Devices and methods for interstitial injection of biologic agents into tissue

Abstract

Apparatus and methods for injecting biological agents into tissue. Devices are provided having elongate shafts and distal injection heads for transversely driving needles into tissue and injecting medical agents into the tissue through the needles. A longitudinal force directed along the shaft can be translated to a needle driving force transverse to the shaft. Some devices provide controllably variable needle penetration depth. Devices include mechanical needle drivers utilizing four link pantographs, rack and pinions, and drive yokes for driving a first needle bearing body toward a second tissue contacting body. Other devices include inflatable members for driving and retracting needles. Still other devices include magnets for biasing the needles in extended and/or retracted positions. The invention includes minimally invasive methods for epicardially injecting cardiocyte precursor cells into infarct myocardial tissue.

1 . A device for injecting medical agents into tissue, the device comprising: 
 an elongate shaft having a longitudinal axis, a proximal region and a distal region,    a plurality of hollow needles having a sharp distal end, at least one discharge port, a length, and a needle axis along the needle length, the needles operably coupled to the elongate shaft distal region such that the elongate shaft distal region is substantially perpendicular to the needle axes;    means for driving the needles along the needle axes in the direction of the needle sharp distal ends; and    means for discharging a fluid from the needle discharge ports.    
     
     
         2 . A device as in  claim 1 , wherein the means for driving the needles along the needle axes includes a first body having the needles fixedly attached thereto and a second body having the needles slidably disposed therethrough.  
     
     
         3 . A device as in  claim 2 , wherein the first and second bodies each include a substantially planar portion substantially perpendicular to the needle axes.  
     
     
         4 . A device as in  claim 2 , wherein the means for driving the needles along the needle axes includes means for driving the first body toward the second body.  
     
     
         5 . A device as in  claim 4 , wherein the first body includes an inclined portion disposed at an angle to the longitudinal axis of the elongate shaft distal region, the device further comprising a third body longitudinally slidably coupled to the second body and being inclinably slidably coupled to the first body along the first body inclined portion, such that longitudinally translating the third body relative to the second body moves the first body relative to the second body.  
     
     
         6 . A device as in  claim 5 , wherein the fist body inclined portion is an inclined slot and the third body is inclinably slidably coupled to the first body through at least one pin coupled to the third body and extending through the first body inclined slot.  
     
     
         7 . A device as in  claim 2 , wherein the means for discharging fluid includes the first body having a fluid manifold and the needles having fluid entry ports in communication with the fluid manifold.  
     
     
         8 . A device as in  claim 1 , wherein the fluid discharge means includes a proximal pressure source and a lumen disposed along the length of the elongate shaft in fluid communication with both the hollow needles and the proximal pressure source.  
     
     
         9 . A device as in  claim 8 , wherein the proximal pressure source includes a syringe.  
     
     
         10 . A device as in  claim 2 , wherein the means for driving the needles includes the first and second bodies each having a first side and a second, opposite side, wherein each of the first and second bodies first and second sides each have a distal arm linkage and a proximal arm linkage, wherein each of the distal and proximal arm linkages have a first linkage arm pivotally coupled to the first body and a second linkage arm pivotally coupled to the second body and pivotally coupled to the first linkage arm about a linkage joint, such that urging the distal linkage joints and proximal linkage joints farther apart urges the first and second bodies closer together, and urging the distal and proximal linkage joints closer together urges the first and second bodies farther apart.  
     
     
         11 . A device as in  claim 10 , wherein the device includes the proximal linkage joint being secured to the elongate shaft, the device including a first elongate member slidably coupled to the elongate shaft and having a first elongate member distal region secured to the distal linkage joint, such that distally sliding the first elongate member relative to the elongate shaft urges the distal and proximal linkage joints further apart and the needles along their needle axes out of the second body, and such that proximally retracting the first elongate member relative to the elongate shaft urges the distal and proximal linkage joints closer together and urges the needles into the second body.  
     
     
         12 . A device as in  claim 11 , wherein the first elongate member is slidably disposed within a lumen in the elongate shaft.  
     
     
         13 . A device as in  claim 10 , wherein the device includes the proximal linkage joint being secured to the elongate shaft, the device including a first elongate member disposed within the elongate shaft and having a first elongate member distal region secured to the distal linkage joint, wherein the first elongate member helically threadably engages at least one of the distal linkage joint and the proximal linkage joint, such that rotating the first elongate member in a first direction urges the distal and proximal linkage joints further apart and the needles along their needle axes out of the second body, such that rotating the first elongate member in a second direction urges the distal and proximal linkage joints closer together and urges the needles toward the second body.  
     
     
         14 . A device as in  claim 2 , wherein the second body includes a plurality of vacuum pods facing away from the first body.  
     
     
         15 . A device as in  claim 2 , wherein the second body includes a rack fixedly coupled to the second body, the device further comprising a pinion rotatably coupled to the first body and having teeth engaging the rack such that rotating the pinion in a first direction urges the first and second bodies closer together and rotating the pinion in a second direction urges the first and second bodies farther apart.  
     
     
         16 . A device as in  claim 15 , wherein the first elongate member is rotatably disposed within the elongate shaft.  
     
     
         17 . A device as in  claim 1 , wherein the plurality of needles have substantially different lengths among the needles.  
     
     
         18 . A device as in  claim 2 , wherein the first and second bodies have a first expandable member disposed therebetween, such that expanding the first expandable member urges the first and second bodies apart and retracts the needles toward the second body.  
     
     
         19 . A device as in  claim 18 , wherein the first expandable member is a fluid inflatable member.  
     
     
         20 . A device as in  claim 20 , wherein the first inflatable member is coupled to the first and second bodies and is deflatable, such that withdrawing fluid from the first inflatable member urges the first and second bodies closer together.  
     
     
         21 . A device as in  claim 18 , further comprising a second expandable member disposed on the first body away from the second body, such that disposing the second body against the tissue and disposing the second expandable member against a body part urges the first body towards the tissue.  
     
     
         22 . A device as in  claim 21 , wherein the second expandable member is a fluid expandable member.  
     
     
         23 . A device as in  claim 2 , wherein the first and second bodies each have magnets disposed opposite each other, such that the first and second bodies are magnetically biased apart.  
     
     
         24 . A device as in  claim 23 , further comprising at least one elongate flexible member fixedly coupled to one of the first and second bodies and slidably received through the other of the first and second bodies, such that proximally retracting the elongate flexible member urges the first and second bodies closer together.  
     
     
         25 . A device as in  claim 2 , wherein the first and second bodies each have magnets disposed opposite each other such that the first and second bodies are magnetically biased toward each other.  
     
     
         26 . A device as in  claim 2 , wherein one of the first and second bodies has at least one magnet facing the other of the first and second bodies, further comprising the other of the first and second bodies having at least a second magnet slidably disposed thereon and having an opposite polarity facing the first magnet, such that the first and second magnet have a first position wherein the first magnet attracts the second magnet, and a second position, wherein the first magnet does not attract the second magnet.  
     
     
         27 . A device as in  claim 2 , wherein one of the first and second bodies has at least one magnet facing the other of the first and second bodies, further comprising the other of the first and second bodies having at least a second magnet slidably disposed thereon and having the same polarity facing the first magnet, such that the first and second magnet have a first position wherein the first magnet repulses the second magnet, and a second position, wherein the first magnet does not repulse the second magnet.  
     
     
         28 . A device as in  claim 27 , wherein one of the first and second bodies has at least a third magnet facing the opposite first or second body, wherein the third magnet is adjacent the first or second magnet and has the opposite polarity of the adjacent magnet, wherein, in the first position the third magnet repulses the opposite body, and wherein, in the second position, the third magnet is attracted to the opposite body.  
     
     
         29 . A device as in  claim 2 , wherein the first body had a first magnet disposed thereon, the second body has a second magnet disposed thereon, one of the first and second bodies have a third magnet disposed thereon, wherein at least one of the three magnets are slidably disposed on the respective body and wherein at least two of the three magnets are adjacent and have opposite polarities from each other, such that the three magnets have a first position wherein two of the three magnets attract the first and second body together and a second position wherein two of the three magnets repulse the first and second body apart.  
     
     
         30 . A device as in  claim 1 , wherein the needles have an outer diameter of smaller than about 25 gauge.  
     
     
         31 . A device as in  claim 1 , further comprising a needle trigger operably coupled to the needle driving means for initiating the needle driving means to drive the needles; and 
 a discharge trigger operably coupled to the fluid discharge means for initiating the fluid discharge from the needles.    
     
     
         32 . A device as in  claim 1 , wherein the needles have a plurality of side holes in at least two different positions along the needle length.  
     
     
         33 . A device as in  claim 1 , wherein the device includes means for controllably varying the needle penetration depth into the tissue.  
     
     
         34 . A device as in  claim 2 , wherein the first and second bodies have a maximum combined transverse dimension of no greater than about 1 inch.  
     
     
         35 . A device as in  claim 2 , wherein the second body includes one or more sensors.  
     
     
         36 . A device as in  claim 35 , wherein the one or more sensors are coupled to a controller.  
     
     
         37 . A device as in  claim 36 , wherein the controller is coupled to a vacuum source.  
     
     
         38 . A device as in  claim 36 , wherein the controller is coupled to means for controllably varying the needle penetration depth into the tissue.  
     
     
         39 . A device for injecting a biological substance into tissue, the device comprising: 
 an elongate shaft including a longitudinal axis, a proximal region, and a distal region;    an injection head coupled to the shaft distal region, the head having a plurality of needles for injecting the substance into the tissue, wherein the needles are oriented substantially perpendicular to the elongate shaft distal region longitudinal axis, the head having a surface for contacting the tissue; and    a needle driver for driving the plurality of needles past the injection head tissue contacting surface and into the tissue.    
     
     
         40 . A device as in  claim 39 , wherein the needle driver includes means for transferring a longitudinal force directed along the shaft to a transverse force at the injection head.  
     
     
         41 . A device as in  claim 40 , wherein the means for transferring force includes two substantially planar members, wherein the first planar member has the plurality of needles fixedly and transversely attached thereto, wherein the second planar member has the plurality of needles transversely and slidably disposed therethrough.  
     
     
         42 . A device as in  claim 41 , wherein the means for transferring force further includes the first planar member being transversely slidably coupled to the second planar member, wherein the first planar member has a least one inclined portion disposed at an angle to the plane of the first planar member; 
 a drive member slidably coupled to the second planar member and bearing against the first planar member inclined portion; and    an elongate drive shaft slidably disposed along the elongate shaft and coupled to the drive member;    such that moving the drive shaft longitudinally urges the drive member to bear against the inclined portion to urge the first planar member toward the second planar member, and to urge the plurality of needles away from the second planar member.    
     
     
         43 . A device as in  claim 39 , further comprising a fluid lumen extending along the shaft and coupled to the needles.  
     
     
         44 . A device for injecting medical substances into tissue, the device comprising: 
 a first body having a plurality of needles fixedly attached thereto;    a second body having the plurality of needles transversely and slidably disposed therethrough, wherein the first body is transversely slidably coupled to the second body, and    a drive member inclinably slidably coupled to the first body and slidably coupled to the second body,    such that longitudinally translating the drive member transversely moves the first body relative to the second body to move the plurality of needles relative to the second body.    
     
     
         45 . A device for injecting a medical substance into tissue, the device comprising: 
 a first and a second body coupled to each other through a pantograph mechanism on two opposing sides, wherein the pantograph includes a proximal arm pair and a distal arm pair,    wherein the arm pairs each include a first member pivotally joined at one end to the first body, a second member pivotally joined at one end to the second body, wherein the first and second members each have second ends pivotally coupled to each other at a central joint,    such that moving the proximal and distal arm pair central joints closer together urges the first and second bodies apart and moving proximal and distal arm pair central joints closer together urges the first and second bodies together.    
     
     
         46 . A device as in  claim 45 , wherein the central joint of each proximal arm pair is joined to the corresponding joint on the opposite side, and wherein the central joint of each distal arm pair is joined to the corresponding joint on the opposite side.  
     
     
         47 . A device as in  claim 45 , further comprising a plurality of vacuum pods disposed on the tissue-contacting surface.  
     
     
         48 . A device for injecting a medical substance into tissue, the device comprising: 
 a first body having a plurality of hollow needles attached thereto and a first plurality of magnets secured thereto;    a second body having the plurality of needles slidably received therethrough;    a third body slidably disposed on the second body and having a second plurality of magnets thereon; wherein the first and second plurality of magnets are disposed and have polarities oriented such that the slidable third body has a first position in which the first and third body are magnetically attracted to each other and a second position in which the first and third body are magnetically repulsed from each other, such that sliding the third member can act to pull the first body toward the second body and can also act to push the first body away from the second body.    
     
     
         49 . A device as in  claim 48 , wherein the third body has longitudinally adjacent magnet pairs having opposite polarities, such that sliding the third member into the first position brings magnets having opposite facing polarities opposite each other and sliding the third member into the second position brings magnets having the same facing polarities opposite each other.  
     
     
         50 . A device for injecting a medical substance into tissue, the device comprising: 
 a first body having a plurality of hollow needles attached thereto;    a second body having the plurality of needles slidably received therethrough,    wherein the second body includes a rack fixedly coupled to the second body, the device further comprising a pinion rotatably coupled to the first body and having teeth engaging the rack such that rotating the pinion in a first direction urges the first and second bodies closer together and rotating the pinion in a second direction urges the first and second bodies farther apart.    
     
     
         51 . A device as in  claim 50 , wherein the plurality of needles have substantially different lengths among the needles.  
     
     
         52 . A device for injecting a medical substance into tissue, the device comprising: 
 a first body having a plurality of hollow needles attached thereto;    a second body having the plurality of needles slidably received therethrough,    wherein the first and second bodies have a first expandable member disposed therebetween, such that expanding the first expandable member urges the first and second bodies apart and retracts the needles toward the second body.    
     
     
         53 . A device as in  claim 52 , wherein the first expandable member is a fluid inflatable member.  
     
     
         54 . A device as in  claim 53 , wherein the first inflatable member is coupled to the first and second bodies and is deflatable, such that withdrawing fluid from the first inflatable member urges the first and second bodies closer together.  
     
     
         55 . A device as in  claim 52 , further comprising a second expandable member disposed on the first body facing away from the second body, such that disposing the second body against the tissue and disposing the second expandable member against a body part urges the first body towards the tissue.  
     
     
         56 . A device as in  claim 55 , wherein the second expandable member is a fluid expandable member.  
     
     
         57 . A method for epicardially injecting a substance into a heart having an epicardial surface and disposed within a torso, the method comprising: 
 providing a substance-injecting device including a plurality of needles, an elongate shaft having a longitudinal axis, a proximal region, a distal region, and a transverse needle driver coupled to the elongate shaft distal region for driving the needles substantially perpendicular to the elongate shaft distal region longitudinal axis and into the tissue;    making an opening into the torso;    advancing the injecting device through the opening to the heart epicardial surface;    transversely driving the needles through the epicardium; and    injecting the substance from the device into the myocardium.    
     
     
         58 . A method as in  claim 57 , wherein the making opening step includes making an intercostal opening.  
     
     
         59 . A method as in  claim 57 , wherein the making opening step includes making a xiphoid opening below the sternum.  
     
     
         60 . A method as in  claim 57 , wherein the injecting the substance step includes injecting a substance selected from the group consisting of bone marrow cells, stem cells, embryonic stem cells, pluripotent stem cells, mesenchymal stem cells, and satellite muscle cells.  
     
     
         61 . A method as in  claim 57 , wherein the injecting the substance step includes injecting a substance selected from the group consisting of growth factors, vascular endothelial growth factors, and angiogenesis promoting agents.  
     
     
         62 . A method as in  claim 57 , wherein the making opening step includes making a sternotomy.  
     
     
         63 . A method as in  claim 57 , further comprising the step of sensing contractions of the heart.  
     
     
         64 . A method as in  claim 63 , wherein the injecting the substance step occurs between contractions of the heart.  
     
     
         65 . A method as in  claim 57 , further comprising: 
 providing a suction assisted positioning device;    engaging the heart with the positioning device; and,    positioning the heart into a non-physiological orientation.    
     
     
         66 . A method as in  claim 65 , wherein the injecting the substance step occurs following the positioning of the heart in a non-physiological orientation step.