US20110152833A1 - Apparatus and methods for treating tissue using passive injection systems - Google Patents

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
• This application is a continuation of U.S. patent application Ser. No. 12/041,561, now U.S. Pat. No. 7,862,551, filed Mar. 3, 2008, which is a continuation of U.S. patent application Ser. No. 10/977,594, now U.S. Pat. No. 7,338,471, filed Oct. 29, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 10/894,810, now U.S. Pat. No. 7,632,262, filed Jul. 19, 2004, the entire contents of all of which are incorporated herein by reference.
FIELD OF THE INVENTION
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Methods of using the apparatus of the present invention also are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
• 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:
• FIGS. 1A-1C are views depicting previously known methods of injecting drugs and other bioactive agents into a tissue mass;
• 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;
• 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;
• 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;
• FIGS. 5A-5C depict operation of the apparatus ofFIG. 4;
• 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;
• FIGS. 7A and 7B are cross-sectional views of another embodiment of the apparatus of the present invention; and
• FIGS. 8A and 8B are cross-sectional views of a further alternative embodiment of apparatus of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
• Referring toFIGS. 1A-1C, some of the drawbacks of previously known bioactive agent delivery systems are described.FIG. 1A illustrates a previously knowninjection needle10 being brought into approximation with tissue mass T. Once the tip ofneedle10 is inserted into the tissue, as shown inFIG. 1B, bioactive agent B, which may comprise stem cells, is injected into the tissue mass.
• 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.
• In addition, as illustrated inFIG. 1C, once needle10 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.
• Referring now toFIGS. 2A to 2C, 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 inFIG. 2A, in accordance with the principles of the present invention,needle20 is first approximated to spinal cord tissue mass T. InFIG. 2B,needle20 is shown inserted into the tissue mass. InFIG. 2C, asneedle20 is withdrawn from the tissue mass, bioactive agent B is delivered from the tip of the needle and deposited in the needle track.
• 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.
• InFIGS. 3A and 3B, apparatus constructed in accordance with the principles of the present invention is described, in whichdistal end25 includes selectively extendable needles26. As depicted in the Figures, needles26 are configured to flare outward when extended beyonddistal end25 of the apparatus, thereby enhancing dispersal of the bioactive agent into tissue mass T. As described above for the embodiment ofFIG. 2, needles26 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. Althoughdistal end25 illustratively includes threeneedles26, a greater or lesser number of needles may be employed without departing from the spirit of the present invention.
• Referring now toFIGS. 4A and 4B, apparatus constructed in accordance with the principles of the present invention is described.Apparatus30 comprises handle31 that is configured to acceptconventional syringe28, which may be loaded with a preselected bioactive agent, such as stem cells in a nutrient solution. The barrel ofsyringe28 is removably coupled totube32 via fluid-tight seal33.Tube32, which carries one or more tissue-piercing needles at its distal end, is arranged to reciprocate throughsleeve34 so that the distal tip of the needle extends beyondbushing35 when the device is actuated.Piston29 ofsyringe28 is removably coupled to block36 and rails37.
• Handle31 includestrigger38 that may be depressed to selectively actuateapparatus30. In particular, trigger38 is coupled totube33 viagear train39 andlinkage40.Clamp41 is configured to grip and reciprocate the body of the syringe in accordance with the degree of actuation oftrigger38. Each ofrails37 preferably includes a portion that forms a rack to permit forward movement ofpiston29 of the syringe during a first range of motion oftrigger38, and then retainpiston29 stationary relative torails37 during a second range of motion of the trigger.
• Link40 is coupled to clamp41 so that, aftersyringe28 andpiston29 are advanced during the initial range of motion of the trigger, the piston is held stationary whileclamp41 retractstube32 and needles from the needle track(s) and simultaneously urges the body ofsyringe28 proximally. This motion causes the bioactive material withinsyringe28 to be dispensed into the needle track(s) (seeFIGS. 2 and 3) at low velocity and with little or no barotrauma. As depicted inFIG. 4B (but omitted elsewhere for clarity),trigger38 and link40 preferably are biased bysprings42 and43, respectively, to return the mechanism to its starting position whentrigger38 is released.
• Referring now also toFIGS. 5A-5C, operation ofapparatus30 is described. InFIG. 5A, trigger38 of the apparatus is shown at its initial position, and withsyringe28 andpiston29 in the proximal-most positions. As shown inFIG. 5B, as thetrigger38 is depressed about half-way through its range of motion,gear train39 and link40urge syringe28,piston29 and rails37 in the distal direction in unison. This in turn causestube32 and clamp41 to be advanced distally, inturn causing needles43 to extend beyondbushing35. Illustratively, the tissue-piercing end oftube33 includes threeneedles43 that flare outward upon entering into a tissue mass, as depicted inFIG. 3A. Becausesyringe28 andpiston29 are moved in unison, the bioactive agent contained withinsyringe28 is subjected to substantially no hydraulic forces, and the distance betweenblock36 and the proximal-most portion ofsyringe28 remains unchanged.
• As further depicted inFIG. 5C, continued depression oftrigger38 causes link40 to begin retractingtube32 in the proximal direction. This motion also drivesclamp41 in the proximal direction. Because the rack portions ofrails37 disengage fromlink40 andgear train39 during proximal movement ofclamp41, rails37 andpiston29 remain stationary. Consequently, proximal movement ofclamp41 andtube32 both retracts needles43 from the needle tracks formed in the tissue, and urges the body ofsyringe28 againstpiston29.
• Still referring toFIG. 5C, proximal translation ofclamp41 also causes the distance betweenblock36 and the proximal-most portion ofsyringe28 to shorten. This action applies sufficient pressure to the contents ofsyringe28 to dispense the bioactive agent into the needle tracks formed byneedles43 as the needles withdraw from the tissue. When the clinician releases trigger38, springs42 and43return tube32 and clamp41 to the starting position, shown inFIG. 5A.Apparatus30 then may be repositioned, and the above process repeated.
• 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.
• With respect toFIGS. 6A and 6B, in accordance with another aspect of the invention, needles43′ ofapparatus30 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 inFIG. 6A, needles43′ 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 inFIG. 6A). Additionally, needles43′ may be arranged to be individually rotated so that the bioactive agent is dispersed in preselected directions.
• FIG. 6B depicts the use ofgrid50 to guideneedles43′ into predetermined locations along spinalcord S. Grid50 comprisesblock51 having a plurality of throughholes52 disposed along its surface to provide a predetermined separation between injection regions. Advantageously,grid50 lends structural support to damaged spinal region D during stem cell injection. As in the method depicted inFIG. 6A,apparatus30 may be used to injectneedles43′ at a first location, and then repositioned using grid50 (as shown in dotted line) to provide subsequent injections.
• With further reference toFIG. 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.
• Referring now toFIGS. 7A and 7B, an alternative embodiment of an injection needle constructed in accordance with the principles of the present invention is described.Needle60 comprises a glass or polymer microfiber adapted to receive and transmit electric signals, and includes tissue-piercingdistal end61 and interior lumen62.Needle60 is loaded with a bioactive agent, preferably comprisingstem cells65, and in addition is coupled topower supply63 that applies an electric field longitudinally alongneedle60.
• When energized bypower supply63, an electric field is applied toneedle60 that attracts negatively chargedstem cells65 towardend61, where they are deposited into the spinal cord. In particular, as depicted inFIG. 7B, a positive charge is induced atdistal end61 ofneedle60, thereby causing negatively chargedstem cells65 to be drawn to the distal tip of the needle.
• Stem cells95 are believed to be negatively charged in the natural state, so that they are drawn toward the positive charge atdistal end61 ofneedle60. 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 ofstem cells65 toward the positive charge causes a predetermined amount of the stem cells to be ejected fromdistal end61 into a target tissue mass, such as a damaged region of spinal cord.Needle60 optionally may transmit a signal that defines a location of the needle when viewed using an MRI or CT device.
• Referring now toFIGS. 8A and 8B, another alternative embodiment of the present invention is described.Needle70 comprises an electroactive polymer that forms an actuator, and includes tissue-piercingdistal end71 andinterior lumen72.Needle70 is loaded with a bioactive agent, preferably comprisingstem cells75, and is coupled topower supply73 that applies an electric field longitudinally alongneedle70. 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.
• InFIG. 8,injection needle70 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.
• 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,needle70 may be contracted such that a predetermined amount of bioactive agent is ejected fromdistal end71 of the needle.
• More specifically,needle70 comprises an electroactive polymer that is configured to contract when an electric charge is applied to the needle bypower supply73.Needle70 has a first diameter (FIG. 8A) and a second, contracted diameter (FIG. 8B) when energized. Referring toFIG. 8B, when an electrostatic charge is applied toinjection needle70, the needle contracts and the diameter oflumen72 decreases, thereby expelling a predetermined amount ofstem cells75 out ofdistal end71 ofneedle70. It is expected that constriction oflumen72 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 fluctuations 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.
• As will of course be understood, the embodiments ofFIGS. 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 toFIG. 6, to deliver the bioactive agent according to a predetermined pattern. As will further be understood, power supplies63 and73 of the embodiments ofFIGS. 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.
• 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.

Claims (21)

1-21. (canceled)

22. A method of atraumatically depositing a bioactive agent into a spinal cord, the method comprising:

removing an amount of cerebrospinal fluid from the spinal cord; and

depositing an amount of a bioactive agent into the spinal cord,

wherein the amount of cerebrospinal fluid is substantially equivalent to the amount of the bioactive agent.

23. The method ofclaim 22, wherein the bioactive agent comprises stem cells.

24. The method ofclaim 23, further comprising providing a device for depositing the bioactive agent atraumatically without inflicting barotrauma on the stem cells.

25. The method ofclaim 24, wherein the device comprises a first needle configured to deposit the amount of the bioactive agent.

26. The method ofclaim 24, wherein the device comprises:

a first needle configured to deposit a first portion of the amount of the bioactive agent substantially equivalent to a first portion of the amount of cerebrospinal fluid removed.

27. The method ofclaim 26, wherein the device further comprises:

a second needle configured to deposit a second portion of the amount of the bioactive agent substantially equivalent to a second portion of the amount of cerebrospinal fluid removed.

28. The method ofclaim 27, wherein the first needle has a predetermined length different from a predetermined length of the second needle.

29. The method ofclaim 28, wherein the depositing comprises depositing the first portion of the of amount of the bioactive agent at a first depth within the spinal cord; and

depositing the second portion of the of amount of the bioactive agent at a second depth within the spinal cord,

wherein the first depth is different from the second depth.

30. The method ofclaim 27, wherein the first and second needles are configured to deposit the bioactive agent at substantially the same time.

31. The method ofclaim 27, further comprising providing a grid having a block with a plurality of through-holes,

wherein a first through-hole is configured to receive the first needle and a second through-hole is configured to receive the second needle.

32. The method ofclaim 31, further comprising, after the depositing, repositioning the grid and then repeating the depositing.

33. A method of atraumatically depositing a bioactive agent into a spinal cord, the method comprising:

removing a first amount of cerebrospinal fluid from a first side of the spinal cord; and

depositing a first amount of a bioactive agent into the first side of the spinal cord,

wherein the first amount of cerebrospinal fluid is substantially equivalent to the first amount of the bioactive agent.

34. The method ofclaim 33, further comprising:

removing a second amount of cerebrospinal fluid from a second side of the spinal cord; and

depositing a second amount of a bioactive agent into the second side of the spinal cord,

wherein the second amount of cerebrospinal fluid is substantially equivalent to the second amount of the bioactive agent.

35. The method ofclaim 34, wherein the first side of the spinal cord is approximately opposite the second side of the spinal cord.

36. The method ofclaim 34, wherein the first amount is different from the second amount.

37. The method ofclaim 33, wherein the bioactive agent comprises stem cells.

38. The method ofclaim 37, further comprising providing a device for depositing the bioactive agent atraumatically without inflicting barotrauma on the stem cells.

39. The method ofclaim 38, wherein the device comprises:

a first needle configured to deposit a first portion of the amount of the bioactive agent substantially equivalent to a first portion of the amount of cerebrospinal fluid removed.

40. The method ofclaim 39, wherein the device further comprises:

a second needle configured to deposit a second portion of the amount of the bioactive agent substantially equivalent to a second portion of the amount of cerebrospinal fluid removed.

41. The method ofclaim 40, further comprising:

providing a grid having a block with a plurality of through-holes, wherein a first through-hole is configured to receive the first needle and a second through-hole is configured to receive the second needle;

positioning the grid adjacent to the first side of the spinal before depositing the first amount of the bioactive agent; and

then repositioning the grid adjacent to the second side of the spinal cord before depositing the second amount of the bioactive agent.

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