HAEMOSTATIC DEVICE

Abstract

A bioresorbable haemostatic foam sponge for adhering to a wound. The sponge has a tissue-contacting surface divided into a plurality of closely-spaced tissue contacting elements. Also disclosed are methods for forming the haemostatic sponge and methods of using the sponge.

Claims

1. A bioresorbable haemostatic foam sponge for adhering to a wound, the sponge having a tissue-contacting surface divided into a plurality of closely-spaced tissue contacting elements, wherein the sponge is manufactured from collagen, starch, gelatin or hyaluronic acid.

2. A haemostatic sponge according to claim 1, wherein the tissue contacting elements are finger-like or columnar.

3. A haemostatic sponge according to claim 1 wherein each tissue contacting element has a depth of at least 2 mm.

4. A haemostatic sponge according to claim 1, wherein each tissue contacting element has a depth of 10 mm or less.

5. (canceled)

6. A haemostatic sponge according to claim 1, wherein the depth of each tissue contacting element is 80% or less of the depth of the sponge.

7. A haemostatic sponge according to claim 1, wherein the cross-sectional shape of each tissue contacting element is substantially rectangular.

8. A haemostatic sponge according to claim 1, wherein each tissue contacting element has a cross-sectional area of 25 mm.sup.2 or less.

9. (canceled)

10. (canceled)

11. A haemostatic sponge according to claim 1 wherein the cross-sectional area of each tissue contacting element is substantially uniform.

12. A haemostatic sponge according to claim 1, wherein the maximum cross-sectional linear dimension of each tissue contacting element is 10 mm or less.

13. (canceled)

14. A haemostatic sponge according to claim 1, wherein the maximum cross-sectional linear dimension is two times or less than the depth of the tissue contacting element.

15. A haemostatic sponge according to claim 1, wherein the tissue contacting elements are arranged such that each tissue contacting element is within at least 1 mm, at least 0.5 mm or at least 0.1 mm of another tissue contacting element.

16. A haemostatic sponge according to claim 1, wherein the tissue contacting elements are arranged such that there are at least 4 tissue contacting elements per 100 mm.sup.2 of the tissue-contacting surface.

17. (canceled)

18. (canceled)

19. A haemostatic sponge according to claim 1, wherein the sponge has pores with a diameter of 3 mm or less, or wherein at least 50% of the pores have a diameter between 1 and 1500 m, or between 5 and 750 m.

20. A haemostatic sponge according to claim 1 which comprises an immobilised haemostatic agent.

21. A haemostatic sponge according to claim 14, wherein the haemostatic agent comprises a clotting factor, preferably thrombin and/or fibrinogen.

22. A haemostatic sponge according to claim 14, wherein the haemostatic agent comprises carriers with a plurality of fibrinogen-binding peptides immobilised to each carrier.

23. A haemostatic sponge according to claim 1, comprising reactive chemical groups that can react to form covalent bonds when contacted with tissue.

24. A haemostatic sponge according to claim 1 in which the tissue contacting elements have been formed by cutting or incising a surface of a sponge.

25. A method for forming a haemostatic sponge according to claim 1, comprising cutting or embossing a surface of a haemostatic sponge.

26. A method of controlling bleeding, comprising administering a haemostatic sponge according to claim 1, to a wound.

Description

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0083] Embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings, in which:

[0084] FIG. 1 is a schematic representation (plan view (left) and side view (right)) of a haemostatic sponge according to an embodiment of the invention;

[0085] FIG. 2 is a schematic representation (plan view (left) and side view (right)) of a haemostatic sponge according to an embodiment of the invention;

[0086] FIG. 3 is a schematic representation (plan view) of a haemostatic sponge according to an embodiment of the invention;

[0087] FIG. 4 is a schematic representation (plan view (left) and side view (right)) of a haemostatic sponge according to a less preferred embodiment of the invention.

[0088] FIGS. 5a to 5d show SEM Images of a haemostatic sponge according to an embodiment of the invention;

[0089] FIGS. 6a to 6d show SEM images of a haemostatic sponge according to an embodiment of the invention;

[0090] FIG. 7 shows an SEM image of a commercially-available haemostatic sponge (GelitaSpon, by Gelita);

[0091] FIGS. 8a and 8b show the in vivo adhesive properties of a haemostatic sponge according to an embodiment of an invention;

[0092] FIGS. 9a and 9b show the in vivo adhesive properties of a commercially-availablehaemo static sponge (GelitaSpon, by Gelita);

[0093] FIG. 10 shows the in vivo adhesive properties of a commercially-available haemostatic sponge (Tachosil by Taekeda);

[0094] FIG. 11 shows the in vitro adhesive properties of a commercially-available haemostatic sponge (Gelita);

[0095] FIG. 12 shows the in vitro adhesive properties of a haemostatic sponge according to a less preferred embodiment of the invention;

[0096] FIG. 13 shows the in vitro adhesive properties of a haemostatic sponge according to an embodiment of the invention;

[0097] FIG. 14 shows the in vitro adhesive properties of a haemostatic sponge according to an embodiment of the invention;

[0098] FIGS. 15a and 15b show a comparison between the adhesive properties of a haemostatic sponge according to the invention (FIG. 15b), and a commercially-available haemostatic sponge (FIG. 15a) (GelFoam);

[0099] FIGS. 16a and 16b show a comparison between the adhesive properties of a haemostatic sponge according to the invention (FIG. 16b), and a commercially-available haemostatic sponge (FIG. 16a) (SpongoStan Standard);

[0100] FIGS. 17a and 17b show a comparison between the adhesive properties of a haemostatic sponge according to the invention (FIG. 17b), and a commercially-available haemostatic sponge (FIG. 17a) (KolSpon);

[0101] FIGS. 18a and 18b show a comparison between the adhesive properties of a haemostatic sponge according to the invention (FIG. 18b), and a commercially-available haemostatic sponge (FIG. 18a) (UltraFoam);

[0102] FIG. 19 shows a cutting tool (plan view) that can be used to manufacture a haemostatic sponge according to an embodiment of the invention as shown in FIGS. 1 and 2;

[0103] FIG. 20 shows a photograph of a haemostatic sponge according the invention where the tissue-contacting elements have been formed using an automated robotic blade; and

[0104] FIG. 21 shows the adhesive properties of the haemostatic sponge of FIG. 20.

[0105] A haemostatic gelatin foam sponge 1 as shown in FIG. 1 has a tissue-contacting surface 3. The tissue-contacting surface is divided into a series of finger-like or columnar tissue-contacting elements 5. The tissue-contacting elements project in a substantially perpendicular orientation from a base portion 7 and each has a rectangular cross-section. Each tissue-contacting element 5 has a first end (or base end) 9 which is attached to the base portion, and a second end (or face) 11, which is furthest from the base portion.

[0106] FIG. 1 indicates the length of the sponge (L), width of the sponge (W), depth of the sponge (Ds) and the depth of the tissue-contacting elements (Dp). The depth of the sponge may also be referred to as the height or thickness of the sponge and the depth of tissue-contacting element may also be referred to as the height (or length) of the tissue-contacting element.

[0107] The sponge 1 is manufactured by making a series of periodic incisions into the surface of a gelatin foam sponge using a razor blade. A series of incisions are made length-wise, followed by a series of incisions width-wise, the incisions extending part-way through the sponge.

[0108] In use, the sponge 1 is applied to a wound such that the tissue-contacting elements 5 of the tissue-contacting surface 3 are in contact with the wound.

[0109] A haemostatic gelatin sponge as shown in FIG. 2, is substantially the same as the haemostatic sponge of FIG. 1, apart from the fact that the incisions are less deep, such that the tissue-contacting elements 5 are shorter. Features similar to those in FIG. 1 have been assigned like reference numerals.

[0110] FIG. 19 shows a schematic plan view of a cutting tool 21 that could be used to manufacture a haemostatic sponge as shown in FIGS. 1 and 2. The tool has a series of blades 13, arranged length-wise and width-wise, to define an array of substantially rectangular voids 15. The tool can be inserted into the surface of a sponge, so as to make a number of simultaneous cuts, and create projections of a pre-determined cross-sectional area.

[0111] A haemostatic gelatin sponge as shown in FIG. 3, is similar to the haemostatic sponges of FIGS. 1 and 2. Similar features have been assigned like reference numerals. However, further diagonal incisions have been made through each tissue-contacting element to create four times as many tissue-contacting elements, each tissue-contacting element having a triangular cross-section with a surface area of approximately one quarter that of the tissue-contacting elements of FIGS. 1 and 2.

[0112] A haemostatic sponge as shown in FIG. 4 has only four tissue-contacting elements, each with a significantly larger cross-sectional area than the sponges of FIGS. 1, 2 and 3. The tissue-contacting elements were formed by making a single incision width-wise and a single incision length-wise. Similar features to those in FIGS. 1, 2 and 4 have been assigned like reference numerals.

Example 1Preparation of Surface Modified Gelatin Foam Sponges

[0113] Sample A: A sponge having the general form shown in FIG. 1 was prepared as follows. A series of incisions were made on a surface of gelatin foam sponges (GelitaSpon by Gelita) using a sharp razor blade (0.1 mm to 0.3 mm width) to create columnar or finger-like tissue-contacting elements on the surface. Incisions were made along the length at 0.5 mm to 2 mm intervals, and to a depth of about 5-8 mm, and a series of widthwise incisions were also made at 0.5 mm to 2 mm intervals at a depth of 5-8 mm. The result was the creation of tissue-contacting elements with substantially rectangular cross-sectional shapes, each having an end face with an area of 0.25 mm2 to 4 mm2 Each sponge had a length of about 30 mm, a width of about 20 mm and a thickness of about 10 mm.

[0114] Sample B: A sponge having the general form shown in FIG. 2 was prepared as follows. A series of incisions were made on a surface of gelatin foam sponges (GelitaSpon by Gelita) using a sharp razor blade (0.1 mm to 0.3 mm width) to create columnar or finger-like tissue-contacting elements on the surface. Incisions were made lengthwise at 0.5 mm to 2 mm intervals, and to a depth of about 1-2 mm, and a series of widthwise incisions were also made at 0.5 mm to 2 mm intervals, also to a depth of about 1-2 mm. The result was the creation of tissue-contacting elements with substantially rectangular cross-sectional shapes, each having an end face with an area of 0.25 mm2 to 4 mm2 Each sponge had a length of about 30 mm, a width of about 20 mm and a thickness of about 10 mm.

[0115] Sample C: A sponge having the general form as shown in FIG. 3 was prepared as follows. A series of incisions were made on a surface of gelatin foam sponges (GelitaSpon by Gelita) using a sharp razor blade (0.1 mm to 0.3 mm width) to create columnar or finger-like tissue-contacting elements on the surface. Incisions were made lengthwise at 0.5 mm to 2 mm intervals, and to a depth of about 5-8 mm, and a series of widthwise incisions were also made at 0.5 mm to 2 mm intervals, also to a depth of 5-8 mm. Further incisions were made diagonally through each tissue-contacting element to a depth of 5-8 mm to form a sponge with tissue-contacting elements having substantially triangular cross-sections and cross-sectional areas of approximately one quarter of those of Samples A and B. Each sponge had a length of about 30 mm, a width of about 20 mm and a depth of about 10 mm.

[0116] Sample D was the control sponge. No incisions were made in the surface of GelitaSpon (Gelita) sponges. Each sponge had a length of about 30 mm, a width of about 20 mm and a depth of about 10 mm.

[0117] Sample E: A sponge having the general form shown in FIG. 4 was prepared as follows. A single incision was made length-wise to a depth of about 5-8 mm and a single incision was made widthwise, also to a depth of about 5-8 mm, to create four tissue-contacting elements, each having an end face with an area of about 150 mm2 Each sponge had a length of about 30 mm, a width of about 20 mm and a depth of about 10 mm.

[0118] Sample F: A sponge was prepared using an automated robotic blade to make lengthwise and widthwise incisions at 1.5 mm intervals. The incisions had a depth of 3 mm By using an automated robotic blade, the process is much faster and the surface of a single 58 cm sponge could be modified in approximately 10 seconds.

Example 2Scanning Electron Microscope Images of Surface-Modified Gelatin Foam Sponges

[0119] Scanning Electron Microscope (SEM) images of the surfaces of the some of the samples were taken using a JEOL 6060LV variable pressure scanning electron microscope with a Leica EM SD005 sputter coater.

[0120] FIGS. 5a, 5b and 5c show SEM images of Sample A (plan view) at various magnifications. The face of the tissue-contacting element in FIG. 5b has a surface area of approximately 1.5 mm2.

[0121] FIG. 5d shows a SEM image (13 magnification) of Sample A (side view) showing tissue-contacting elements with a depth of about 8 mm.

[0122] FIGS. 6a, 6b and 6c show SEM images of Sample B (plan view) at various magnifications.

[0123] FIG. 6d shows an SEM image (14 magnification) of Sample B (side view) showing tissue-contacting elements with a depth of about 2 mm.

[0124] FIG. 7 shows an SEM image (13 magnification) of Sample D (plan view).

Example 3Testing Adhesion of the Surface-Modified Gelatin Sponges in a Surgical Procedure

[0125] Rabbits (New Zealand White males weighing approximately 3 kg) were prepared and anaesthetised using standard procedures, and the liver uncovered. Biopsy punch holes (5 mm diameter and 4-5 mm deep) were made in the liver lobes, and Samples B and D (control) were placed on the wound and compressed for 1 minute with gauze. Lightly bleeding biopsy wounds were selected such that the sponges would not be fully soaked with blood when placed on the wound. After three minutes the sponge was lifted at one corner with forceps. A further control was also tested: Tachosil (Takeda), a collagen sponge with immobilised thrombin and fibrinogen. Each treatment was replicated three times and the observations were consistent.

Results

[0126]

TABLE-US-00001 Sponge Image Comment Sample B See Figures 8a Adhesion is very strong. Lifting and 8b the sponge causes the liver to be pulled. The sponge stretches but remains attached to the liver. Sample D See Figures 9a Adhesion is very weak. The and 9b sponge lifts off easily Tachosil See Figure 10 Good adhesion observed. Corner (collagen sponge can be lifted in some cases but with thrombin majority of sponge remains well and fibrinogen) adhered.

Example 4In Vitro Adhesion Tests

4.1 Experiment 1

Method:

[0127] A 1 cm diameter biopsy hole of 5 mm depth was punched out of lamb's liver (Marks & Spencer, UK). A solution of human plasma (0.1 ml, A1174 EXP-2016-10, Alpha Labs) was applied to the hole. All materials were heated to 37 C. prior to the experiment. Surface-modified Gelatin sponges (Gelita, Gelita Standard, Lot TO1554/6), prepared to form Samples A, B and E (as described in Example 1) were applied face down onto and overlapping the biopsy hole, and compressed with cotton gauze for 1 minute. The plasma was added to the biopsy hole such that the sponges would not be fully soaked with plasma when placed onto the biopsy hole (to simulate a lightly bleeding wound). Using a pair of tweezers an attempt was made to lift the sponge by a corner. The level of adhesion was observed visually by comparison with control Sample D (i.e. an unmodified sponge).

Results:

[0128] The in vitro test was designed to mimic aspects of Example 3, and the overall results were broadly similar in that foam sponges without surface modification were not adhesive, and that those with finger-like tissue-contacting elements having an external surface area of 4 mm.sup.2 or less were strongly adhesive. It was observed that the sponges with the longer tissue-contacting elements (Sample A) were more effective than those with the shorter tissue-contacting elements (Sample B) in vitro, but that the level of adhesion of the sponge with the longer tissue-contacting elements (Sample A) was not greater than that observed in the animal trial with a sponge of a shorter tissue-contacting elements (Sample B). In Experiment 3 (see below), Sample C demonstrated an improvement of adhesion.

[0129] The poor adhesion of Sample E shows that in some circumstances, sponges with larger tissue-contacting elements (e.g. with a cross-sectional area of approximately 150 mm2) are less preferred. Sponges having tissue-contacting elements with a smaller cross-sectional area may be preferred in certain circumstances because they can result in stronger adhesion.

[0130] The in vitro test is therefore useful for testing permutations of the surface modification, and for optimisation of adhesion. For example, the various sizes and shapes of tissue-contacting elements, and types of sponge materials could be readily tested.

TABLE-US-00002 Sample Sponge Images Comment Sample D See Figure 11 Poor adhesion Sample E See Figure 12 Poor adhesion Sample B See Figure 13 Strong adhesion observed, as most of the sponge stayed in place when the corner was lifted Sample A See Figure 14 Strong adhesion observed. Improved adhesion compared to Sample B. The sponge had to be ripped from the surface leaving finger-like tissue- contacting elements attached

4.2 Experiment 2

Method:

[0131] A 1 cm diameter biopsy hole of 5 mm depth was punched out of lamb's liver (Marks & Spencer, UK). A solution of deionised water (0.5 ml) was applied to the hole. All materials were at either at room temperature or heated to 37 C. prior to the experiment. The surface-modified Gelatin sponges (Gelita, Gelita Standard, Lot TO1554/6), were prepared to form Sample C (as described in Example 1). The sponges were applied face down onto and overlapping the biopsy hole, and compressed with cotton gauze for 30 seconds. The water was added to the biopsy hole such that the sponges would not be fully soaked with water when placed onto the biopsy hole (to simulate a lightly bleeding wound). Adhesion was observed visually. The maximum force required to remove the sponge from the surface of the liver was also measured using a DGD3 50G Gram Gauge (Mecmesin, Part No: 890-003).

[0132] The level of adhesion was observed visually by comparison with control Sample D.

Results:

[0133]

TABLE-US-00003 Room temperature Sample D Sample C Maximum Maximum Force required Force required to remove the to remove the sponge (G) sponge (G) 5 15 5 16 6 16

TABLE-US-00004 37 C. Samples Sample D Sample C Maximum Maximum Force required Force required to remove the to remove the sponge (G) sponge (G) 40 >60 Note: Gram Gauge's maximum force measurement is 60 g. The Sample C sponge exceeded this.

4.3 Experiment 3

Method:

[0134] A 1 cm diameter biopsy hole of 5 mm depth was punched out of lamb's liver (Marks & Spencer, UK). A solution of human plasma (0.1 ml, A1174 EXP-2016-10, Alpha Labs) was applied to the hole. All materials were heated to 37 C. prior to the experiment. The surface-modified Gelatin sponges (GelFoam, Pfizer and SpongoStan Standard, Ferrosan,) and Collagen Sponges (Kolspon, Medira and Ultrafoam, Bard) were prepared to form Sample C (as described in Example 1). These were applied face down onto and overlapping the biopsy hole, and compressed with cotton gauze for 1 minute. The plasma was added to the biopsy hole such that the sponges would not be fully soaked with plasma when placed onto the biopsy hole (to simulate a lightly bleeding wound). Using a pair of tweezers an attempt was made to lift the sponge by a corner. The level of adhesion was observed visually by comparison with control Sample D (i.e. no modifications to the respective sponges).

Results:

[0135]

TABLE-US-00005 Sponge Control Sample Sample D Sample C Comment GelFoam See figure 15a See Figure 15b Sample C sponge significantly more adhesive than Sample D. SpongoStan See Figure 16a See Figure 16b Sample C sponge Standard significantly more adhesive than Sample D. Was able to pick whole liver piece up with Sample C. KolSpon See Figure 17a See Figure 17b Sample C sponge significantly more adhesive than Sample D. Was able to pick whole liver piece up with Sample C. UltraFoam See Figure 18a See Figure 18b Sample C sponge significantly more adhesive than Sample D. Was able to pick whole liver piece up with Sample C.

4.4 Experiment 4

[0136] Comparison of the Adherence of a Modified Sponge with 1.51.5 Mm Tissue-Contacting Elements Produced Using an Automated Robotic Blade (Sample F) Versus an Un-Modified Sponge.

Materials:

[0137] Spongostan gelatin foam sponges (Ferrosan MS0002)

Human fibrinogen @ 3 mg/ml (Enzyme Research Inc.) warmed to 37 C.
Ox liver (Marks & Spencer) cut into 5, 10 and 25 gram segments warmed to 37 C.

Method:

[0138] 150 microlitres of fibrinogen was pipetted onto the surface of an ox liver segment. Three weights of ox liver were tested: 5, 10 and 25 grams. The modified and unmodified sponge test articles (121.4 cm) were compressed onto the pool of fibrinogen on the ox liver for 3 minutes, and then lifted to a height of approximately 30 cm. The duration over which the sponge held the ox liver was measured over a ten minute period.

Results:

[0139] The control sponge without surface modification held a 5 gram liver segment for 1 minute only, and failed to lift a 10 gram or 25 gram segment. In contrast, the modified sponge held a 25 gram liver segment for at least ten minutes, demonstrating the significantly increased adherence of the modified sponge in comparison with the unmodified sponge.