Abstract:
An intraocular shunt can be manufactured using a system that includes a liquid bath and a wire, which is moved through the bath. The wire can be moved through a first liquid bath to produce a first tubular layer of drug-infused gelatin. Further, the wire can be moved through a second liquid bath to produce a second tubular layer of drug-free gelatin. The first and second tubular layers can be dried on the wire in a humidity-controlled space, thereby manufacturing a drug-loaded gelatin shunt.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application a continuation of U.S. patent application Ser. No. 14/834,158, filed on Aug. 24, 2015, which is a continuation of U.S. patent application Ser. No. 14/295,020, filed on Jun. 3, 2014, now U.S. Pat. No. 9,113,994, which is a continuation of U.S. patent application Ser. No. 13/314,950, filed on Dec. 8, 2011, now U.S. Pat. No. 8,765,210, the entirety of each of which is incorporated herein by reference. 
     
    
     BACKGROUND 
       [0002]    Field 
         [0003]    The invention generally relates to systems and methods for making gelatin shunts. 
         [0004]    Description of the Related Art 
         [0005]    Glaucoma is a disease of the eye that affects millions of people. Glaucoma is associated with an increase in intraocular pressure resulting either from a failure of a drainage system of an eye to adequately remove aqueous humor from an anterior chamber of the eye or overproduction of aqueous humor by a ciliary body in the eye. Build-up of aqueous humor and resulting intraocular pressure may result in irreversible damage to the optic nerve and the retina, which may lead to irreversible retinal damage and blindness. 
         [0006]    Glaucoma may be treated in a number of different ways. One manner of treatment involves delivery of drugs such as beta-blockers or prostaglandins to the eye to either reduce production of aqueous humor or increase flow of aqueous humor from an anterior chamber of the eye. Glaucoma may also be treated by surgical intervention that involves placing a shunt in the eye to result in production of fluid flow pathways between an anterior chamber of an eye and various structures of the eye involved in aqueous humor drainage (e.g., Schlemm&#39;s canal, the sclera, or the subconjunctival space). Such fluid flow pathways allow for aqueous humor to exit the anterior chamber. 
         [0007]    A problem with implantable shunts is that they are composed of a rigid material, e.g., stainless steel, that does not allow the shunt to react to movement of tissue surrounding the eye. Consequently, existing shunts have a tendency to move after implantation, affecting ability of the shunt to conduct fluid away from the anterior chamber of the eye. To prevent movement of the shunt after implantation, certain shunts are held in place in the eye by an anchor that extends from a body of the shunt and interacts with the surrounding tissue. Such anchors result in irritation and inflammation of the surrounding tissue. Further, implanting a rigid shunt may result in the shunt causing blunt trauma upon insertion into an eye, such as producing a cyclodialysis cleft, or separation of the ciliary body from the scleral spur, creating hypotony by allowing the uncontrolled escape of aqueous humor through the cleft into the suprachoroidal space. 
         [0008]    To address the problems associated with shunts made of rigid material, people have begun to make shunts from flexible material, such as gelatin. See for example, Yu et al. (U.S. Pat. No. 6,544,249and U.S. Patent Application Publication No. 2008/0108933). Gelatin shunts may be reactive to pressure, and thus can be implanted without the use of anchors. Consequently, gelatin shunts will maintain fluid flow away for an anterior  5  chamber of the eye after implantation without causing irritation or inflammation to the tissue surrounding the eye. Additionally, the flexibility of a gelatin shunt prevents it from causing blunt trauma upon insertion into an eye, and thus reduces or eliminates the risk of producing a cyclodialysis cleft. 
         [0009]    However, there are numerous issues associated with making gelatin shunts. For example, it is difficult to control and manipulate liquid gelatin, which is important in order to produce a gelatin shunt with a uniform cross-section and uniform shape along a length of the implant. Additionally, there are challenges associated with the drying process that also make it difficult to produce a gelatin shunt with a uniform cross-section and uniform shape along a length of the implant. 
       SUMMARY 
       [0010]    The invention generally provides systems and methods for making gelatin shunts. Particularly, systems and methods of the invention address and solve the above-described problems with manufacturing gelatin shunts. 
         [0011]    Certain aspects of the invention address the problems of controlling and manipulating liquid gelatin. The invention recognizes that simply routing a wire through a temperature controlled gelatin bath is not sufficient to produce a gelatin shunt with a uniform cross-section and uniform shape along a length of the implant. Heated gelatin alone forms a skin layer on top of the gelatin. Pulling a wire through a gelatin bath alone results in the wire passing through the skin layer, which makes it impractical to control the gelatin uptake on the wire. The invention solves this aspect of the problem by adding a water layer on top of the gelatin. The water layer eliminates the skin effect, and allows for production of a uniform cone of gelatin upon pulling a wire through the gelatin and then the water layer. Where the gelatin cone intersects the water-air boundary, a spot forms. This spot is exposed to air, and gelatin from this spot is taken up the wire. 
         [0012]    However, the invention also recognizes that more gelatin reaches the top of the water than can be taken up by the wire. This results in cast-off, which renders the cone, and thus the spot at the boundary layer, unstable, i.e., the gelatin deposit is inconsistent in diameter. To solve this aspect of the problem, the systems and methods of the invention use a plate having an aperture, which aperture controls the gelatin spot. The plate having the aperture is situated in the water layer, and with the aperture plate in place, the cone of gelatin that feeds the spot is consistent and yields a uniform uptake of gelatin onto the wire. 
         [0013]    Other aspects of the invention address the problems associated with the drying process that also make it difficult to produce a gelatin shunt with a uniform cross-section and uniform shape along a length of the implant. As the water evaporates from the gelatin on the wire, the gelatin shrinks in diameter. However, the wire constrains the gelatin from shrinking axially. If humidity is left uncontrolled, an outer skin of the gelatin dries and hardens before the gelatin has completed shrinking. This results in non-uniform cross sections and shapes along the implant length. The invention recognizes that drying the gelatin on the wire in a humidity-controlled space produces a uniform implant along the length of the wire. One manner by which this is accomplished involves immersing the gelatin in an ultrasonic fog that keeps the outer skin of the gelatin hydrated as the internal volume of the gelatin shrinks. 
         [0014]    Systems and methods of the invention incorporate these solutions to the above-described problems associated with manufacturing a gelatin shunt. Methods of the invention may involve moving a wire through a bath including a bottom layer of liquid gelatin and a top layer of water, thereby coating the wire with gelatin, moving the gelatin-coated wire through an aperture, and drying the gelatin on the wire in a humidity-controlled space, thereby manufacturing a gelatin shunt. The dried shunt includes a uniform shape and a uniform cross-section. 
         [0015]    Movement of the wire may be controlled manually or mechanically. In certain embodiments, the moving wire is mechanically controlled, by for example, by a stepper motor. Any method for controlling humidity may be used with methods of the invention. In particular embodiments, the humidity is controlled by drying in the presence of an ultrasonic water fog. The aperture is generally located in the water layer, and the wire is preferably moved vertically through the bath, such that the gelatin-coated wire is vertical during the drying step. In certain embodiments, the manufactured shunt is sized and dimensioned to be an intraocular shunt. 
         [0016]    In certain embodiments, the liquid gelatin may include a drug, and thus produces shunts that may be coated or impregnated with at least one pharmaceutical and/or biological agent or a combination thereof. Any pharmaceutical and/or biological agent or combination thereof may be used with shunts of the invention. The pharmaceutical and/or biological agent may be released over a short period of time (e.g., seconds) or may be released over longer periods of time (e.g., days, weeks, months, or even years). Exemplary agents include anti-mitotic pharmaceuticals such as Mitomycin-C or 5-Fluorouracil, anti-VEGF (such as Lucentis, Macugen, Avastin, VEGF or steroids). Exemplary agents are shown in Darouiche (U.S. Pat. Nos. 7,790,183; 6,719,991; 6,558,686; 6,162,487; 5,902,283; 5,853,745; and 5,624,704) and Yu et al. (U.S. Patent Application Ser. No. 2008/0108933). The content of each of these references is incorporated by reference herein its entirety. 
         [0017]    Systems of the invention may include a motor, a wire operably coupled to the motor for movement of the wire, a temperature controllable bath, an aperture plate situated in a top portion of the bath, and an ultrasonic fogger, the system being configured such that the wire moves through the bath, through the aperture plate, and into the ultrasonic fogger. Generally, the wire initially moves down toward a bottom of the bath and then turns to move vertically out of the bath. From there, the wire moves through the aperture plate, and then the wire moves vertically through the ultrasonic fogger. Systems of the invention may also include a first camera positioned to view the wire as it moves through the aperture plate. Systems of the invention may also further include a second camera that includes software to measure the gelatin-coated wire as it passes into the fogger. 
         [0018]    The bath may be filled with liquid gelatin and water. The liquid gelatin fills a bottom layer of the bath and the water fills a top layer of bath. In certain embodiments, the liquid gelatin includes a drug. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0019]      FIG. 1  is a schematic showing an embodiment of a system of the invention. 
           [0020]      FIG. 2  is a schematic showing a magnified view of  FIG. 1 , focusing on the wheels that carry the wire. 
           [0021]      FIG. 3  is an image of the aperture plate with a wire running through the aperture. 
           [0022]      FIG. 4  shows the images captured by the first and second camera as the wire emerges from the aperture in the aperture plate. 
           [0023]      FIG. 5  is a schematic showing the wire being pulled through the gelatin and water layers and through the aperture in the aperture plate. 
           [0024]      FIG. 6  is a schematic showing a magnified view of a gelatin cone interacting with the aperture plate as the wire moves through the aperture plate. 
           [0025]      FIG. 7  is a schematic showing an exploded view of a spool. 
           [0026]      FIG. 8  is a schematic showing the final assembled spool. 
       
    
    
     DETAILED DESCRIPTION 
       [0027]      FIG. 1  shows an embodiment of a system  100  of the invention for manufacturing a gelatin shunt. Device  100  includes a base  101  and a vertically extending shaft  102 . There is a bath  103  at a junction of the base  101  and the shaft  102 , such that the shaft  102  is aligned with the bath  103 . The bath  103  can be any vessel configured to hold a liquid. In systems of the invention, the bath  103  holds the liquid gelatin and the water. The bath is operably connected to a temperature control unit  104 . The temperature control unit  104  regulates the temperature of the bath  103 , and any liquids within the bath  103 . For making a shunt, the bath is maintained at about 55° C. 
         [0028]    In particular embodiments, the bath  103  is a jacketed flask and the temperature control unit  104  is a water circulator with a heating component. The heater of the temperature control unit is set to a particular temperature, for example 55° C., which heats the water in the water circulator to the set temperature. The heated water is then circulated by the water circulator to the jacketed flask, which heats the flask, and its contents, to the temperature defined by the temperature control unit. Generally, the water level in the jacketed flask will be above the level of the gelatin inside the flask. 
         [0029]    To the top of the bath  103  is affixed an aperture plate  105 , i.e., a plate having an aperture  106  therethrough. The plate  105  is affixed to the bath  103  such that the aperture  106  is aligned with the shaft  102 . An exemplary shaped aperture plate  105  is shown in  FIG. 3 . In this figure, the plate  105  has a base portion and a protruding portion affixed to the base. The aperture runs through the base and through the protruding portion. 
         [0030]    System  100  includes a plurality of wheels  107   a - 107   e . The wheels  107   a - 107   e  support a wire  108  and are arranged in a path that the wire  108  will travel.  FIG. 2  is a magnified view of the system  100  shown in  FIG. 1 .  FIG. 2  better shows the positioning of wheels  107   a - 107   e  and the path of travel of wire  108 . Wheel  107   a  is mounted approximately halfway up the shaft  102 . The exact position of wheel  107   a  on shaft  102  is not important and other positions of wheel  107   a  are envisioned for the systems of the invention. Wheel  107   b  is mounted on a support near the base  101  and is positioned to be directly below wheel  107   a . Although, such exact positioning is not critical and wheel  107   b  may be placed in other places along the base. Wheel  107   c  is mounted at a top right edge of the bath  103 . Wheel  107   d  is mounted at a bottom of bath  103 . Wheel  107   d  is mounted such that it is in alignment with aperture  106  of aperture plate  105  and shaft  102 . Wheel  107   e  is positioned at the top of shaft  102 . The exact position of wheel  107   e  on shaft  102  is not important and other positions of wheel  107   e  are envisioned for the systems of the invention. Wheel  107   f  is mounted on a support near the base  101 . Wheel  107   f  is operably coupled to stepper motor  109 . An exemplary stepper motor is commercially available from Automation Direct (Cumming, Ga.). 
         [0031]    The wheels  107   a - 107   e  are arranged such that when wire  108  is mounted on wheels  107   a - 107   e , the wheels provide a constant tension for wire  108 . Wire  108  is spooled on wheel  107   a . Wire  108  is then run under wheel  107   b , over wheel  107   c , under wheel  107   d , over wheel  107   e , and spools again onto wheel  107   f . The arrangement provides that wire  108  travels down into the base of bath  103 , and makes a turn at the base of bath  103 , such that after the turn, wire  108  travels vertically up through the bath  103 , through the aperture  106  of the aperture plate  105 , and vertically up the length of the shaft  102  to wheel  107   e.    
         [0032]    Stepper motor  109  in connection with wheel  107   f  drives movement of wire  108  and controls the speed at which wire  108  travels. The thickness of the walls of the formed shunt will depend on the speed at which the wire  108  is traveling. Increasing the pull speed will increase the diameter of the shunt, while decreasing the pull speed will decrease the diameter of the shunt. Stepper motor  109  is controlled by computer  114  and powered by DC power supply  115 . 
         [0033]    Wire  108  is preferably stainless steel, which may optionally be coated with a biocompatible, lubricious material such as polytetrafluoroethylene (Teflon). The coating helps in removing the dried gelatin shunt from the wire  108 . The gauge of the wire will depend on the desired inner diameter of the shunt being produced. Generally, wires are used that produce a shunt having an inner diameter from approximately 10 μm to approximately 250 μm, preferably from about 40 μm to about 200 μm. 
         [0034]    System  100  may include at least one camera for real time monitoring of the manufacturing of the shunt.  FIGS. 1-2  show an embodiment that includes two cameras  110  and  111 . Camera  110  monitors the wire  108  at the point that it is emerging from the aperture  106 . Camera  111  is a high magnification camera that includes measurement software to allow for real time measurement of the thickness and diameter of the gelatin coating the wire  108  as it emerges from the aperture  106 . Exemplary cameras are DINO-LITE cameras, commercially available from (AnMo Electronics Corporation, Torrance, Calif.).  FIG. 4  shows the images captured by cameras  110  and  111 . The top image is the image produced by camera  111 , and the bottom image is the image produced by camera  110 ). Cameras  110  and  111  are operably coupled to computer  114 , which controls the cameras. 
         [0035]    System  100  also includes an ultrasonic fogger  112  coupled to a tube  113 . The tube  113  runs most of the length of the shaft  102 , extending from the top of the shaft  102  down to the top camera  111 . The tube  113  is positioned such that the wire  108  passes into the tube  113  upon emerging from the aperture  106 . The fogger  112  is positioned such that the produced fog enters the tube  113 . The fog produced by the fogger  112  keeps the outer skin of the gelatin hydrated as the internal volume of the gelatin shrinks. An exemplary fogger is commercially available from Exo-terra (Mansfield, Mass.). 
         [0036]    To make the gelatin shunt, the bath  103  is pre-heated to a temperature of about 55° C. During the pre-heating, the liquid gelatin  116  is made. In a certain embodiment, the gelatin used for making the shunt is known as gelatin Type B from bovine skin. An exemplary gelatin is PB Leiner gelatin from bovine skin, Type B, 225 Bloom, USP. Another material that may be used in the making of the shunt is a gelatin Type A from porcine skin, also available from Sigma Chemical. Such gelatin is available from Sigma Chemical Company of St. Louis, Mo. Under Code G-9382. Still other suitable gelatins include bovine bone gelatin, porcine bone gelatin and human-derived gelatins. In addition to gelatins, the flexible portion may be made of hydroxypropyl methylcellulose (HPMC), collagen, polylactic acid, polyglycolic acid, hyaluronic acid and glycosaminoglycans. 
         [0037]    In an exemplary protocol, the gelatin solution is typically prepared by dissolving a gelatin powder in de-ionized water or sterile water for injection and placing the dissolved gelatin in a water bath at a temperature of approximately 55° C. with thorough mixing to ensure complete dissolution of the gelatin. In one embodiment, the ratio of solid gelatin to water is approximately 10% to 50% gelatin by weight to 50% to 90% by weight of water. In an embodiment, the gelatin solution includes approximately 40% by weight, gelatin dissolved in water. The resulting gelatin solution should be devoid of air bubbles and has a viscosity that is between approximately 200-500 cp and more particularly between approximately 260 and 410 cp (centipoise). 
         [0038]      FIGS. 5 and 6  illustrate the process of the gelatin  116  being taken up the wire  108 . Once prepared, the liquid gelatin  116  is poured into bath  103  that has been pre-heated to 55° C., thus maintaining the liquid gelatin at 55° C. After the gelatin  116  has been poured into the bath  103 , a water layer  117  is added on top of the gelatin layer  116 . The water envelops the aperture plate  105  such that a top surface of the plate  105  is submerged about 1 mm below the surface of water  117 . The bottom of the plate  105  is positioned so that it does not touch the gelatin layer  116 . Powered by stepper motor  109 , the wire  108  is pulled down into the base of the bath  103  and then turns vertically up through the gelatin layer  116 , the water layer  117 , and the aperture  106  in the aperture plate  105 . In this manner, the wire  108  becomes coated with gelatin  116  as it passes through the gelatin layer  116 . Upon pulling the gelatin  116  through the water layer  117 , a uniform cone  118  of gelatin  116  forms. Where the cone  118  intersects the water-air boundary, a spot forms. The cone  118  feeds into the aperture  106  in the aperture plate  105 . The aperture  106  controls the gelatin  116  and the spot, such that the cone  118  of gelatin  116  that feeds the spot is consistent and yields a uniform uptake of gelatin  116  onto the wire  108 . 
         [0039]    The wire  108  then advances past cameras  110  and  111 , which provide a real-time check of the thickness of the gelatin  116  that is being taken up the wire  108 . Feedback from the camera can be used to adjust the speed of the wire  108 , thus adjusting the thickness of the gelatin  116 . Increasing the pull speed will increase the diameter of the shunt, while decreasing the pull speed will decrease the diameter of the shunt. 
         [0040]    After passing the cameras, the gelatin-coated wire moves into tube  113  that is already being supplied with fog from fogger  112 . The wire  108  is advanced until the wet gelatin  116  reaches the wheel  107   e  at the top of the shaft  102 . The gelatin  116  on the wire  108  becomes immersed in the fog from fogger  112 . The fogger is run for approximately 5-10 minutes after the gelatin-coated wire enters the fogger. The fogger is turned off and the gelatin is allowed to dry. Having the outer skin of the gelatin  116  in a humidity-controlled environment, keeps the skin of the gelatin  116  hydrated as an internal volume of the gelatin  116  shrinks. In this manner, a uniform implant is produced along the length of the wire  108 . 
         [0041]    The wire  108  is then cut below wheel  107   e  and above the top camera  111 , using for example, stainless steel surgical sheers. The wire is cut into sections using the stainless steel surgical sheers to produce sections of a desired length. At this point, a cross-linking procedure can be performed on the gelatin. In one embodiment, the gelatin may be cross-linked by dipping the wire sections (with gelatin thereon) into the 25% glutaraldehyde solution, at pH of approximately 7.0-7.8 and more preferably approximately 7.35-7.44 at room temperature for at least 4 hours and preferably between approximately 10 to 36 hours, depending on the degree of cross-linking desired. In one embodiment, the gelatin is contacted with a cross-linking agent such as glutaraldehyde for at least approximately 16 hours. Cross-linking can also be accelerated when it is performed a high temperatures. It is believed that the degree of cross-linking is proportional to the bioabsorption time of the shunt once implanted. In general, the more cross-linking, the longer the survival of the shunt in the body. 
         [0042]    The residual glutaraldehyde or other cross-linking agent is removed from the gelatin by soaking the tubes in a volume of sterile water for injection. The water may optionally be replaced at regular intervals, circulated or re-circulated to accelerate diffusion of the unbound glutaraldehyde from the gelatin. The gelatin is washed for a period of a few hours to a period of a few months with the ideal time being 3-14 days. The now cross-linked gelatin may then be dried (cured) at ambient temperature for a selected period of time. It has been observed that a drying period of approximately 48-96 hours and more typically 3 days (i.e., 72 hours) may be preferred for the formation of the cross-linked gelatin. 
         [0043]    Where a cross-linking agent is used, it may be desirable to include a quenching agent. Quenching agents remove unbound molecules of the cross-linking agent from the gelatin. In certain cases, removing the cross-linking agent may reduce the potential toxicity to a patient if too much of the cross-linking agent is released from the gelatin. In certain embodiments, the gelatin is contacted with the quenching agent after the cross-linking treatment and, may be included with the washing/rinsing solution. Examples of quenching agents include glycine or sodium borohydride. 
         [0044]    In certain embodiments, drug-coated/drug-impregnated shunts are produced. Shunts may be coated or impregnated with at least one pharmaceutical and/or biological agent or a combination thereof. Any pharmaceutical and/or biological agent or combination thereof may be used with shunts of the invention. The pharmaceutical and/or biological agent may be released over a short period of time (e.g., seconds) or may be released over longer periods of time (e.g., days, weeks, months, or even years). Exemplary agents include anti-mitotic pharmaceuticals such as Mitomycin-C or 5-Fluorouracil, anti-VEGF (such as Lucentis, Macugen, Avastin, VEGF or steroids). Exemplary agents are shown in Darouiche (U.S. Pat. Nos. 7,790,183; 6,719,991; 6,558,686; 6,162,487; 5,902,283; 5,853,745; and 5,624,704) and Yu et al. (U.S. patent application Ser. No. 2008/0108933). The content of each of these references is incorporated by reference herein its entirety. 
         [0045]    In certain embodiments, an implant is produced with a thin layer of drug infused gelatin on an inside of the shunt. The thin inner layer will dissolve over time, thus delivering the drug. To produce such a shunt, the wire is pulled through a gelatin solution that has been infused with a drug to deposit a thin wall (e.g., 3-20 μm) of drug-infused gelatin on the wire. Alternatively, the wire is pulled through a gelatin solution that does not include a drug and the gelatin is instead soaked in the drug after it is pulled on the wire. In either case, the drug infused gelatin is then subjected to cross-linking with a controlled glutaraldehyde concentration for a controlled time to effect a non-permanent cross-linking that dissolves over time in tissue. Once this drug infused gelatin has been produced, the drug-infused gelatin is then pulled through the standard gelatin bath to coat the drug infused gelatin with a layer of gelatin that does not include a drug. This produces the final diameter of the shunt. The drug free layer of gelatin is then permanently cross-linked, thus producing a shunt with a thin layer of drug infused gelatin on an inside of the shunt. 
         [0046]    In other embodiments, an implant is produced with a thin layer of drug infused gelatin on an outside of the shunt. The thin inner layer will dissolve over time, thus delivering the drug. To produce such a shunt, the wire is pulled through the standard gelatin solution in the bath to a diameter of about 3-50 μm smaller than the desired diameter of the final implant. This layer is permanently cross-linked. The gelatin-coated wire is then pulled through a drug infused gelatin solution to deposit a thin wall (e.g., 3-50 μm) onto the gelatin-coated wire. Alternatively, the wire is pulled through a gelatin solution that does not include a drug and the gelatin is instead soaked in the drug after it is pulled on the wire. In either case, the drug infused gelatin is then subjected to cross-linking with a controlled glutaraldehyde concentration for a controlled time to effect a non-permanent cross-linking that dissolves over time in tissue. 
       INCORPORATION BY REFERENCE 
       [0047]    References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. 
       Equivalents 
       [0048]    The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 
       EXAMPLES 
     Example 1 
     Gelatin Preparation 
       [0049]    Into a 600 mL beaker was added 98±1 grams of porcine gelatin. An amount of about 172±1 grams of USP sterile water was measured and poured into the beaker containing the porcine gelatin. The beaker was sealed with parafilm, and the covered beaker was placed in a water bath at 55±1° C. for a minimum of 8 hours (maximum 36 hours). Ensure water level is higher than mixture in beaker. The lid of the water bath was checked to ensure that it was closed and after the minimum time period had elapsed, the beaker was removed from bath. The beaker was visually observed to verify that all gelatin in the mixture was dissolved and that mixture appeared homogeneous. 
       Example 2 
     Gelatin Transfer 
       [0050]    The water circulator was checked to make sure that it was at a sufficient level (between the high and low marks). The circulator was set and run at 40.5° C. and allowed to come to temperature before proceeding to the next step. The gelatin mixture from Example 1 was poured into the jacketed beaker on a fixture so that the meniscus was about 20 mm from the top. Within 1 minute of adding the gelatin mixture, 60 cc&#39;s of USP sterile water was added above the gelatin surface using a syringe. The water was added slowly so as not to disturb the gelatin. The mixture was allowed to settle for minimum 30 min. 
       Example 3 
     System Set-Up 
       [0051]    A spool was assembled onto an axle using parts as shown in  FIG. 7 . The final assembled spool is shown in  FIG. 8 . The M6 screw (Item  8 ) was finger tightened, and pinch bolt (Item  7 ) was fastened onto the mount. In order to increase the friction on the spool, the M6 screw (Item  8 ) was advanced approximately a ¼ turn. The wire was then threaded onto the spool, and the spool was slid up the shaft. The spindle assembly was lowered into the gelatin mixture, about 5 mm from the bottom of flask. The aperture plate was lowered into the water layer under a top surface was submerged about 1 mm below the surface of water. The bottom surface of the aperture plate was above the gelatin layer. 
         [0052]    The first and second cameras were positioned on the shaft so as to properly view the wire as it emerged from the aperture in the aperture plate. The tube of the fogger assembly was lowered over the shaft until a bottom of the tube is positioned just above the second camera. In this position, a top of the tube was approximately 2 inches above the upper wheel on the shaft. The fogger was started, and the volume and velocity on the fogger was adjusted until the fog was barely visible flowing at the bottom of the tube. The computer was initiated and the images produced by the camera were checked to ensure proper positioning of the cameras. The cameras were focused until edges of the wire had sharp contrast. 
       Example 4 
     Shunt Manufacturing 
       [0053]    The computer was used to initiate the stepper motor and begin pulling the wire. The initial pull speed was 8,000 rpm. The aperture was checked for dry gelatin, and any dried gelatin was cleared by grasping the wire above the top camera using a gloved hand and swirling the wire around lightly for a few seconds while monitoring the aperture cameras. The concentration of the gelatin on the wire was fine-tuned by monitoring the cameras. Turning the X-axis stage micrometer in the clockwise direction moved the wire to the right relative to the gelatin. Turning the Y-axis stage micrometer in the clockwise direction moved the wire to the left relative to the gelatin. Active measures of the gelatin thickness on the wire were taken. The total diameter of the gelatin in both the X and Y views was measured. The relative wall thickness of the gelatin on each side of the wire in both the X and Y views was obtained by measuring from the left edge of the gelatin to the left edge of the wire and from the right edge of the gelatin to the right edge of the wire. The pull speed was adjusted to achieve a target wet diameter of the gelatin. 
         [0054]    Once the target wet diameter was achieved, the fixture was run until gelatin reached the upper wheel at the top of the shaft. The movement of the wire was stopped at this point. After terminating the movement of the wire, the fog from the fogger was allowed to continue to flow over the wire for a minimum of 5 additional minutes. After five minutes, the fogger was turned off and the gelatin was allowed to dry for a minimum of 3 additional minutes. The wire was then cut below the upper wheel and above the top camera using stainless steel surgical shears. The cut wire was then subsequently cut into 4-4.25 inch sections using stainless steel surgical shears and prepared for cross-linking. The individual sections were cross-linked. The shunts were then cut to a desired length (e.g., 2-20 mm), and each shunt was removed from the wire.