CA2407706C - Method and apparatus for calendering and coating/filling sutures - Google Patents

Abstract

The present invention provides a method for filling a suture comprising passing the suture lengthwise through a filling head. The filling head has a contacting region in which the suture is contacted by a filling agent substantially continuously supplied to the filling head as the suture passes therethrough.

Description

METHOD AND APPARATUS FOR CALENDERING AND
COATING/FILLING SUTURES
BACKGROUND OF THE INVENTION
This application is a divisional application of co-pending Canadian Application Serial No. 2,059,245 filed January 13, 1992.
1. Field of the Invention This invention pertains to a method and apparatus for mechanically treating .sutures, and especially to a method and apparatus for calendering multifilament surgical sutures.

2. Background of the Art An important consideration in performing surgery is the "hand" or "feel" of the suture being used to close wounds, which is reflected at least in part by the knot t:ie-down and run-down characteristics of the suture. "Tie-down characteristics" refers to the facility with which a surgeon can tie a knot, and the ability of the suture to remain knotted without spontaneously unravelling. "Run-down characteristics" refers to the ability of a surgeon to make one or more "throws" of a knot in the suture and have it run down a suture to the knot site. Generally, hand or feel of a suture and tie-down characteristics relate to the lubricity and stiffness of the suture: lubricity facilitates the tying of a knot whereas stiffness makes tying a tight:
knot more difficult and increases the probability of kind;ing of the suture and/or unravelling of the knot.
Both multifilament sutures and monofilament sutures are known in the art. Multifilament sutures, such as braided or twisted sutures, have better softness and flexibility than monofilament sutures and can be more eaaily knotted. However, multifilament sutures can have a roughen surface or "grabbiness" than monofilament sutures and a significant percentage of dead space or interstices between the filaments. The dead space can be reduced by impregnating the multifilament suture with a filler material. Filler material can help lubricate the suture fibers and enhance flexibility.
Coatings improve the knot run down characteristir_s of a suture, although they also tend to increase stiffness.
Another source of stiffness arises from the commonly employed process of "heat setting" or "hot stretching" the suture, such as described in U.S. Patent Nos. 3,322,125, 3,257,702, 3,379,552, and 3,838,524, for example. It has been proposed to improve the flexibility of heat set sutures by flexing the suture as disclosed in U.S. Patent Nos.
3,839,524 and 3,257,702.
Known materials for filling or coating sutures a.re described in U.S. Patent Nos. 3,322,125, 3,379,552, 3, 867, 190, 3, 942, 532, 4, 047, 533, 4, 532, 929, 4, 201, 216, anti 4,711,241, for example.
However, the uniformity of the filling or coating remains as an important concern in the fabrication of sutures. Non-uniformity can hamper the effectiveness of ~~he filler and coating, and an apparatus and method which addresses this issue is needed.
SUMMARY OF THE INVENTION
One feature of the present invention is the suture filling method and apparatus. The suture is filled by passing the calendered suture lengthwise through a region in which the suture is contacted by a filling agent which is substantially continuously applied to the filling head as.
the suture passes therethrough. The filling agent is supplied by a metering pump. The filling process is optimized for any given multifilament braided suture by a computer program based upon the denier of the suture, pump capacity, suture velocity, desired or target fill level and calculating and setting a pump speed based on the foregoing parameters.
There is also disclosed a method and apparatus for treating a multifilament surgical suture. A compressive force is applied to the suture in a first linear direction generally transverse to the longitudinal orientation of the suture. The compressive force is of sufficient predetermined magnitude so as to expand the diameter of the suture in a direction orthogonal to the direction in which the compressive force is applied. Preferably a second application of compressive force is administered to the suture in a direction generally transverse to that of the first compressive force as well as transverse to the longitudinal direction of the suture. The second compressive force is substantially equal in magnitude to the first compressive force so that the suture returns to its original round configuration.
The apparatus for implementing this method includes at least one pair of rollers which are biased towards each other to apply a compressive force to a suture which is passed between them. A second pair of rollers is oriented at angle (preferably 90°) to the first set of rollers and transverse to the longitudinal extension of the suture. The second pair of rollers is positioned such that a suture, passing between both the first pair or rollers and the second pair of rollers, will be alternately compressed:
in a first direction, then in a second direction at an angle to the first direction. The application of compressive force expands the diameter of the suture in a direction orthogonally to the application of force. Thus, with two pairs of rollers, the suture will be expanded in two directions, thereby opening up the filaments to make the suture more receptive to the application of fillers, coatincf materials, and the like.
In a particularly preferred embodiment, braided synthetic absorbable sutures coated with a lubricant coating to enhance knot run down are calendered in accordance with the invention and thereafter are filled with a storage stabilizing agent. Calendering the braided synthetic absorbable suture prior to filling is believed to open up the braid structure to permit the storage stabilizing agent:
to penetrate substantially all interstices of the suture.
In alternative embodiments, braided absorbable or non-absorbable sutures are calendered in order to facilitate coating of the suture with one or more lubricant coatings and/or fillers, such as the aforementioned storage stabilizing agent, containing one or more therapeutic agents or growth factors.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a diagrammatic illustration of a calendering apparatus:
Fig. 2 is a perspective view of the calendering apparatus Fig. 3 is an exploded perspective view of the upper calendering portion;

Fig. 4 is a partially cutaway sectional vie:: of the spring mounting of the calender apparatus;
Fig. 5 is an elevatienal view of the suture filling apparatus of the present ~nven~ion;
Fig. 6 is a partially cutaway perspective view of the filling head;
Fig. 7 is a flowchart of a computer program for controlling the filling method of the present invention.
DETAILED DESCRIPTION OF PREFERRED EM$ODIMENTS
The present invention is primarily directed to the treatment of braided surgical sutures to facilitate and promote substantially uniform and complete coating andior filling of the suture. In tre preferred e;«bodiment braided synthetic absorbable sutures are calendered prior to filling with a storage stabilizing agent, preferably a mixture containing glycerol, in order to promote substantially complete penetration of the filler throughout the braid structure.
However, the calendering method and apparatv,s may also find application to coating and/or filling of absorbable or non-absorbable sutures. To facilitate understanding the invention, possible suture material: and braid constructions, coatings and fillers, possibly 25~ containing one or more therapeutic agents or growth factors, will be discussed prior to describing in detail the preferred calendering apparatus and method and the preferred method for calendering braided synthetic absorbable sutures prior to filling with a stabilizing agent.

1 Suture Material and Construction As stated, the calendering method and apparatus finds particular application to the treatme:a of braided multifilament surgical sutures. The term "braid" means a substantially symmetrical strand formed by crossing a number (at least three) of individual strands composed of one or more filaments diagonally in such manner that each strand passes alternatively over and under one or more of the others. The braid may include a core section composed of one or more filaments around which the braid is externall~r fabricated, although such core may be excluded, if desired.
The braid may be of traditional construction (so-called "hollow" or "tubular" braid). or may be of spiroid construction, with or without a core. Preferred braid constructions of the traditional type are disclosed and claimed in United States Patents No. 5,019,093 issued May 28, 1991.
The braided suture can be fabricated from a wide variety of natural and syn~retic fibrous materials such as any of those heretofore disclosed for the construction oi=
sutures. Such materials include non-absorbable as well as partially and fully bio-absorbable (i.e., resorbable) natural and synthetic fiber-forming polymers. Non-., 25~ absorbable materials which are suitable for fabricating the braided suture of this invention include silk, polyamides, polyesters, polypropylene, silk, cotton, linen, etc. Carbon fibers, steel fibers and other biologically acceptable inorganic fibrous materials can also be employed. Bio-absorbable resins from which the suture can be fabricated include those derived from glycolic acid, glycolide, lactic i acid, lactide, dioxanone, epsilon-caprolactone, trimethylene carbonate, etc., and various combinations of these and related monomers. Sutures prepared frcm resins of this tl~=
are known in the art, e.~g., as disclosed in U.S. Patent L~cs.
2,568,162; 2,703,316; 2,748,987, 3,225,766; 3,297,033;
3,422,181; 3,531,561; 3,565,077; 3,565,869; 3,620,218;
3,262,948; 3,636,956; 3,736,646; 3,772,420; 3,773,919;
3,792,010; 3,797,499; 3,839,297; 3,867,190; 3,787,284;
3,982,543; 4,047,533; 4,060,089; 4,137,y2i; 4,157,437;
4,234,775; 4,237,920; 4,300,565; and 4,523,591; U.K. Pa~ent No. 779,291; D.K. Gilding et al., "Biodegradable polymers for use in surgery - -polyglycolic/poly(lactic acid) homo-and copolymers: 1, Polymer, Volume 20, pages 1459-1464 (1979), and D.F. Williams (ed), Biocompatibility of Clinical I~rnlant Materials, Vol. II, Ch. 9: "Biodegradable Polymers"
(1981).
Filling Agent When a multifilament suture is fabricated from a ~aterial ~~hich is susceptible to hydrolysis, e.g:, any of the absorbable resins previously t;,entioned, prior patents teach that extreme care must be taken to rigorously exclude moisture from contacting the suture during storage or t:o otherwise preserve the suture from excessive hydrolytic.
attack which would compromise its in vitro strength to the point where the suture would no longer be serviceable.
Thus, according to U.S. Patent Nos. 3,728,839 and 4,135,622, the in vivo strength of polyglycolic acid surgical elements such as sutures undergoes significant deterioration on long term standing in the package even on exposure of the contents to very small amounts of water for very short periods of time, e.g., 20 minutes or Less, just _8_ prior to packaging due to the tendency of a moisture impervious package to seal the moisture in with the suture.
To prevent or minimize the extent of hydrolytic degradaticr.
of an absorbable suture during storage, U.S. Patent r~os~.
3,728,839 and 4,135,622 disclose removing substantiall~~ all moisture front the suture before sealing the package. 'This approach to improving the suture's storage stability, while effective, is in practice difficult and expensive to carry out. Prior to sealing the suture within its moisture impervious package, it is essential that the suture be "bone dry", a condition achieved by heating the suture for a sufficient period to remove essentially all water therefrom, e.g., 180-188° for 1 hour under a 26 inch vacuum. However, once the water is removed, the suture cannot be allacYed to 75 contact a moisture-containing environment even for a limited duration since as previously noted, the patents teach that even brief exposure to moisture can cause severe deterioration of suture in vivo strength. It therefore beco:~:~s necessar 4T f all ow ing the wa ter r emoval s top '~o temporarily store the suture in a dry area, i.e., an environment which is essentially free of moisture, where the possibility of contact with moisture is largely eliminated.
These operations for improving the storage stability of an absorbable suture are time consuming, expensive and .
constitute a relatively complex solution to the storage stability problem.
In an entirely different approach to improving the storage stability of an absorbable suture, one that avoids the foregoing drawbacks associated with the method of U.S.
patent Nos. 3,728,839 and 4,135,622, the storage stability _g_ 1 of an absorbable braided,suture which is susceptible to hydrolysis is improved by applying to the suture a storage stabilizing amount of a filler material containi.~.g at le~s~
one water soluble liquid polyhydroxy co~apound and/or ester thereof. In addition to imparting an enhanced degree of storage stability to the suture, practice of this embodiment of the present invention confers other benefits as well.
So, for example, a braided suture which has been filled with a storage stabilizing amount of, e.g., glycerol, exhibit) better flexibility and "hand" characteristics than the untreated suture. Moreover, since the polyhydroxy compounds are generally capable of dissolving a variety of medico-surgically useful substances, they can be used as vehicles to deliver such substances to a wound or surgical site at the tiMe the suture is introduced into the bodv.
The useful storage stabilizing agents are generally selected from the water soluble, liquid polyhydroxy compounds and/or esters of such compounds, r=efe=ably those having no appreciable toxicity for the body at the levels present. The expression "liquid polyhydroxy compound" contemplates those polyhydroxy compounds which in the essentially pure state are liquids, as opposed to solids, at or about ambient temperature, e.g., at from about 15°C to about 40°C. The preferred polyhydroxy compounds .
possess up~to about 12 carbon atoms and where the esters are concerned, are preferably the monoesters and diesters.
Among the specific storage stabilizing agents which can be used with generally good results are glycerol and its mono-and diesters derived from low molecular weight carboxylic acids, e.g., monoacetin and diacetin (respectively, glyceryl monoacetate and glyceryl diacetate), ethylene glycol, y -1 diethylene glycol, triethylene glycol, 1,3-propanediol, trimethylolethane, trimethylolproprane, pentaerythritol, sorbitol, and the like. Glycerol is especially preferr~:d.
Mixtures of storage stabilizing agEnts, e.g., sorbitol dissolved in glycerol, glycerol combined with monoacetin and/or diacetin, etc., are also useful.
To prevent or minimize run-off or separation of the storage stabilising agent from the suture, a tenden~~y to which relatively low viscosity c.o,-,;,;pounds such as gllcerol are especially prone, it can be advantageous to combine the agent with a thickener. Many kinds of pharmaceutically acceptable non-aqueous thickeners can be utilized including water-soluble polysaccharides, e.g., hydroxypropyl methylcellulose (HPi~:C) , and the other materials of t~-.is type which are disclosed in European Patent Application O 267 015, polysaccharide gums such as guar, xanthan, and the like, gelatin, collagen, etc. An especially preferred class of thickeners are the saturated aliphatic h f~droxycar boxylic ac i ds of up to about 6 carbon atoms and the alkali metal and alkaline earth metal salts and hydrates thereof. Within this preferred class of compounds are those corresponding to the general formula OH
I
R ---C -(CHz) p COOR' H
wherein R is hydrogen or methyl, R' is a metal selected from the group consisting of alkali metal and alkaline earth metal and n is 0 or 1, and hydrates thereof. Specific examples of such compounds include salts of lactic acid such as calcium lactate and potassium lactate, sodium lactate, salts of glycolic acid such as calcium glycolate, potassium glycolate and sodium glycolate, salts of 3-hydroxy prop~~.noic acid such as the calcium, potassium and sodium salts thereof, salts of 3-hydroxybutanoic acid such as calciL.m, potassium and sodium salts thereof, and the like. As stated hereinabove, hydrates of these compounds can also be used.
Calcium lactate, especially calcium lactate pentahydrate, is a particularly preferred thickener.
~r'I1EZ'2 a thlCkener is 1.2~iii?~~, it will be incorporated in the filling composition in at least that amount required to increase the Overall viscosity of the storage stabilizing agent to the point where the agent no longer readily drains away from the suture in a relatively short period. In the case of a preferred storage 1S stabilizing agent-thickener combination, namely, glycerol and calcium lactate, the weight.ratio of glycerol to calcium lactate can vary from about 1:1 to about 10:i and prezerably is from about 6:1 to 8:1.
If necessary or desirable, the storage stabilizing agent together with optional thickener can be dissolved in any suitable non-aqueous solvent or combination of solvents prior to use. To be suitable, the solvent must (1) be miscible with the storage stabilizing agent and optional thickener, if present (2) have a sufficiently high vapor ZS pressure to be readily removed by evaporation, (3;. not appreciably affect the integrity of the suture and (4) be capable of wetting the surface of the suture'. Applying these criteria to a preferred storage stabilizinc,~ agent, glycerol, advantageously in admixture with a prel:erred thickener, calcium lactate, lower alcohols such as methanol and ethanol are entirely suitable solvent carriers. When a solvent is utilized in the preparation of the stabilizing agent, e.g., methanol, such solvent can be employed in anounts providing a solution concentration of from about 20%
to about 50$, preferably about 3G% to about 45$, by weight of the storage stabilizing agent including any optional thickener.
Preparing the storage stabilizing agent for application to the suture is a relatively simple procedure.
For example, 111 1..110 L.ajC Of d .W,ixture of gly~:erol ~nd calcium lactate, the desired amount of glycerol is first introduced to a suitable vessel followed by the addition thereto of the desired amount of calcium lactate. If no solvent is to be uses, the mixture is then thoroughly mixed.
Where a solvent such as methanol is employed, the solvent is 75 added to the mixture of glycerol and calcium lactate and the solution is then thoroughly mixed to dissolve the compounds.
Application of the storage stabilizing agent to the suture can be carried out in any number of ways. Thus, for eXai:lple, the suture can be submerged in the storage stabilizing agent or solution thereof until at least a storage stabilizing amount of agent is acquired or otherwise retained by the suture, even after the optional removal of any excess agent and/or accompanying solvent (if present) such as by drainage, wiping, evaporation, etc. In many '25 cases, contact times on the order of from just a few seconds, e.g., about 10 seconds or so, to several hours, e.g., about 2 hours and even longer, are sufficient to impart a substantial improvement in the storage stability of the treated suture compared to the same suture which has not been treated with storage stabilizing agent.

1 The foregoing method of contacting the suture with the storage stabilizing agent can be conducted continuously or in batch. Thus, a running len,th of the suture can be continuously passes through a quantity of stabilizing agent at a velocity which has been previously determined to provide the necessary degree of exposure, or contact time, of the suture with the storage stabilizing agent. As the suture emerges from the storage stabilizing agent, it can be r a trio r ~~r1 -P eY CC~
passed through a wiper or similai ..e. a to ..~..~ c___ agent prior to the packaging operation. Preferably, the suture is passed through a coating head supplied by a metering pump with a constant supply of filling solution, with the suture emerging from the coating head and passing through an evaporation oven to re:.~,ove the filling solution solvent prior to any further surface contact, i.e., with rollers, etc. In a batch operation, a quantity of suture is merely submerged within the storage stabilizing agent for the requisite period of time with any excess agent being removed from the suture if desired.
Alternatively, the storage stabilizing agent and solutions thereof can be applied to the suture by spraying, brushing, wiping, etc. such that the suture receives and retains at least a storage stabilizing amount of the agent.
Yet another procedure which can be used to apply .the storage stabilizing agent involves inserting suture in a package containing an effective amount of the agent such that intimate contact between the suture and the agent is achieved.
Whatever the contacting procedure employed, it is necessary that the suture being treated acquire a storage stabilizing amount of the storage stabilizing agent. In general, amounts from about 2 to about 25, and preferably from about 5 to about 15, weight percent of storage stabilizing agents) (exclusive of any solvent) by weight of the suture contacted there::it:: is sufficient to provide significantly improved storage stability compared to that of the untreated suture.
As previously pointed out, a filled braided suture component in accordance with the invention need not be packaged and iualiitained undEr t :2 ~TEry d~y ~:.vuCitiCn~
required for prior synthetic absorbable sutures. Instead, it is preferred that the filled sutures be equilibrated so that the level of moisture or other stabilizing agent solvent is sufficient to result in an appropriate viscosity level for the stabilizing agent and thickener in order to 75 keep the stabilizing agent on the suture. In the preferred embodiment of a braided suture filled with a mixture of glycerol and calcium lactate, the moisture level may be equilibrated to as low as about 0.2% by weight of the suture, and is preferably above 0.3% or, even more preferably, above 0.5% by weight of the suture.
Indeed, it has been found that a braided suture filled with a glycerol/calcium lactate composition tends to undergo undesirable changes if exposed to a very dry environment. More particularly, if such a filled suture is exposed to a very dry environment, the surface of the suture may accumulate a flaked or powdered substance which could possibly interfere with, or render more difficult, the removal of the suture from its package. Exposure of sutures filled with a glycerol stabilizing agent to vacuum has been found to adversely decrease the level of glycerol filler, possibly by vaporizing the glycerol. Equilibrating the 1 filled suture, such as in a dew point controlled environment, so that the suture contains a relatively high .;,oisture level, e.g., in excess of 0.2~ and preferabl:.~ in excess o~ 0.5~ by weight of the suture, pre-:ents such accumulation of flaked or powdered substances which might.
otherwise result were the suture exposed to an extremely dry environment. Conversely, the presence of too much moisture can also have deleterious effects, such as causing the glycerol filling to run. Therefore, it is pref~rabl= .o control the moisture level within a range having preset upper and lower limits.
Therapeutic Agents andjor Growth Factors It is also within the scope of the invention to impregnate the braided suture of this invention with, or otherwise apply thereto, one or more medico-surgically useful substances, e.g., those which accelerate or beneficially modify the healing process when the suture is applied to a wound or surgical site. So, for example, the braided suture herein can be provided with a therapeutic agent which will be deposited at the sutured site. The therapeutic agent can be chosen for its antimicrobial properties, capability for promoting wound repair and/or tissue growth or for specific indications such as thrombosis. Antimicrobial agents such as broad spectrum antibiotics (gentamicin sulphate, erythromycin or derivatized glycopeptides) which are slowly released into the tissue can be applied in this manner to aid in combating clinical and sub-clinical infections in a surgical or trauma wound site.

To promote wound repair and/or tissue growth, one or more biologically active materials known to achieve either or both of these objectives car_ be applied to the braided suture. Such materials incluue any of se~~eral F,u:.~an Growth Factors (HGFs;, magainin, tissue or kidney plasminogen activator to cause thrombosis, superoxide dismutase to scavenge tissue damaging free radicals, turlor necrosis factor for cancer therapy, colony stimulating factor, interferon, interieukin-2 or other ly~~p:.okine to enhance the immune system, and so forth.
The term "Human Growth Factor" or "HGF" embra~~es those materials, known in the literature, which are ref~arred to as such and include their biologically active: loose ly related derivatives. The HGFs can be derived from naturally 1S occurring sources including human and non-human sources, e.g., bovine sources, and are preferably produced by recombinant DNA techniques. Specifically, any of the HGFs which are mitogenically active and as such are effective in stimulating, accelerating, pctentiating or otherwise enhancing the wound healing process can be usefully applied to the suture herein, e.g., hEGF (urogastrone), TGF-beta, IGF, PDGD, FGF, etc. These and other useful HGFs and closely related HGF derivatives, methods by which they can be obtained and methods and compositions featuring the use of HGFs to enhance wound healing are variously disclosEad, inter alia, in U.S. Patent Nos. 3,883,497, 3,91i',824, 3,948,875, 4,338,397, 4,418,691, 4,528,186, 4,621,052, 4,743,679, 4,717,717, 4,861,757, 4,874,746 and 4,944,948.
European Patent Application Nos. 46,039, 128,733, 131,.368, 136,490, 147,178, 150,572, 177,915 and 267,015, PCT
International Applications WO 83/04030, WO 85/003698, WO 85/01284 and WO 86/02271 and UK Patent Applications GB 2 092 155 A, 2 162 851 A and GB 2 172 890 A, and, "Growth Factors in Wound Healing", Lynch et al., J. Clin. Invest., Vol. 84, pages 640-645 (August 1989). Of the known HGFs, hEGF, TFG-beta, IGF, PDGF and FGF are preferred, either singly or combination.
In a preferred embodiment of a braided suture, a fiilir.g composition comcrisino a surgical wound healing enhancing amount of at least one HGF and as carrier therefor at least one water soluble, liquid polyhydroxy compound and/or ester thereof is applied to the suture. The carrier protects the HGF component of the filling composition from excessive degradation or loss of biopotency during storage and as disclosed above, when the suture is fabricated from an absorbable resin which is susceptible to hydrolysis, the carrier improves the storage stability of the suture as well. In addition to the carrier, the HGF can contain a thickener such as any of those previously mentioned in order to reduce the tendency of carrier run-off.
The filling composition can contain one or more additional components which promote or enhance the wound healing effectiveness of~the HGF component. Thus, e.g., site-specific hybrid proteins can be incorporated in the ' filling composition to maximize the availability of the HGF
at the wound site and/or to potentiate wound healing. See e.g., Tomlinson (Ciba-Geigy Pharmaceuticals, West Sussex, U.LK.), "Selective Delivery and Targeting of Therapeutic Proteins", a paper presented at a symposium held June 12-14, 1989 in Boston, MA. The HGFs can also be associated wi'~h carrier proteins (CPs), e.g., in the form of CP-bound HGF(s), to further enhance availability of the HGF(s) at a wound site as disclosed in "Carrier Protein-Based Delivery of Protein Pharmaceuticals", a paper e~ BioGrewth, Inc., Richmond, CA presented at the aforementioned symposium, The HGFs can also be incorporated in liposomes to provide for their release over an extended period.
Lactate ion can be present to augment the would healing activity of the HGF. Protectants for the HGF can also be utilized, e.g., polyoxyethylene glycols, acetoxyphenoxy polyethoxy, ethanols, polyoxyethylene sorbitans, dextrans, albumin, poly-D-alanyl peptides and N-(2-hydroxypropyl)-methacrylamide (HPMA).
The amounts of HGF, carrier and optional components) such as thickener, site-specific hybrid protein, carrier protein, etc., identified above can vary widely and in general will be at least that amount of a particular component which is required to perform its respective function in an effective way. Those skilled in the art employing known or conventional procedures can readily determine optimum amounts of each component for a particular filling composition and particular braided suture filled therewith.
In general, the HGF(s) can be present in the total composition at a level ranging from about 0.1 to about 25,000 micrograms per gram of such composition, preferably from about 0.5 to about 10000~micrograms per gram of composition and most preferably from about 1 to about 5000 micrograms per gram of composition.

1 Application of the HGF-containing composition to the braided suture of this invention can be carried out by any suitable technique, e.g., by any of the procedures described above ~cr apphling a storage stabilizing agent: to the suture.
Suture Coatinct It is also advantageous to apply one or more coating compositions to a braideu suture component wher:~
particular functional properties are desired. For example, the suture can be coated with a material which improves its surface lubricity and/or knot tie-down characteristics.
Coating materials for sutures are known and include non-bioabsorbable substances such as silicone, beeswax, or polytetrafluoroethylene, as well as absorbable substances such as homopolymers and/or copolymers of glycolide and lactide, polyalkylene glycols, and higher fatty acids or salts or esters thereof. Other suitable materials which impart either or both characteristics have been proposed in United States Patents 3,867,190; 3,942,532; 4,047,533;
4,452,973; 4,624,256; 4,649,920; 4,716,203; and 4,826,945.
Preferred bioabsorbable coating compositions can be obtained by copolymerizing in accordance with known procedures (1) a polyether glycol selected~form the group consisting of relatively low molecular weight polyalkylene glycol, e.g., one corresponding to the general formula HO(RO)yH wherein R
is an alkylene group of from 2-4 carbon atoms and y is an integer of from about 100-350, and polyethylene oxide-polypropylene oxide block copolymer, e.g., one corresponding to the eneral formula H OCH CH OC H OCH CH OH wherein x g ~ 2 2)x~ 3 6)y~ 2 2)z is an integer of from about 45-90, y is an integer of from about 60-85 and z is an integer of from about 45-90 with (2) a :aixture of lactide ronomer and glycolide rtono:«er or a preformed copol .~er of lactide and giycolide, the weight ratio of (1) to (2) preferably ranging from about 4:1 to about 1:4 and more preferably from about 2:1 to about 1:2.
The ratio of lactide to glycolide in the monomer mixture or in the copolymer of these monomers preferably varies from about 65-90 mole percent lactide and i0-35 ~«ole percent glycolide. Polyether glycols which can be used to prepare the bioabsorbable coating composition advantageously include polyethylene glycols having molecular weights of about 3,500-25,000 and preferably from about 4,000-10,000 and polyethylene oxide-polypropylene oxide block copol .,ers having molecular weights of from about 5,000-10,000 and preferably from about 7,500 to about 9,000, e.g., those disclosed in UPS. Patent Nos. 2,674,619, 3,036,118, 4,043,344 and 4,047,533 and commercially available as the *Pluronics (BASF-Wyandotte). Where preformed copolymers of lactide and glycolide are employed in preparing the bioabsorbable coating compositions, they may be prepared as described in U.S. Patent No. 4,523,591. The amounts of bioabsorbable coating composition to be applied to the suture, e.g., by coating, dipping, spraying or other appropriate techniques, will vary depending upon the specific construction of the suture, the size and the material of this construction. In general, the coating composition applied to an unfilled suture will constitute from about 1.0 to about 3.0 percent by weight of the coated suture, but the amount of coating add on may range from as little as about 0.5 percent, by weight, to as much as 4.0 *Trade-mark percent or higaer . For ~ pr a°er r e-? f il led ( i , a . coma i ning a storage stabilizing agent) braided suture, amounts of coating composition will generally vary from about 0.5o to 2.0% with as little as 0.2% to as much as 3.0%. As a practical matter and for reasons cf eco:,omy and general performance, it is generally preferred to apply the minimum amount of coating composition consistent with good surface lubricity and/or knot tie-down characteristics and this level of coating add on is readily determined experimentally for any particular suture., Suture Calenderina In accordance with the invention, it has been found to be desirable to calender the braided suture prior to coating and/or filling in order to facilitate penetration of the coating or filler into the interstices of the b='aid suture.
Referring to Fig. l, a braided suture 1 is moved axially in the direction indicated by arrow A. The suture is first passed between two cylindrical calendering ro:~lers 2 and 3, each of which has a smooth, polished surface. The rollers are rotatably mounted in a calendering apparatus (not shown) such that one of the rollers is fixed with respect to translational movement whereas the other of the two rollers is biased, for example by a spring means, towards the fixed roller. The biasing force may be set to any desired predetermined magnitude. Alter:lati~,relz, bit::
rollers may be biased towards each other.
The rollers 2 and 3 are parallel to each other, but transverse to the axial orientation of suture 1. They 1 aptly a ~echa.~.ical compression force to the suture in a direction as shown by arrows B.
When the suture 1 passes between rollers 2 and 3, it is compressed radially inward in direction B, but it.
expands laterally in the transverse direction, which opens up the braid structure. After passing between the fir:~t pair of rollers 2 and 3, suture 1, without turning or twisting, then preferably passes between a second pair of calendering rollers 4 and 5 which operate in the same manner as rollers 2 and 3, except that the second pair of rollers are oriented transversely to the first pair of rollers 2 and 3, as well as transversely to the suture 1. Thus, rollers 4 and 5 compress the suture laterally in a direction C which is transverse to direction B. The suture braids are then opened in a direction transverse to C and the suture is causEd to return to its original, substantially round configuration. Preferably, the upper and lower roller pairs are positioned so that the suture rests against the surface of the fixed roller and is contacted and compressed by the action of the spring-loaded roller pressing against the suture and fixed roller.
Having passed between both pairs of rollers, the braids are uniformly opened to a predetermined extent, which facilitates application of filler material and/or coating material.
Figs. 2 and 3 respectively illustrate a perspective view of the calendering apparatus and an exploded perspective view of the upper portion 11 of the apparatus 10 for calendering sutures. Fig. 4 is a partially cut away detailed view of the spring mounting of the apparatus of the present invention.

1 Referring to Fia. 2, adapter plate 20 provides a means for mounting the apparatus to any appropriate receiving surface. Bolts 21 disposed through apertures in the adapter plate 20 secure the adapter plate 20 to the receiving surface.
Upper calender fixture 11 includes a backplate 30, and a fixed roller 50 rotatably mounted between left and right guides 60 and 61 respectively. The fixed roller _'i0 has a platen 51 with a surface of sufficient smoothness not to damage the suture. Bearing ends 52 fit into countersunk holes 62 in the left and right guides. Slide plates 80 and 81 are slidably mounted within respective slots 63 and 64 in the left and right guides. Floating roller 55 is rotatably mounted between slide plates 80 and 81 and is parallel to roller 50. Platen 56 of roller 55 has a surface of sufficient smoothness so as not to damage a suture being calendered. Surface smoothness for the calendering rollers of the present invention is preferably a fine surface finish in the range cf about 4 to 16 microinches, and most preferably about 8 microinches, (i.e. the root mean square difference between the surface peaks and valleys) and can be achieved by electropolishing, lapping, or superfinishing.
Since slide plates 80 and '81 are movable within slots 63 and 64, floating roller 55 is movable toward a,nd~
away from fixed roller 50. Compression springs 90 urge: the floating roller 55 toward the fixed roller 50 by applying a biasing force of predetermined magnitude. Springs 90 are disposed around retainer rods 70 between front support plate 40 and respective slide plates 80 and 81. Retainer rods 70 are disposed through apertures 41 in the front support plate 40. Threaded ends 72 of the retainer rods are received into 1 tapped holes 83 a;,d 8: of the slide plates 80 and 81. 'The spring size and type is chosen so as to apply an appropriate biasing force. The biasing force must be sufficient magnitude to compress the suture, but less than that which would cause permanent damage to the suture.
In an attempt to qualify the amount of suture compression during calendering, sutures of different sizes were passed through one set of calender rolls, e.g. the.
upper portion 11 of the calendering device. The average 70 diameter of the suture prior to application of the cale:nder rolls and the average diameter in the narrowest direction, i.e. the direction of compression, were determined using an optical microscope. The percentage of compression of t:he suture is determined from the following formula: D_~~Dz x 100 wherein:
D, = average suture diameter before calendering D~ = average suture diameter after calendering (in one direction only) as measured across the narrowest direction, i.e. the direction in which the compression force is applied.
An acceptable range of suture compression is from about 0 to 20%. A preferred range of suture compression is about 0 to 10%. Most preferred is a suture compression of about 5%.
A helical compression spring 90 should be chosen so as to apply biasing force to achieve suture compre~~sion 1 within the above mentioned ranges. As stated, springs X30 are disposed around rods 70 between the inside surface of plate 40 and slide plates 80 and 81. In a preferred configuration with rollers 50 and 55 touching, the space between plate 40 and slide plates 80 ar.3 81 is slightly less than about 2 inches, such 'as about 1; inches. In this configuration, a spring wh-ich has been found to be suitable has a free length of about 2" and a spring rate of 2.0 lbs./in.
The bottom portion of the fixture 12 is similar to the top portion 11 except that it is mounted to the adapter plate 20 in an orientation orthogonal to that of top portion 11. It has been found that most sutures can be calendered at relatively high velocity, on the order of about 50 meters per minute, which is conducive to calendering in line immediately before the coating or filling operation, a=>
explained in more detail below. However, smaller size sutures, e.g. sizes 6/0, 7/0 and 8/0, may require calendering at a slower speed, cn the order of about 25 meters per minute, to provide more gentle suture handling and avoid filament breakage.
Filling After the-suture has been calendered it may be, filled with appropriate filling agents as described above by passing the suture through a filling head. Filling heads are applicators for applying a fluid medium to the running length of an indefinite length work, such as a fiber or thread. Such an apparatus is available from Bouligny Company of Charlotte, North Carolina, and may include the applicator head designated as part number 503'488 of the -2s-Bouligny Company. An example of such a filling head is illustrated in Fig. 6. Filling solution may be continuously delivered from a reservoir by means of a standard metering pump.
In contrast tc batch processes wherein the entire length of a suture is immersed in a trough of filling solution, use of the filling method of the present invention possesses the advantage of efficient use of filling solution. Only a small quantity of filling solution need be prepared at any one time. Thus, the method of the present iwention enables the use of HGFs or other therapeutic agents such as those discussed above, which may be prohibitively expensive to formulate in solution in large quantity.
Fig. 5 illustrates the preferred apparatus for filling the suture in conjunction with the calendering apparatus. Suture 1 is drawn off a winding roll (not shown) and passes around roller 201 and up through calendering portio:.s i2 and 11. The _suture 1 is then guided around rollers 202, 203, 204 and 205, and passed vertically through filling head 210.
Referring now to Fig. 6, filling head 210 includes two wing portions 211 and 212 which define a V-shaped notch 216 through which the suture 1 is passed. A filler supply tube 213 provides means for carrying filling solution from a metering pump to the filling head 210. The filling solution passes through aperture 214 so as to enter the V-shaped notch region 216 along the corner edge defined by the intersection of the inner surfaces of wing portions 27.1 and 212. The filling solution accumulates to some extent along the interior walls of the V-shaped notch 216. As suture 10 1 passes through V-shaped notch 216 it is wetted and filled by the filling solution, which is substantially continuously applied by means of the metering pump. The term "substantially continuously" also includes the intermittent application of filling solution to maintain a predetermined minimum accumulation of filling agent in the filling head as the suture continuously passes therethrough. The filling head 210 can be fabricated from any material suitable for the purpose described herein, such u5 metal or plastic.
Referring again to Fig. 5, excess filling soaution is collected and returned through a return conduit 213a to the filling solution reservoir, further conserving fil:Ling solution. After the suture is passed through the filling head 210 it is passed into a vertical cven 207 wherein it is heated so as to dry the suture. The oven is preferably maintained at a temperature of about 84 degrees Centigrade.
The suture passes to the top of the oven without contacting any surface until it passes around a driver roller at the top of the oven. The filler dries rapidly in the heated oven, so that the suture substantially dries in the time required for the suture to travel to the top of the oven.
Optionally, the suture may be guided around roller 20E~ and up again into oven 207 far as many multiple passes through the oven 207 as is desired. After calendering tension may 2S be applied to the suture so as to produce up to about a 50 stretch in the suture. The suture speed is held cons':ant throughout the procedure. After the final pass through the oven 207, suture 1 is guided around rollers 208, 209, 221, 222, 223 and onto a winding spool (not shown) or other suitable receiver.

.28.
1 The filling operation is controlled to consistently apply a uniform amount of filler to a given size suture. For each suture size a particular fillinc~~
solution is used and a target filling amount, expressed as percent weight of tr.e final suture, is selected. The pump capacity, braid velocity, suture denier, filling solutuon concentration, and target fill value are used to determine the appropriate pump speed to achieve the desired °ill:ing ef the suture.
In accordance with the invention, the metering pump rate in rotations per minute, RPM, is calculated for any given suture using equations (1) to (5):
RPM - (REQD/CNC)/CAP (1) READ = BRD x TARG./(100-TARG) (2) BRD - GMET x VEL (meters per min.) (3) GMET (grams per meter) - DEN/9,000 (4) CNC (gm/ml.) - grams ql~cerol in solution (5) milliliters of solution wherein:
BRD - suture mass velocity in grams per minute TARG = target fill rate in percentage of suture weight GMET = suture linear density in grams per meter VEL - suture velocity in meters per minute DEN - suture denier CNC - glycerol concentration in grams per ml. or grams per cc.
CAP - pump capacity in cc. per revolution.
One appropriate concentration is about 370 grams of glycerol per 933 milliliters of solution, so for this -29' 1 case CNC = .3956. For suture sizes 6/0, 7/0 and 8/0 the preferred filling solution has a ratio of glycerol to calcium lactate of about 10:1 is used, and for all ot:-:er suture sizes the ratio preferably is about 6.5:1. PrefE:rred values for the remaining parameters (other than denier) needed to determine the pump rate are set forth in TablE: 1.
Variable pump capacity may be achieved with a single metering pump by providing a variable setting flow valve with recirculating loops. Thus, at less than maximum pump capacity at least some filling solution is returned to 'the reservoir instead of to the applicator head.

Suture VEL TARG CAP

Size (Meters per Min.) (~ suture weight) (cc per rev.) 8/0 50 15 .02 7/0 50 15 .02 6/0 50 15 .02 5/0 50 13 .08 4/0 50 12 .08 3/0 50 12 .08 2/0 50 ~ 12 .OS

0 50 12 .08 1 50 12 .08 2 50 12 .08 3 50 12 .08 Denier of the suture material to be filled is measured and a metering pump rate is calculated for the suture material using equation (1) and the values set forth above.
In order to facilitate implementation of the:
filling operation in production, a computer program h~~s been developed and may be used to reduce operator error. F~ flow chart of tha pro7ram is shown in Fig. 7, the steps of which are described below.
The user initiates the program and the computer proceeds according to the following steps as shown in rig. 7.
Step 101 - Start of program Step 102 - The computer asks the user the following questions:
1) What is the size of the braid?
2) What is the braid lot number?
3) What is the denier of the braid?
Step 103 - The user inputs size, lot number, and de=nier of the suture to be filled.
Step 104 - The computer then determines whether the suture size specified by the user was 8/G.
If no, the program proceeds Step 108. If yes, the program proceeds to Step 105.
Step 105 - The computer selects a pump capacity flow valve setting of 0.02 cc per revolution, a~
suture velocity of 50 meters per minute'; a target add on percentage of 15% fill; <ind a drying oven temperature of 84°C.

1 Step 106 - The computer determines whether the denier input by the user in Step 103 was less than 33. If yes, then the program goes to Step 147 and the user is told that the denier does not match the braid size, and that another denier sample should be taken before continuing. If no, then the program proceeds to Step 107.
Step 107 - The computer determines whether the denier input by the user in Step 103 was greater than 50. If yes, the program moves to Step 147. If no, the program proceeds to Step 144 wherein pump rotations per minute (RPM) is calculated using equation (1) and the procedure advances to step 145.
Step 108 - The computer determines whether the size of braid input by the user ir. Step 103 was 7/0.
If no, the program moves to Step 112. If yes, the program advances to Step 109.
Step 109 - The computer selects the following settings:
Pump capacity - 0.02 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 15% fill Drying oven.temp. - 84°C

1 Step 110 - The computer determines whether the denier size input by the user in Step 103 is less than 40. If yes, the program proceeds to Step 147. If no, the program advances to Step 111.
Step 111 - The computer determines whether the denier size input by the user is above 60. IL yes, the program goes to Step 147. If no, the program advances to Step 144.
Step 112 - The computer determines whether the size of the braid input by the user in Step 103 was 6/0. If no, the program goes to Step 116.
If yes, the program advances to Step 113.
Step 113 - The computer selects the following settings:
Pump capacity - 0.02 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 15% fill Drying oven temp. - 84°C
Step 114 - The computer determines whether the denier input~by the user in Step 103 is less than 50. If yes, the program goes to Step 147.
If no, the program proceeds to Step 115.
Step 115 - The computer determines whether the denier input by the user is above 160. If yes, the program goes to Step 147. If no, the program proceeds to Step 144.

1 Step 116 - The computer determines whether the size of the braid input by the user in Step 103 was 5/0. If no, the prcgram goes to Step 120.
If yes, the program advances to Step 117.
Step 117 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meters/min.
Target add on - i3 % fill Drying oven temp. - 84°C
Step 118 - The computer determines whether the denier input by the user in Step 103 is less than 250. If yes, the program goes to Step 147.
If not, the program proceeds to Step 119.
Step 119 - The computer determines whether the denier input by the user is above 340. If yes, the program moves to Step 147. If no, the computer proceeds to Step 144.
Step 120 - The computer determines whether the size of the braid input by the user in Step 103 was 4/0. If no, the program 'goes to Step 124., If yes, the program advances to Step 121.
Step 121 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 5o meters/min.
Target add on - 12 % fill Drying oven temp. - 84°C

1 Step 122 - The computer determines whether the denier input by the user in Step 103 is less than 350. If yes, the program goes to Step 1~7.
If no, the program advances to Step 123.
Step 123 - The computer determines whether the denier input by the user is above 500. If yes, the program goes to Step 147. If no, the program advances to Step i44.
Step 124 - The computer determines whether the size of the braid input by the user in Step 103 was 3/0. If no, the program moves to Step 128.
If yes, the program advances to Step 125.
Step 125 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 12 % fill Drying oven temp. - 84°C
Step 126 - The computer determines whether the denier input by the user in Step 103 is less than 500. If yes, the program moves to Step 147.
If no, the program advances to Step 127.
Step 127 - The computer determines whether the denier input by the user in Step 103 is above 900.
If yes, the program moves to Step 147. Tf no, the program proceeds to Step 144.

1 Step 123 - The computer determines whether the size of the braid input by the user in Step 103 was 2/0. If no, the program gees to Step 132.
If yes, the program goes to Step 129.
Step 129 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meterslmin.
Target add on - 12 % fill Drying oven temp. - 84°C
Step 130 - The computer determines whether the denier input by the user in Step 103 is less than 1,000. If yes, the program moves to Step 147. If no, the program goes to Step 131.
Step 131 - The computer determines whether the denier input by the user in Step 103 is above 1,350.
If yes, the program moves to Step 147. If no, the program advances to Step 144.
Step 132 - The computer determines whether the size of the braid input by the user in Step 103 was size 0. If no, the program goes to Step 136.
If yes, the program proceeds to Step 133.
Step 133 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 12 % fill Drying oven temp. - 84°C

1 Step 134 - The computer determines whether the denier input by the user in Step 103 is less than 1,400. If yes, the program moves to Step 147. I' no, the program advances to Step 135.
Step 135 - The computer determines whether the denier input by the user is above 1,950. If yes, th°_ prOgrc:u C~. G2S :.O Step 147 . Tf nG, tha program goes to Step 144.
Step 136 - The computer determines whether the size of the braid input by the user iri'Step 103 ~~as size 1. If no, the program advances to Step 140. If yes, the program proceeds to Step 137.
Step 137 - The computer selects the following settings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 12 o fill Drying oven temp. - 84°C
Step 138 - The computer determines whether the denier input by the user in Step~103 is Less than 2,000. If yes, the program goes to Step 147.
If no, the. program goes to Step 139.

1 Step 139 - The computer determines whether the denier input by the user is above 2,600. If yes, the program goes to Step 147. If no, the program goes to Step 144.
Step 140 - The computer determines whether the size ef the braid input by the user in Step 103 is size 2. If no, the program goes to Step 146.
If yes, the program goes to Step 141.
Step 141 - The computer selects the following set~ings:
Pump capacity - 0.08 cc/rev.
Suture velocity - 50 meters/min.
Target add on - 12 % fill Drying oven temp. - 84°C
Step 142 - The computer determines whether the denier input by the user in Step 103 is less than 3,000. If yes, the program does to Step 147.
If no, the program goes to Step 143.
Step 143 - The computer determines whether the denier input by the user in Step 103 is above 3,500.
If yes, the program goes to Step 147. If. no, the program goes to Step 144.
Step 144 - The computer calculates the pump speed in rotations per minute in accordance with equation (1) and proceeds to step 145.

Step 145 - The user is informed by printout or by monitor as to the lot number specified, the appropriate. braid speed, pump rate, pump capacity setting, filling target percentage, and temperature of the dr~~ing chamber. The suture size, denier and filling solution identification are also displayed. The program thereafter runs to completion to Step 148.
Step 146 - This step is arrived at if the suture size input by the user in Step 103 does not match any of the designated suture sizes pre-programmed in the computer. The user is informed that he has chosen an incorrect size designation. The program then moves to Step 148, which is the end.
Step 14~ - The user is warned that the denier which he has input in size 103 does not match the size of braid which he has also input in 103. The user is advised to take another denier sample before continuing. The program then moves to Step 148.
Step 148 - End of program.
The program may be expanded to accommodate different size sutures, and the processing conditions for any particular suture may readily be modified without affecting the conditions for other size sutures. Although 1 the program has been described in the context of printing out processing conditions in terms of settings to be adjusted by the user, it is contemplated that one or -ore processing conditions could be set automatically by cor.~puter control. Thus, the flow valve could be adjusted by electromechanical controls to the appropriate position, the godet or roller motor(s)~could be automatically set to achieve the appropriate braid speed including, if desired, a stretch condition, the drying oven temperature could be set automatically and the metering pump could be electronically set to the appropriate RPM calculated from equation (1).
While many specifics have been described, it is contemplated that a wide range of processes could be developed which take advantage of the calendering and coating/filling operations described herein. Thus, the apparatus and computer program for filling may also be used to advantage to coat sutures with a lubricant coating in order to improve knot run down, irrespective whether the suturs is absorbable er non-absorbable and is or is not to be filled. In this regard, numerous advantageous processes are contemplated.
By way of example, the apparatus, method and/or computer program described above for filling may be used to coat absorbable or non-absorbable sutures, and the sutures may be calendered prior to coating to improve coating efficiency. By way of further example, absorbable or non-absorbable sutures may be calendered and subsequently filled. Because the filling may contain desirable therapeutic agents and/or growth factors, filling may be desirable for both absorbable or non-absorbable sutures in order to administer such agents or growth factors. It has been found desirable to apply a lubricant coating, if any, prior to calendering and filling, but it is also contemplated that calendering and filling could precede the coating operation.
tlumerous variations and modifications of the invention will occur to a person of ordinary skill in th~~
art or will be learned by or from experimentation with the invention all within the scope of the appended claims.

2~

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for filling a suture comprising passing the suture lengthwise through a filling head, said filling head having a contacting region in which the suture is contacted by a filling agent substantially continuously supplied to the filling head as the suture passes therethrough.

2. The method of claim 1, wherein said contacting region is a substantially V-shaped notch defined by two wing portions, said filling agent being supplied to said contacting region along the inner edge thereof.

3. The method of claim 1 or 2, wherein said filling agent comprises a storage stabilizing agent.

4. The method of claim 3, wherein said storage stabilizing agent comprises glycerol.

5. The method of claim 3, wherein said stabilizing agent contains a thickener.

6. The method of claim 5, wherein said thickener is calcium lactate.

7. The method of claim 1 or 2, wherein said filling agent comprises a therapeutic agent.

8. The method of claim 7, wherein said therapeutic agent is selected from the group consisting of antibiotics, human growth factors, magainin, tissue plasminogen activator, kidney plasminogen activator, superoxide dismutase, tumor necrosis factor, colony stimulating factor, interferon, and interleukin-2.