Abstract:
Methods and apparatus are provided for treating damaged tissue using apparatus that atraumatically delivers a bioactive agent within the tissue, wherein the apparatus provides a column of stem cells may be advanced simultaneously with a needle during needle insertion, and then held stationary or injected at low pressure while retracting the needle. Alternatively, the needle may employ electromotive forces, or to change a dimension of the needle, to expel the bioactive agent into the needle track.

Description:
REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application is a continuation-in-part of U.S. patent application Ser. No. 10/894,810, filed Jul. 19, 2004. 
     
    
     FIELD OF THE INVENTION  
       [0002]     The present invention relates to apparatus and method for treating an injured spinal cord and other injured tissue using passive injection systems that reduce barotrauma to the injected material and collateral damage to the host tissue.  
       BACKGROUND OF THE INVENTION  
       [0003]     Spinal cord injuries may arise from car accidents, violent crimes, falls and sports injuries. Spinal cord injury is a major neurological problem since most damage resulting from the injury is irreversible. Injured nerves fibers do not normally regenerate with resulting loss of nerve cell communication, leading to paralysis and loss of sensation.  
         [0004]     After spinal cord severance, a new glial basal lamina forms to cover the exposed surface of the cord end regions. The glial cells also secrete barrier molecules that are difficult to penetrate, further suppressing reestablishment of nerve interconnections. The spinal cord tissue bordering the severed region becomes necrotic, detaches from the spinal cord, and develops irregular cavities.  
         [0005]     Most tissue in the human body originates from undifferentiated cells known as stem cells. These fundamental building blocks differentiate into specific target parenchymal tissue based on hormonal and other local signals. Scientific evidence suggests that stem cells injected into a target tissue will differentiate into a cell line specific to the host tissue. This capability is of particular interest in treating conditions involving organs, such as the spinal cord, heart and brain that cannot regenerate.  
         [0006]     Initial enthusiasm concerning stem cell implantation in patients was tempered by the ethical and logistic concerns of utilizing embryonic stem cells. Recent developments in stem cell research suggest adult stem cells can be harvested from the bone marrow and other tissues. Many such “cell lines” have been generated and are undergoing clinical evaluation. If successful, this work will obviate the moral and ethical dilemma of utilizing tissue from embryos for research.  
         [0007]     Pressurized direct injection of certain bioactive agents, such as stem cells, is expected to inflict physical damage to the cell membranes due to fluid turbulence and pressure fluctuations (referred to herein as “barotrauma”) during the injection process. The damage may include lysis of the cells or injury to the cells that may significantly reduce the yield of viable cells delivered at the injection site and/or trauma to the target tissue. Forceful injection of any material into tissue also may disrupt the delicate intercellular matrix, thereby causing target tissue cellular injury.  
         [0008]     In view of these drawbacks of previously known apparatus and methods, it would be desirable to provide methods and apparatus for treating severed or injured spinal cords by atraumatically delivering a bioactive agent, e.g., stem cells, within or adjacent to the injured spinal cord to promote nerve regeneration.  
         [0009]     It would be also desirable to provide methods and apparatus for treating spinal cord injury by delivering a bioactive agent so as to reduce the risk of barotrauma to the agent and target tissue during delivery.  
         [0010]     It would be further desirable to provide apparatus and methods for treating spinal cord injury by delivering a bioactive agent to damaged tissue to promote tissue regeneration, wherein the apparatus and methods enhance the proportion of viable material delivered to the damaged tissue.  
         [0011]     It further would be desirable to provide apparatus and methods for treating a spinal cord injury to cause nerve regeneration of both the sensory and motor nerves in the spinal cord.  
       SUMMARY OF THE INVENTION  
       [0012]     In view of the foregoing, it is an object of the present invention to provide methods and apparatus for treating spinal cord injury or other nerve or muscle tissue by atraumatically delivering a bioactive agent within or adjacent to an injured portion of the nerve or muscle to promote regeneration.  
         [0013]     It is another object of this invention to provide methods and apparatus for treating spinal cord injury by delivering a bioactive agent so as to reduce the risk of barotrauma to the agent and target tissue during delivery.  
         [0014]     It also is an object of this invention to provide apparatus and methods for treating spinal cord injury by delivering a bioactive agent to damaged tissue to promote tissue regeneration, wherein the apparatus and methods enhance the proportion of viable material delivered to the damaged tissue.  
         [0015]     It is a further object of the present invention to provide apparatus and methods for treating spinal cord injury to cause nerve regeneration of both the sensory and motor nerves in the spinal cord.  
         [0016]     These and other objects of the present invention are accomplished by providing methods and apparatus for delivering bioactive agents, preferably including stem cells or other precursor cells, to treat spinal cord injury, wherein the stem cells are delivered atraumatically. In the context of the present invention, “atraumatic” deployment means deployment of the stem cells without generating turbulent fluid motion that inflicts physical damage to the stem cells, e.g., due to high shearing stresses or pressure fluctuations. The bioactive agent preferably is delivered in a solution comprising nutrients to foster stem cell survival after implantation, and one or more drugs or hormones to suppress inflammatory response, etc.  
         [0017]     In accordance with the principles of the present invention, the bioactive agent is directly deployed in a needle track formed in a target tissue mass following formation of the needle track. In this manner, the bioactive agent is not subject to barotrauma during delivery, nor does forceful impingement of the injectate during delivery disrupt the pre-existing intercellular matrix.  
         [0018]     Deployment of stem cells preferably is accomplished using needle arrangements that avoid impingement of the stem cells against target tissue at high velocity by employing low-pressure injection, capillary action or electrostatic forces to eject the stem cells out of the needle during needle withdrawal. In one preferred embodiment, a column of stem cells may be advanced simultaneously with a needle during needle insertion, and then held stationary while retracting the needle. In another embodiment the needle comprises an electroactive polymer that contracts along its length to expel the stem cells into the needle track. In a further embodiment, electromotive forces are employed to deposit the stem cells into the needle track. According to some embodiments, a grid may be positioned over the injured portion of the spinal cord to guide injections of the bioactive agent.  
         [0019]     While the present invention is described in the context of promoting regeneration of spinal cord tissue, the apparatus and methods of the present invention advantageously may be employed wherever it is desired to promote tissue regeneration, such as in the heart, kidney, liver, brain and other organs and muscles.  
         [0020]     Methods of using the apparatus of the present invention also are provided.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0021]     Further features of the invention, its nature and various advantages will be more apparent from the accompanying drawings and the following detailed description of the preferred embodiments, in which:  
         [0022]      FIGS. 1A-1C  are views depicting previously known methods of injecting drugs and other bioactive agents into a tissue mass;  
         [0023]      FIGS. 2A-2C  are views depicting a method of injecting drugs and other bioactive agents into a tissue mass in accordance with the principles of the present invention;  
         [0024]      FIGS. 3A and 3B  are views depicting apparatus of the present invention for injecting drugs and other bioactive agents into a tissue mass at multiple sites simultaneously;  
         [0025]      FIGS. 4A and 4B  are, respectively, a side view, partly in section, and isolation view of the internal components of apparatus of the present invention;  
         [0026]      FIGS. 5A-5C  depict operation of the apparatus of  FIG. 4 ;  
         [0027]      FIGS. 6A and 6B  are cross-sectional views of apparatus and methods of the present invention for injecting a bioactive agent into an injured spinal cord;  
         [0028]      FIGS. 7A and 7B  are cross-sectional views of another embodiment of the apparatus of the present invention; and  
         [0029]      FIGS. 8A and 8B  are cross-sectional views of a further alternative embodiment of apparatus of the present invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0030]     Referring to  FIGS. 1A-1C , some of the drawbacks of previously known bioactive agent delivery systems are described.  FIG. 1A  illustrates a previously known injection needle  10  being brought into approximation with tissue mass T. Once the tip of needle  10  is inserted into the tissue, as shown in  FIG. 1B , bioactive agent B, which may comprise stem cells, is injected into the tissue mass.  
         [0031]     Applicant has discovered that pressurized injection of a bioactive agent may have a substantial detrimental effect both on the agent delivered and the tissue to be treated. For example, applicant has conducted studies in which it had been observed that pressurized injection causes the injectate stream to impinge violently against the tissue as it leaves the tip of the injection needle. During injection, the injectate stream is turbulent, and may experience rapid localized pressure fluctuations. These effects may damage the bioactive agent, particularly where the agent comprises stem cells, by rupturing the cell membrane or injuring the cellular components.  
         [0032]     In addition, as illustrated in  FIG. 1C , once needle  10  has been withdrawn from the needle track N, the potential exists for the injected bioactive agent B to be expelled from the needle track, with concomitant risk of embolization. Applicant has concluded that a higher yield of viable cells may be delivered to a target tissue if apparatus and methods could be provided that reduce the effects of pressurized injection, including lysis and expulsion.  
         [0033]     Referring now to  FIGS. 2A  to  2 C, apparatus and methods of the present invention are described that overcome the drawbacks of previously known systems for delivering fragile bioactive agents, such as stem cells. As shown in  FIG. 2A , in accordance with the principles of the present invention, needle  20  is first approximated to spinal cord tissue mass T. In  FIG. 2B , needle  20  is shown inserted into the tissue mass. In  FIG. 2C , as needle  20  is withdrawn from the tissue mass, bioactive agent B is delivered from the tip of the needle and deposited in the needle track.  
         [0034]     In accordance with the principles of the present invention, the bioactive agent is injected into the tissue under little pressure and with substantially less turbulence and localized pressure fluctuation than in previously known injection systems. Also, the bioactive agent will not damage the tissue mass by splitting the tissue along naturally-occurring striations. These benefits of atraumatic injection may be particularly advantageous in the repair of an injured or severed spinal cord.  
         [0035]     In  FIGS. 3A and 3B , apparatus constructed in accordance with the principles of the present invention is described, in which distal end  25  includes selectively extendable needles  26 . As depicted in the Figures, needles  26  are configured to flare outward when extended beyond distal end  25  of the apparatus, thereby enhancing dispersal of the bioactive agent into tissue mass T. As described above for the embodiment of  FIG. 2 , needles  26  are configured to delivery bioactive agent B into the tissue mass while minimizing barotrauma to the bioactive agent and the injury to the tissue mass. Although distal end  25  illustratively includes three needles  26 , a greater or lesser number of needles may be employed without departing from the spirit of the present invention.  
         [0036]     Referring now to  FIGS. 4A and 4B , apparatus constructed in accordance with the principles of the present invention is described. Apparatus  30  comprises handle  31  that is configured to accept conventional syringe  28 , which may be loaded with a preselected bioactive agent, such as stem cells in a nutrient solution. The barrel of syringe  28  is removably coupled to tube  32  via fluid-tight seal  33 . Tube  32 , which carries one or more tissue-piercing needles at its distal end, is arranged to reciprocate through sleeve  34  so that the distal tip of the needle extends beyond bushing  35  when the device is actuated. Piston  29  of syringe  28  is removably coupled to block  36  and rails  37 .  
         [0037]     Handle  31  includes trigger  38  that may be depressed to selectively actuate apparatus  30 . In particular, trigger  38  is coupled to tube  33  via gear train  39  and linkage  40 . Clamp  41  is configured to grip and reciprocate the body of the syringe in accordance with the degree of actuation of trigger  38 . Each of rails  37  preferably includes a portion that forms a rack to permit forward movement of piston  29  of the syringe during a first range of motion of trigger  38 , and then retain piston  29  stationary relative to rails  37  during a second range of motion of the trigger.  
         [0038]     Link  40  is coupled to clamp  41  so that, after syringe  28  and piston  29  are advanced during the initial range of motion of the trigger, the piston is held stationary while clamp  41  retracts tube  32  and needles from the needle track(s) and simultaneously urges the body of syringe  28  proximally. This motion causes the bioactive material within syringe  28  to be dispensed into the needle track(s) (see  FIGS. 2 and 3 ) at low velocity and with little or no barotrauma. As depicted in  FIG. 4B  (but omitted elsewhere for clarity), trigger  38  and link  40  preferably are biased by springs  42  and  43 , respectively, to return the mechanism to its starting position when trigger  38  is released.  
         [0039]     Referring now also to  FIGS. 5A-5C , operation of apparatus  30  is described. In  FIG. 5A , trigger  38  of the apparatus is shown at its initial position, and with syringe  28  and piston  29  in the proximal-most positions. As shown in  FIG. 5B , as the trigger  38  is depressed about half-way through its range of motion, gear train  39  and link  40  urge syringe  28 , piston  29  and rails  37  in the distal direction in unison. This in turn causes tube  32  and clamp  41  to be advanced distally, in turn causing needles  43  to extend beyond bushing  35 . Illustratively, the tissue-piercing end of tube  33  includes three needles  43  that flare outward upon entering into a tissue mass, as depicted in  FIG. 3A . Because syringe  28  and piston  29  are moved in unison, the bioactive agent contained within syringe  28  is subjected to substantially no hydraulic forces, and the distance between block  36  and the proximal-most portion of syringe  28  remains unchanged.  
         [0040]     As further depicted in  FIG. 5C , continued depression of trigger  38  causes link  40  to begin retracting tube  32  in the proximal direction. This motion also drives clamp  41  in the proximal direction. Because the rack portions of rails  37  disengage from link  40  and gear train  39  during proximal movement of clamp  41 , rails  37  and piston  29  remain stationary. Consequently, proximal movement of clamp  41  and tube  32  both retracts needles  43  from the needle tracks formed in the tissue, and urges the body of syringe  28  against piston  29 .  
         [0041]     Still referring to  FIG. 5C , proximal translation of claim  41  also causes the distance between block  36  and the proximal-most portion of syringe  28  to shorten. This action applies sufficient pressure to the contents of syringe  28  to dispense the bioactive agent into the needle tracks formed by needles  43  as the needles withdraw from the tissue. When the clinician releases trigger  38 , springs  42  and  43  return tube  32  and clamp  41  to the starting position, shown in  FIG. 5A . Apparatus  30  then may be repositioned, and the above process repeated.  
         [0042]     As will be appreciated, the volume of injected material delivered into the target tissue may be adjusted depending upon the target tissue milieu. For example, for tissue or muscle that is fairly elastic, such as heart muscle, additional material may be injected to create low-pressure compartments within the tissue. On the other hand, lower volumes may be employed in less resilient structures, such as the spinal cord and brain.  
         [0043]     With respect to  FIGS. 6A and 6B , in accordance with another aspect of the invention, needles  43 ′ of apparatus  30  may have different predetermined lengths so as to deliver the bioactive agent at various depths within spinal cord S to treat injured region D. As illustrated in  FIG. 6A , needles  43 ′ may first be used to deliver bioactive agent on a first side of a severed region D of spinal cord S, and then moved and applied to the opposite side of the severed region (shown in dotted line in  FIG. 6A ). Additionally, needles  43 ′ may be arranged to be individually rotated so that the bioactive agent is dispersed in preselected directions.  
         [0044]      FIG. 6B  depicts the use of grid  50  to guide needles  43 ′ into predetermined locations along spinal cord S. Grid  50  comprises block  51  having a plurality of through holes  52  disposed along its surface to provide a predetermined separation between injection regions. Advantageously, grid  50  lends structural support to damaged spinal region D during stem cell injection. As in the method depicted in  FIG. 6A , apparatus  30  may be used to inject needles  43 ′ at a first location, and then repositioned using grid  50  (as shown in dotted line) to provide subsequent injections.  
         [0045]     With further reference to  FIG. 6 , according to some methods of the present invention, a predetermined amount of cerebrospinal fluid may be removed from spinal cord S prior to injecting the bioactive agent. Preferably, the amount of cerebrospinal fluid removed is substantially equivalent to the amount of bioactive agent, e.g., stem cell solution, injected into the spinal cord. This step of the method is expected to enhance atraumatic delivery of the bioactive agent by reducing the risk that the injection prevents injury to the spinal artery or surrounding delicate tissue during injection.  
         [0046]     Referring now to  FIGS. 7A and 7B , an alternative embodiment of an injection needle constructed in accordance with the principles of the present invention is described. Needle  60  comprises a glass or polymer microfiber adapted to receive and transmit electric signals, and includes tissue-piercing distal end  61  and interior lumen  62 . Needle  60  is loaded with a bioactive agent, preferably comprising stem cells  65 , and in addition is coupled to power supply  63  that applies an electric field longitudinally along needle  60 .  
         [0047]     When energized by power supply  63 , an electric field is applied to needle  60  that attracts negatively charged stem cells  65  toward end  61 , where they are deposited into the spinal cord. In particular, as depicted in  FIG. 7B , a positive charge is induced at distal end  61  of needle  60 , thereby causing negatively charged stem cells  65  to be drawn to the distal tip of the needle.  
         [0048]     Stem cells  95  are believed to be negatively charged in the natural state, so that they are drawn toward the positive charge at distal end  61  of needle  60 . Alternatively, an ionic solution containing negatively charged particles may be added to the bioactive agent prior to injection to increase the attraction of the stem cells towards a positive charge. The movement of stem cells  65  toward the positive charge causes a predetermined amount of the stem cells to be ejected from distal end  61  into a target tissue mass, such as a damaged region of spinal cord. Needle  60  optionally may transmit a signal that defines a location of the needle when viewed using an MRI or CT device.  
         [0049]     Referring now to  FIGS. 8A and 8B , another alternative embodiment of the present invention is described. Needle  70  comprises an electroactive polymer that forms an actuator, and includes tissue-piercing distal end  71  and interior lumen  72 . Needle  70  is loaded with a bioactive agent, preferably comprising stem cells  75 , and is coupled to power supply  73  that applies an electric field longitudinally along needle  70 . Electroactive polymers are members of the family of plastics referred to as “conducting polymers,” and are preferred for the practice of the present invention due to their small size, large force and strain and low cost.  
         [0050]     In  FIG. 8 , injection needle  70  comprises an electroactive polymer that is adapted to contract in response to electrical stimulation. Suitable electroactive polymers include, but are not limited to, polypyrrole, polyacetylene, polyaniline and polysulfone. Oxidation or reduction of these polymers leads to a charge imbalance that results in a flow of ions (dopants) into the material in order to balance charge. The ions enter the polymer from an ionically conductive electrolyte medium that is coupled to the polymer surface. Conversely, if ions are already present in the polymer when it is oxidized or reduced, they may exit the polymer.  
         [0051]     Dimensional changes in electroactive polymers may be triggered by the mass transfer of ions into or out of the polymer. For some electroactive polymers, the expansion is due to ion insertion between chains, whereas repulsion between chains is the dominant effect for other electroactive polymers. The mass transfer of ions into and out of the electroactive polymer leads to an expansion or contraction of the polymer. In this manner, needle  70  may be contracted such that a predetermined amount of bioactive agent is ejected from distal end  71  of the needle.  
         [0052]     More specifically, needle  70  comprises an electroactive polymer that is configured to contract when an electric charge is applied to the needle by power supply  73 . Needle  70  has a first diameter ( FIG. 8A ) and a second, contracted diameter ( FIG. 8B ) when energized. Referring to  FIG. 8B , when an electrostatic charge is applied to injection needle  70 , the needle contracts and the diameter of lumen  72  decreases, thereby expelling a predetermined amount of stem cells  75  out of distal end  71  of needle  70 . It is expected that constriction of lumen  72  is a bulk phenomenon that imposes a low-level distributed compressive force to the bioactive agent disposed in the lumen. Accordingly, substantially smaller local pressure fluctations will be imposed on the bioactive agent as compared to pressurized injection using a syringe, thereby reducing barotrauma and leading to substantially better viability of the implanted stem cells.  
         [0053]     As will of course be understood, the embodiments of  FIGS. 7 and 8  may include multiple needle tips to deliver bioactive agent at several sites or depths simultaneously, and may be used with a grid, such as described with respect to  FIG. 6 , to deliver the bioactive agent according to a predetermined pattern. As will further be understood, power supplies  63  and  73  of the embodiments of  FIGS. 7 and 8 , respectively, may include controllers that control operation of the electric fields applied to the needles so that predetermined amounts of bioactive agent are delivered by the needles when activated.  
         [0054]     While preferred illustrative embodiments of the invention are described above, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the invention. The appended claims are intended to cover all such changes and modifications that fall within the true spirit and scope of the invention.