Patent Publication Number: US-6659996-B1

Title: Device for delivering biological agents

Description:
RELATED APPLICATION 
     This application is a continuation-in-part application of U.S. application Ser. No. 09/266,380, filed Mar. 11, 1999, which is a continuation-in-part application of U.S. application Ser. No. 08/552,467, filed Nov. 9, 1995 now U.S. Pat. No. 5,906,599, the entire teachings of which are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     Much effort has been expended in recent years to find an effective and superior way of administering drugs to patients&#39; bodies. Products such as the transdermal patch and once-a-day orally administered pills that more precisely deliver drugs have been developed. Such products are a boon to patients for they boost the effectiveness of the drugs and limit side effects by precisely controlling how quickly drugs are released in the body; by keeping drugs at a constant level and by delivering them exactly where needed. 
     One such development is the injection or implantation of drugs in the form of in microscopic particles or pellets at a disease site. The drugs are encapsulated in polymers or fatty compounds, such as liposomes which permit slow release of the encapsulated drug over time thereby potentially lowering the drugs toxicity. 
     In addition, there are times when it is desirable to deliver a biological agent that is in a non-conventional form to a disease site such as a drug in a loose particulate form, or a quantity of cells, cell clusters or cellular extracts in a bibcompatible solution. A particulate biological agent can be in a granular, powdered, or microsphere form. The problem with biological agents in these forms is that they are difficult to properly deliver to a diseased tissue site. 
     SUMMARY OF THE INVENTION 
     The present invention provides a novel device with a distal end insertable into the tissue or a body cavity of a patient for delivering both particulate and liquid biological agents in a quick, predictable, safe and easy manner without damaging the biological agent. This is important in the delivery of cells or microspheres. 
     The present invention is directed to a biological agent delivery device including a sheath having a longitudinally extending wall surrounding an interior region, and a closed tip at a distal end. A flexible pouch formed in the sheath wall for containing a biological agent is capable of being displaced radially or laterally outwardly for radially displacing the biological agent. 
     In preferred embodiments, a displacement member is disposed within the sheath for causing displacement of the pouch radially with respect to the sheath to radially or laterally deliver the biological agent. The sheath is flexible and the pouch is preformed in the sheath wall. A guide wire extends within the sheath for guiding the delivery device. Preferably, the pouch system encircles the sheath. In one preferred embodiment, the displacement member includes a spring member. In another preferred embodiment, the displacement member includes a volume of fluid. The volume of fluid can be either a liquid or a gas. Optionally, a light source is included for directing light within the sheath. The light is transmitted to the tip of the delivery device by the fluid within the sheath. In yet another embodiment, the light is transmitted to the tip of the delivery device by a fiber optic disposed within the sheath. The tip is formed in a manner to produce or deliver a desired pattern of light. In still another preferred embodiment, a balloon extends from the sheath for controlling fluid flow within body cavities. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. 
     FIG. 1 is a plan view of a preferred biological agent delivery device. 
     FIG. 2 is a side sectional view of the biological agent delivery device of FIG. 1 with the distal end of the device inserted into tissue. 
     FIG. 3 is a side sectional view of the distal end of the biological agent delivery device with the outer tube  102  retracted to expose the cannula notch  104   b  and the support surface  105   a  of the flexible membrane  105 . 
     FIGS. 4 and 5 are side sectional views of the distal end of the biological agent delivery device of FIG. 2 depicting the delivery of a quantity of a biological agent to a tissue site. 
     FIGS. 6 and 7 are side sectional views of the distal end of another preferred biological agent delivery device depicting the delivery of a quantity of a biological agent to a tissue site. 
     FIG. 8 is a side sectional view of the distal end of yet another preferred biological agent delivery device. 
     FIG. 9 is a side sectional view of the distal end of still another preferred biological agent delivery device. 
     FIG. 10 is a side sectional view of the distal end of still another preferred biological agent delivery device. 
     FIG. 11 is a side schematic view of a preferred biological agent delivery catheter. 
     FIG. 12 is a side schematic view of the catheter of FIG. 11 positioned within a body passage with the pouches displaced laterally outward to release the biological agents. 
     FIG. 13 is a side sectional view of another preferred biological agent delivery catheter. 
     FIG. 14 is a side-sectional view of still another preferred biological agent delivery catheter. 
     FIG. 15 is a side view of another preferred pouch arrangement. 
     FIG. 16 is a side-sectional view of still another preferred pouch arrangement. 
     FIG. 17 is a cross-sectional view of yet another preferred pouch arrangement. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring to FIGS. 1 and 2, biological agent delivery device  100  is an apparatus suitable for single-handed subcutaneous delivery of a biological agent  106  such as a quantity of a loose particulate drug, or a quantity of cells, cell clusters or cellular extracts in solution with a biological compatible carrier. For purposes of illustrating the invention, we have selected a delivery device similar to the device disclosed in U.S. Pat. No. 5,562,613 which is incorporated herein by reference in its entirety. However, other mechanisms for inserting and retracting the various members may substitute therefore. Additionally, for illustration purposes, the biological agent  106  depicted in the drawings is a particulate drug. 
     Delivery device  100  has a housing  12  with a pair of finger grips  14  extending transverse the longitudinal axis of the housing. A driving member  16  is slideably engaged with a track  20  formed along the longitudinal length of housing  12 . The housing  12  has an external cylindrical bore  18  formed therein which extends along the longitudinal axis of the housing  12 . A tubular member or cannula  104 , having an internal bore  104   c  is mounted within the external cylindrical bore  18  and extends along the longitudinal axis of bore  18 . A piston  108  is shown disposed within internal bore  104   c . Cannula  104  has a solid distal tip  104   a  which is angled for penetration into tissue. A radially lateral opening in the cannula  104  near tip  104   a  forms a cannula notch  104   b  (FIG.  3 ). An outer tube  102  is secured to housing  12  and is mounted concentrically about cannula  104 . Cannula  104  is axially slideable relative to cylindrical bore  18  and outer tube  102  for extending or retracting cannula  104  relative to outer tube  102  in order to enclose or expose cannula notch  104   c . A flexible membrane  105  having a collapsible support surface  105   a , a tubular portion  105   b  and a closed distal end  105   c  is positioned coaxially within bore  104   c  of cannula  104 . The distal end  105   c  of membrane  105  extends into cannula notch  104   b  and abuts the distal end  103  of cannula notch  104   b . Flexible membrane  105  extends across the opening of cannula notch  104   b  and prevents bore  104   c  from communicating with regions outside cannula  104  through cannula notch  104   b . Piston  108  is mounted coaxially within the tubular portion  105   b  of the flexible membrane  105 . Piston  108  is axially slideable relative to cannula  104  and tubular portion  105   b  and acts as a displacement member for radially, laterally displacing support surface  105   a . Since the bore  104   c  within cannula  104  terminates at the distal end  103  of cannula notch  104   b , piston  108  is restricted from extending past cannula notch  104   b.    
     The support surface  105   a  of flexible membrane  105  is located near the distal end  105   c  of the membrane  105  for supporting a quantity of a biological agent  106 . The support surface  105   a  is changeable from an undisplaced or collapsed position to a displaced position. When membrane  105  is an undisplaced position, support surface  105   a  is indented downwardly (or inwardly) into flexible membrane  105  to form a pouch with support surface  105   a  contacting the opposite side of the membrane  105 . The pouch is typically formed by pushing support surface  105   a  downwardly (inwardly). The support surface  105   a  provides the surfaces of the pouch. Alternatively, the pouch can be preformed into membrane  105  such as by molding. When membrane  105  is in a displaced position, the pouch disappears with the support surface  105   a  being relatively horizontal. Membrane  105  is preferably formed from a flexible polymeric material which can either be stretchable or non-stretchable and can be transparent. Alternatively, membrane  105  can also be formed from other suitable flexible materials such as fabrics. Although tubular portion  105   b  is typically flexible, alternatively, tubular portion  105   b  can be rigid with only the support surface  105   a  being flexible. 
     The piston  108  and cannula  104  are secured at their respective proximal ends by a piston grip  48 , and a cannula grip  50 . The proximal end of tubular portion  105   b  of membrane  105  of has a flange  105   d  which secures tubular portion  105   b  to cannula  104  at the proximal end of cannula grip  50 . Additionally, if needed, tubular portion  105   b  can be bonded within bore  104   c  with an adhesive. The piston grip  48  and cannula grip  50  are disc-shaped with a diameter which approximates the diameter of the cylindrical bore. The piston grip  48  and the cannula grip  50  are slideably engaged within the housing bore  18 . The piston grip  48  and cannula grip  50  have respective channels formed therein through which drive pins  32  and  34  respectively extend for engagement with the proximal ends of the piston  108  and cannula  104  respectively. 
     Piston drive pin  32  and cannula drive pin  34  both extend through a single elongate slot  128  in housing  12 . Housing slot  128  has a notch  128   a  located at its distal end for engaging cannula drive pin  34  when cannula drive pin  34  is in the advanced position. Piston drive pin  32  extends through driving member  16  through a hole  32   a . Cannula drive pin  34  extends through driving member  16  through an elongate driving member slot  126 . Driving member slot  126  has a notch  126   a  located at its distal end for engaging cannula drive pin  34 . 
     The piston  108 , cannula  104  and outer tube  102  are preferably formed of rigid sterilizable material such as stainless steel. Other components of the device, including the housing, driving member, piston and cannula grips, etc. are preferably made from low cost plastic material. The use of molded plastic components for the manufacture of the instrument is preferred to lower the cost so that the device can be disposed of after use. 
     In operation, in order to subcutaneously deliver a quantity of a biological agent  106  to a desired tissue site, the surface  112   a  of tissue  112  is first cut with a scalpel. The tip  104   a  of cannula  104  is then inserted into the incision within tissue  112  while driving member  16  is in a retracted position and the distal end  101  of delivery device  100  is advanced into tissue  112  until reaching a desired location. When driving member  16  is in a retracted position, cannula notch  104   b  is enclosed by outer tube  102  with the tip of piston  108  being at the proximal end of cannula notch  104   b . Outer tube  102  protects the biological agent  106  and prevents it from spilling out of cannula notch  104   b  prematurely. Alternatively, tip  104   a  of cannula  104  can be inserted into tissue  112  by puncturing the surface  112   a  of tissue  112  with tip  104   a.    
     Driving member  16  is then moved distally along track  20  toward the distal end  101  of delivery device  100 . Cannula drive pin  34  is engaged within notch  126   a  of driving member slot  126  and piston drive pin  32  is engaged by hole  32   a . As the driving member  16  is advanced, cannula  104  is extended from outer tube  102  such that cannula notch  104   b  and the biological agent  106  are exposed beyond the tip  102   a  of outer tube  102  as seen in FIG.  4 . At the same time, driving member  16  advances piston  108  by engaging piston drive pin  32  with hole  32   a  such that the cannula  104  and the piston  108  advance together in unison. Cannula  104  is extended until cannula drive pin  34  reaches the distal end of housing slot  128  where cannula drive pin  34  engages housing slot notch  128   a.    
     As driving member  16  is further advanced, cannula drive pin  34  disengages from notch  126   a  in driving member slot  126  and piston drive pin  32  is advanced further, thereby advancing piston  108  forward relative to cannula  104 . As piston  108  is extended into cannula notch  104   b , piston  108  laterally displaces the support surface  105   a  of membrane  105  thereby laterally displacing the biological agent  106  from cannula notch  104   b  into the surrounding tissue  112  as seen in FIG.  5 . Piston  108  is extended into cannula notch  104   b  until the proximal end of driving member slot  126  reaches cannula drive pin  34 , thereby preventing further advancement of driving member  16 . Further advancement of piston  108  is also prevented by the distal end  103  of cannula notch  104   b.    
     Once the biological agent  106  is deposited into tissue  112 , the distal end  101  of delivery device  100  can be removed from tissue  112 . To remove distal end  101  from the tissue  112 , the cannula  104  and the piston  108  are first retracted relative to outer tube  102  by retracting driving member  16 . This leaves behind the biological agent  106  within tissue  112 . Distal end  101  of delivery device  100  is then pulled from tissue  112  leaving behind a small puncture wound. 
     FIGS. 6 and 7 depict the distal end of biological agent delivery device  130  which is another preferred embodiment of the present invention differing from delivery device  100  in that piston  108  and the components associated with advancing and retracting piston  108  are omitted. Instead, in order to deliver a biological agent  106 , a fluid  107   a  such as a gas or a liquid is introduced into cavity  107  within membrane  105  to serve as a displacement member in order to laterally displace the support surface  105   a . If desired, the fluid can outwardly displace support surface  105   a  past the outer surface of cannula  104  thereby forming an outward bulge in membrane  105 . The fluid is preferably air if a gas is employed or saline solution if a liquid is employed and is preferably introduced into cavity  107  by a piston/plunger type mechanism or a closed loop pump mechanism within or attached to delivery device  130 . Such a mechanism can be a syringe-type device or a calibrated ampoule-type device. Alternatively, the fluid can be introduced from a reservoir by a pump or from a pressurized tank and can be any other suitable gas or liquid. 
     Referring to FIGS. 8 and 9, flexible membrane  117  differs from flexible membrane  105  in that it does not include a tubular portion  105   b  but consists of a flexible membrane extending across and sealed over the lateral opening of cannula notch  104   b . As a result, in the embodiment shown in FIG. 8, the piston  108  contacts and slides within bore  104   c  of cannula  104 . In the embodiment depicted in FIG. 9, the support surface  105   a  of membrane  117  is laterally displaced by a fluid such as gas or liquid introduced into bore  104   c  of cannula  104 . 
     Referring to FIG. 10, biological agent delivery device  132  is a flexible catheter for insertion into body cavities of a patient. In order to provide flexibility of the catheter, the cannula  104  and outer tube  102  are made of flexible material. As in delivery device  130 , the support surface  105   a  of flexible membrane  105  is displaced by fluid introduced into cavity  107 . Cannula  104  has a blunt tip  115  to facilitate the passage of delivery device  132  through body cavities. Although delivery device  132  is shown to include flexible membrane  105 , alternatively, flexible membrane  117  may be employed instead. 
     An optional fiber optic bundle  109  including optical fibers  109   a ,  109   b  and  109   c  is positioned within bore  104   c  of cannula  104  alongside tubular portion  105   b  of membrane  105 . Optical fiber  109   c  is directed laterally with respect to cannula  104  to provide light to a desired drug delivery site for optimized drug absorption. Illumination is also useful when delivering cells, subcellular extracts, plasmids or gene products for genetic therapy because it facilitates gene transfer. In addition, other forms of electromagnetic radiation can be delivered by optical fiber  109   c , for example, ultra-violet light for altering cell membranes or for sterilization, or to increase cell membrane permeability with blue light. Furthermore, optics for viewing the delivery site are provided by laterally positioning optical fiber  109   b  and lens  111 . Finally, optics for forward viewing are provided by optical fiber  109   a  and lens  113 . 
     The fluids (liquids or gases) employed for displacing the support surface  105   a  in the embodiments depicted in FIGS. 6,  7 ,  9  and  10  can be temperature controlled over a range of different temperatures for therapeutic purposes. The temperature of the fluid is controlled by a cooling/heating system which is coupled to the fluid delivery system. For example, a cold fluid can be used for cooling the tissue surrounding the delivery site for constricting the capillaries in that tissue so that the delivered biological agent passes into the bloodstream more slowly. Alternatively, a heated fluid can be used for heating the tissue surrounding the delivery site for widening the capillaries so that the delivered biological agent passes into the bloodstream more rapidly. In this manner, the delivery rate of the biological agent can be controlled. In addition, extreme cold or hot fluids can be used to freeze or coagulate tissue, if desired. 
     Although the present invention biological agent delivery devices of FIGS. 1-10 have been described above for primarily delivering particulate or liquid biological agents, biological agents in pellet form can also be delivered. The term “biological agent” is meant to encompass any substance that can be introduced into tissue or a body cavity for treating a patient such as drugs, microspheres, cells, cell clusters, cells transfected with foreign DNA, cellular components, cellular extracts or gene products. The term “drug” as used herein is intended to have a broad construction so as to include any type of medication capable of being administered in the manner described herein. When biological agents in a liquid form are delivered, a sealing arrangement can be provided around cannula notch  104   b  to reduce the possibility that liquid will not leak prematurely from cannula notch  104   b  when outer tube  102  encloses cannula notch  104   b.    
     Referring to FIGS. 11 and 12, biological agent delivery catheter  210  is another preferred biological agent delivery device for delivering biological agents  222 . Catheter  210  includes an elongate tubular sheath  212  formed of flexible material. The distal end of sheath  212  terminates at a curved blunt tip  214 . A guide wire  216  for guiding catheter  210  within a body cavity extends within the interior  226  of sheath  212  along the longitudinal axis of sheath  212  and is secured to tip  214 . Two displaceable pouch systems  224   a  and  224   b  for containing and delivering biological agents  222  are positioned near the tip  214  of catheter  210 . 
     The pouch systems  224   a / 224   b  are spaced apart from each other along the length of sheath  212  and each include an annular pouch or pocket  220  encircling the circumference of the sheath  212 . The pouches  220  are preferably formed of a thinner, more flexible membrane  252  than sheath  212  and are bonded to the wall  213  of sheath  212 . The pouches  220  are radially inwardly indented into the interior  226  of sheath  212  and can be preformed into this shape. Pouches  220  form recessed regions for containing or storing biological agents  222  away from the outer perimeter of sheath  212  and include a support surface  220   a  for supporting biological agents  222  therein. Opposing edges  215  of the wall  213  of sheath  212  are positioned adjacent to each other which causes the membranes of pouches  220  to form a substantially enclosed inward loop to so that the biological agents  222  do not prematurely spill from the pouches  220 . This protects the biological agents  222  during insertion of the catheter  210  within a body cavity. The biological agents  222  are similar to the biological agents  106  previously described above. A spring member  218  is coupled to tip  214  between the guide wire  216  and the tip  214  for causing the delivery of the biological agents  222 . 
     Referring to FIG. 12, in operation, catheter  210  is inserted within a body lumen or cavity  228 . Catheter  210  is advanced within the cavity  228  while being guided by guide wire  216  until reaching a desired location for the delivery of the biological agents  222 . Release of the spring member  218  causes stretching or lengthening of sheath  212  in the direction of arrow  217  which pulls edges  215  away from each other as shown by arrows  219  and displaces pouches  220  radially or laterally outward into a flattened state relative to the longitudinal axis of sheath  212 . This causes the release of the biological agents  222  radially or laterally outward from catheter  210  relative to the longitudinal axis to the desired treatment location. 
     Although pouches  220  are preferably formed from a membrane  252  that is bonded to sheath  212 , alternatively, pouches  220  can be integrally formed from the wall  213  of the sheath  212 . In such a case, the pouches  220  would be formed to be more flexible than the surrounding wall  213 . 
     Referring to FIG. 13, biological agent delivery catheter  230  is another preferred catheter. Catheter  230  differs from catheter  210  in that a fluid  232  is introduced into the interior  226  of sheath  212  for lengthening sheath  212  to radially or laterally outwardly displace the pouches  220  of pouch systems  224   a / 224   b . Fluid  232  can be a liquid or a gas depending upon the application at hand. Also, depending upon the pressure of fluid  232 , the outwardly displaced pouches  220  can be displaced flush with the wall  213  of sheath  212  or outwardly bulging as depicted in phantom. Tip  214  is formed of an optically transmissive material for transmitting light  234  received from a light source  233 . The light  234  is transmitted through the interior  226  of sheath  212  by fluid  232 . Tip  214  is preferably formed from a solid piece of material that is secured to sheath  212 , but alternatively, can be hollow or integrally formed with sheath  212 . The shape and design of tip  214  is made to produce a desired pattern of transmitted light. As a result, tip  214  can be of other suitable shapes depending upon the application at hand and can include mirrors if desired. Various types of light can be transmitted as previously discussed with respect to FIG.  10 . 
     Referring to FIG. 14, biological agent delivery catheter  240  is another preferred catheter which differs from catheter  230  in that catheter  240  includes a balloon  246  for controlling the flow of fluids such as blood around catheter  240  when catheter  240  is introduced within a passage such as a vein or artery. A central tube  242  is positioned within the interior  226  of sheath  212 , thereby forming an outer annular region  236  into which the fluid  232  is introduced for radially or laterally outwardly displacing the pouches  220 . Tube  242  has an interior region  244  which is coupled in fluid communication with the interior  248  of balloon  246  via passages  250  so that balloon  246  can be inflated independently from the operation of pouch systems  224   a / 224   b . Finally, a fiber optic  238  extends within the interior  244  of tube  242  for transmitting light to tip  214 . 
     FIG. 15 depicts another preferred pouch system  235  which includes a shallow preformed indented annular pouch  236  within sheath  212 . The edges  215  of the wall  213  of sheath  212  are positioned further apart from each other than with pouches  220 . A rupturable membrane  237  having a weakened region  237   a  (for example, perforations) covers pouch  236  to prevent premature release of the biological agents  222 . 
     Referring to FIG. 16, pouch  221  is another preferred pouch which differs from pouch  220  in that instead of being a single annular pouch encircling sheath  212 , pouch  221  is only one of multiple pouches  221  encircling sheath  212 . Membrane  252  is bonded to the edges of a circular or oval opening  254  within sheath  212 . Membrane  252  can be preformed to extend inwardly into the interior  226  of sheath  212 . The biological agent  222  is released when the membrane  252  is displaced outwardly as shown in phantom. A flexible outer sleeve  256  is included which extends around sheath  212 . Sleeve  256  is longitudinally slidable relative to sheath  212  as shown by arrows  258  to cover pouch  221  (shown in phantom) during insertion into a patient to prevent premature release of biological agent  222 . Sleeve  256  is slidably retracted relative to pouch  221  to allow biological agent  222  to be delivered. 
     FIG. 17 is another preferred pouch system  260  in which the pouches  258  differ from pouch  221  (FIG. 16) in that pouches  258  are integrally formed from the wall  213  of sheath  212 . The sheath can be hardened in the areas surrounding the pouches  258  so that the pouches  258  remain flexible. In order to prevent premature release of the biological agents  222 , the rupturable membrane  237  (FIG. 15) or the slidable outer sleeve  256  (FIG. 16) can be employed. Although four pouches  258  are depicted to encircle the circumference of sheath  212 , alternatively more than four or less than four can be employed. The number of pouches  258  can be determined by the diameter of sheath  212 . 
     While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. For example, other mechanisms can be employed for advancing and retracting cannula  104  and piston  108 . Such mechanisms can include motor or hand-operated gears and power screws, or fluid operated cylinders. In addition, the present invention delivery devices and catheters can be employed for implanting non-therapeutic, solid or rigid objects into tissue or body cavities such as tracking devices, radio transmitters or pumps. Furthermore, various features of the above discussed delivery devices and catheters can be combined or omitted.