Sodium containing sol-gel derived bioactive glasses and uses thereof including hemostasis

Abstract

A sol-gel bioactive glass precursor, method for making sol-gel glasses, resultant sol-gel bioactive glasses, and methods of use thereof, which include introducing Na.sub.2O into the glass network during the sol-gel process through the use of Na-ethoxide, NaCl, or sodium silicate rather than sodium nitrate. Medical and industrial uses of such glasses.

Claims

1. A method of making a sol-gel bioactive glass comprising: mixing a sol-gel bioactive glass precursor including a source of Si, Ca, P, and Na, wherein the source of Na is selected from the group consisting of sodium tert-butoxide, sodium hydroxide, sodium oxalate, sodium sulfate, sodium thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash, baking soda, sodium silicate, and sodium acetate; aging the mixture; drying the mixture to form the sol-gel bioactive glass; and sintering the sol-gel bioactive glass at 550-650 C. for 15 to 50 hours.

2. The method of claim 1, wherein said aging is conducted at a temperature of 50-80 C. for 40-70 hours.

3. The method of claim 1, wherein the drying step is at a temperature of 100 C. or lower.

4. The method of claim 1, further comprising adding a biologically active molecule.

5. The method of claim 1, wherein the source of Si is selected from the group consisting of tetraethylorthosilicate (TEOS), tetramethylorthosilicate (TMOS), fumed silica, colloidal silica, silica gel, sodium silicate, and silicon tetrachloride.

6. The method of claim 1, wherein the source of Ca is selected from the group consisting of calcium methoxide, calcium chloride dihydrate, calcium hydroxide, calcium oxalate hydrate, calcium citrate tetrahydrate, calcium sulfate dehydrate, calcium carbonate and, calcium acetate hydrate.

7. The method of claim 5, wherein the source of Ca is selected from the group consisting of calcium methoxide, calcium chloride dihydrate, calcium hydroxide, calcium oxalate hydrate, calcium citrate tetrahydrate, calcium sulfate dehydrate, calcium carbonate and, calcium acetate hydrate.

8. The method of claim 1, wherein the source of P is triethylphosphate or sodium hexametaphosphate.

9. The method of claim 1, wherein the source of Na is present in an amount to provide for 20-30% by weight of Na.sub.2O in the sol-gel bioactive glass.

10. The method of claim 1, wherein the source of Si is present in an amount to provide for 20-30% by weight of SiO.sub.2 in the sol-gel bioactive glass.

11. The method of claim 1, wherein the source of Ca is present in an amount to provide for 20-30% by weight of CaO in the sol-gel bioactive glass.

12. The method of claim 1, wherein the source of phosphate is triethylphosphate and is present in an amount to provide for 20-30% by weight of P.sub.2O.sub.5 in the sol-gel bioactive glass.

13. A sol-gel bioactive glass comprising Si, Ca, P, and Na, produced by the method of claim 1 wherein sintering consists of sintering the sol-gel bioactive glass at 550-650 C. for 15-50 hours.

14. The sol-gel bioactive glass of claim 13, the sol-gel bioactive glass having a porous structure and a significantly higher specific surface area as compared to a melt-derived bioactive glass of the same composition, wherein the sol-gel bioactive glass is strontium free.

15. The sol-gel bioactive glass of claim 13, wherein Si, Ca, P, and Na are present in their oxide form of SiO.sub.2, Ca.sub.2O, P.sub.2O.sub.5, and NaO.

16. The sol-gel bioactive glass of claim 15, further comprising one or more of K, Mg, Zn, B, F, or Ag.

17. The sol-gel bioactive glass of claim 13, wherein the bioactive sol-gel glass is in a granular form, particulate form, matt form, fiber form, hemostatic sponge form, foam form, paste or putty form, or sphere or bead form, or a combination thereof.

18. The sol-gel bioglass of claim 14, wherein the significantly higher specific surface area is at least 30 times higher than the melt-derived bioactive glass specific surface area.

19. A method for achieving hemostasis in a patient in need of treatment thereof comprising contacting the patient with the sol-gel bioactive glass produced by the method of claim 1 wherein sintering consists of sintering the sol-gel bioactive glass at 550-650 C. for 15-50 hours.

20. A method of inducing rapid coagulation in a bleeding patient comprising contacting the patient with the sol-gel bioactive glass produced by the method of claim 1 wherein sintering consists of sintering the sol-gel bioactive glass at 550-650 C. for 15-50 hours.

21. A method of treating wounds in a patient comprising contacting the patient with the sol-gel bioactive glass produced by the method of claim 1 wherein sintering consists of sintering the sol-gel bioactive glass at 550-650 C. for 15-50 hours.

22. A method of repairing bone in a patient comprising contacting the bone in need of treatment with the sol-gel bioactive glass prepared by the method of claim 1 wherein sintering consists of sintering the sol-gel bioactive glass at 550-650 C. for 15-50 hours.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

(2) A sol-gel bioactive glass precursor, method for making sol-gel glasses, and resultant sol-gel bioactive glasses are disclosed herein which include introducing Na.sub.2O into the glass network during the sol-gel process through the use of Na-ethoxide or NaCl rather than sodium nitrate. The precursor includes organometallic or inorganic salts of elements such as, for example, Si, Ca, Na, P, Ca, and/or B that are converted to their respective oxides after heat treatment. The resultant gels provide a homogenous material. This gel may be heat treated at relatively low temperature of 100 C. or less to preserve the porous structure with a high specific surface area thereby avoiding a sintering step and providing the possibility of adding biologically active molecules such as disclosed in U.S. Pat. No. 5,830,480, the contents of which is hereby incorporated by reference in its entirety. The sol-gel glasses are optionally sintered at 500-1000 C. or preferably 500-900 C., or more preferably, 550-650 C. Bioactive sol-gels made in accordance with the present invention provide significantly improved hemostatic properties as compared to melt-derived 45S5 Bioglass, and other sol-gel compositions. In addition, bioactive sol-gels made in accordance with the present invention exhibited equivalent or better hemostatic properties as compared to some current commercially available hemostasis products.

(3) In certain embodiments, a sol-gel bioactive glass precursor in accordance with the present invention is a mix of ingredients that provide sources of Si, Ca, and Na to provide a phosphate-free sol-gel derived bioglass.

(4) In certain other embodiments, a sol-gel bioactive glass precursor in accordance with the present invention is a mix of ingredients that provide sources of Si, Ca, P, and Na. Many organometallic compounds or inorganic salts (other than sodium nitrate) providing a source of Si, Ca, P, or Na can be used. For example, an alkoxysilane such as tetraethoxy silane may be used as a source of silica, calcium methoxide may be used as a source of calcium and triethylphoshpate may be used as a source of phosphorous. Sodium chloride or sodium ethoxide may be used as a source of sodium. Sol-gel bioactive precursors and sol-gels made therefrom may further contain K, Mg, Zn, B, F, Ag, Cu, Fe, Mn, Mo, Sr, and Zn.

(5) Silicon oxide is typically present in amounts of 20-86%, or 30-60%, or 30-45% by weight of the bioactive sol gel glass. Many organosilicon or silicon salts may be used as precursors and may be present in amounts sufficient to yield 0-86% by weight SiO.sub.2 in the bioactive glass. Colloidal silica or salycic acid may also be used. Other precursors of silica include sodium organometallics (e.g., tetraethylorthosilicate (TEOS) and tetramethylorthosilicate (TMOS)), fumed silica, colloidal silica, silica gel, sodium silicate, and silicon tetrachloride.

(6) The sol gel bioactive glass may further contain sodium. Many organosodium or inorganic sodium salts may be used as a precursor including but not limited to sodium chloride, sodium ethoxide or sodium silicate. Other precursors of sodium include other sodium organometallics (e.g., sodium methoxide, and sodium tert-butoxide), sodium salts (e.g., sodium hydroxide, and sodium oxalate), sodium nitrates (e.g., sodium nitrate), sodium sulfates (e.g., sodium sulfate, sodium thiosulfate, and sodium dodecyl sulfate), sodium carbonates (e.g., sodium bicarbonate, soda ash, and baking soda) and others, such as sodium silicates and sodium acetate.

(7) Such precursors may be used in an amount sufficient to yield 0-40%, 1-55%, 5-15%, 25-30%, or about 10% by weight Na.sub.2O in the bioactive sol gel glass.

(8) The sol-gel bioactive glass may further comprise potassium. The potassium precursors may include but are not limited to organopotassium compounds or inorganic potassium salts such as potassium nitrate (KNO.sub.3), potassium sulphate (K.sub.2SO.sub.4) and potassium silicates. It is advantageous to provide a bioactive glass composition in which the potassium content is low. If a potassium precursor is included, it may be present in amounts sufficient to yield 0-8 K.sub.2O in the bioactive glass.

(9) The bioactive glass of the present invention preferably comprises calcium. Calcium precursors include but are not limited to organocalcium compounds or inorganic salts of calcium such as calcium nitrate (Ca(NO.sub.3).sub.2), calcium nitrate tetrahydrate (CaNo.sub.3.4H.sub.2O), calcium sulphate (CaSO.sub.4), calcium silicates or a source of calcium oxide (Lime). Other precursors of calcium include calcium organometallics (e.g., calcium methoxide), calcium salts (e.g., calcium chloride diydrate, calcium hydroxide, calcium oxolate hydrate, and calcium citrate tetrahydrate), calcium nitrates (e.g., calcium nitrate tetrahydrate), calcium sulfates (e.g., calcium sulfate dehydrate), calcium carbonates (e.g., calcium carbonate) and other precursors, such as calcium acetate hydrate. A source of calcium oxide includes any compound that decomposes to form calcium oxide. Release of Ca.sup.2+ ions from the surface of the bioactive glass aids the formation of the calcium phosphate-rich layer on the surface of the glass. The provision of calcium ions by the bioactive glass can increase the rate of formation of the calcium phosphate-rich layer. However it should be appreciated that the calcium phosphate-rich layer can form without the provision of calcium ions by the bioactive glass, as body fluid itself contains calcium ions. Thus, for the purposes of this invention, bioactive glasses containing no calcium can be used. The calcium precursor may be present in the precursor in an amount sufficient to yield at least 5%, 0-40%, 10-20%, 20-30% or about 25% CaO in the resultant sol-gel glass.

(10) The bioactive glass of the present invention preferably comprises P.sub.2O.sub.5. Phosphate precursors include many organophosphates and inorganic phosphate salts including but not limited to triethylphosphate and/or polyphosphates, such as, e.g. sodium hexametaphosphate. Release of phosphate ions from the surface of the bioactive glass aids in the formation of hydroxycarbonated apatite. While hydroxycarbonated apatite can form without the provision of phosphate ions by the bioactive glass, as body fluid itself contains phosphate ions, the provision of phosphate ions by the bioactive glass increases the rate of formation of hydroxycarbonated apatite. The phosphate precursor may be present in an amount sufficient to yield at 0-80%, 0-50%, 20-70%, 20-30%, 25-30%, or about 25% P.sub.2O.sub.5 in the resultant glass.

(11) The sol-gel bioactive glass of the present invention may comprise zinc. Zinc precursors include but are not limited to organozinc compounds or inorganic salts containing zinc such as zinc nitrate (Zn(NO.sub.3).sub.2), zinc sulphate (ZnSO.sub.4), and zinc silicates and any such compounds that decompose to form zinc oxide. When present, the zinc precursor should be present in amounts sufficient to yield 0.01-5% ZnO in the glass.

(12) The bioactive glass of the present invention may comprise magnesium. Magnesium precursors include but are not limited to organomagnesium compounds or inorganic magnesium salts such as magnesium nitrate (Mg(NO.sub.3).sub.2), magnesium sulphate (MgSO.sub.4), magnesium silicates and any such compounds that decompose to form magnesium oxide. When included the magnesium source should be present in an amount sufficient to yield 0.01 to 5% MgO in the bioactive glass.

(13) The sol-gel bioactive glass of the present invention also includes boron. The boron precursors include but are not limited to organoborate compounds, inorganic borate salts, boric acid, and trimethyl borate. A sufficient amount of boron precursor may be used sufficient to provide B.sub.2O.sub.3 in amounts of at least 25%, 30% to 50%, 35-45%, or up to 80% by weight in the glass.

(14) The bioactive glass of the present invention may comprise fluorine. Fluorine precursors include but are not limited to organofluorine compounds or inorganic fluorine salts such as calcium fluoride (CaF.sub.2), strontium fluoride (SrF.sub.2), magnesium fluoride (MgF.sub.2), Sodium fluoride (NaF) or potassium fluoride (KF). Fluoride stimulates osteoblasts, and increases the rate of hydroxycarbonated apatite deposition. When present, an amount of fluorine precursor is used to provide 0-35% or 0.01-5% calcium fluoride.

(15) The bioactive sol-gels may further comprise sources of Cu, Fe, Mn, Mo, or Sr. When present, such sources include organometallic and inorganic salts thereof. Each may be present to provide in 0.01 to 5% or more by weight of the respective oxide in the glass.

(16) Bioactive sol-gels in accordance with the present invention are hemostatic materials that are bioabsorbable, that provide for superior hemostasis, and may be fabricated into a variety of forms suitable for use in controlling bleeding from a variety of wounds, both internal and external. Bioactive sol-gel glasses may be in granular or particulate form, matt or fiber form, a hemostatic sponge, incorporated into a foam, or in the form of a paste or putty. The sol-gel glasses may also be in a form of a sphere or a bead, or a combination of all the forms. Exemplary spherical forms were described in U.S. Provisonal Application No. 61/786,991, filed Mar. 15, 2013, content of which is incorporated by reference in its entirety. They may also be formulated into settable and non-settable carriers.

(17) Sol-gel bioactive glass is suitable for use in both surgical applications as well as in field treatment of traumatic injuries. For example, in vascular surgery, bleeding is particularly problematic. In cardiac surgery, the multiple vascular anastomoses and cannulation sites, complicated by coagulopathy induced by extracorporeal bypass, can result in bleeding that can only be controlled by topical hemostats. Rapid and effective hemostasis during spinal surgery, where control of osseous, epidural, and/or subdural bleeding or bleeding from the spinal cord is not amenable to sutures or cautery, can minimize the potential for injury to nerve roots and reduce the procedure time. In liver surgery, for example, live donor liver transplant procedures or removal of cancerous tumors, there is a substantial risk of massive bleeding. An effective hemostatic material can significantly enhance patient outcome in such procedures. Even in those situations where bleeding is not massive, an effective hemostatic material can be desirable, for example, in dental procedures such as tooth extractions, as well as the treatment of abrasions, burns, and the like. In neurosurgery, oozing wounds are common and are difficult to treat.

(18) The bioactive sol-gels may be further combined with a bioactive agent. The bioactive agent comprises one of antibodies, antigens, antibiotics, wound sterilization substances, thrombin, blood clotting factors, conventional chemo- and radiation therapeutic drugs, VEGF, antitumor agents such as angiostatin, endostatin, biological response modifiers, and various combinations thereof. The bioactive sol-gels may also be combined with polymers to provide further structural support. For example, porous bioactive glass hemostatic agents may be prepared by a sol gel process described herein that further uses a block copolymer of ethyleneoxide and propylene oxide.

(19) Other uses for the sol-gel compositions of the present invention include filling bone defects, bone repair/regeneration, limb salvage, drug delivery, repair of osteochondral defects, reparing osseous defects, dental hypersensitivity, tooth whitening, and guided tissue regeneration.

EXAMPLES

(20) Preparation of Sol-Gels

(21) Sol Gel Bioactive glasses were prepared with the compositions set forth in Table 1 and as described in 1-1 through 1-6 below:

(22) TABLE-US-00001 TABLE 1 Compositions of Sol-gel Bioactive Glasses Na2O Sample ID SiO2 (wt %) CaO (wt %) P2O5 (wt %) (wt %) 45S5 (melt) 45 24.5 6 24.5 45S5 (Sol-gel) 45 24.5 6 24.5 58S 58 33 9 0 77S 77 14 9 0 100S 100 0 0 0

(23) Preparation of 1-1. 100S gel (Comparativeno Na, Ca, or P source): the gel was prepared by mixing D. I. water, HCl, TEOS (Tetraethoxysilane) followed by mixing for 60 minutes to facilitate the completion of hydrolysis reaction. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the gel was transferred into drying vessel for drying to 180 C., then heated at 700 C. in the same procedures as reported in U.S. Pat. No. 5,074,916 (the contents of which are hereby incorporated by reference in its entirety). The heat treated gels were ground to <300 m powders for analysis and testing.

(24) Preparation of 1-2. 77S gel (Comparativeno Na source): the gel was prepared by mixing D. I. water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP (Triethylphosphate) into the solution and mixing for another 20 minutes, then adding CaNO.sub.3.4H.sub.2O (Calcium Nitrate tetra-hydrate) while mixing for an additional 60 minutes to complete the dissolution of the Calcium Nitrate. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the gel was transferred into drying vessel for drying to 180 C., and then heated at 700 C. in the same procedures as reported in the U.S. Pat. No. 5,074,916. The heat treated gels were ground to <300 m powders for analysis and testing.

(25) Preparation of 1-3 (Comparativeno Na source). 58S gel: the gel was prepared by mixing D. I. water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP (Triethylphosphate) into the solution and mixing another 20 minutes, then adding CaNO3.4H2O (Calcium Nitrate tetra-hydrate) while mixing for an additional 60 minutes to complete the dissolution of the Calcium Nitrate. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the gel was be transferred into drying vessel for drying to 180 C., and then heated at 700 C. in the same procedures as reported in the U.S. Pat. No. 5,074,916. The heat treated gels were ground to <300 m powders for analysis and testing.

(26) Preparation of 1-4. 45S5 gel#1 (Includes sodium ethoxide as Na source): the gel was prepared by mixing half the amount of D. I. water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP (Triethylphosphate) into the solution and mixing another 20 minutes, then adding the rest of D. I. water, Calcium Methoxide, and Sodium Ethoxide, while mixing for 60 minutes to complete the hydrolysis reaction. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the gel was transferred into drying vessel for drying to 180 C., and then heated at 550 C. in the same procedures as reported in the U.S. Pat. No. 5,074,916. The heat treated gels were ground to <300 m powders for analysis and testing.

(27) Preparation of 1-5. 45S5 gel#2 (Includes NaCl as Na source): the gel was prepared by mixing D. I. water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP(triethylphosphate) into the solution and mixing another 20 minutes, then adding CaNO.sub.3.4H.sub.2O (Calcium Nitrate tetra-hydrate) and NaCl while mixing for an additional 60 minutes to complete the dissolution of the Calcium Nitrate and NaCl. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the gel was transferred into drying vessel for drying at 180 C., and then heated to 550 C. using the same procedure as reported in U.S. Pat. No. 5,074,916.

(28) Preparation of 1-6. 45S5 gel#3 (Comparativeincludes sodium nitrate as Na source): the gel was prepared by mixing D. I. water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP(triethylphosphate) into the solution and mixing another 20 minutes, then adding CaNO.sub.3.4H.sub.2O (Calcium Nitrate tetra-hydrate) and NaNO.sub.3 (Sodium Nitrate), while mixing for an additional 60 minutes to complete the dissolution of the Calcium Nitrate and Sodium Nitrate. Then, the mixture was transferred into a polypropylene mold for aging at 60 C. for 55 hours. After aging, the precipitation could be seen visually. After aging, the gel was transferred into drying vessel for drying at 180 C., and then heated to 550 C. using the same procedure as reported in U.S. Pat. No. 5,074,916.

(29) The following porous structure data was obtained from the foregoing compositions:

(30) TABLE-US-00002 Specific Surface Pore Size Area Diameter Sample ID m.sup.2/gram (Angstroms) Standard 216 203 Specifications 45S5(Melt) 0.1 0 45S5(Sol-gel) 31 98 58S 166 96 77S 414 30 100S 561 40
Hemostasis Studies

(31) The male adult Wistar rats were anesthetized by intraperitoneal injection of pentobarbital (40 mg/kg). An abnormal incision was made and the left kidney was isolated. A thin flexible plastic tray was placed under the kidney and the kidney is wrapped with pre-weighted degrease cotton. Heparin sodium (300 IU/kg) was then intravenous injected. Five minutes later, an atraumatic clamp was placed across the renal vascular pedicle, the caudal pole of the kidney was extruded through the ring about 4 mm protruded above the plate and the tissue was severed with a scalpel blade. The hemostatic agent was applied to the cutting surface of the kidney before the clamp was removed. Bleeding time and the amount of blood dropped(Blood Wt) were measured.

(32) 4-1. Study #1 The tested samples: 45S5(Melt), Sol-gel 58S Control group: FloSeal, Starch (both are commercially available products used in the worldwide market) Blank Control: No material applied Each test article was tested in 50 mg, and conducted 6 tests.

(33) TABLE-US-00003 TABLE 3 Test Results Bleeding Time and Blood Drop for Study #1 in the Rat Model of Partial Nephrectomy Bleeding time Blood dropped Group Number (Seconds) (ml) No-treatment Control 5 624 36 4.3 0.4 Edible starch 5 408 24 3.0 0.5 Melt-derived 45S5 5 264 24 2.1 0.3 Bioglass Bioglass 58S Gel 5 216 12 1.0 0.1 FloSeal 5 186 12 1.0 0.1

(34) Based on the statistic results of this test, the sol-gel 58S demonstrated a comparable hemostatic effect to FloSeal, a commercial available product in the market. The order is, 58S>melt 45S5>Starch. All of the test materials are better than No-treatment control.

(35) 4-2. Study #2 The tested samples: 45S5(Melt), 45S5(Sol-gel), 58S, 77S, 100S Control group: NexStat(Hemostasis, LLC), Blank Control: No material applied Each test article was tested in 3 doses: 5 l, 15 l and 50 l, and each dose was conducted 6 tests.

(36) Test Results

(37) TABLE-US-00004 TABLE 4 Blank Control Bleeding time (s) Blood Wt Collected (g) 647 25.57 5.35 0.17

(38) TABLE-US-00005 TABLE 5 Bleeding Time and Blood Drop for Study #2 in the Rat Model of Partial Nephrectomy Materials 45S5(Sol-gel) NexStat 1-4 58S 77S 100S Bleeding Blood Bleeding Blood Bleeding Blood Bleeding Blood Bleeding Blood Dose Time (s) Wt (g) Time (s) Wt (g) Time (s) Wt (g) Time (s) Wt (g) Time (s) Wt (g) 5 l 341 17.5* 3.22 0.16* 220.6 1.9 552 16.7 4.68 0.21 466 32.3* 4.10 0.18 587 16.7 4.90 0.13 15 l 166 9.7* 1.65 0.10* 178 1.12 396 9.6* 3.83 0.24 240 16.2* 2.43 0.15* 450 13.3* 3.67 0.20* 50 l 80 7.2* 1.00 0.08* 78 0.66 216 7.7* 2.15 0.20* 92 7.8* 0.98 0.07* 286 8.5* 2.48 0.18*

(39) Based on the statistic results of this test, the sol-gel 45S5 demonstrated the best hemostatic effect. The order is, sol-gel 45S5>NexStat>77S>58S>77S>melt 45S5.

(40) Sol-gel 45S5 demonstrated the best hemostatic effect compared with other tested materials, even some commercially available hemostasis products. Sol-gel 45S5, with porous structure, has 30 times higher surface area then melt derived 45S5 Bioglass. The high surface is functions to adsorb water from the blood rapidly and concentrate clotting proteins and platelets to promote instantaneous clot formation. In addition, calcium ions release from the glass function to complex with the carboxylic acid functional groups of the proteins within the site to facilitate clot formation. Although sol-gel 45S5 specific surface area is not the highest compared with other sol-gel materials such as the 58S, 77S and 100S, it can be assumed that the ionic exchange between Na+ inside sol-gel 45S5 and OH would create a large amount of silanol groups on the sol-gel 45S5 surface or inside pores, which would facilitate the physical and chemical absorption of water onto the surface of the glass.

(41) Due to its fast surface activity, Ca.sup.2+ release from sol-gel 45S5 would also be very dramatic. As previously described the calcium ions will complex with the surrounding proteins most notably fibrin acting as a type of glue to hold the fibrin monomers to each other to form the polymeric fiber. The resultant fibrin fibers form a loose meshwork, which functions to entrap erythrocytes, thus forming a clot that stops the flow of blood. All of these factors contribute to the hemostatic effect exhibited by the sol-gel 45S5 Bioglass.

(42) Throughout this specification various indications have been given as to preferred and alternative embodiments of the invention. However, the foregoing detailed description is to be regarded as illustrative rather than limiting and the invention is not limited to any one of the provided embodiments. It should be understood that it is the appended claims, including all equivalents, that are intended to define the spirit and scope of this invention.