HEMOSTATIC DEVICE AND METHOD

Abstract

Use of a solid calcium compound in the fabrication of a hemostatic agent for reducing bleeding from a surgical site during and/or after a surgical treatment in a patient is provided, wherein the solid calcium compound is selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, and a combination thereof.

Description

FIELD OF THE INVENTION

The present invention is related to a synthetic hemostatic agent, and in particular related to a synthetic hemostatic agent for reducing bone bleeding.

BACKGROUND OF THE INVENTION

Bone tissue is one of the most frequently transplanted tissues, second only to blood. A wide range of orthopedic, cardiothoracic, neurological, and maxillofacial procedures requires that the bone be cut or resected, either to operate on the osseous tissue itself or to gain access to other organs. Like any living tissue, bone bleeds when cut or fractured. To reduce the risk of post-operative complications, bone bleeding needs to be managed during surgery. Uncontrolled continuous bleeding can obscure the surgical field, prolong operating time, increase the risk of physiologic complications, and expose the patient to additional problems associated with blood transfusion. For example, for patients undergoing elective coronary artery bypass graft surgery, allogeneic blood transfusion has been shown to double the risk of infection (Rogers et al., 2009).

The hematopoietic elements are contained within a honeycombed network of vascular channels and can be a source of profuse bleeding. Electrocautery, which is useful in soft tissue hemostasis, functions primarily to collapse and seal blood vessels. To be effective in controlling bone bleeding, it would have to generate sufficient heat to create a coagulum that would physically block vascular channels. However, the thermal injury to the adjacent bone would be of such magnitude that any hemostatic benefit would be offset by the resultant bone necrosis.

Bone wax, a beeswax-based blend, sticks to bone blocking the vascular channels, providing immediate bone hemostasis. Although inexpensive and easy to use, bone wax has a number of troublesome side effects. Once applied to bone, bone wax remains at the site indefinitely. Bone wax is known to interfere with bone healing, elicit chronic inflammatory reactions, and increase infection rates (Chun et al., 1988; Finn et al., 1992; Johnson and Fromm, 1981; Nelson et al., 1990; Sawan et al., 2010).

Products made of water-soluble alkylene oxide copolymers (AOC), such as Ostene® (Baxter International, Inc.), were reported to provide immediate hemostasis yet remain at the site for only a few days. Research in animal models showed that AOC-based products did not increase infection rate or interfere with bone healing (Sawan et al., 2010; Wellisz et al., 2006).

Bleeding from bone can also be controlled with soft tissue hemostats which can aid in the activation of the body's natural clotting mechanism and resorb from days to months. Examples of soft tissue hemostats include gelatin, thrombin, oxidized regenerated cellulose (ORC), collagen, platelet rich plasma (PRP) and fibrin sealants. All these soft tissue hemostats have their respective advantages and disadvantages. For example, gelatin products, if left in the wound, may act as a nidus for infection and abscess formation (Lindstrom, 1956). Gelatin-based agents have also been reported to delay bone healing (Schonauer et al., 2004). Thrombin works quickly and is easy to use. However, bovine thrombin has been known to trigger immunologic reactions (Achneck et al., 2010).

The low pH of ORC products was shown to have an antimicrobial effect. However, the acidity may cause inflammation of surrounding tissue and interfere with healing (Tomizawa, 2005). ORC has also been shown to promote a foreign body reaction and reduce bone repair in rat studies (Ibarrola et al., 1985). Microfibrillar collagen products derived from bovine corium, though shown promising in their ability to promote clotting in reconstructive spinal surgery (Block, 2005), were found related to infection and delayed bone healing. Inflammation and residual material upon resection at up to 90 days were found by Barbolt et al. (2001).

Fibrin sealants are made up of human thrombin and fibrinogen, that are combined at the time of surgery. Fibrin sealants are most frequently used for soft tissue hemostasis and often used as an adjunct to other hemostasis materials. PRP is derived from the patient's own blood by separating red blood cells from the fibrin and plasma in a centrifuge. The plasma, which forms a gel, is applied where hemostasis is needed. This technique relies on growth factors that trigger early wound healing said to be present in the PRP. The true benefit for PRP in bone hemostasis has yet to be confirmed (Griffin et al., 2009), and the technique has shown to be a markedly expensive bone hemostasis alternative.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide a method for reducing bleeding during and/or after a surgical treatment in a patient comprising applying a hemostatic composition to a surgical site prior to a closure of a wound created by the surgical treatment in said patient, so that bleeding from the surgical site is reduced, wherein said hemostatic composition comprises a solid calcium compound selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, and a combination thereof.

Another objective of the present invention is to provide a novel use of a solid calcium compound in the fabrication of a hemostatic agent for reducing bleeding from a surgical site during and/or after a surgical treatment in a patient, wherein the solid calcium compound is selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, and a combination thereof.

Still another objection of the present invention is to provide a hemostatic composition for reducing bleeding from a surgical site during and/or after a surgical treatment in a patient, wherein said hemostatic composition comprises a solid calcium compound selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, and a combination thereof.

Preferably, the hemostatic composition further comprises a phosphorus source, a sulfur source, or a phosphorus source and a sulfur source.

Preferably, the solid calcium compound has a porous structure with a porosity of about 30 vol % to about 90 vol %, and more preferably about 60 vol % to about 80 vol %.

Preferably, the solid calcium compound is in a form of porous granules having a granular size of about 0.1 mm to about 2.5 mm, and more preferably about 0.5 mm to about 1.5 mm.

Preferably, pores of the porous structure have a pore size in a range of about 30 μm to about 300 μm, more preferably about 50 μm to about 250 μm.

Preferably, the pores comprise interconnected pores.

Preferably, the surgical site comprises a bone cavity or a bone cut, and the bleeding is a bone bleeding, wherein the applying a hemostatic composition to a surgical site comprises contacting the bone cavity or the bone cut with the hemostatic composition.

Preferably, bone marrow is exposed by the bone cavity or the bone cut.

Preferably, the surgical treatment is a sternum closure treatment and the surgical site comprises a surgically-created sternum cavity.

Preferably, the phosphorus source comprises a phosphate, and the sulfur source comprises a sulfate.

Preferably, the solid calcium compound is calcium phosphate, calcium sulfate, or a mixture thereof, and more preferably the solid calcium compound is calcium phosphate.

Preferably, the calcium phosphate comprises tetracalcium phosphate (TTCP), dicalcium phosphate (DCP), tricalcium phosphate, monocalcium phosphate, hydroxyapatite, or a mixture thereof.

Preferably, the calcium phosphate comprises hydroxyapatite, tetracalcium phosphate and dicalcium phosphate.

Preferably, the solid calcium compound is a mixture of calcium phosphate and calcium sulfate.

Preferably, the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), anhydrous calcium sulfate, or a mixture thereof. More preferably, the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD) or a mixture thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes (but not limited to) the following aspects:

1. A hemostatic agent for reducing bleeding during and after a surgical treatment, wherein said hemostatic agent comprises a calcium source; wherein said hemostatic agent is in a porous form and has a porosity of about 40-90 vol %, preferably 60-80 vol %.

2. The composition of said hemostatic agent in (1) contains at least 10 at % inorganic calcium ions.

3. The calcium ions in (2) exist in an inorganic, biocompatible calcium compound comprising at least one selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, and calcium hydroxide.

4. The composition of said hemostatic agent in (2) further comprising a phosphorus source and/or a sulfur source.

5. Said porous form in (1) is a porous granular form.

6. The granules of said porous granular form in (5) have a size of about 0.1-2.5 mm and preferably about 0.5-1.5 mm.

7. The pores of said granules in (6) have a pore size in the range of about 30 to 300 μm and preferably 50 to 250 μm, and are preferably interconnected.

8. Said bleeding in (1) is a bone bleeding.

9. Said bone in (8) is a sternum.

10. A hemostatic treatment for sternum closure surgery comprising inserting a hemostatic agent into the bony cavity prior to closure of the surgically opened sternum; wherein said hemostatic agent is a synthetic, inorganic agent containing at least 10 at % inorganic calcium ions; wherein said calcium ions exist in any form of inorganic, biocompatible calcium compounds comprising at least one of the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, and calcium hydroxide; wherein said hemostatic agent is in a porous form and has a porosity of about 40-90 vol %, preferably 60-80 vol %.

Advantages of the present inventive hemostatic device and method for reducing bone bleeding during and post surgeries

(1) Unlike the existing organic and animal/human tissue-derived hemostatic devices which all have their aforementioned respective potential problems, the present inventive hemostatic agent is a 100% inorganic and entirely synthetic agent.

(2) The inventive device is designed to promote hemostasis during and post bone surgeries without potential organic and especially human or animal tissue-related safety risks. For this purpose, the composition of the present inventive device is designed to contain at least 10 at % inorganic calcium ions. The calcium ions in the product may exist in any form of inorganic, biocompatible calcium compounds such as calcium phosphate, calcium sulfate, calcium oxide, calcium hydroxide, etc.

(3) To enhance the hemostatic effect, the hemostatic agent may further comprise phosphorus and/or sulfur ions.

(4) For the purpose of minimally invasive delivery, the hemostatic agent is designed to have a granular form. The granules are designed to have a size of about 0.1-2.5 mm and preferably about 0.5-1.5 mm.

(5) In order to maximize the exposure of the hemostatic agent and at the same time to avoid the disintegration of the porous structure during delivery, the granules of the hemostatic agent are designed to have a highly porous form with a porosity level of about 40-90 vol % and preferably about 50-80 vol %.

(6) To assist blood to penetrate into the interior of each granule, the pores of the granules are designed to have a pore size substantially in the range of 30 to 300 μm, preferably 50 to 250 μm, and to be substantially interconnected.

To the knowledge of the present inventors, there have not been any prior art hemostatic device having all these characteristics.

Clinical Trials

Two complicated cases of open heart surgeries were completed using the hemostatic agent of the present invention in National Cheng Kung University Hospital, Tainan, Taiwan. The doctors used EZECHBONE® Granule to promote the union of median sternotomy of the patients. The doctors surprisingly found EZECHBONE® Granule also possesses good efficacy on hemostasis of bone marrow. 1st case was a 49 y/o female who was a CKD case receiving regular hemodialysis. Osteoporosis is one major problem of her. She underwent CABG*4 due to recent myocardial infarction. 0.24 g EZECHBONE® Granule was used. 2nd case was a 74 y/o old man who was noted huge aortic aneurysm (maximal diameter was 7.1 cm) extending from ascending aorta, aortic arch, and proximal descending aorta. Total ascending aorta and arch were replaced by prosthetic graft. Proximal descending aorta was implanted with cover stent graft, i.e. frozen elephant trunk stenting. Besides, right and left coronary arteries were bypassed with saphenous vein grafts. Innominate, left carotid and left subclavian arteries were also revascularized with prosthetic grafts. After operation, two cases recovered smoothly. Also, EZECHBONE® Granules showed wonderful hemostatic efficacy on them. For 1st case, 1st day after operation, only 80 c.c. blood was noted from drainage tubes (greatly less than the average amount of HD open heart patient: 200-300 c.c./day). Therefore, chest tubes were removed on the 2nd day after operation (also shorter than the average HD patients). For 2nd case, overall blood drainage was 170 c.c. (pericardial tubes 110 c.c. and left pleural chest tube: 60 c.c.). In this hospital, averaged POD-1 drainage amount≥800 c.c. The 2nd day: overall 170 c.c. but pleural chest tube: 50 c.c. So, left pleural chest tube was removed. The 3rd day: pericardial tubes 100 c.c. and the doctors separated them into 2 individual tubes. The 4th day: 1st tube 70 c.c. and the 2nd tube 20 c.c. So the 2nd tube was removed. The 5th day: 1st tube <70 c.c. and was removed. So, from these 2 cases experiences, the doctors found EZECHBONE® Granule not only promotes well bone union, but also possesses good effectiveness on hemostasis.

EZECHBONE® Granule is available from JOY MEDICAL DEVICES CORPORATION, 1F., No. 63, Luke 2nd Road, Luzhu District, Kaohsiung City, Taiwan. EZECHBONE® Granule has a particle size of about 0.4-1.2 mm, and a porosity of about 70-80 vol %, and is TTCP/DCPA/CSH-derived porous granules prepared based on the method disclosed in U.S. Pat. No. 8,784,551. The porous granules of calcium compound can be prepared from a mixed powers of TTCP/DCP/calcium sulfate (preferably TTCP/DCPA/CSH; more preferably TTCP/DCPA/CSH/CSD) and a pore forming agent, which is then mixed with a NH⁴⁺ solution to form a paste. The paste is hardened into a block in a mold, followed by washing the pore forming agent from the hardened block and breaking the block into porous granules; or breaking the block prior to washing. The porous granules are composed of hydroxyapatite, calcium sulfate (primarily CSD), and less significantly unreacted TTCP, DCP, and CSH. (DCPA: dicalcium phosphate anhydrous)

REFERENCES

• Achneck H E, Sileshi B, Jamiolkowski R M, Albala D M, Shapiro M L, Lawson J H “, A comprehensive review of topical hemostatic agents: efficacy and recommendations for use”, Ann Surg 251:217-28, 2010.
• Barbolt T A, Odin M, Leger M, Kangas L, “Pre-clinical subdural tissue reaction and absorption study of absorbable hemostatic devices”, Neurol Res 23: 537-42, 2001.
• Block J E, “Severe blood loss during spinal reconstructive procedures: the potential usefulness of topical hemostatic agents”, Med Hypotheses 65(3): 617-21, 2005.
• Chun P K C, Virmani R, Mason T E, Johnson F, “Bone wax granuloma causing saphenous vein thrombosis.” Am. Heart J. 115:1310-1313, 1988.
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Claims

1. Use of a solid calcium compound in the fabrication of a hemostatic agent for reducing bleeding from a surgical site during and/or after a surgical treatment in a patient, wherein the solid calcium compound is selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, and a combination thereof.

2. The use of claim 1, wherein the hemostatic agent further comprises a phosphorus source, a sulfur source, or a phosphorus source and a sulfur source.

3. The use of claim 1, wherein the solid calcium compound has a porous structure with a porosity of about 30 vol % to about 90 vol %.

4. The use of claim 3, wherein the porosity is of about 60 vol % to about 80 vol %.

5. The use of claim 3, wherein the solid calcium compound is in a form of porous granules having a granular size of about 0.1 mm to about 2.5 mm.

6. The use of claim 5, wherein the granular size is of about 0.5 mm to about 1.5 mm.

7. The use of claim 3, wherein pores of the porous structure have a pore size in a range of about 30 μm to about 300 μm.

8. The use of claim 7, wherein the pores comprise interconnected pores.

9. The use of claim 1, wherein the surgical site comprises a bone cavity or a bone cut, and the bleeding is a bone bleeding, wherein the hemostatic agent is for contacting the bone cavity or the bone cut to reduce the bleeding.

10. The use of claim 9, wherein bone marrow is exposed by the bone cavity or the bone cut.

11. The use of claim 1, wherein the surgical treatment is a sternum closure treatment and the surgical site comprises a surgically-created sternum cavity.

12. The use of claim 1, wherein the solid calcium compound is calcium phosphate, calcium sulfate, hydroxyapatite or a mixture thereof.

13. The use of claim 1, wherein the solid calcium compound is a mixture of hydroxyapatite, calcium phosphate and calcium sulfate.

14. The use of claim 13, wherein the calcium phosphate is tetracalcium phosphate (TTCP), dicalcium phosphate, tricalcium phosphate, monocalcium phosphate or a mixture thereof; and the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), anhydrous calcium sulfate, or a mixture thereof.

15. The use of claim 14, wherein the calcium phosphate is tetracalcium phosphate (TTCP), dicalcium phosphate, or a mixture thereof; and the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), or a mixture thereof.

16. The use of claim 5, wherein pores of the porous structure have a pore size in a range of about 30 μm to about 300 μm.

17. The use of claim 16, wherein the pores comprise interconnected pores.