Abstract:
A system and method for infusing a drug under continuous positive pressure (such as convection enhanced deliver) to a target tissue to be treated is particularly useful for post-resection anticancer drug therapy. The system comprises a drug infusion catheter having an expandable device which is expanded within the target tissue such that the target tissue conforms to an outer surface of the expandable device, thereby creating a form of seal around the target volume in order to maintain an effective drug pressure gradient within the target tissue. The system further comprises a sensor to measure a parameter which can be correlated to the degree of conformance between the target tissue and the outer surface of the expandable device. The sensor is coupled to a feedback control system to determine whether there is a loss of conformance, and to adjust the expansion of the expandable device in order to maintain good conformance.

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to devices and methods for use in directly delivering drugs to tissue within a patient&#39;s body, and more particularly to devices and methods for the continuous drug infusion directly to target tissue with feedback control of the infusion pressure. 
     BACKGROUND OF THE INVENTION 
     Malignant tumors are often treated by surgical resection of the tumor to remove as much of the tumor as possible. Infiltration of the tumor cells into normal tissue surrounding the tumor, however, can limit the therapeutic value of surgical resection because the infiltration can be difficult or impossible to treat surgically. Direct chemo-drug (anticancer drug) delivery therapy and radiation therapy are the two common post-resection treatment methods used to supplement surgical resection by targeting the residual malignant cells after resection, with the goal of sterilizing them, reducing the rate of recurrence, and/or delaying the time to recurrence. Radiation therapy can be administered through one of several methods, or a combination of methods, including permanent or temporary brachytherapy implants, and external-beam radiation. Direct chemo-drug delivery therapy is typically administered by inserting a catheter device into the resected cavity and infusing chemo-drugs through a lumen in the catheter and into the resected cavity where the drugs diffuse into the surrounding tissue. In some cases, direct chemo-drug therapy is applied to a tumor without resection in order to shrink the tumor prior to resection, or in the case of where surgery is contraindicated (e.g. inoperable tumors). 
     However, in certain treatment areas of the body, it is very difficult for the drugs to penetrate the target tissue (either a tumor itself, or the tissue surrounding the area of a resected tumor). For example, it is difficult for large molecule drugs to penetrate the brain parenchyma when treating brain tissue. Thus, in these situations, the chemo-therapy does not treat a sufficient thickness of tissue (typically 1-2 cm) to target the residual malignant cells. In order to improve drug penetration in these types of situations, a method of directly delivering the drugs to the target tissue under positive pressure has been developed. This method is commonly referred to as convection-enhanced delivery (CED). CED uses continuous positive pressure drug infusion to generate a pressure gradient to cause the drug to diffuse into the desired thickness of target tissue. 
     However, current methods and devices have several drawbacks. For one, at some point during infusion, the drugs tend to leak out of the target volume (the volume of target tissue) through the space in the tissue created by the catheter. The drugs can then follow the catheter pathway through the tissue and out of the patient&#39;s body. Moreover, once this occurs, it is difficult to maintain the pressure gradient within the target volume resulting in ineffective drug penetration into the target tissue. 
     Accordingly, there remains a need for methods and devices which can provide for effective direct delivery of drugs under continuous positive pressure drug infusion. 
     SUMMARY OF THE INVENTION 
     The present invention provides devices and methods for use in providing direct delivery of drugs under continuous positive pressure drug infusion. In one aspect, a drug infusion catheter comprises an elongate tubular member having a distal portion which is adapted to be inserted within a patient&#39;s body to a treatment site having a target volume of target tissue to be treated. The tubular member has a proximal portion and a proximal end which are adapted to extend out of the patient. An expandable device is provided on the distal portion of the tubular member and a hub is provided on the proximal end of the tubular member. The expandable member has a contracted position and an expanded position. 
     The tubular member has a drug delivery lumen which extends from a drug delivery outlet (the outlet can comprise one or more outlet openings) provided on the distal portion of the tubular member to a drug infusion port provided on the hub. The tubular member also has an inflation lumen (or expansion link, depending on the configuration of the expandable device) which extends from the expandable device to an inflation port on the hub. 
     The method of using the infusion catheter comprises first inserting the catheter, with the expandable device in its contracted position, into a resected space within the target volume of target tissue. The expandable device is then expanded to its expanded position, for example, by delivering a source of pressurized inflation fluid through the inflation port and into the expandable device. The tissue surrounding the expandable device con forms to the surface of the expandable device which, at least to some extent, seals the space in the tissue through which the catheter extends. Now, drug is infused through the drug infusion port at a continuous positive pressure. The drug travels through the infusion lumen, out of the delivery outlet and into the target tissue. The expandable device provides a sealing effect to the space such that an effective drug pressure gradient is maintained in the target volume. The drug is continuously infused at a positive pressure for a relatively long period of time, for example, at least 3 hours, 6 hours, 1 day, 2 days, 3 days, or more. 
     In another aspect of the present invention, a feedback control system is provided which controls the expansion of the expandable device in order to maintain conformance of the expandable device with the surrounding tissue in order to maintain an effective seal between the expandable device and the target volume. In one aspect of the feedback control system, the feedback control system measures certain parameters related to the drug infusion procedure which can be correlated to the conformance of the expandable device to the surrounding tissue, such as balloon pressure, force at the expandable device/tissue interface, drug infusion pressure within the infusion pump or catheter lumen, and/or the drug infusion pressure in the target volume. The feedback control system then correlates one or more of these measured parameters to the degree of conformance between the expandable device and the tissue and uses the measured parameter(s) and the correlated conformance to adjust the volume of the expandable device. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In order to better understand and appreciate the invention, reference should be made to the drawings and accompanying detailed description, which illustrate and describe exemplary embodiments thereof. For ease in illustration and understanding, similar elements in the different illustrated embodiments are referred to by common reference numerals, and the description for such elements shall be applicable to all described embodiments, wherever relevant. In particular: 
         FIG. 1  is a schematic view of an exemplary drug infusion system according to the present invention; 
         FIG. 2  is an enlarged, side, schematic view of the drug infusion catheter of  FIG. 1 ; 
         FIG. 3  is an enlarged schematic view of the balloon and tissue region of  FIG. 1  which depicts the drug flow when there is good conformance between the expandable device and the surrounding tissue; 
         FIG. 4  is an enlarged schematic view of the balloon and tissue of  FIG. 1  which depicts the drug flow when there is loss of conformance between the expandable device and the surrounding tissue; 
         FIG. 5  is an exemplary graph of pressure within a balloon as it is inflated within a resected cavity, in which the graph shows inflection points which can be correlated to conformance of the balloon with the surrounding tissue; 
         FIGS. 6   a  and  6   b  are exemplary graphs of drug infusion pressure showing the pressure during an infusion process, in which  FIG. 6   a  shows a stabilized pressure indicating good conformance maintained between the balloon and tissue and  FIG. 6   b  shows a drop in pressure indicating a loss of conformance between the balloon and the tissue; 
         FIG. 7  is a flow chart of an exemplary algorithm used by the Feedback Control System of  FIG. 1 , according to the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the devices and methods disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those of ordinary skill in the art will understand that the devices and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present invention is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention. 
     Referring first to  FIG. 1 , a drug infusion system  10  having feedback control according to the present invention is schematically illustrated. The drug infusion system  10  will be described in reference for infusing drug to tissue  12  within a brain  14 , with the understanding that the present invention is not limited to procedures within the brain, but can be used for drug infusion to tissue anywhere in a patient&#39;s body. The drug infusion system  10  comprises a drug infusion catheter  16 , which is operably coupled to a drug infusion device  18 , an expansion control device  20  and a feedback control system  22 . 
     With reference also to the enlarged view of  FIG. 2 , the drug infusion catheter  10  comprises an elongate tubular member  24  having a distal portion  24   a  and a proximal portion  24   b , and a main lumen  14  extending therebetween. The distal portion  24   a  is adapted to be inserted into the patient&#39;s body to the treatment location comprising a target volume of target tissue. The proximal end  24   b  is adapted to extend outside the patient&#39;s body. The walls of the tubular member  24  are substantially impermeable to fluids, except for any intended apertures and openings in the walls of the tubular member. 
     The distal portion  24   a  of the tubular member  24  has a drug delivery outlet  26  which is in fluid communication with the main lumen  14 . The drug delivery outlet  26  may comprise a single opening, as shown, or it may comprise multiple openings which are spaced apart about the distal portion  24   a  of the tubular member  24 . 
     An expandable device  28  is provided on the distal portion  24   a  of the tubular member  24 . The expandable device  28  can be any device which can be controllably expanded and contracted to retract tissue, such as a balloon, a cage, or other device. The expandable device  28  can have any suitable shape, including for example, spherical, oblong, etc. An expansion link  30 , such as a balloon inflation lumen, is disposed within the main lumen  14  and extends from the expandable device  28  to the proximal end  24   a  of the tubular member  24 . Depending on the form of the expandable device  28 , the expansion link  30  could comprise a mechanical linkage, an electrical connection, or other suitable link for remotely expanding and contracting the expandable device  28 . Alternatively, the expansion link  30  can be provided on the exterior of the tubular member  24 , or it can be integrally formed with the tubular member  24 . The expansion link  30  allows the expandable device  28  to be controllably expanded and contracted through the link  30 , such as by delivering an inflation fluid to a balloon through an inflation lumen. In order to simplify the following description, the expandable device  28  will be assumed to be a balloon  28  and the expansion link  30  will be assumed to be an inflation lumen  30 , with the understanding that the present invention is not limited to a balloon and an inflation lumen, as discussed above. Accordingly, the distal end of the inflation lumen  30  has an inflation fluid port  32  which is in fluid communication with the balloon  28 . 
     A hub  32  is disposed on the proximal end  24   b  of the tubular member  24 . The hub  32  has a drug delivery port  34  and an inflation port  36 . The drug delivery port  34  is in fluid communication with the main lumen  14 . The inflation port  36  is in fluid communication with the inflation lumen  30 . 
     The hub  32  may be formed in any suitable fashion as known by those skilled in the art. For example, the hub  32  may be integrally formed of plastic or other suitable material. Moreover, the hub  32  may include additional ports, as needed for the particular application of the catheter  16 . For instance, the catheter  16  could have more than one balloon, wherein each of the balloons is independently inflatable. Thus, the hub  32  could have an additional port for each additional balloon. 
     Turning back to  FIG. 1 , the drug delivery port  34  on the catheter  16  is connected to one end of a drug supply tube  38 . The other end of the drug supply tube  38  is connected to the drug infusion device  18 . The drug infusion device  18  is adapted to controllably provide a supply of drug, typically in fluid form, through the supply tube  38  to the drug delivery port  34  on the catheter  16 . The drug infusion device can be, for example, a syringe pump, other automated drug pump, or even a manual syringe. The inflation port  36  on the catheter is connected to one end of an inflation tube  40  and the other end of the inflation tube  40  is connected to the expansion control device  20 . The expansion control device  20  is adapted to controllably expand and contract the expandable device  28 , which for the balloon embodiment, comprises supplying a pressurized inflation fluid. The expansion control device  20  may provide the pressurized inflation fluid using a syringe pump, or any other suitable device for supplying a source of pressurized fluid. 
     One objective of the system  10  according to the present invention is to utilize feedback control in order to maintain effective drug pressure gradient during an infusion procedure. As discussed above, a loss in conformance can cause a degradation of the drug infusion pressure gradient resulting in ineffective drug penetration into the target tissue. This condition is graphically illustrated in  FIGS. 3 and 4 . The dashed lines in  FIGS. 3 and 4  depict the border of the tissue  12  surrounding the balloon  28  and the arrows depict the drug flow. As shown in  FIG. 3 , the tissue  12  is conforming very well to the balloon  28  and the drug flow shows effective penetration into the target tissue. On the other hand, in  FIG. 4 , the tissue has moved away from the balloon  28  and has lost conformance. As a result, there is significant backflow of the drug out of the resected space and a loss of drug pressure gradient resulting in ineffective drug penetration into the target tissue. 
     In order to provide the feedback control according to the present invention, the system  10  comprises one or more sensors to measure various parameters of the operation of the system  10  which can be correlated to conformance of the balloon  28  and the surrounding tissue  12 . The feedback control allows the system  10  to adjust for a loss in conformance between the inflated balloon  28  and the surrounding tissue in the resected cavity. The system  10  in  FIG. 1  includes a plurality of sensors, however, as described below, the system  10  according to the present invention need only have any one of the sensors, and can have any combination of two or more of the sensors. 
     The system  10  includes a force sensor  50 , a balloon pressure sensor  52 , a drug infusion pressure sensor  54 , and a drug diffusion pressure sensor  56 . Each of the sensors,  50 ,  52 ,  54  and  56 , is operably coupled to the feedback control system  22  to transmit s signal to the feedback control system indicative of the parameter measured by the respective sensors. 
     The force sensor  50  is a force sensor which is placed between the surface of the balloon  28  and the surrounding tissue  12  to measure the force between the surface of the balloon  28  and the surrounding tissue  12 . The sensor  50  quite directly measures the conformance of the tissue  12  to the balloon  28 . Thus, the correlation between this measured parameter of force between the balloon  28  and the tissue  12  is as follows. With the balloon  28  first located in a resected cavity with the balloon uninflated, the sensor  50  will measure little or no force. As the balloon  28  is inflated, at some point in the inflation the balloon will push the sensor  50  into the wall of tissue  12  and the sensor  50  will indicate a sharp increase in force. As the balloon  28  is further inflated, the sensor  50  will indicate a continued increase in force. When the inflation is stopped, the sensor  50  will indicate a relatively constant force. As the infusion process continues, the tissue may compress away from the sensor  50 , which will be indicated by a drop in the force as measured by the sensor  50 . This will indicate a decrease in the conformance of the balloon  28  to the tissue  12 . The feedback control system  20  is adapted to detect this decrease, and will adjust the balloon  28  inflation accordingly. 
     Multiple force sensors  50  may be utilized, such that multiple locations around the interface between the balloon  28  and the tissue  12  may be detected. In this way, the feedback control system  20  can detect the conformance at multiple points and adjust the volume of the balloon  28  to maintain the desired level of conformance. 
     The balloon pressure sensor  52  is a pressure sensor which measures the pressure of the inflation fluid in the balloon  28 . The balloon pressure sensor  52  may be placed in-line of the inflation tube  40 , or even directly within the balloon  28 . The correlation between the balloon pressure sensor and the conformance of the balloon  28  and the tissue  12  is similar to that of the force sensor. With the balloon  28  first located in a resected cavity with the balloon uninflated, the sensor  52  will measure little or no force. As soon as balloon  28  inflation starts, the sensor  52  will measure an increase in pressure. As the balloon  28  is further inflated, the sensor  52  will indicate a continued increase in pressure. When the inflation is stopped, the sensor  52  will indicate a relatively constant force. If, during the infusion process, the balloon  28  begins to lose conformance with the tissue, the pressure indicated by the sensor  52  will decrease. A drop in pressure can be correlated to a decrease in the conformance of the balloon  28  to the tissue  12 .  FIG. 5  shows an exemplary graph of the pressure readings of a balloon pressure sensor  52  as it is inflated in a tissue cavity.  FIG. 5  shows the pressure increasing at the start of the inflation process. Then, there is a range of pressure which is considered to be optimal for balloon conformance. Less than good conformance is indicated if the pressure measured by the sensor  52  is lower than the optimal range. Excess pressure may be indicated if the sensor  52  measures a pressure labeled as excess inflation pressure in  FIG. 5 . The feedback control system  20  is adapted to detect the pressure reading from sensor  52 , and to adjust the balloon  28  inflation accordingly. 
     The drug infusion pressure sensor  54  is a pressure sensor which measures the pressure of the drug fluid being infused through the catheter  16  (back pressure). The drug infusion pressure sensor  54  is placed in-line of the drug infusion tube  40 , but may also be placed anywhere else along the drug infusion pathway. The correlation between the drug infusion pressure sensor  54  and the conformance of the balloon  28  and the tissue  12  is generally as follows. With the balloon  28  located in the resected cavity and the balloon  28  properly inflated, the drug infusion device  18  is operated to supply drug, in fluid form, to the drug delivery port  34  on the infusion catheter  16  The infusion catheter  16  directs the drug to the target volume of tissue  12 . When the drug is first delivered, the pressure in the delivery line, as measured by the sensor  54 , will gradually increase as the tubes and lumens are filled with drug and are pressurized, until a steady state pressure is achieved. As long as balloon/tissue conformance is maintained, the pressure measured by sensor  54  will remain relatively stable. If there is a loss in conformance, the drug infusion pressure at the sensor  54  will drop as the relative volume in the cavity increases. Thus, a drop in pressure detected by sensor  54  can be correlated to a decrease in the conformance of the balloon  28  to the tissue  12 .  FIGS. 6   a  and  6   b  show exemplary graphs of the pressure readings of a drug infusion pressure sensor  54  during a drug infusion procedure.  FIG. 6   a  shows a stabilized pressure indicating good conformance, while  FIG. 6   b  shows a drop in pressure indicating a loss of conformance.  FIGS. 6   a  and  6   b  also illustrate an exemplary range of optimal acceptable pressure drop which correlates to good balloon conformance. Any drop in pressure below the threshold amount may be used to indicate excessive loss of conformance. Upon detecting the threshold amount of pressure drop at sensor  54 , the feedback control system  20  is adapted to adjust the balloon  28  inflation accordingly. 
     The drug diffusion pressure sensor  56  is a pressure sensor which measures the pressure of the drug fluid at or near the target tissue. For example, the drug infusion pressure sensor  56  may be placed at the outside surface of the balloon  28  at a spaced apart location from the drug delivery outlet  26 . The correlation between the drug diffusion pressure sensor  56  and the conformance of the balloon  28  and the tissue  12  is substantially the same as the drug infusion pressure sensor  43 . Indeed, a graph of the pressure readings of a drug diffusion pressure sensor  56  during a drug infusion procedure would look very similar to those of  FIGS. 6   a  and  6   b , except that the magnitude of the pressures would be less. In the same way as for the drug infusion pressure sensor  54 , upon detecting a threshold amount of pressure drop at sensor  56 , the feedback control system  20  is adapted to adjust the balloon  28  inflation accordingly. 
     The feedback control system  22  is operably coupled to each of the sensors  50 ,  52 ,  54  and  56  and receives input signals from these sensors. In one implementation of the feedback control system, the feedback control system computes the inflation volume of the balloon  28  based on the input from the sensors  50 ,  52 ,  54  and  56  and a pre-defined set of algorithms. Then, the feedback control system computes the necessary adjustment to the inflation volume of the balloon  28  in order to provide the desired conformance of the balloon  28 . The feedback control system  22  is operably coupled to the expansion control device  20  so that the feedback control system  22  can control the expansion control device  20  to adjust the inflation volume of the balloon  28 . As the inflation volume of the balloon  28  is adjusted, the feedback control system continues to receive input signals from the sensors, which can be used to re-compute the inflation volume of the balloon  28  and/or the required adjustment to the inflation volume. This forms the closed-loop control system of the present invention. A flow chart for an exemplary algorithm by which the feedback control system  22  may operate is shown in  FIG. 7 . 
     As mentioned above, any one or more of the sensors  50 ,  52 ,  54 , and  56  may be used in the system  10 . In one exemplary implementation, only the balloon inflation pressure sensor  52  and the force sensor  50  are used. In another exemplary implementation, only the drug infusion pressure sensor  54  and the drug diffusion pressure sensor  56  are utilized. In still another implementation, only one of the sensors  50 ,  52 ,  54  and  56  are utilized and one or more of the other parameters is determined using a pre-defined correlation between the measured parameter and the other parameters. For example, the system  10  may utilize only the drug infusion pressure sensor  54 , such the system  10  can effectively monitor and adjust conformance using only a single parameter. 
     One skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.