Method and device for stopping CSF leakage

Abstract

A method and kit for stopping cerebrospinal fluid (CSF) leakage, comprising penetrating and passing an applicator through dural tissue to access the inner dural space, injecting a fibrinogen-containing solution from the applicator into the dural space, applying a sealing member containing a fibrinogen polymerizing agent to the outer surface of the dural tissue, and forming polymerized fibrinogen or a polymerized fibrin clot by contacting the injected fibrinogen-containing solution with the fibrinogen polymerizing agent.

Description

Technical Field

[0001] The present invention relates to a method for stopping leakage of cerebrospinal fluid from the dural space that may be formed as a result of injury or surgery. Background Art

[0002] The dura mater is located between the skull and the brain and around the spinal cord. Its main function is to protect the brain and spinal cord and prevent the leakage of cerebrospinal fluid (CSF).

[0003] The dura mater may be perforated accidentally or intentionally. Unintentional perforation of the dura mater may occur as a result of a traumatic event (such as an automobile accident) or through accidental perforation during surgery. Intentional perforation of the dura mater may occur when performing certain surgical procedures, such as to provide access to the brain, spinal cord, or other structures within the central nervous system.

[0004] In both cases, it is important to quickly and reliably seal the dura mater to minimize the loss of cerebrospinal fluid, which plays a key role in supporting the brain within the skull. Additionally, the body has a limited ability to produce cerebrospinal fluid to replace what is lost. If the loss of cerebrospinal fluid is not stopped quickly, the patient may experience serious health complications and possibly death.

[0005] Previous attempts to seal CSF leaks typically involve placing a hemostatic dressing or other hemostatic sealant at the site of the leak or leaks. However, the efficacy of such approaches depends on identifying the location of the leak or leaks, which can be difficult. Once the location of the leak is identified, sufficient access to the site must be obtained for application of the dressing or sealant, which can be challenging due to the anatomical structures surrounding the brain and spinal cord. Summary of the Invention

[0006] A method for stopping cerebrospinal fluid (CSF) leakage is provided, comprising penetrating and passing an applicator through dura mater tissue to enter an interior dura mater space, injecting a fibrinogen-containing solution from the applicator into the dura mater space, applying a sealing member containing a fibrinogen polymerizing agent to an outer surface of the dura mater tissue, and forming polymerized fibrinogen or a polymerized fibrin clot by contacting the injected fibrinogen-containing solution with the fibrinogen polymerizing agent.

[0007] In one form, the fibrinogen polymerizing agent may be selected from thrombin, thrombin with Factor XIII, and thrombin-like enzymes, such as those found in snake venom.

[0008] In another form, the fibrinogen polymerizing agent may be a fibrinogen binding peptide or a fibrinogen binding precursor peptide.

[0009] In yet another form, the sealing member may be in the form of a patch, powder, paste, gelatin, spray, foam, or liquid.

[0010] Advantageously, fibrinogen may be injected into the dura mater space prior to applying the sealing member, or the sealing member may be applied prior to injecting fibrinogen into the dura mater space. In some forms, fibrinogen may be injected into the dura mater space adjacent to the defect in the dura mater tissue.

[0011] In one form, the dura mater tissue may be located beneath the patient's skull.

[0012] In another form, the dura mater tissue may be located in the lumbar portion of the patient's spinal cord.

[0013] In yet another form, the dura mater tissue may be located between the patient's skull and the lumbar portion of the spinal cord.

[0014] Advantageously, the amount of fibrinogen injected into the dural space can be sufficient to increase the concentration of fibrinogen in a 15 mL local volume of CSF fluid to at least about 0.75 mg / mL, such as about

[0015] 0.75 mg / mL to about 3 mg / mL.

[0016] In one form, the fibrinogen-containing solution may be thrombin-free.

[0017] Also presented herein is a kit for plugging a CSF leak site, comprising a syringe containing a fibrinogen-containing solution and a patch slidably disposed on a needle of the syringe, the patch containing a fibrinogen polymerizing agent.

[0018] In one form, the fibrinogen polymerizing agent may be selected from thrombin, thrombin with Factor XIII, and thrombin-like enzymes, such as those found in snake venom.

[0019] In another form, the fibrinogen polymerizing agent may be a fibrinogen binding peptide or a fibrinogen binding precursor peptide. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present disclosure is susceptible to various modifications and alternative forms, but specific exemplary implementations thereof have been shown in the drawings and are described in detail herein. However, it should be understood that the description of specific exemplary implementations herein is not intended to limit the present disclosure to the specific forms disclosed herein.

[0021] The present disclosure is intended to encompass all modifications and equivalents defined by the appended claims. It should also be understood that the drawings are not necessarily drawn to scale, but rather focus on clearly illustrating the principles of the exemplary embodiments of the present disclosure. In addition, certain dimensions may be exaggerated to help convey such principles visually. In addition, where deemed appropriate, reference numerals may be repeated in the drawings to indicate corresponding or similar elements. In addition, two or more blocks or elements depicted as different or separate in the drawings may be combined into a single functional block or element. Similarly, a single block or element shown in the drawings may be implemented as multiple steps or collaboratively implemented by multiple elements.

[0022] The forms disclosed herein are illustrated by way of example and not limitation in the figures of the accompanying drawings and in which like reference numerals refer to similar elements and in which:

[0023] Figure 1 presents an illustration of a method of sealing a CSF leak from the dural space according to the present disclosure; and

[0024] Figure 2 Presents a suitable implementation Figure 1 A kit for the method. DETAILED DESCRIPTION

[0025] Various aspects will now be described with reference to specific forms chosen for illustrative purposes. It should be understood that the spirit and scope of the apparatus, systems, and methods disclosed herein are not limited to the forms chosen. Furthermore, it should be noted that the drawings provided herein are not drawn to any particular scale or proportion, and that many variations of the forms shown are possible.

[0026] Each of the following terms written in the singular grammatical form: As used herein, "a," "an," and "the" may also refer to, and

[0027] A plurality of stated entities or objects is encompassed unless specifically defined or stated otherwise herein, or unless the context clearly dictates otherwise. For example, as used herein, the phrases "a device," "a component," "a mechanism," "an element," and "an element" may also refer to and encompass a plurality of devices, components, mechanisms, devices, and elements, respectively.

[0028] As used herein, each of the following terms: “including,” “having,” and “comprising,” and their linguistic or grammatical variations, derivatives, and / or cognate variations mean “including but not limited to.”

[0029] Throughout the detailed description, examples, and appended claims, the numerical values ​​of parameters, features, objects, or dimensions may be indicated or described in a numerical range format. It should be fully understood that the indicated numerical range format is provided to illustrate specific implementations of the forms disclosed herein and should not be interpreted or considered to inflexibly limit the scope of the forms disclosed herein.

[0030] In addition, for indicating or describing a numerical range, the phrase "within the range between about a first value and about a second value" should be considered equivalent to and have the same meaning as the phrase "within the range of about a first value to about a second value", and thus these two equivalent phrases can be used interchangeably.

[0031] It should be understood that, unless otherwise specifically indicated herein, the various forms disclosed herein are not intended to limit their application to the details of the order or sequence of steps or processes and sub-steps or sub-processes, and the number of operations or specific implementations of the forms of the method; or to the details of the type, composition, construction, arrangement, order, and number of materials in the forms of the systems, system subunits, devices, components, sub-components, mechanisms, structures, devices, elements, and configurations, and peripheral equipment, facilities, accessories, and systems described in the following exemplary descriptions, figures, and examples. The devices, systems, and methods disclosed herein may be practiced or implemented according to various other alternative forms and in various other alternative ways.

[0032] It should also be understood that, unless otherwise specifically defined or stated herein, all technical and scientific words, terms and / or phrases used herein throughout this disclosure have the same or similar meaning as commonly understood by one of ordinary skill in the art. Throughout the present invention, the words, terms, and annotations employed herein are for illustrative purposes and should not be construed as limiting.

[0033] Concentration, size, amount and other numerical data can be presented in range format herein.It should be understood that the use of such range format is only for convenience and simplicity, and should be flexibly interpreted to include not only the numerical value clearly stated as range limit, but also all single numerical values ​​or sub-ranges encompassed within the range, just as each numerical value and sub-range is clearly stated.For example, a range of about 1 to about 200 should be interpreted as including not only the clearly stated limits of 1 and about 200, but also a single size, such as 2, 3, 4, etc., and sub-ranges such as 10 to 50, 20 to 100, etc. Similarly, it should be understood that when a numerical range is provided, such range is understood to provide textual support for claim limitations that only state the lower limit of the range and claim limitations that only state the upper limit of the range.For example, the disclosed numerical range of 10 to 100 provides textual support for claims that state "greater than 10" (without an upper bound) and claims that state "less than 100" (without a lower bound). In the drawings, like numbers represent like or analogous structures and / or features; and each of the illustrated structures and / or features will be discussed in detail herein with reference to the drawings. Similarly, each structure and / or feature may not be explicitly labeled in the drawings; and any structure and / or feature discussed herein with reference to the drawings may be utilized with any other structure and / or feature without departing from the scope of the present disclosure.

[0034] Unlike blood leaking from blood vessels (which has fibrinogen to help seal "blood" leaks), cerebrospinal fluid (CSF) does not typically contain significant concentrations of fibrinogen, so there is nothing in the CSF that can polymerize at the defect site to stop the leak. CSF contains about 1 / 1000 of the fibrinogen of plasma, which is insufficient to promote hemostasis at the leak site in the dura mater using conventional hemostatic coverings. Conventional hemostatic agents containing or used in combination with thrombin are known, such as thrombin-containing ... and or

[0035] It has been found that CSF leakage can be stopped by increasing the CSF fibrinogen concentration from the natural CSF concentration to a higher concentration, such as high to plasma levels or higher, by injecting a fluid containing fibrinogen into the dura mater space through the dura mater and allowing it to leak outside the dura mater, thereby forming fibrin outside and inside the leaking area channels by reacting with thrombin in these areas and stopping the leakage. A sealing member (patch, powder, paste, gelatin, liquid, etc.) containing thrombin or another fibrinogen cross-linking agent is applied to the leaking site, resulting in the leaking site being blocked by fibrin.

[0036] refer to Figure 1The present disclosure relates to a method for stopping leakage of CSF 300, comprising penetrating and passing an applicator 100 (such as a syringe) through dura mater tissue 200 to enter the inner dura mater space 250, injecting a fibrinogen-containing solution from the applicator into the dura mater space 250, applying a sealing member 400 containing a fibrinogen polymerizing agent to the outer surface of the dura mater tissue, and forming polymerized fibrinogen or a polymerized fibrin clot by contacting the injected fibrinogen-containing solution with the fibrinogen polymerizing agent. Thus, the fibrinogen-containing CSF fluid 350 exits through the dura mater tissue defect 220, and the fibrinogen polymerizes in the presence of the fibrinogen polymerizing agent located in the sealing member 400. The fibrinogen may not contain thrombin.

[0037] Fibrinogen polymerizing agents can be selected from thrombin, thrombin with factor XIII and thrombin-like enzymes, such as those present in snake venom. Thrombin can be human-derived, recombinant or animal-derived (cattle, pig, salmon or other species), and include intermediates or derivatives of thrombin, for example metathrombin (which has activity on fibrinogen) or degraded forms of thrombin, for example beta thrombin, which has reduced activity on fibrinogen.

[0038] Polymerizing agents can be derived from snake venom enzymes with thrombin-like activity. There are many, but three commonly used agents are: (1) Batroxobin from the snake species Bothrops atrox; (2) Ancrod from the snake species Agkistrodon rhodostoma; and (3) Venzyme from the snake species Agkistrodon contortrix. Polymerizing agents can also include recombinant forms of these snake venom enzymes.

[0039] Alternatively, the fibrinogen polymerizing agent may be a fibrinogen binding peptide or a fibrinogen binding precursor peptide, such as those described in U.S. Published Application No. 2014 / 0031293, which is incorporated herein by reference. For example, a suitable polymerizing agent may be one of the following general formula (I):

[0040] [Peptide-CO-AXB-]n carrier (I)

[0041] in:

[0042] • "Peptide-CO" means a fibrinogen binding peptide or a fibrinogen binding precursor peptide and a backbone α-carbonyl group at the carboxyl terminus of the peptide;

[0043] "-AXB-" represents a non-peptide spacer, wherein A is a first linker of the non-peptide spacer directly covalently attached to the backbone α-carbonyl group of the peptide, X is a spacer group, and B is a second linker of the non-peptide spacer covalently attached to the carrier; and

[0044] • n>1, and thus indicates that a plurality of fibrinogen binding peptides or fibrinogen binding precursor peptides are covalently linked to the carrier.

[0045] Preferably, X is suitably of the formula -(CH2CH2O) x - a hydrophilic group, preferably a linear hydrophilic group, more preferably a polyethylene oxide group, wherein x is at least 1, 2, 4, 6, 8, 10 or 20. Preferably, x is up to 50, such as 1-50, preferably 2-24.

[0046] In one form, the linker A comprises an -NH- group which, together with the backbone α-carbonyl group of the peptide, forms an amide bond. Preferably, the linker A suitably comprises a -CH2) a - a linear group, wherein a is 1-20, preferably 1-15, 1-10, 1-5 or 2-4. Preferably, the linker A is covalently linked to the spacer group X via an amide bond. Therefore, in a preferred arrangement, the linker A comprises the following general formula:

[0047] —NH—(CH2) a —NHCO—,

[0048] wherein a=1-20, preferably 1-15, 1-10, 1-5 or 2-4.

[0049] Preferably, Linker B does not comprise a disulfide bond. Preferably, Linker B (and the remainder of the non-peptide spacer) does not comprise more than one cyclic moiety. Preferably, Linker B comprises a thioether bond. Such bonds are more stable than disulfide bonds.

[0050] The sealing member may be in the form of a patch, powder, paste, gelatin, spray, foam or liquid. Suitable examples of sealing members include EviThrom topical human thrombin, Hemostatic matrix, soaked with thrombin Absorbable gelatin sponge mixed with thrombin Absorbable gelatin powder. Advantageously, the fibrinogen may be injected into the dural space prior to applying the sealing member, or the sealing member may be applied prior to injecting the fibrinogen into the dural space.

[0051] In one form, the dura mater tissue may be located between the patient's skull and the lumbar portion of the spinal cord, such as beneath the patient's skull or in the lumbar portion of the patient's spinal cord.

[0052] Advantageously, the amount of fibrinogen injected into the dural space can be sufficient to increase the local volume concentration of fibrinogen in the CSF fluid to at least about 0.75 mg / mL, such as about 0.75 mg / mL to about 3 mg / mL. Although higher concentrations can be used, little additional benefit is achieved. The "local volume" within the dural space can be about 5 mL to about 20 mL.

[0053] like Figure 2 As shown in , the present disclosure also relates to a kit for plugging a CSF leak site, comprising a syringe 100 containing a fibrinogen-containing solution and a patch 400 slidably disposed on the needle of the syringe, the patch containing a fibrinogen polymerizing agent. Inserting the syringe needle into the dura mater tissue 200 allows the fibrinogen-containing solution to be injected into the dura mater space, and applying the patch 400 at the site seals the defect created by the needle to prevent CSF leakage.

[0054] In one form, the fibrinogen polymerizing agent may be selected from thrombin, thrombin with Factor XIII, and thrombin-like enzymes, such as those found in snake venom, as described in more detail above.

[0055] In another form, the fibrinogen polymerizing agent may be a fibrinogen binding peptide or a fibrinogen binding precursor peptide, as described in more detail above.

[0056] Example

[0057] The following examples illustrate the principles and practices of the present disclosure but are not limited thereto.

[0058] A study was performed to evaluate the effects of different concentrations of fibrinogen that can be used in the presently disclosed method. The model utilizes the dura mater as the tissue matrix, and the fluid beneath the dura mater is saline with varying concentrations of fibrinogen. The defect is a 1 mm diameter perforation in the dura mater, and thrombin lyophilized The sponge was applied to the tissue and maintained at 37°C for 5 minutes. A control was tested without fibrinogen in the fluid beneath the tissue. The average burst pressure of the fibrinogen-containing fluid was an order of magnitude higher than that of the control without fibrinogen, as shown in the table below. A significant increase in burst pressure was observed with fibrinogen levels as low as 0.75 mg / mL (25% plasma). Plasma levels of fibrinogen (approximately 3 mg / mL) produced similar burst pressures.

[0059] surface

[0060]

[0061] Additional illustrative, non-exclusive examples of methods and kits according to the present disclosure are presented in the following enumerated paragraphs. Within the scope of the present disclosure, individual steps of the methods described herein (including in the following enumerated paragraphs) may be referred to additionally or alternatively as "steps" for performing the described actions.

[0062] PCT1. A method for stopping cerebrospinal fluid (CSF) leakage, comprising: penetrating and passing an applicator through dura mater tissue to enter the internal space of the dura mater; injecting a fibrinogen-containing solution into the dura mater space from the applicator; applying a sealing member containing a fibrinogen polymerizing agent to the outer surface of the dura mater tissue, and forming polymerized fibrinogen or a polymerized fibrin clot by contacting the injected fibrinogen-containing solution with the fibrinogen polymerizing agent.

[0063] PCT2. The method according to paragraph PCT1, wherein the fibrinogen polymerizing agent is selected from thrombin, thrombin with factor XIII, and thrombin-like enzymes such as those present in snake venom.

[0064] PCT3. The method according to paragraph PCT1, wherein the fibrinogen polymerizing agent is a fibrinogen binding peptide or a fibrinogen binding precursor peptide.

[0065] PCT4. The method of any preceding paragraph, wherein the sealing member is in the form of a patch, powder, paste, gelatin, spray, foam, or liquid.

[0066] PCT5. The method of any preceding paragraph, wherein the fibrinogen is injected into the dura mater space prior to applying the sealing member.

[0067] PCT6. The method of any preceding paragraph, wherein the sealing member is applied prior to injecting the fibrinogen into the dura mater space.

[0068] PCT7. The method of any preceding paragraph, wherein the dura mater tissue is located beneath the patient's skull.

[0069] PCT8. The method of any preceding paragraph, wherein the dura mater tissue is located in the lumbar portion of the patient's spinal cord.

[0070] PCT9. The method of any preceding paragraph, wherein the dura mater tissue is located between the patient's skull and the lumbar portion of the spinal cord.

[0071] PCT10. The method of any preceding paragraph, wherein the amount of fibrinogen injected into the dural space is sufficient to increase the local bulk concentration of fibrinogen in the CSF fluid to at least about 0.75 mg / mL.

[0072] PCT11. The method of any preceding paragraph, wherein the amount of fibrinogen injected into the dural space is sufficient to increase the concentration of fibrinogen in the local volume of CSF fluid to about 0.75 mg / mL to about 3 mg / mL.

[0073] PCT12. The method of any preceding paragraph, wherein the fibrinogen-containing solution does not contain thrombin.

[0074] PCT13. The method of any preceding paragraph, wherein the fibrinogen is injected into the dural space adjacent to the defect in the dural tissue.

[0075] PCT14. A kit for plugging a CSF leakage site, comprising: a syringe containing a solution containing fibrinogen; and a patch slidably disposed on a needle of the syringe, the patch containing a fibrinogen polymerizing agent.

[0076] PCT15. The kit according to paragraph PCT14, wherein the fibrinogen polymerizing agent is selected from thrombin, thrombin with factor XIII, and thrombin-like enzymes such as those present in snake venom.

[0077] PCT16. The kit according to paragraph PCT14, wherein the fibrinogen polymerizing agent is a fibrinogen binding peptide or a fibrinogen binding precursor peptide.

[0078] Industrial Applicability

[0079] The systems and methods disclosed herein are applicable to the medical device and healthcare industries.

[0080] It is believed that the disclosure described above encompasses a plurality of different embodiments with independent practicality. Although each of these has been disclosed in its preferred form, the specific embodiments of the present invention disclosed and illustrated herein should not be considered as restrictive, because many variations are possible. The subject matter of this embodiment includes all novel and non-obvious combinations and sub-combinations of the various elements, features, functions and / or characteristics disclosed herein. Similarly, if a claim quotes "one" or "first" element or its equivalent, such claim should be understood to include the incorporation of one or more such elements, neither requiring nor excluding two or more such elements.

[0081] It is believed that the following claims particularly point out certain combinations and subcombinations that are novel and unobvious to one of the disclosed embodiments. Protection may be claimed in other combinations and subcombinations of features, functions, elements, and / or properties by amendment of the present claims or by presentation of new claims in this or a related application. Such amended or new claims, whether different, broader, narrower, or equal in scope to the original claims, whether directed to a different embodiment or to the same embodiment, are deemed included within the subject matter of the disclosed embodiments.

Claims

1. Use of an applicator comprising a fibrinogen-containing solution and a sealing member comprising a fibrinogen polymerizing agent in the preparation of a kit for stopping cerebrospinal fluid (CSF) leakage, the method comprising: causing the applicator to penetrate and pass through the dura mater tissue to access the intradural space; injecting a fibrinogen-containing solution from the applicator into the dura mater space; and applying the sealing member containing the fibrinogen polymerizing agent to the outer surface of the dura mater tissue, wherein polymerized fibrinogen or a polymerized fibrin clot is formed by contact between an injected fibrinogen-containing solution and the fibrinogen polymerizing agent, wherein the fibrinogen-containing solution does not contain thrombin, and wherein the kit comprises the applicator and the sealing member, and wherein the sealing member is a patch that is applied to the site of leakage, causing the leakage site to be blocked by fibrin, and wherein the fibrinogen polymerizing agent 1) is selected from thrombin and thrombin-like enzymes or 2) is a fibrinogen binding peptide or a fibrinogen binding precursor peptide.

2. The use according to claim 1, wherein the fibrinogen polymerizing agent is a thrombin-like enzyme present in snake venom.

3. The use according to claim 1, wherein the fibrinogen polymerizing agent is a fibrinogen binding peptide.

4. The use according to claim 1, wherein the fibrinogen polymerizing agent is thrombin with factor XIII.

5. The use according to claim 1, wherein the fibrinogen is injected into the dural space before applying the sealing member.

6. The use of claim 1, wherein the sealing member is applied prior to injecting the fibrinogen into the dural space.

7. The use according to claim 1, wherein the dura mater tissue is located beneath the patient's skull.

8. The use according to claim 1, wherein the dura mater tissue is located in the lumbar portion of the patient's spinal cord.

9. The method of claim 1, wherein the dura mater tissue is located between the patient's skull and the lumbar portion of the spinal cord.

10. The use of claim 1, wherein the amount of fibrinogen injected into the dural space is sufficient to increase the local bulk concentration of fibrinogen in the CSF fluid to at least 0.75 mg / mL.

11. The use of claim 1, wherein the amount of fibrinogen injected into the dural space is sufficient to increase the concentration of fibrinogen in the local volume of CSF fluid to 0.75 mg / mL to 3 mg / mL.

12. The use according to claim 1, wherein the solution of fibrinogen is injected into the dural space adjacent to the defect in the dural tissue.

13. A kit for plugging CSF leakage, comprising: a syringe containing a solution containing fibrinogen; and a patch slidably disposed on the needle of the syringe, the patch containing a fibrinogen polymerizing agent, which is applied to the site of leakage, causing the leakage site to be blocked by fibrin, wherein polymerized fibrinogen or a polymerized fibrin clot is formed by contact between an injected fibrinogen-containing solution and the fibrinogen polymerizing agent, wherein the fibrinogen-containing solution does not contain thrombin; and The fibrinogen polymerizing agent 1) is selected from thrombin and thrombin-like enzymes or 2) is a fibrinogen binding peptide or a fibrinogen binding precursor peptide.

14. The kit according to claim 13, wherein the fibrinogen polymerizing agent is thrombin with factor XIII.

15. The kit according to claim 13, wherein the fibrinogen polymerizing agent is a thrombin-like enzyme present in snake venom.

16. The kit according to claim 13, wherein the fibrinogen polymerizing agent is a fibrinogen binding peptide.

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