Patent Abstract:
A system for convection enhanced delivery of therapeutic comprises one or more flexible, biocompatible microcatheters that are directed to a target location to deliver a therapeutic agent. The microcatheter is releasably coupled to a guide tube and directed to the desired location. The microcatheters are small and flexible in order to reach the target areas, minimize trauma at the injection site, and minimize reflux of the injectable therapeutic.

Full Description:
RELATED APPLICATIONS 
     This application is a divisional of U.S. Non-Provisional patent application Ser. No. 12/123,031, entitled “Apparatus and Method for Convection Enhanced Therapeutic Delivery,” filed on May 19, 2008, which application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/938,784, entitled “Convection Enhanced Delivery System,” filed May 18, 2007, each of which is herein incorporated by reference in its entirety for all purposes. 
    
    
     FIELD OF THE INVENTION 
     The present invention is related to convection enhanced delivery of a therapeutic for treatment of tumors, more specifically, treating tumors in the brain. 
     BACKGROUND 
     Malignancies of the brain are among the most devastating diseases known. In the US, the prevalence of brain cancer is 360,000, with 15,000 deaths per year. A large percentage of these malignancies are found to be glioblastoma multiforme (GBM), having a very rapid, aggressive, and uncontrolled growth. Very little progress has been made in the treatment of GBM over the past 25 years. Present therapeutic approaches involve surgical excision, chemotherapy, and radiation therapy. The death rate of patients who have been diagnosed as having GBM, however, is 98%. Patients rarely survive for more than one year from diagnosis, often dying within six months. There is on-going research in how to effectively treat GBM. 
     One experimental approach is “targeted toxin therapy,” in which chemotherapeutics are directly infused into the tumor and the surrounding tissue where the tumor cells begin to infiltrate. This method, while requiring a surgical procedure, has been shown to reduce the debilitating side effects seen with systemic administration. It also reduces concerns regarding medicine crossing the blood brain barrier (BBB), and may achieve very high concentrations of therapeutic agent directly within, and in the vicinity of, the tumor. 
     Numerous agents for targeted toxin therapy are currently in clinical development. One such targeted toxin is cintredekin besudotox (CB), which is a recombinant protein made up of interleukin-13 and an active toxic protein derived from  Pseudomonas  exotoxin TP-38. CB binds selectively to the IL-13-overexpressing malignant glioma cells. Other agents being evaluated include standard anti-mitotic chemotherapy agents, transferrin-conjugated toxins, and radioisotope conjugates. 
     A delivery method for these medicines currently being evaluated is known as “convection-enhanced delivery” (CED), in which the tumor and surrounding tissue are deluged with high volumes of therapeutic agent under positive pressure. This method was designed by NIH researchers to facilitate the infiltration into brain tissue of high molecular weight therapeutic molecules that would not ordinarily diffuse over appreciable distances if simply injected. The parameters for effective CED have been extensively studied and modeled. 
     Delivery devices to accomplish CED remain under development. Presently, large bore catheters are surgically placed within the malignant mass and an infusion pump is used to drive flow at a rate of approximately 3 mL per hour for extended periods, e.g., up to 4 days. Various catheters have been designed and tested, usually having outer diameters (OD) of 1 mm or greater. Human CED trials are being performed using ventricular shunt tubing (2.1 mm OD) or spinal drains, e.g., 18 gauge, or 1.2 mm in diameter, as delivery cannulas. 
     These CED delivery methods have a number of shortcomings associated with the size of the delivery catheters. Under high-flow conditions, backflow (or reflux) of the injectable therapeutic occurs in a proximal direction along the outer catheter walls, resulting in a loss of the therapeutic into spaces and regions where it is not intended, and a loss of the pressure required to enable convection of the therapeutic molecules within an interstitial space. These shortcomings are particularly problematic in situations where the tumor is more superficial, as the segment of catheter that is surrounded by brain tissue is reduced. For targets that are deep within the brain, the length of catheter that is surrounded by tissue is increased, and the resistance to back flow is, therefore, also increased. To mitigate this situation, surgery is planned so that the cannula trajectory traverses the longest possible track through the parenchyma to minimize reflux. It has been observed, however, that the larger diameter catheters do not permit precise placement, which is an issue as it is required for more targeted or discrete delivery. Moreover, inserting multiple larger catheters is cumbersome and may limit wide distribution of the therapeutic. 
     Smaller diameter catheters have been shown to decrease backflow because the amount of backflow decreases as a function of the catheter diameter to the power of four-fifths. 
     Smaller diameter catheters have less rigidity, therefore, they have required construction in a telescoping, or “step design,” in order to obtain a final catheter diameter of approximately 0.168 mm. Known telescope designs use smaller diameter tubing glued to the end of a rigid stainless steel cannula. The rigid tube, however, is problematic for situations in which it must be left in place, e.g., in the brain, for extended periods of time measured in hours or days. The rigid portion presents a risk to the patient due to, for example, accidental contact and/or movement. Furthermore, while a final diameter of 0.168 mm minimizes reflux, the rate of delivery may be compromised. 
     SUMMARY 
     In one embodiment, an apparatus for delivering a therapeutic to a location in a body comprises: a hollow guide tube comprising a lumen therethrough with distal and proximal openings, the guide tube comprising an outer diameter in a range of 0.5 to 1.2 mm; a stylet, having proximal and distal portions, disposed within the guide tube lumen, wherein the stylet distal portion extends distally from the guide tube distal opening; a catheter having a catheter lumen running from a distal opening to a proximal opening, the catheter lumen having a diameter in a range of 0.03 to 2.11 mm; and a loop attached to a catheter distal portion, the loop releasably coupled to the stylet distal portion. 
     In another embodiment, a method of delivering a therapeutic to a target region in a body, the method comprises: providing a hollow guide tube comprising a lumen therethrough with distal and proximal openings, the guide tube having an outer diameter in a range of 0.5 mm to 1.2 mm; disposing a stylet, having proximal and distal portions, within the guide tube lumen, and extending the stylet distal portion distally from the guide tube distal opening; providing a catheter having a distal portion and releasably coupling the catheter distal portion to the stylet distal portion, the catheter comprising a catheter lumen having a diameter in a range of 0.03 mm to 2.11 mm and running from a distal opening to a proximal opening; distally inserting the releasably coupled guide tube, stylet and catheter into the body and locating the distal portion of the catheter in the target region; withdrawing the stylet proximally through the tube and releasing the catheter from the stylet; withdrawing the guide tube from the body and leaving the distal opening of the catheter in the target region; coupling the catheter to a source of the therapeutic; and delivering the therapeutic to the target region through the catheter. 
     In one embodiment, a method of delivering a therapeutic to a target region in a body comprises: providing a catheter having a catheter lumen having a diameter in a range of 0.03 mm to 2.11 mm and running from a distal opening to a proximal opening; disposing a stylet within the catheter lumen; distally inserting the coupled stylet and catheter into the body and locating the distal opening of the catheter in the target region; withdrawing the stylet proximally through the catheter and leaving the distal opening of the catheter in the target region; coupling the catheter to a source of the therapeutic; and delivering the therapeutic to the target region through the catheter. 
     In yet another embodiment, a kit for delivering a therapeutic by convection enhanced delivery to a location in a body comprises: a hollow guide tube comprising a lumen therethrough with distal and proximal openings, wherein the guide tube has an outer diameter in a range of 0.5 mm to 1.2 mm; a stylet, having proximal and distal portions, configured to be disposed within the guide tube lumen, wherein the stylet distal portion is configured to extend distally from the guide tube distal opening; a catheter having a catheter lumen running from a distal opening to a proximal opening, the catheter lumen having a diameter in a range of 0.03 mm to 2.11 mm; a loop coupled to a distal portion of the catheter and configured to be releasably coupled to the stylet distal portion; and instructions for using the hollow guide tube, stylet, and catheter to deliver a therapeutic by convection enhanced delivery by: disposing the stylet within the guide tube lumen, and extending the stylet distal portion distally from the guide tube distal opening; releasably coupling the loop on the catheter distal portion to the stylet distal portion; distally inserting the releasably coupled tube, stylet and catheter into the body and locating the distal portion of the catheter in a target region; withdrawing the stylet proximally through the tube and releasing the catheter from the stylet; withdrawing the guide tube from the body and leaving the catheter distal opening in the target region; coupling the catheter to a source of the therapeutic; and delivering the therapeutic to the target region through the catheter. 
     In yet another embodiment, a kit for delivering a therapeutic by convection enhanced delivery to a location in a body comprises: a catheter having a catheter lumen running from a distal opening to a proximal opening, the catheter lumen having a diameter in a range of 0.03 mm to 2.11 mm; a stylet, having proximal and distal portions, configured to be disposed within the catheter lumen; and instructions for using the stylet and catheter to deliver a therapeutic by convection enhanced delivery by: disposing the stylet within the catheter lumen; distally inserting the stylet and catheter into the body and locating the distal opening of the catheter in a target region; withdrawing the stylet proximally through the catheter lumen and leaving the catheter distal opening in the target region; coupling the catheter to a source of the therapeutic; and delivering the therapeutic to the target region through the catheter. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Embodiments of the present invention may be better understood by referring to the following description in conjunction with the accompanying drawings in which: 
         FIG. 1  represents a microcatheter according to one embodiment of the present invention; 
         FIGS. 2A and 2B  represent an inserter and the microcatheter of  FIG. 1  arranged in accordance with an embodiment of the present invention; 
         FIG. 3  is a close-up view of a distal portion of the system shown in  FIGS. 2A and 2B ; 
         FIG. 4  is a schematic diagram showing the configuration of an array of microcatheters placed within a tumor in the brain in accordance with one embodiment of the present invention; 
         FIG. 5  is a method of inserting a microcatheter in accordance with one embodiment of the present invention; 
         FIG. 6  is an alternate system in accordance with one embodiment of the present invention; 
         FIG. 7  is an alternate system in accordance with another embodiment of the present invention; 
         FIG. 8  is an alternate system where a fiber optic waveguide is provided in accordance with one embodiment of the present invention; and 
         FIG. 9  is an alternate system in accordance with another embodiment of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     The various embodiments of the invention are herein described with reference to the accompanying drawings. It is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only. These are presented in the cause of providing, what is believed to be, the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms and embodiments of the present invention may be embodied in practice. 
     Prior to explaining at least one embodiment of the present invention in detail, it is to be understood that the present invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or as illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. 
     It is advantageous to be able to direct a small diameter catheter to a specific location, e.g., a tumor in a brain, to deliver a therapeutic as the smaller diameter minimizes backflow and, therefore, more therapeutic is delivered where needed. Small diameter catheters, however, do not have sufficient rigidity to allow for repeatable and accurate placement. As will be described in more detail below, in various embodiments of the present invention, a convection enhanced delivery system (“CEDSYS”) and corresponding method employs an array of microcatheters or micro-cannula that can be stereotactically placed in order to distribute a therapeutic to, for example, uniform or irregularly-shaped intracerebral targets. 
     The term “therapeutic” is defined herein as any substance that is deliverable using the methods described below. These substances are typically, but not limited to, medicines in a fluid medium used to treat disease, to restore or improve function of central nervous system (CNS) regions, i.e., tissues comprised by the brain and spinal cord, or to destroy or impair dysfunctional or rogue tissue or other material within the CNS. In addition, a therapeutic may comprise a capsule or micro-capsule, powder, gel, solid, or gas. 
     Referring now to  FIG. 1 , in accordance with an embodiment of the present invention, a microcatheter  100  is composed of bio-compatible tubing, e.g., polyimide, with an internal diameter (ID) range of about 0.03 mm to 2.11 mm, and an outer diameter (OD) ranging from about 0.05 mm to 3 mm. As known to those of ordinary skill in the art, a length of the microcatheter  100  is sufficient to allow for connection to any equipment needed for the procedure. The microcatheter  100  may also be referred to as a micro-cannula, however, the terms as used herein are interchangeable and not meant to be limiting. 
     A distal portion  102  of the microcatheter  100  may be impregnated with an MRI detectable or otherwise radio-opaque material to facilitate viewing and evaluation of placement. This material may be confined to the distal portion  102  of the tubing. In an alternate embodiment, the entire microcatheter  100  may be radio-opaque or MRI detectable. A proximal end  104  of the microcatheter  100  is attached to a universal adaptor  106 , e.g., a Luer fitting. A loop or ring  108  is affixed to the distal portion  102  of the microcatheter  100 . The loop  108  is approximately 0.5-1.5 mm in diameter, and, in one embodiment, is composed of fine suture, e.g., 6-0, 7-0, 8-0, 9-0, or 10-0 suture, or other similar material. The material may be absorbable to minimize potential tissue disruption upon removal of the microcatheter  100 . Alternatively, the loop  108  may be made from an inert material, e.g., very thin stainless steel or the like. The loop  108  may be integral to the microcatheter  100  or attached by any one of a number of ways, for example, but not limited to, gluing, tying, and welding. 
     Referring now to  FIG. 2A , a small-gauge stereotactic inserter or guide tube  200 , e.g., an inserter similar to one produced by Preferred Instruments, Inc. is provided. The inserter  200  is composed of stainless steel hollow tubing with a diameter of 0.5-1.2 mm. A solid stylet  202  with a rounded distal portion  204  is placed within the guide tube  200  and extends beyond a distal portion  206  of the guide tube  200  by approximately 0.5 to 1 mm. The solid stylet  202  may be a metal such as: stainless steel, platinum, cobalt, titanium, or tantalum, or similar metal, any of which could be in either an alloy or pure form. The stylet  202  may have a diameter in the range of 0.1 to 2.0 mm. In an alternate embodiment, the stylet is not solid but sufficiently stiff or resistant to bending so as to facilitate insertion as explained below. 
     As shown in  FIG. 2B , an enlarged cross-sectional view of that shown in  FIG. 2A , a proximal end  208  of the stylet  202  is fixed permanently to a thumbscrew  210  that treads within a threaded portion  212  of the guide tube  200 . Thus, upon turning the thumbscrew  210  the stylet  202  is moved within the guide tube  200 . 
     The inserter  200  may also incorporate a stop  214  that may be moved along the length of the guide tube  200  and locked at any location along the length. The stop  214  may comprise a set screw or the like. The stop  214  provides an indicator to allow for precise depth placement of the guide tube  200  during a stereotactic procedure. 
     In accordance with one embodiment of the present invention, a method  500 , referring to  FIG. 5 , for inserting one or more microcatheters  100  in, for example, the brain of a patient, will be described. 
     Initially, step  502 , neuroimaging is performed and the patient is prepared for stereotactic surgery as known to those of ordinary skill in the art. The preparation may include determining sites in the brain  300  for microcatheter  100  placement with respect to an affected area  306 . 
     Subsequently, or at the same time as the preparation above, the microcatheters  100  are releasably coupled to the inserters  200  and prepared for stereotactic insertion, step  504 . As shown in  FIG. 3 , the loop  108  at the distal portion  102  of the microcatheter  100  is placed around the distal portion  204  of the stylet  202 . The length of the microcatheter  100  rests apposed to the inserter  200  tubing, temporarily being held together with the loop  108  distally and proximally by bone wax or other suitable material to fix the microcatheter  100  to the guide tube  200 . This step may include prefilling the microcatheters  100  with therapeutic and attaching them to a filled syringe  302 . Alternatively, the filled microcatheter may be capped until attached to the syringe  302 . The system may be prepared in advance and purged of air, if necessary. 
     At step  506 , one or more burr hole(s) are drilled, the dura is incised, and each microcatheter  100  is advanced, in turn, to the predetermined target area  306  as directed by the inserter  200 . A single burr hole may accommodate multiple microcatheters  100 , or two or more burr holes may be created based on the configuration of microcatheters  100  required to reach the desired targets. 
     The inserter  200  with the microcatheter  100  coupled, via the loop  108 , to the distal portion  204  of the stylet  202  is directed, or “pushed through” to the target location or region. The rigidity of the inserter  200  and the stylet  202  combine to “pull” the microcatheter  100  along as the microcatheter itself is too flexible to be “pushed” through the body, e.g., through brain matter. 
     At step  508 , the stylet  202  is withdrawn through the inserter  200  to release the loop  108 . As above, the thumbscrew  210  is unscrewed, allowing the stylet  202  to be withdrawn proximally from within the stainless steel guide tube  200  thus releasing the microcatheter loop  108  and allowing the microcatheter  100  to be positioned at the desired location independently. 
     Once a microcatheter  100  is in the desired location, the inserter  200  is withdrawn and the microcatheter  100  is anchored to the rim of the burr hole using, for example, a small amount of adhesive, step  510 . The adhesive produces a “spot weld” which will hold the microcatheter  100  in place but release the microcatheter  100  when sufficient force in a direction opposite of insertion is applied at the time of microcatheter  100  removal. A fast-curing, FDA-approved, silicon adhesive, or the like, may be used. 
     Alternatively, the surgeon can, after all the desired microcatheters  100  are positioned, fill the burr hole, with an array of microcatheters  100  emerging therefrom, with fibrin glue such as Tisseal, or the like. 
     The scalp is then closed around the microcatheters  100  using standard procedures. The microcatheters  100  may be looped atop the patient&#39;s head, to allow freedom of movement or “slack” in the event that the microcatheters  100  are inadvertently pulled. The syringes  302  attached to each microcatheter  100  are mounted into the infusion pump  304 . 
     Alternatively, or in addition, the microcatheters  100  can be provided together, i.e., as a bundle, and threaded through larger-diameter flexible tubing (not shown) to provide protection to individual microcatheters  100 . 
     The therapeutic is then delivered at the appropriate rate, or sequence of rates, using the infusion pump  304 , for the duration of the infusion protocol (minutes to days), step  512 . After insertion of a microcatheter  100  at a desired location in, for example, a brain  300 , as shown in  FIG. 4 , the proximal end  106  is attached to a therapeutic-filled syringe  302  connected to an infusion pump  304 . An infusion pump  304 , as known to those of ordinary skill in the art, may be used to control the rate of infusion of the therapeutic. As shown in  FIG. 4 , multiple microcatheters  100  may be inserted, each of which is connected to a respective single syringe  302 . In an alternative embodiment, two or more microcatheters  100  may be connected to the same syringe  302 . In yet another embodiment, a single microcatheter  100  may be connected to multiple syringes  302 , for example, in order to deliver alternate therapeutics or therapeutics that are combined at delivery. 
     Upon completion of the infusion protocol, the microcatheters  100  are removed by applying a pulling force in the direction opposite to that of microcatheter  100  entry so as to overcome the adhesive anchor at the rim of the burr hole, step  514 . The anchor is the only point of fixation and is designed to release the microcatheters  100 . The microcatheters  100  can be removed by pulling until their entire length is withdrawn from the brain, exiting through the burr hole and the closed scalp incision. 
     The removal of the microcatheters  100  does not necessarily require reopening the scalp incision. The decision of whether or not to open the incision, however, is up to the physician and based on the circumstances of the case. 
     The systems and methods described herein are suitable for short-term, long-term, or permanent ongoing delivery of therapeutic within the brain or spinal cord including malignant or non-malignant brain tumors. The malignant brain tumor may be one of: a tumor of the neural cells, a tumor of the glial cells, or a tumor of both neural and glial cells. 
     Other applications may include infusion of growth factors, angiogenesis factors, antioxidants, vectors to deliver genes, or any fluid material to be infused within the CNS or elsewhere in the body. 
     Similarly, these systems and methods can be adapted for delivery of therapeutic to virtually any other area of the body, such as internal organs, e.g., liver, pancreas, spleen, kidney, heart, and skin. Still further, tissue can be treated including, but not limited to, normal tissue, ischemic tissue, cystic tissue, neurodegenerating tissue, or otherwise diseased or dysfunctional tissue. 
     Infusion of therapeutics using these systems and methods may employ other pumping devices as alternatives to the infusion pump described. Pumping devices may be positioned outside of the body or they may be implanted within the body, such as subcutaneously or within a cavity, e.g., intraperitoneally. Pumping devices may be automated, may operate through an osmotic mechanism, e.g., mini-osmotic pump, or may be controlled by the health care provider or the patient herself. 
     The microcatheter  100  may come loose from the guide tube  200  and stylet  204  during insertion. It may be possible for the physician or operator to detect that the microcatheter  100  is no longer progressing toward the target area due to a loss of tension on the microcatheter  100 . In a situation where the tension, or loss thereof, cannot be detected by feel, however, inaccurate placement of the microcatheter  100  may result. 
     Referring now to  FIG. 6 , in accordance with one embodiment of the present invention, a system  600  is provided where the tension on the microcatheter  100  is monitored as it is being placed in position. A strain gauge  602  is coupled, via a connector  604 , to the microcatheter  100  and to the stylet  202  via a connector  606 . The strain gauge  602  measures the tension on each of the stylet  202  and the microcatheter  100 . The strain gauge  602  can be set to issue an alarm if there is a relative change between the two measurements. Alternatively, the strain gauge may be connected to only the microcatheter  100  and when there is either a loss of tension detected, or the level of tension falls below a predefined threshold, an alarm indicating that, perhaps, the microcatheter  100  has uncoupled from the stylet  202 , would sound. 
     Referring now to  FIG. 7 , a system  700  provides an alternate embodiment, according to one aspect of the present invention, for determining that the microcatheter  100  has disconnected from the stylet  202 . In this embodiment, a loop  702  is made from stainless steel or a similar conductive material and couples the microcatheter  100  to the stylet  202 . A continuity tester  704  is coupled, via a very thin wire  706  to the loop  702 . In addition, the continuity tester  704  is coupled, via a second wire  708  to the thumbscrew  210  and, therefore, completes a circuit through the stylet  202 , the loop  702 , and the wire  706 . If the loop  702  disconnects from the stylet  202 , the circuit will be broken and an indication of such, for example, an alarm, will notify the operator or physician. The wire  706  may run down through the microcatheter  100  and be connected to the loop  702  or the wire  706  may run along the outside of the microcatheter  100  and connect to the loop  702 . 
     In one embodiment, referring now to  FIG. 8 , in a system  800  the microcatheter  100  is replaced by an optical waveguide  802 , e.g., fiber optic material. Similar to that shown in  FIGS. 2A and 3 , the waveguide  802  is coupled to the guide tube  200  by the loop  108  for insertion at the desired location. A proximal end of the waveguide  802  is coupled to a light energy source and/or camera device  804 . The device  804  may either provide light energy through the waveguide or capture images. The light energy may be IR, UV or any other frequency necessary to provide, for example, photodynamic therapy or the like. The choice of material for the optical waveguide  802  is understood by one of ordinary skill in the art and will depend on, among other parameters, the frequency of the light energy to be delivered, the power of the device  804  and the distance over which the light energy is directed. 
     Thus, where a plurality of microcatheters  100  are inserted, one could be an optical waveguide in order to facilitate photodynamic therapy at the desired location. Photodynamic therapy is performed by injecting a photoreactive agent into a tumor site, via one or more of the microcatheters  100 , and then transmitting light through the optical waveguide to irradiate the photoreactive agent. 
     In an alternate embodiment, shown in  FIG. 9 , the microcatheter  100  contains a rigid guide  900 , thus allowing the microcatheter  100  to be placed at any depth within the brain without the need for being “piggy-backed” on the inserter. The rigid guide  900  may be a stylet, as described above, in order to provide the microcatheter  100  with sufficient rigidity during insertion. 
     In operation, the microcatheter  100 , with the rigid guide  900  within, is directed to the target location in, for example, the brain. As above, a number of microcatheters  100  may be provided where each is directed to a different location in order to provide therapeutic to the desired targets. Once the microcatheter  100  is fixed into position, the guide is removed from within. Similar to the process described above, a therapeutic is delivered through the lumen of the microcatheter  100  by connection to, for example, a syringe  302 . 
     The microcatheter  100  of the embodiments of the present invention provide therapeutic via convection enhanced delivery with minimum backflow. Further, the patient is more comfortable due to the flexibility of the catheter and its ease of positioning. Multiple microcatheters can be positioned to provide full coverage of the therapeutic to one or more targeted regions. The microcatheter  100  is guided to, and positioned at, the desired location by operation of being either “piggy-backed” on the guide tube or by operation of a guide releasably placed in the microcatheter lumen. 
     It is appreciated that certain features of the invention, which are, for the sake of clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. 
     Although various exemplary embodiments of the present invention have been disclosed, it will be apparent to those skilled in the art that changes and modifications can be made which will achieve some of the advantages of the invention without departing from the spirit and scope of the invention. It will be apparent to those reasonably skilled in the art that other components performing the same functions may be suitably substituted.

Technology Classification (CPC): 0