solution all do not contain corticosteroid.

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