WO2011115828A1

WO2011115828A1 - Absorbent bioabsorbable composite surgical biomaterial

Info

Publication number: WO2011115828A1
Application number: PCT/US2011/028048
Authority: WO
Inventors: Devon Anderson; Jonathan Guerrette; Nathan Niparko
Original assignee: Devon Anderson; Jonathan Guerrette; Nathan Niparko
Priority date: 2010-03-13
Filing date: 2011-03-11
Publication date: 2011-09-22

Abstract

A bioabsorbable surgical biomaterial that is a composite matrix of cross-linked alginate fibers and cellulose fibers is described. The composite matrix is at least partially oxidized throughout and results in a biomaterial with the desired fluid absorption and bioabsorption characteristics for surgical applications, such as use as a bioabsorbable surgical sponge. A method of manufacturing the bioabsorbable surgical biomaterial by electrospinning is also disclosed.

Description

ABSORBENT BIOABSORBABLE COMPOSITE SURGICAL BIOMATERIAL

Devon Anderson

Jonathan Guerrette

Nathan Niparko

Technical Field

This invention relates to the field of sponges and other surgical materials and, more specifically, absorbent surgical biomaterials that are bioabsorbable such that they can be safely left within the patient following an operation. Background Art

The post-operative retention of surgical sponges, or gossypiboma, is a well- documented problem in operating rooms worldwide. Sponges are frequently misplaced during surgery when the surgical sponge, most commonly made of cotton, loses its visual differentiation from human tissue. Currently, operating room best practices require a nurse to maintain a count of every sponge that is inserted into and removed from a patient, and the process is prone to miscounts and faulty

documentation even under ideal operating conditions. This tracking system is further strained in emergency or unexpected surgical situations as communication between surgeon and nurse often breaks down when the surgeon must move quickly.

The problem has been widely acknowledged by the medical industry, as nearly all sponges above 4 inches squared and many smaller sponges contain a radio-opaque strip that allows for X-Ray visualization and a streamlined sponge-removal process. Smaller sponges that require more deformability or a consistent, supple texture do not contain a radio-opaque element and, due to their tendency to camouflage with blood and tissue, are more difficult to detect post-operatively.

Gossypiboma poses a significant risk to patient safety. Current sponge designs - when retained in a patient - can impact the patient's well-being in two ways. Sponges can have a direct impact on patient health through obstruction or formation of an abscess or granuloma. Indirectly, retained sponges pose health risks and lifestyle disruption because removal of the retained sponge requires either a prolonged surgery if the missing sponge is recognized before the conclusion of a surgery, or a follow-up procedure if the missing sponge is not identified until after the procedure. Gossypiboma also places significant financial burden on the surgeon and hospital involved in the sentinel event, as these entities are held liable in litigation and must cover all costs associated with the resolving the case.

One solution to the problem of gossypiboma is to use a surgical sponge that can be safely left within the patient and will be absorbed by the body without causing additional complications— a sponge that is bioabsorbable (sometimes referred to as bioresorbable). This approach is similar to the use of bioabsorbable sutures for closing wounds. The portion of the suture within the patient dissolves without the need for a separate removal procedure. Further examples of commercially available bioabsorbable surgical materials include gelatin and collagen bioabsorbable hemostats. While these materials have admirable absorbency and bioresorption characteristics, they are too expensive to gain widespread use for most common surgical applications.

Another bioabsorbable surgical material is oxidized cellulose. Oxidized regenerated cellulose is presently employed as a hemostat in operating rooms.

Alginate, which is a polymer derived from algae, is used by medical professionals as a hydrocolloid wound dressing and is not bioabsorbable. Oxidation of alginate, similar to cellulose, induces bioabsorbability; however, oxidized alginate is not commonly used in operating rooms. Neither oxidized cellulose nor oxidized alginate have achieved widespread use as a low-cost bioabsorbable surgical sponge due to their respective physical characteristics.

The beneficial combination of a water soluble polymer for absorbency and a bioabsorbable polymer for structural integrity in a hemostat has also been considered, though the material is constrained to a core/sheath composite and does not directly claim the use of oxidized materials. The resulting composite is limited to a hemostat because of its inherent breakdown in structure due to the water soluble polymer; thus, it is not fit to serve as a bioabsorbable surgical sponge with widespread application and functionality.

In addition to the material choice, the method of manufacture substantially impacts both the absorbency and cost of surgical materials, such as sponges.

Electrostatic spinning (electrospinning for short) is a preferred manufacturing method for the production of a matrix of polymeric nanofibers with a high surface area to volume ratio for maximum absorbency. Electrospinning also affords the benefit of uniform sized nanofibers, which present all monomers of a polymer for chemical modification. This becomes relevant in the modification of polymers following electrospinning to ensure the polymer is modified throughout the entire matrix. To perform electrospinning, a polymer is dissolved in a solvent and placed in a small vessel with a nozzle at one end. A voltage is applied between the polymer solution and a collector (or target) a specified distance from the nozzle. As the electric field overcomes the surface tension of the polymer in solution, a continuous jet of polymer nanofibers is ejected from the solution, through the electric field, and onto the grounded target. The collector surface is moved relative to the nozzle to create a desired matrix pattern from the deposited fibers. Electrospinning techniques require careful consideration of the contents of the polymer solution to ensure the stability of the polymer, concentration, and viscosity. Additional variables in the process include the electric field strength, flow rate, distance from the nozzle to the target, and the relative movement of the nozzle and target. Electrospinning of composites with distinct fibers has been achieved through the use of two polymer solutions being electrospun on the same target simultaneously.

Disclosure of Invention

The invention is a bioabsorbable surgical biomaterial made of cross-linked alginate fibers and cellulose fibers that form a matrix. The matrix is at least partially oxidized throughout and results in a composite surgical material with the desired fluid absorption and bioabsorption characteristics. The bioabsorbable surgical biomaterial may form a bioabsorbable surgical sponge. The ratio of cellulose fibers to alginate fibers in the matrix may be at least 2: 1 and the matrix may be 16-24 percent oxidized. The fibers may have mean diameter of less than 1 micron and a dry weight to saturated weight ratio of 1 : 10 to 1 :30. The matrix may form a mat of fibers with substantially random orientations or a matrix of substantially parallel fibers. The cellulose fibers may be substantially de-acetylated, meaning that they were made from cellulose acetate and have trace amounts of residual cellulose acetate in the resulting cellulose fibers.

The bioabsorbable surgical material is made in accordance with a method of manufacture including the steps of: electrospinning separate cellulose acetate solution and alginate solution onto a common target to produce a matrix of cellulose acetate fibers and alginate fibers; cross-linking the alginate fibers in the matrix to create cross-linked alginate; de-acetylating the cellulose acetate fibers in the matrix to create cellulose fibers in the matrix; and oxidizing at least a portion of the cross-linked alginate fibers and cellulose fibers in the matrix. The alginate solution may comprise sodium alginate, polyethylene oxide, water, surfactant, and dimethyl sulfoxide. The cellulose acetate may be dissolved in a solution of acetone and dimethylacetamide for electrospinning. The common target used for electrospinning may be a rotating collecting target. The step of cross-linking the alginate fibers may comprise soaking the matrix in ethanol, calcium chloride, and water to create cross-linked alginate fibers and congruently removing non-alginate materials present in the alginate polymers, such as the polyethylene oxide polymer needed to initially disaggregate the sodium alginate in solution. The step of de-acetylating the cellulose acetate may comprise soaking the matrix in sodium hydroxide and ethanol. The step of oxidizing may comprise a ring opening mechanism, such as soaking the matrix in aqueous sodium periodate.

The bioabsorbable surgical biomaterial may additionally be formed into a surgical sponge of desired morphology, freeze dried, and sterilized by an irradiation method.

Brief Description of Drawings

Figure 1 is a process diagram of a method of manufacturing in accordance with the present invention.

Figure 2 is a 5000X image produced by scanning electron microscopy of an electrospun mat of unlinked alginate fibers and cellulose acetate fibers with substantially random orientations (intermediate product).

Figure 3 is a 5000X image produced by scanning electron microscopy of an electrospun mat of cross-linked alginate fibers and cellulose fibers in substantially random orientations and which have been partially oxidized.

Figure 4 is a 500X image produced by scanning electron microscopy of an electrospun mat of cross-linked alginate fibers and cellulose fibers in substantially random orientations and which have been partially oxidized.

Best Mode of Carrying Out the Invention

The present invention is directed to a bioabsorbable surgical biomaterial that is a composite matrix of cross-linked alginate fibers and cellulose fibers. The composite matrix is at least partially oxidized throughout and results in a biomaterial with the desired fluid absorption and bioabsorption characteristics for surgical applications, such as use as a bioabsorbable surgical sponge.

The bioabsorbable surgical biomaterial can most easily be understood in terms of the method of manufacturing the material. It will be appreciated by those of ordinary skill in the art that various parameters of the manufacturing process may be varied to optimize various characteristics of the resulting material based on the desired fluid absorption, rate of bioabsorption, and intended morphology and medical application.

The bioabsorbable surgical biomaterial is a composite matrix of cross-linked alginate fibers and cellulose fibers formed by electrospinning two polymer solutions on a common target to form a matrix and then treating the matrix in a series of finishing steps, which chemically modify the fibers in the matrix. This process is described below with reference to Figure 1 , showing a process diagram of the preferred method of manufacture.

In step 110, an alginate solution is prepared. Low viscosity sodium alginate is dissolved at 4% weight in water with constant stirring for 12 hours to prepare a base sodium alginate solution. In parallel, polyethylene oxide (PEO) of molecular weight 900-l,000kD is dissolved at 4% weight in water with constant stirring for 12 hours to prepare a base PEO solution. Six parts of the base sodium alginate solution is mixed with four parts of the base PEO solution in a Falcon tube. The PEO component disrupts aggregation of the sodium salt of alginate to facilitate electrospinning. 5% weight dimethyl sulfoxide (DMSO) and 0.5% weight surfactant are added to the Falcon tube. A preferred surfactant is Triton X-100 nonionic surfactant available from Dow Chemical Co. DMSO and surfactant act to reduce the viscosity of the solution. DMSO is a co-solvent to water and the surfactant reduces the surface tension within the solution to further prevent aggregation of molecules. The resulting alginate solution is mixed thoroughly on a vortex for at least 10 minutes.

In step 111, a cellulose acetate solution is prepared. 15% weight cellulose acetate is dissolved in a 2: 1 solution of acetone and dimethylacetamide (DMAc) with constant stirring for 12 hours to prepare the cellulose acetate solution. The acetone and DMAc act as complementary polar solvents to adjust the viscosity of the cellulose acetone solution. They are more effective in combination than either solvent would be on its own. The ratio is selected to give a preferred viscosity of cellulose acetate solution.

In step 112, the alginate solution and cellulose acetate solution are electrospun onto a common collector target. This step uses a conventional electrospinning apparatus with two source solutions and a common collector target. The initial setup of the electrospinning apparatus includes adding 5-10 ml of the alginate solution to one luer lock 10 cc syringe and 5-10 ml of the cellulose acetate solution to a second luer lock 10 cc syringe. The syringes may be glass or plastic, and other functionally equivalent vessels can be used based upon the specifications of the electrospinning apparatus being employed. The syringes are then placed in separate syringe pumps. A collecting target is attached to the shaft of a motor used for moving the collecting target during the electrospinning process. The collecting target may be a disc, rod, or plate and may be rotated by the shaft of the motor. The motor used may be a high RPM motor for creating a matrix with parallel oriented fibers or a more slowly rotating motor for creating a matrix with randomly oriented fibers. The resulting matrix may be referred to as a mat. Parallel oriented fibers may be referred to as threads. Threads and randomly oriented mats have distinct applications in creating bioabsorbable surgical biomaterials. The syringe pumps with the syringes are placed on either side of the collecting target and oriented adjacent the collecting target at a distance appropriate to the electrospinning equipment and desired fiber and matrix characteristics. The collecting target is then grounded on a high voltage power source. Containing the needle tips of the syringes and the collecting target in an acrylic box can minimize fiber loss and metal interference.

Continuing step 112, the active electrospinning process is initiated. The motor is turned on to start moving the grounded collecting target, preferably in a rotating motion about the shaft of the motor and between the two syringe pumps. The syringe pumps are turned on simultaneously. The pump rate of the individual pumps will vary based on the viscosity of the solution, the needle gage, and the electric field strength and should be adjusted while electrospinning to produce the best taylor cone. For freshly prepared solutions, both will spin between 0.75 and 1.5 ml/hour with a 16 gage needle. The high voltage power source is turned on with a voltage of 15-25 kV and can be adjusted during spinning to influence the formation of the taylor cone. The electrospinning process should be monitored for the duration of the spinning, which generally continues until one or both of the syringes are empty. After the syringes empty, all components are turned off and the collector target is removed from the motor shaft. The resulting matrix mat or thread can then be peeled off of the collector target. This completes the electrospinning process.

The matrix of fibers resulting from the electrospinning process is an intermediate product in the manufacture of the desired bioabsorbable surgical biomaterial. The matrix of fibers is an interlaced composite of: a) fibers of alginate and PEO, and b) cellulose acetate fibers. Cellulose acetate is used for electrospinning because cellulose polymers without the added acetyl group are not compatible with electrospinning. An image of the intermediate product following step 112 of the method of manufacture can be seen in Figure 2, a 5000X image produced by scanning electron microscopy of an electrospun mat of unlinked alginate fibers and cellulose acetate fibers with substantially random orientations. Figure 2 includes a 5 micron scale. The mean diameter of the resulting fibers is well under 1 micron. The material still contains PEO, which is integrated into the fibers emerging from the alginate solution during electrospinning. The solvents and surfactants used in the solutions are not incorporated into the resulting fibers.

In step 113, the matrix of fibers is chemically modified to cross-link the alginate fibers and remove the PEO. The matrix of fibers is weighed, then soaked in 200 proof ethanol for 5 minutes to wash away impurities. It is then soaked in 75% ethanol, which is saturated with calcium chloride, for 10 minutes to cross-link alginate fibers to one another through a salt bridge. It is then soaked in an aqueous solution of 5% calcium chloride for 1 hour to ensure thorough cross-linking of all alginate polymers in the matrix. Finally, it is soaked in de-ionized water for at least 1 hour to wash away any unused calcium chloride salt by dissolution.

The intermediate product produced by step 113 is a matrix of substantially cross-linked alginate fibers and cellulose acetate fibers. Step 113 also removes the PEO that was present in the material immediately after electrospinning.

In step 114, the matrix of fibers is chemically modified to de-acetylate the cellulose acetate fibers. The matrix of fibers is soaked in 0.05M sodium hydroxide in ethanol for 1 hour to remove acetyl groups from the cellulose acetate fibers, resulting in de-acetylated cellulose fibers.

The intermediate product produced by step 114 is a matrix of substantially cross-linked alginate fibers and cellulose fibers. The resulting cellulose fibers may include residual cellulose acetate that is not de-acetylated by step 114. In step 115, the matrix of fibers is chemically modified to oxidize fibers throughout the matrix. The matrix of fibers is soaked in aqueous sodium periodate with the molarity based on the desired percent oxidation. A preferred range of oxidation is between 16-24 percent. The matrix of fibers is soaked for 24-48 hours in a dark reaction flask. The reaction is then quenched with stoichiometric amount of ethylene glycol and then thoroughly washed with de -ionized water.

The product of step 115 is the final chemical and micro/nano structure of the bioabsorbable surgical biomaterial. The resulting composite matrix is comprised of cross-linked alginate fibers and cellulose fibers in a mat either where the fibers are substantially random in orientation or where the fibers are substantially parallel in orientation. A desired percentage of the fibers throughout the matrix are oxidized. The partial oxidation is in accordance with the desired rate of bioabsorption for the intended application. The ratio of the cellulose fibers to cross-linked alginate fibers in the matrix is at least 2: 1 and may be varied to meet structural and fluid absorption requirements for the intended application. For example, the fluid absorption capability as measured by the ratio of dry weight to saturated weight may be between 1 : 10 and 1 :30. De-acetylation of the cellulose fibers in the product may be detectable due to residual cellulose acetate that was not completely de-acetylated in step 114.

In step 116, the matrix of fibers is formed into a desired morphology and dried. Matrices in thread form can be teased apart and physically processed to produce individual thread or fabric morphologies. Matrices in mat form can be cut, folded, stacked, or otherwise manipulated to produce various surgical sponge or other morphologies. For example, the matrix may be formed to morphologies that substantially mimic existing standard cotton surgical sponges in various sizes. These manipulations of the morphology can generally be accomplished while the material is still saturated with water. Once the desired morphology is achieved, the matrix can be freeze dried, for example using a 12 hour freeze dry.

In step 117, the matrix of fibers is sterilized for medical use. A preferred method of sterilization for surgical sponges or similar applications is an irradiation method, such as gamma or electron beam sterilization. The resulting bioabsorbable surgical biomaterial can then be stored in a controlled environment for packaging, and/or use.

Figures 3 and 4 show the final bioabsorbable surgical biomaterial. Figure 3 is a 5000X image produced by scanning electron microscopy of an electrospun mat of cross-linked alginate fibers and cellulose fibers in substantially random orientations and which have been partially oxidized. Figure 3 includes a 5 micron scale. After chemical modification of the electrospun matrix, the mean diameter of the resulting fibers is still under 1 micron. Figure 4 is a 500X image produced by scanning electron microscopy of an electrospun mat of cross-linked alginate fibers and cellulose fibers in substantially random orientations and which have been partially oxidized. Figure 4 includes a 50 micron scale and captures an edge portion of the matrix.

Industrial Applicability

The bioabsorbable surgical biomaterial described herein and related method of manufacturing have clear industrial application in at least the production and sale of surgical materials and implements.

Claims

1. A bioabsorbable surgical biomaterial, comprising: cross-linked alginate fibers; cellulose fibers forming a matrix with the cross-linked alginate fibers; and wherein the cross-linked alginate fibers and cellulose fibers are at least partially oxidized.

2. The bioabsorbable surgical biomaterial of claim 1, wherein the matrix forms a bioabsorbable surgical sponge.

3. The bioabsorbable surgical biomaterial of claim 1, wherein the ratio of cellulose fibers to cross-linked alginate fibers in the matrix is at least 2: 1.

4. The bioabsorbable surgical biomaterial of claim 1, wherein the cross-linked alginate fibers and cellulose fibers in the matrix are within the inclusive range of 16- 24 percent oxidized throughout the matrix.

5. The bioabsorbable surgical biomaterial of claim 1, wherein the cross-linked alginate fibers and cellulose fibers have a mean diameter of less than 1 micron.

6. The bioabsorbable surgical biomaterial of claim 1, wherein the matrix has a dry weight to saturated weight ratio in the inclusive range of 1 : 10 to 1 :30.

7. The bioabsorbable surgical biomaterial of claim 1, wherein the matrix forms a mat of fibers in substantially random orientations. 8. The bioabsorbable surgical biomaterial of claim 1, wherein the matrix forms a plurality of fibers in substantially parallel orientation.

9. The bioabsorbable surgical biomaterial of claim 1, wherein the cellulose fibers are substantially de-acetylated.

1

10. A method of manufacturing a bioabsorbable surgical biomaterial, comprising the steps of: electrospinning separate cellulose acetate solution and alginate solution onto a common target to produce a matrix of cellulose acetate fibers and alginate fibers; cross-linking the alginate fibers in the matrix to create cross-linked alginate fibers in the matrix; de-acetylating the cellulose acetate fibers in the matrix to create cellulose fibers in the matrix; and oxidizing at least a portion of the cross-linked alginate fibers and cellulose fibers in the matrix.

11. The method of claim 10, wherein the alginate solution in the electrospinning step is comprised of sodium alginate, polyethylene oxide, water, surfactant, and dimethyl sulfoxide. 12. The method of claim 10, wherein the cellulose acetate in the electrospinning step is dissolved in a solution of acetone and dimethylacetamide.

13. The method of claim 10, wherein the matrix produced in the electrospinning step forms a matrix of the cellulose acetate fibers and alginate fibers in substantially parallel orientation. 14. The method of claim 10, wherein the matrix produced in the electrospinning step forms a mat of the cellulose acetate fibers and alginate fibers in substantially random orientation.

15. The method of claim 10, wherein the common target is a rotating collecting target.

16. The method of claim 10, wherein the step of cross-linking comprises soaking the matrix including the alginate fibers in ethanol, calcium chloride, and water to create cross-linked alginate fibers from the alginate fibers and congruently removing residual non-alginate materials present in the alginate solution.

2

17. The method of claim 10, wherein the step of de-acetylating comprises soaking the matrix including the cellulose acetate fibers in sodium hydroxide and ethanol to create de-acetylated cellulose fibers from the cellulose acetate fibers.

18. The method of claim 10, wherein the step of oxidizing comprises a ring opening mechanism.

19. The method of claim 10, wherein the step of oxidizing comprises soaking the matrix in aqueous sodium periodate.

20. The method of claim 10, further comprising the step of forming the matrix into a desired morphology. 21. The method of claim 10, further comprising the step of freeze-drying the oxidized matrix of cross-linked alginate fibers and cellulose fibers.

24. The method of claim 10, further comprising the step of sterilizing the oxidized matrix of cross-linked alginate fibers and cellulose fibers by an irradiation method.

23. The method of claim 10, wherein the oxidized matrix of cross-linked alginate fibers and cellulose fibers form a bioabsorbable surgical sponge.

24. A bioabsorbable surgical biomaterial manufactured by the method of claim 10.

3