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Publication numberUS3093440 A
Publication typeGrant
Publication dateJun 11, 1963
Filing dateJul 5, 1961
Priority dateJul 5, 1961
Publication numberUS 3093440 A, US 3093440A, US-A-3093440, US3093440 A, US3093440A
InventorsJames W Bothwell
Original AssigneeJohnson & Johnson
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Process for preparing collagenous material tanned with polyacrolein
US 3093440 A
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Description  (OCR text may contain errors)

United States Patent Ofiice 3,093,440 Patented June 11, 1963 This invention relates to the tanning of collagenous material of mammalian origin in sheet or tubular form suitable for implanting permanently or temporarily in a mammal, and more particularly relates to the tanning of collagenous material by the use of polyacrolein. A particularly suitable collagenous material for use in the practice of this invention is described in US. Patent No. 2,900,644, August 25, 1959, wherein it is disclosed that such material may be obtained from mammalian tubular blood vessels and especially from a bovine tubular blood vessel from which the objectionable parenchymatous protein is removed by digestion with a proteolytic enzyme such as ficin.

In order for collagenous material and particularly tubular collagenous material of mammalian origin to be suitable for implanting permanently or temporarily in a mammal, it must be tanned so that it has increased resistance to breakdown by normal body processes and have a high resistance to rupture because of the normal flexes and strains to which it is subjected during the time of its implantation. Short abdominal grafts of tubular collagenous material prepared from bovine tubular blood vessels which have been tanned with tanning agents such as aqueous formaldehyde, glyoxal, and chromic oxide have been shown to have a high order of success and resistance to rupture when implanted in dogs. However, when short segments of such tanned tubular collagenous material of bovine arterial origin are used as thoracic and long segments are used as thoraco abdominal grafts in dogs, the incidence of rupture within one or two weeks following implantation has been found to be increased significantly. This demonstrates that tanning of grafts with formaldehyde does not produce a bonding with sufficient durability to resist the natural breakdown processes of the body so that it is considered necessary to develop a tanning agent and tanning procedure for tubular collagenous material of bovine arterial origin able to insure a high degree of resistance to rupture when used as thoracic and thoraco abdominal grafts in dogs and particularly when used as long grafts.

The discoveries associated with the invention and relating to the solution of the above problems and the objectives achieved in accordance with the invention as set forth herein include: The provision of collagenous material of mammalian origin in sheet or tube form tanned with polyacrolein so that it has increased resistance to breakdown by normal body processes; the provision of tubular collagenous material of mammalian origin in Y or T form tanned by treatment with polyacrolein so that it has increased resistance to breakdown by normal body processes; the provision of a process for preparing tubular collagenous material of mammalian origin from which the objectionable parenchymatous protein is substantially removed by digestion With a proteolytic enzyme to increase the collagenous solid content to at least 80% and tanning to increase resistance to rupture when used as an abdominal, thoracic or thoraco abdominal graft in dogs by treatment with polyacrolein; the provision of a tubular collagenous material of mammalian origin substantially in its naturally-produced forrn containing at least 80% collagenous solids and not over 20% objectionable protein and tanned to provide increased resistance to rupture when used as an abdominal, thoracic or thoraco abdominal graft in dogs by treatment with polyacrolein; the provision of such a process and followed by storing the washed product in a storage fluid such as 50% aqueous U.S.P. alcohol or isopropyl alcohol which may contain a sterilizing agent such as 1% propylene oxide; and other objectives which will be apparent as details or embodiments of the invention are set forth hereinafter.

In order to facilitate a clear understanding of the invention the following specific embodiments are detailed.

Example 1 Twenty inch long segments of fresh beef carotid artery were removed between the origin at the innorninate and the cephalic bifurcation in the head immediately following carcass splitting operation, washed in cold water, freed of adherent connective tissue, digested for two hours and fifteen minutes at 37 C. in a solution of one percent (weight/volume) commercial ficin buttered at pH 5.1 with an 0.1 M citric acid-sodium citrate buffer, washed for two hours in five changes of distilled water, treated for 2.4 hours with 0.1% aqueous sodium chlorite solution to inactivate any ficin which may have been adsorbed to the collagen fibers of the digested artery, and immersed for eighteen hours at room temperature in a 0.5% (weight/volume), aqueous, polyacrolein tanning solution prepared by slowly bubbling gaseous sulfur dioxide with stirring into a suspension of two and one-half grams of polyacrolein, having an average molecular weight of 220,000, in ten cc. of water. The gaseous sulfur dioxide was bubbled into the supsension until all of the polyacrolein was in solution and the solution had no gelling tendencies on standing. The pH of the resulting aqueous solution of polyacrolein was adjusted to 6.0 with concentrated sodium hydroxide and the resulting solution was diluted with water to provide a 0.5% (weight/volume) tanning solution. The arteries after immersion in the tanning solution for eighteen hours were removed from the tanning solution and washed with distilled water for two hours to remove excess tanning agent. The shrinkage temperature of tanned bovine artery segments prepared as above came within the range of 83-88 C. The shrinkage temperature of bovine artery segments prepared and tanned according to the above procedure is used as a measure of the degree of tanning obtained and also to determine the stability against reversal of tanning by sterilization procedures.

Shrinkage temperature (Ts), the temperature at which twenty percent of the potential shrinkage has occurred, is recommended in the tanning industry to indicate the degree of tanning (Gustavson, K. H., The Chemistry and Reactivity of Collagen, Academic Press, N.Y., 1956, p. 277) wherein it is stated that tanning of collagen increases its shrinkage temperature and the shrinkage temperature is therefore important in controlling tanning processes. The shrinkage temperature of tanned bovine artery segments was determined by the method and device described by McLaughlin and Theis (McLaughlin, G. D., and Theis, E. R., Chemistry and Leather Manufacture, Am. Chem. Soc. Monograph No. 101, New York Reinhold Publishing Co., 1945, p. 135).

Bovine artery segments prepared and tanned according to the above method were sterilized by immersion for 14 days at F. in 50% aqueous ethanol containing 1% propylene oxide and then had a shrinkage temperature within the range of 8388 C., which corresponds to the shrinkage temperature before immersion in the sterilizing solution. The absence of change in shrinkage temperature range established that tanning with polyacrolein results in the production of a tanned bovine artery segment which is stable in the sterilizing solution.

A twenty-two pound mongrel dog was anesthetized with pentobarbital sodium to achieve general anesthesia and a respirometer was attached to facilitate breathing. Two incisions were made to permit insertion of a thoraco abdominal graft. One was prepared in the left lateral aspect of the abdomen and the other was a left thoracotorny at the level of the seventh intercostal space. The left lung Was collapsed and respiration was maintained in the right lung by intermittent positive pressure.

A graft prepared as described above and tanned for eighteen hours at room temperature at pH 6.0 in 'a 0.5% (\t eight/volume) aqueous polyac'rolei'n solution and sterilized as described had a shrinkage temperature of 83 C. before sterilization and a shrinkage temperature of 87 C. after sterilization. The sterile graft which had a length of 24.0 centimeters and a diameter of 11.5 millimeters at both the proximal and distal ends, was implanted in the anesthetized dog according to the following procedure: An end to side anastomosis was first completed with the graft and abdominal aorta at a point just above the inferior mesenteric artery. On completion of the anastomosis the graft was threaded through an artificial hiatus produced in the diaphragm. The thoracic aorta was transected and the graft was anastomosed with the proximal cut end of the aorta. The distal end was closed with a double layer and remained as a blind pouch. The incisions were closed and the dog allowed to recover.

An aortogram was taken after three weeks, the dog was sacrificed and the graft removed for gross and microscopic findings. The aortogram showed no change in diameter or shape of the graft. On gross inspection the adventitial coat appeared to show greater invasion of host tissue in the abdominal section than in the thoracic section. On microscopic inspection a minimal tissue reaction with evidence of fibroblast invasion of the adventitia but not the media, was observed.

Example 2 A thirty pound mongrel dog was grafted with a thoraco abdominal graft as in Example 1. The graft, which had been prepared, tanned, and sterilized in the same manner as the graft used in Example 1, was 20.7 centimeters long and had a diameter of 14.0 millimeters at the proximal end and 13.0 millimeters at the distal end and had a shrinkage temperature before sterilization of 85 C. and a shrinkage temperature after sterilization of 84 C.

An aortogram was taken at five weeks, the dog sacrificed, and the graft removed for gross and rniscroscopic findings. The aortogram showed no dilatation. On gross examination the graft looked good with apparent adventitial invasion especially in the abdominal area. On microscopic examination the graft appeared well infiltrated in all zones except for the media. There were occasional lymphocytic foci on the periphery of the tissue surrounding the graft.

Example 3 A twenty-nine pound mongrel dog was grafted with a thoraco abdominal graft as in Example 1. The graft, which had been prepared, tanned and sterilized in the same manner as the graft used in Example 1, was 21.0 centimeters long and had a diameter of 13.5 millimeters at the proximal end and 13.0 millimeters at the distal end and had a shrinkage temperature before sterilization of 85 C. and a shrinkage temperature after sterilization of 84 C.

An aortogram was taken in nine weeks, the dog sacrificed, and the graft removed for gross and microscopic findings. The aortogram showed some irregularity of the intima in the thoracic end. On gross inspection it was apparent that an aneurysmal dilatation had occurred at the flexed lower end of the graft. In addition there was a thick cheesy thrombus in the lower end and a relatively thick one in the upper region. On dissection the graft did not appear as good as the others although the adventitia was well infiltrated. There was some petechial hemorrhages at the lower end. Microscopic examination showed poor invasion in some parts although adequate in others and a slightly undesirable tissue response characterized by the presence of lymphocytes and plasma cells. Portions of the mural thrombus were becoming organized and were very thick in some areas. In some zones the fibroblastic invasion was very heavy but only minimal amounts of collagen had been deposited.

Example 4 A twenty-five pound mongrel dog was subjected to hypothermia to reduce body temperature to 31 C. The animal was anesthetized with pentobarbital sodium to achieve general anesthesia and a respirometcr was attached to facilitate breathing. The thoracic aorta was approached by a left thoracotorny at the level of the seventh intercostal space. The left lung was collapsed and respiration maintained in the right lung only by intermittent positive pressure. The intercostals likely to interfere with the procedure were tied and transected. A piece of umbilical tape passed under the aorta and used as traction greatly facilitated identification and tying of the tributaries. Having mobilized a desired length of aorta, non-crushing vascular clamps (Potts coaraction forceps) were placed at the most proximal and distal free points and the section of artery between the clamps was resected. Care was taken to leave sufficient cult to permit suturing. The two vascular clamps were placed in a dorsoventral manner. Their position tended to orient the graft at the time of anastomosis.

The proper length of graft (6.2 centimeters) required to fill the defect was determined by accurate measurement and the prosthesis was cut accordingly. The graft used was 6.2 centimeters long and had a diameter of 9.0 millimeters. The graft had been prepared, tanned and sterilized in the same manner as the graft used in Example l and had a shrinkage temperature before sterilization of 84 C. and a shrinkage temperature after sterilization of 87 C. Using 50 arterial silk swedgcd to a half circle needle, two guy sutures were placed through the lateral edges of the proximal cut end of the aorta and the graft. Mosquito forceps attached to one end of the suture were allowed to hang outside the incision thereby creating traction. This helped to bring the line of anastomosis into view and simplified the suturing procedure. The distal free end of the graft was flipped dorsad to expose the underside of the anastomatic line. The lower half was closed with a continuous over and over stitch using one of the long needle ends of a previously placed guy suture. The graft was returned to the horizontal position and the upper half of the proximal anastomatic line was closed in a similar fashion. The graft was returned to the horizontal position and the upper half of the proximal anastomatic line was closed in a similar fashion. The distal anastomosis was started by placing two guy sutures in such a manner as to bisect the lumen laterally. Sutures so placed permitted rotation of the graft in a horizontal plane and allowed easy placement of sutures throughout the entire circumference. The anastomosis was accomplished in the same manner as the proximal end using a continuous over and over suture. On completion of the anastomosis, the distal clamp was released and the graft permitted to fill by retrograde flow. The proximal clamp was then released to reestablish circulation. Hemorrhage occurred at both suture lines but was arrested by wrapping the suture line with a gauze sponge and gently applying pressure. The incision was closed and the dog allowed to recover.

After five weeks the dog was subjected to aortography to evaluate in situ appearance of the graft and then sacrificed. The graft was removed for gross and microscopic findings. The aortogram showed no dilatation. On gross examination the graft appearance had not significantly changed. The suture line was covered with pseudo intima. On microscopic examination it was determined that the adventiti'al coat was completely invaded with new fibrous tissue. A thick layer of collagen completely surrounded the graft. Some of the original adventitial collagen bands were visible. The intima was intact and smooth. A few fibroblasts had invaded the media but had not started to produce collagen.

Example 5 An eighteen pound mongrel dog was subjected to hypothermia to reduce the body temperature to 3 1 C. The animal was anesthetized with pentobarbital sodium to achieve general anesthesia and a respirometer was attached to facilitate breathing. The graft inserted was 5.3 centimeters long and had a diameter of 12.0 millimeters. A thoracic implant operation was performed as in Example 4. The graft used in the operation had been prepared, tanned and sterilized in the same manner as the graft used in Example 1 and had a shrinkage temperature before sterilization of 83 C. and a shrinkage temperature after sterilization of 87 C.

After nine weeks the dog was subjected to aortography to evaluate in situ appearance, the dog was sacrificed and the graft was removed for gross and microscopic findings. The aortogram showed no dilatation. On gross examination the graft did not appear to have been significantly changed except there was noticeable adventitial invasion. On microscopic examination it was observed that the surrounding collagen was about the same thickness as at five weeks but was much more mature and it was difiicult to identify the original adventitial collagen. There were some plaques of acute inflammation not unlike a phlegmon. There were also some giant cells in this section and large macrophages with vesicular nuclei. These reactive areas were focal in distribution.

Example 6 Bovine arteries were prepared in the same manner as in Example 1 except they are tanned by immersion for eighteen hours in an aqueous 1.0% formalin solution buffered with 0.1 Molar sodium-potassium phosphate at pH 7.2. The tanned grafts had shrinkage temperatures within the range of 86 C. to 91 C. before immersion in the sterilizing solution and shrinkage temperatures within the range of 70 C. to 76 C. after immersion in the sterilizing solution. The substantial lowering of the shrinkage temperature following tanning by formalin showed that the tanned product was substantially less stable than the product tanned by polyacrolein. The tanned grafts were sterilized in the same manner as in Example 1.

A twenty-eight pound mongrel dog was anesthetized with pentobarbital sodium to achieve general anesthesia and maintenance of respiration was achieved by means of a Burns type valve. The dog was grafted with a thoraco abdominal graft prepared as above using the implantation technique described in Example 1. The graft used was 24.5 centimeters long and had a proximal diameter of 11.0 millimeters and a distal diameter of 10.0 millimeters and had a shrinkage temperature before sterilization of 87 C. and a shrinkage temperature after sterilization of 73 C.

The dog died eleven days postoperatively due to an ill-defined rupture in the thoracic cavity.

Example 7 A thirty-one pound mongrel dog was grafted with a thoraco abdominal graft using the implantation technique described in Example 1. The graft had been prepared, tanned and sterilized in the same manner as the graft used in Example 6. The graft was 22.0 centimeters long and had a diameter of 11.0 millimeters at the proximal end and 10.0 millimeters at the distal end and had a shrinkage temperature before sterilization of 86 C. and a shrinkage temperature after sterilization of 73 C.

The dog died seventeen days postoperatively due to a rupture in the abdominal cavity.

Example 8 A thirty pound mongrel dog was grafted with a thoraco abdominal graft using the implantation technique described in Example 1. The graft had been prepared, tanned and sterilized in the same manner as the graft used in Example 6. The graft was 23.0 centimeters long and had a proximal diameter of 10.5 millimeters and a distal diameter of 10.5 millimeters and had a shrinkage temperature before sterilization of 91 C. and a shrinkage temperature after sterilization of 75 C.

After nine weeks the dog was subjected to aortography to evaluate in situ appearance of the graft, and then sacrificed for closer evaluation of its gross and miscroscopic appearance. The aortogram indicated no dilatation. Gross appearance indicated that the artery was in good condition and would be considered satisfactory at this stage. There was some thinning at the proximal end possibly due to too severe dissection at the time of autopsy. Pseudo intima extended from both suture lines for 2 to 2.5 centimeters. There was one focal zone in the proximal end with relatively thick thrombus associated with inflammation. Microscopic examination indicated good invasion of the graft. Close to the suture line the fibroblasts were oriented in a longitudinal manner but they were randomly oriented further down. There was a lymphocytic, plasmacytic, and fribroblastic response in the region of the suture. In other areas there was a modest polymorphonuclear reaction within the pre-existing adventitial layer with somewhat less invasion of the graft. There was moderate mural thrombus in other areas. There was extensive capillary proliferation on the periphery. In general the overall reaction to the graft was good.

Comparable or analogous results to the foregoing may be accomplished with various modifications thereof including the following.

A tubular mammalian vessel is used as the starting material, and particularly preferred is a bovine tubular vessel, including those having a Y or T branch form.

Tubular mammalian vessels prepared and tanned according to the method of this invention are particularly suitable for implantation as replacements for defective vascular, esophagus, bile duct, and ureter segments, but may also be used in sheet form for hernia repair.

The enzyme solution may be commercial ficin material or a purified or concentrated material containing the proteolytic enzyme and may be used in a concentration in the range of about 0.25 to 5.0% of active ficin, desirably 0.5 to 2.0%, and preferably 0.5 to 1.5%, the higher concentration resulting in faster digestion. The digestion temperature may be at the range of 30 to 45 C., desirably 34 to 40 C., and preferably 36 to 38 C.; the higher temperature giving faster digestion. The parts by weight of artery (wet) relative to enzyme solution may be in the range of 1 to 3 per 10 parts of solution, desirably 1 to 2, and preferably 1.5. The treating solution should be buffered and the pH may be in the range of 4.0 to 7.0, desirably 4.5 to 6.0, and preferably 5.0 to 5.5, the latter giving the faster digestion. The digestion times may be in the range of 2.0 to 8.0 hours, desirably 2.5 to 6.0, and preferably 2.5 to 3.0 hours. The concentration, amount, pH, temperature and time are selected to give the desired increase in collagenous solids content.

In collagenous material prepared by enzyme treatment of a mammalian tubular vessel in the above manner, objectionable parenchymatous protein is removed by enzyme digestion and the collagen fibrils are present substantially in their naturally produced relationship and contain at least collagenous solids and not over about 20% of other or objectionable protein based on the weight of solids therein.

The polyacrolein used in the tanning process of this invention may have an average molecular weight within the range of from about 20,000 to about 500,000, the preferred average molecular weight being within the range of from about 25,000 to about 250,000. If tubular mammalian vessel is tanned with polyacrolein having an average molecular weight below about 20,000 or above about 500,000, the tanned tubular mammalian vessel is not tanned s'ufiiciently and upon implantation rapidly dilates and ruptures. Polyacrolein may be solubilized by passing gaseous sulfur dioxide with stirring through an aqueous suspension thereof or by stirring a suspension of poly acrolein in an aqueous solution of sulfurous acid, such as a 7% aqueous sulfurous acid solution, until solubilization is complete. Solubilization is complete when the solution does not gel on standing. The concentration of the polyacrolein solution prepared as above is generally higher than the concentration used in tanning a tubular mammalian vessel and may be about 5% (weight/volume). For use in tanning, the solution is diluted to a (weight/volume) concentration of from about 0.2% to about 1.0%, and preferably from about 0.4% to about 0.8%. If the concentration of polyacrolein in the tanning solution is less than about 0.1%, tanning is undesirably slow and if the concentration is greater than about 1.0%, no advantage is obtained with respect to degree or speed of tanning. The diluted tanning solution is adjusted with a base such as sodium hydroxide to a pH of from about 5 to about 9, and preferably from about 8 to about 9. If the pH is lower than about 5, the walls of the tanned tubular mammalian vessel do not have sufficient rigidity so that rupture occurs on implantation. If the pH is higher than about 9, the walls are so stiff and rigid there is a tendency to form permanent Wrinkles at flexion points which act as foci for thrombus formation and eventual occlusion. The diluted tanning solution may be buttered at the desired pH with any suitable buffer such as a sodium-potassium phosphate buffer. The use of a butfered solution is preferred in order that there not be a drop in the pH of the tanning solution during tanning. Tanning is preferably accomplished at room temperature. In order that tanning be stopped, the mammalian vessel is removed from the tanning solution and washed with distilled water until the excess tanning agent is removed. This requires about two hours.

About eighteen hours is required for satisfactory tanning of a tubular mammalian vessel by the use of a 0.5% (weight/volume) aqueous polyacrolein solution, and this is the preferred concentration. The speed of tanning is increased with an increase in the concentration of polyacrolein in the tanning solution.

Satisfactory tanning is considered to have been accomplished if the shrinkage temperature of the tanned tubular mammalian vessel is within the range of from about 83 C. to about 88 C., the preferred shrinkage temperature being from about 86 C. to about 88 C., and for this purpose the shrinkage temperature is considered to be the temperature at which 20% f the potential shrinkage has occurred.

In view of the foregoing disclosures, variations or modifications thereof will be apparent, and it is intended to include within the invention all such variations and modifications except as do not come Within the scope of the appended claims.

What is claimed is:

1. Collagenous material of mammalian origin tanned with polyacrolein and useful for implanting in a mamma i 2. Collagenous material of mammalian origin useful for implanting in a mammal, having its collagen fibrils present substantially in their naturally produced relationship and containing at least collagenous solids and not over about 20% of other protein based on the weight of solids therein and tanned with polyacrolein having an average molecular weight within the range of from about 20,000 to about 500,000 so that it has increased resistance to breakdown by normal body processes.

3. Collagenous material of mammalian origin useful for implanting in a mammal, having its collagen fibrils present substantially in their naturally produced relationship and containing at least 80% collagenous solids and not over about 20% of other protein based on the weight of solids therein and tanned with polyacrolein having an average molecular weight within the range of from about 25,000 to about 250,000, and having a shrinkage temperature of from about 83 C. to about 88 C.

4. A material of claim 3 in which the shrinkage temperature is from about 86 C. to about 88 C.

5. A material of claim 3 in sheet form.

6. A material of claim 3 in tube form.

7. A process for preparing tanned collagenous material of mammalian origin useful for implanting in a mammal which comprises immersing collagenous material of mammalian origin which contains at least 80% by weight collagenous solids in an aqueous solution of polyacrolein having a concentration from about 0.5 to about 10% (weight/volume) and a pH within the range of about 5.0 to about 12 for sufficient time to bring the shrinkage temperature of the tanned collagen to from about 83 C. to about 88 C.; removing the tanned collagen from the tanning solution and washing the tanned collagen with distilled water until excess tanning agent is removed therefrom.

8. A process of claim 7 followed by sterilization.

9. A process of claim 8 wherein the sterilization is by means of propylene oxide.

References Cited in the file of this patent UNITED STATES PATENTS 2,215,453 Buchgraber Sept. 24, 1940 2,583,574 Jones et al. Jan. 29, 1952 2,640,752 Davis et al. June 2, 1953 2,750,251 Bloch et al. June 12, 1956 2,886,401 Wells et al. May 12, 1959 2,925,315 Pasternak Feb. 16, 1960 2,977,182 Adams et al. Mar. 28, 1961 OTHER REFERENCES ].S.L.T.C., vol. 24, November 1940, pp. 379-389.

Patent Citations
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US2215453 *Oct 7, 1938Sep 24, 1940Jeno RakonitzMethod for the manufacture of sterilized catgut
US2583574 *Aug 30, 1949Jan 29, 1952Jones Harrison WAcrolein and sulfur halide process to strengthen protein fibers
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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4083066 *Nov 7, 1975Apr 11, 1978Solco Basel AgHeterologous arterial transplants
US4349026 *Feb 28, 1980Sep 14, 1982Collagen Development Corp.Regenerated fiber collagen condom and method of preparation
US4406853 *Sep 15, 1981Sep 27, 1983Collagen Development CorporationMethod of preparation of regenerated fiber collagen condom
Classifications
U.S. Classification8/94.11, 8/94.19C, 8/127.6, 606/229, 128/DIG.800, 8/94.33, 604/8
International ClassificationA61L17/08, A61L27/24, A61F2/00, C07K14/78
Cooperative ClassificationA61L27/24, A61L17/08, Y10S128/08, A61F2310/00365, C07K14/78
European ClassificationA61L27/24, A61L17/08, C07K14/78