Electrode Arrays For Electroporation, and Related Systems and Methods

An electrode array for use with an electroporation device includes a support member having a top surface and a bottom surface and defines a plurality of injection channels extending from the top surface to the bottom surface. A plurality of needle electrodes are coupled to the support member, such that distal ends of the plurality of needle electrodes extend to a needle depth below the bottom surface. The plurality of needle electrodes are arranged in a matrix pattern having rows of the needle electrodes and columns of the needle electrodes disposed along the support member. The plurality of injection channels are dispersed within the matrix pattern.

TECHNICAL FIELD

The present invention relates to electroporation devices, and more particularly to electrode arrays having adapted to provide increased injection volumes and a more voluminous electroporation field in tissue.

BACKGROUND

The classical mode of administering vaccines and other pharmaceutical agents into the body tissues is by direct injection into muscle or skin tissues using a syringe and needle. Incorporating electroporative pulses of electric energy at or near the injection site is known to facilitate delivery of such vaccines or agents directly into the cells within the tissue. Such direct delivery to cells using electroporative electric pulses can have a profound clinical effect on the quality of the response of the body's metabolic and/or immune systems over that of simple syringe and needle injection. Moreover, the capability of direct delivery of agents into the cell via electroporation has enabled the effective delivery of therapeutic agents (e.g., DNA-encoded monoclonal antibodies (dMAb), expressible naked DNA encoding a polypeptide, expressible naked DNA encoding a protein, recombinant nucleic acid sequence encoding an antibody, and the like) having any number of functions, including antigenic for eliciting of immune responses, or alternatively, metabolic for affecting various biologic pathways that result in a clinical effect.

SUMMARY

According to an embodiment of the present disclosure, an electrode array for use with an electroporation device includes a support member having a top surface and a bottom surface and defines a plurality of injection channels extending from the top surface to the bottom surface. A plurality of needle electrodes are coupled to the support member, such that distal ends of the plurality of needle electrodes extend to a needle depth below the bottom surface. The plurality of needle electrodes are arranged in a matrix pattern having rows of the needle electrodes and columns of the needle electrodes disposed along the support member. The plurality of injection channels are dispersed within the matrix pattern.

According to another embodiment of the present disclosure, an electroporation device for causing in vivo reversible electroporation in cells of tissue includes an electrode array and a plurality of injection needles. The electrode array includes a support member having a top surface and a bottom surface and defining a plurality of injection channels extending from the top surface to the bottom surface. A plurality of needle electrodes are coupled to the support member, such that distal ends of the plurality of needle electrodes extend to a needle depth below the bottom surface of the support member. The plurality of needle electrodes are arranged in a matrix pattern having rows of the needle electrodes and columns of the needle electrodes disposed along the support member. The plurality of injection channels are dispersed within the matrix pattern. The injection needles are configured to extend through at least some of the plurality of injection channels and into the tissue.

According to another embodiment of the present disclosure, an electroporation system for causing in vivo reversible electroporation in cells of tissue includes an electrode array having a support member that has a top surface and a bottom surface and defines a plurality of channels extending from the top surface to the bottom surface. A plurality of needle electrodes are coupled to the support member and extend through the plurality of channels, such that distal ends of the plurality of needle electrodes extend to a needle depth below the bottom surface of the support member. The plurality of needle electrodes are arranged in a matrix pattern having rows of the needle electrodes and columns of the needle electrodes disposed along the support member. At least some of the plurality of needle electrodes are dual-purpose needle electrodes configured to inject an agent into the tissue and to deliver one or more electroporation pulses to the tissue for causing the reversible electroporation in the cells thereof.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The term “plurality”, as used herein, means more than one. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

The terms “approximately”, “about”, and “substantially”, as used herein with respect to dimensions, angles, ratios, and other geometries, takes into account manufacturing tolerances. Further, the terms “approximately”, “about”, and “substantially” can include 10% greater than or less than the stated dimension, ratio, or angle. Further, the terms “approximately”, “about”, and “substantially” can equally apply to the specific value stated.

The term “agent”, as used herein, means a polypeptide, a polynucleotide, a small molecule, or any combination thereof. The agent may be a recombinant nucleic acid sequence encoding an antibody, a fragment thereof, a variant thereof, or a combination thereof. The agent may be a recombinant nucleic acid sequence encoding a polypeptide or protein. The agent may be formulated in water or a buffer, such as saline-sodium citrate (SSC) or phosphate-buffered saline (PBS), by way of non-limiting examples.

The term “intradermal” as used herein, means within the layer of skin that includes the epidermis (i.e., the epidermal layer, from the stratum corneum to the stratum basale) and the dermis (i.e., the dermal layer).

The term “intramuscular” as used herein, means within muscle tissue, including skeletal muscle tissue and smooth muscle tissue.

The term “adipose”, as used herein, means the layer containing adipocytes (i.e., fat cells) that reside in the subcutaneous layer.

The term “electroporation”, as used herein, means employing an electrical field within tissue that temporarily and reversibly increases the permeability and/or porosity of the cell membranes of cells in the tissue, thereby allowing an agent, for example, to be introduced into the cells. It should be appreciated that the type of electroporation disclosed herein refers to reversible electroporation (also referred to as “reversible poration”), meaning that the electroporated cell membranes (or at least a majority thereof) return to a substantially non-permeable and/or non-porous state following electroporation.

The term “electroporation field”, as used herein, means an electric field capable of electroporating cells. In instances where an electric field includes a portion that is capable of electroporating cells and another portion that is incapable of electroporating cells, the “electroporation field” refers specifically to that portion of the electric field that is capable of electroporating cells. Thus, an electroporation field can be a subset of an electric field.

The embodiments disclosed herein pertain to electroporation devices that employ an electrode array having a plurality of needle electrodes arranged in a pattern and also having a plurality of fluid injection channels interspersed within the pattern. The array with the plurality of fluid injection channels allows greater injection volumes for increased spatial dispersion within a more voluminous electroporation field within target tissue. This can allow agent uptake into target cells on a greater scale, including within intradermal (ID) tissue, adipose tissue, and intramuscular (IM) tissue.

Referring toFIGS.1A-1B, an electroporation system2according to an exemplary embodiment of the present disclosure includes a hand-held electroporation device4that includes a housing6. The hand-held electroporation device4can also be referred to as an “applicator”4. The electroporation device4includes a handle8and a mounting portion10(also referred to herein as a “mounting head” or “applicator head”10) extending distally from the handle8. The handle8and applicator head10can be defined by the housing6. The applicator head10can carry an array assembly212that includes one or more electrodes,14such as a plurality of electrodes14in a spatial arrangement, which arrangement can be referred to as an “electrode array”215. The electrodes14extend from a support member216in a distal direction D that is opposite a proximal direction P. The electrodes14of this embodiment are penetrating electrodes that have distal tips18configured to penetrate tissue, particularly for penetrating through dermal tissue and into muscle tissue. One or more and up to all of the distal tips18can be a trocar tip having planar surfaces that converge to a point at a distal end19of the electrode14, by way of a non-limiting example.

The electrodes14are configured to deliver one or more pulses of electrical energy to cells of the target tissue, specifically for reversibly electroporating the cells. The device4includes circuitry for providing electrical communication between the electrodes14and an energy source110. As shown, the circuitry can be configured to connect with one or more cables109configured to couple with an energy source110located remote from the hand-held electroporation device4, such as a power generator. Additionally or alternatively, the circuitry can be configured to connect with an on-board energy source, such as a battery unit disposed within the housing6.

The energy source110can be in electrical communication with a pulse generator112, such as a waveform generator, for generating and transmitting an electric signal in the form of one or more electrical pulses having particular electrical parameters to the electrodes14for electroporating cells within the tissue. Such electrical parameters include electrical potential (voltage), electric current type (alternating current (AC) or direct current (DC)), electric current magnitude (amperage), pulse duration, pulse quantity (i.e., the number of pulses delivered), and time interval or “delay” between pulses (in multi-pulse deliveries). The pulse generator112can include a waveform logger for recording the electrical parameters of the pulse(s) delivered. The pulse generator112can be in electrical communication with a control unit114(also referred to herein as a “controller”), which can include a processor116configured to control operation of the electroporation system2, including operation of the pulse generator112. The processor116can be in electronic communication with computer memory118, and can be configured to execute software and/or firmware including one or more algorithms for controlling operation of the system2.

The processor116can be in electrical communication with a user interface, which can be located on the device4or remote from the device4. The user interface can include a display for presenting information relating to operation of the system2and inputs, such as a keypad or touch-screen, that allow a physician to input information, such as commands, relating to operation of the system2. It should be appreciated that the interface can be a computer interface, such as a table-top computer or laptop computer, or a hand-held electronic device, such as a smart-phone or the like.

The applicator head10is configured to receive at least one fluid delivery device that includes an elongate tubular member, which in the embodiments disclosure herein is an injection needle20, configured to deliver an injectate to a target region of tissue. Preferably, the applicator head10is configured to receive a plurality of fluid delivery devices (e.g., injection needles20), as described in more detail below.

As shown inFIG.1B, the hand-held electroporation device4can include one or more mounting members26for mounting the support member216to the applicator head10. The mounting members26can define respective apertures through which portions of the electrodes14extend. The support member216can include a hub or platform32, which can define a plurality of electrode apertures34, through which the electrodes14can extend, respectively. In this manner, the spacing of the electrode apertures34in the platform32can define the pattern of the electrode array212. The support member216defines a plurality of injection channels236, through which the injection needle20can extend. The support member216preferably also includes a plurality of elongated proximal tube formations238(also referred to herein as “chimneys” or “risers”) that extend from a top surface262of the platform32. The chimneys238define proximal extensions of the injection channels36from the platform32. The platform32can be configured to abut one or more of the mounting members26when the array assembly212is in an assembled configuration and coupled to the applicator head10.

It should be appreciated that at least one the mounting members26can define a plurality of sockets44arranged correspondingly with the electrode apertures34of the support member216for receiving proximal ends17of the electrodes14and providing electrical communication between the pulse generator112and the electrodes14. Additionally, one or more of the mounting members26can also define respective injection channels48that are in alignment with the injection channel236of the support member216and through which the chimneys238can extend.

As shown, the chimneys238can protrude proximally from the applicator head10when in the assembled configuration. A distal end56of the chimney238can be configured to mount with a connection member58(also referred to herein as a “connector”) attached to the injection needle20. The connector58is configured to couple with a reservoir of the injectate, such as a syringe, a single-dose cartridge, an injection manifold, and the like. As shown, the connector58can be a Luer-type connector, although other connector types and designs are within the scope of the present embodiments.

In some embodiments, the electroporation system2can employ the CELLECTRA® 2000 system, which has an external, battery powered pulse generator112(i.e., the CELLECTRA® Pulse Generator) that is connected via cable to the hand-held electroporation device4, which can be an adapted version of the CELLECTRA® 5P-IM Applicator, by way of non-limiting examples. It should be appreciated that the array assembly212is preferably a sterile disposable array assembly212. The electrodes14can be constructed of stainless steel and can be gold-coated for enhanced conductivity. The injection needles20can be pre-packaged with the array assembly212. It should be appreciated that the CELLECTRA® products and components described above are produced by Inovio Pharmaceuticals, Inc., headquartered in Plymouth Meeting, Pa., United States.

As shown inFIG.1B, the array assembly212is preferably configured to control a maximum depth L1at which the electrodes14penetrate the surface of the subject's skin. This depth L1, also referred to herein as “electrode penetration depth” or “electrode depth,” can be governed by a contact or “stop” surface260of the array assembly212that is configured to abut the subject's skin and halt further advancement of the electrodes14into the tissue. As shown, the stop surface260can be defined by a distal or bottom surface of the support member216, by way of a non-limiting example. The array assembly212is preferably also configured to control a maximum depth L2of the injection needles20, measured from the stop surface260to the distal ends of the injection needles20. This depth L2can also be referred to herein as “injection depth.” The support member216is preferably configured such that the injection depth L2is shallower than the electrode depth L1by an injection offset distance L3, which is tailored so that the injected agent is located primarily within the electroporation field created by the electrodes14. It should be appreciated that the depths L1, L2can be adjusted as needed to specifically target intradermal (ID) tissue, adipose tissue, intramuscular tissue (IM), or any combination of the foregoing tissues, depending on patient needs.

Referring now toFIGS.1C-1D, the example support member216can carry the needle electrodes14so that the electrode array215is a grid or “matrix” pattern. The illustrated embodiment employs a matrix having five (5) rows217and two (2) columns219of electrodes14(i.e., a 5×2 electrode array215, in which each row has two electrodes, and each column has five electrodes). The rows217are spaced at intervals along a longitudinal direction X1, while the columns219are spaced at intervals along a lateral direction Y1that is substantially perpendicular to the longitudinal direction X1. In this manner, the array215can be elongated along the longitudinal direction X1. It should be appreciated that the electrodes14of each row217can be aligned along a row axis247, which can intersect central axes245of the electrodes14in the row217. Additionally, the electrodes14of each column219can be aligned along a column axis249, which can intersect the central axes245of the electrodes14in the row219. The array215can employ equidistant row and column spacing X2, Y2, although in other embodiments the row spacing X2can differ from the column spacing Y2. The row and column spacing X2, Y2is preferably measured between adjacent row axes247and column axes249, respectively. The electrodes14can be configured similarly to those described above with respect to the circular pattern electrode arrays15, although in other embodiments the electrodes14of the present array215can be adapted as needed.

The support member216has first and second ends202,204opposite each other along the longitudinal direction X1and opposed first and second sides206,208opposite each other along the lateral direction Y1. The bottom surface260of the support member can effectively define the stop surface, as mentioned above. As shown, the support member216can include three (3) injection channels236, which can be aligned with each other along the longitudinal direction X1and can be equidistantly spaced between the first and second columns219. A first one of the injection channels236can also be equidistantly positioned between the first and second rows217, a second one of the injection channels236can be laterally aligned in the third row217, and a third one of the injection channels236can be equidistantly positioned between the fifth and sixth rows217. Each chimney238can be configured to receive a respective injection needle20, which can be configured according to any of the embodiments described above. As shown inFIG.1C, the chimneys238can extend from the upper surface262of the support member216proximally to a chimney height of L4along a vertical direction Z1, which height L4can be configured to place the distal ends of the injection needles20at a favorable position relative to distal ends19of the electrodes14, such as at a favorable injection offset distance L3described above.

As shown inFIG.1D, the injection needles20can each eject their injectate, which can disperse radially outward toward the adjacent needle electrodes14. By employing multiple injection channels236, the array215can be configured to disperse greater volumes of injectate within larger electroporation fields. According to one example of the present embodiment, the array215can be configured to deliver a total injection volume of about 3 mL from the injection needles20, particularly at 1 mL per injection needle20. It should be appreciated that, when used for intramuscular (IM) electroporation, the elongated array215allows a physician to orient the array215so that that the longitudinal direction X1generally aligns with the direction of muscle fiber extension, thereby further enhancing the fluid dispersion in the muscle tissue of the patient.

Referring now toFIGS.2A-2D, another example array assembly312includes a support member316having an array315of needle electrodes14arranged in a matrix having six (6) rows317and four (4) columns319(i.e., a 6×4 matrix electrode array315). As above, the rows317are spaced at intervals along the longitudinal direction X1, while the columns319are spaced at intervals along the lateral direction Y1, such that the array315can be elongated along the longitudinal direction X1. The array315can employ equidistant row and column spacing. By way of a non-limiting example, the rows317can be spaced from each other at a distance X2of about 10 mm and the columns319can be spaced from each other at a distance Y2of about 10 mm. It should be appreciated that such 10 mm spacing approximates the diameter of the circular electrode array of the CELLECTRA® 5P-IM Array, as shown for reference inFIG.2C.

In other embodiments, as shown inFIGS.3A-3B, the row spacing can differ from the column spacing. In this example, the columns can be spaced at distances X2of about 10 mm, and the rows can be spaced at distances Y2of about 7.5 mm. Additional spacing distances are discussed below.

The support members316of the arrays315shown inFIGS.2A-2Bpreferably includes a plurality of injection channels336, which can be defined within vertically elongated chimneys338. As shown, the plurality of injection channels336can include six (6) injection channels336, which can be arranged along two (2) rows340of channels, such as a first row340of channels336equidistantly spaced between the second and third rows319of electrodes14, and a second row340of channels336equidistantly spaced between the fourth and fifth rows319of electrodes14. As shown inFIG.2D, the channel rows340can be spaced from each other at spacing distance X3, as measured between respective channel row axes351that intersect central axes355of the injection channels336in the channel row340. In the illustrated embodiment, spacing distance X3is 2× the electrode row spacing distance X2. The channels336can also be arranged into columns342of channels336, such as a first, second, and third column342of channels336. The channel columns342can be spaced from each other at spacing distance Y3, as measured between respective channel column axes353that intersect the central axes355of the injection channels336in the channel column342. In the illustrated embodiment, spacing distance Y3is equivalent to the electrode column319spacing distance.

According to one example of the present embodiments, the arrays315can be configured to deliver a total injection volume of about 6 mL from the injection needles20, particularly at 1 mL per injection needle20. It should be appreciated that the arrays315can be used for delivering injection volumes greater than 6 mL and less than 6 mL. As with the array215described above, the present arrays315can be oriented favorably with respect to the direction of muscle fiber extension, thereby enhancing the fluid dispersion in the muscle tissue. Additionally, the chimneys338have heights L4that can be configured to place the infusion regions of the injection needles20at a favorable position relative to distal ends19of the electrodes14. It should be appreciated that the electrode and channel spacing distances X2, Y2, X3, Y3, electrode depths L1, and/or the chimney heights L4of the matrix arrays215,315described above can be varied as needed. For example, spacing distances X2, Y2, X3, Y3can be in a range from about 2.5 mm to about 50 mm, and more particularly in a range from about 4.0 mm to about 20 mm, and more particularly in a range from about 5.0 mm to about 15.0 mm. The electrode spacing distances X2, Y2along the direction of muscle fiber extension is preferably in a range of about 10.0 mm to about 15.0 mm. The electrode spacing distances X2, Y2along a directional that is perpendicular to the direction of muscle fiber extension is preferably in a range of about 5.0 mm to about 10.0 mm. It should be appreciated that the foregoing spacing distances can be adapted particular to the anatomy of the target tissue, particularly when the target tissue has anisotropic electrical and fluidic properties.

Referring now toFIG.3C, a computer model illustrates an example of an electric field generated by the array315shown inFIGS.3A-3B. As shown, the electric field can have a substantially even field magnitude, shown in V/cm, along the longitudinal direction X1between adjacent columns. In this manner, the array315can provide both favorable longitudinal fluid dispersion, and favorable “smooth” electroporation fields along the longitudinal direction X1. The physician can take advantage of such smooth electroporation fields by orienting the array315in a favorable manner relative to the underlying target tissue. For example, when used for IM electroporation, the physician can orient the array315so that the longitudinal direction coincides with the direction of muscle fiber extension.

In further embodiments, the matrix arrays215,315can be further configured for selective or “modular” use of the electrodes14and/or injection channels236,336thereof. Referring now toFIG.4A, an example array415having electrodes14arranged in a matrix, such as a 6×4 matrix with even electrode row417and column419spacing X2, Y2, by way of a non-limiting example, can include a total of fifteen (15) chimneys438(and channels436), arranged in rows440and columns442in a 5×3 chimney array configured such that each chimney438is equidistantly spaced between the adjacent columns419and rows417of the electrodes14. The array415can include circuitry for connecting each electrode14individually to the pulse generator112, such that the pulse generator112can deliver electroporation pulses to any subset of the electrodes14. Similarly, any subset of the chimneys438can be employed to receive a respective injection needle20. In this manner, a single matrix array438can provide the functionality of numerous matrix arrays438. For example, the depicted 6×4 matrix array can be selectively employed as any of a 1×1, 1×2, 1×3, 1×4, 2×1, 2×2, 2×3, 2×4, 3×1, 3×2, 3×3, 3×4, 4×1, 4×2, 4×3, 4×4, 5×1, 5×2, 5×3, 5×4, 6×1, 6×2, 6×3, and 6×4 electrode array, utilizing any one of a 1×1, 1×2, 1×3, 2×1, 2×2, 2×3, 3×1, 3×2, 3×3, 4×1, 4×2, 4×3, 5×1, 5×2, and 5×3 chimney array.

Referring now toFIGS.5A-5C, an example of an electroporation system602is shown that includes an electrode array assembly612having a plurality of needle electrodes625arranged in rows617and columns619in a matrix array615, generally similar to the embodiments described above. However, in the present embodiment, one or more and up to all of the electrodes20in the matrix array615can be a dual-purpose injection needle electrode625that is configured to both inject fluid within target tissue and also to deliver one or more electroporative pulses to the target tissue.

The electroporation system602of this embodiment can include tubing659for delivering the fluid injectate to each dual-purpose injection needle electrode625in the matrix array615. The tubing659can connect proximal ends657of the dual-purpose injection needle electrodes625to a reservoir, such as via a manifold of a reservoir assembly and/or via a plurality of individual reservoirs. The array assembly612can be configured to couple with an applicator head610of a hand-held electroporation device604. For example, the array assembly612can include a support member616configured to couple with one or more complimentary mounting members of the applicator head610, similar to the manner described above with reference toFIG.1B. The dual-purpose electrodes625can extend through dual-purpose channels636defined through the support member616. It should be appreciated that the support member616can be employed in modular fashion, similar to the manner described above with reference toFIG.4. For example, the dual-purpose electrodes625can be inserted within a select sub-set of the available dual-purpose channels636, which sub-set can be selected based on the fluid delivery and electroporation field parameters needed, which parameters (and thus sub-set selection) can be adapted to the target tissue. It should be appreciated that the matrix array615can employ various combinations and patterns of needle electrodes14, injection needles20, and dual-purpose injection needle electrodes625.

As shown inFIG.5C, the matrix array615can be placed with respect to muscle tissue675so that the dual-purpose injection needle electrodes625are oriented as desired with respect to the muscle tissue, particularly with respect to the direction of muscle fiber extension M1. For example, the matrix array615can be oriented so that the longitudinal direction X1of the array615extends along the direction of muscle fiber extension M1, as indicated by the array615position shown in dashed lines. Alternatively, the physician can elect to orient the array615so the longitudinal direction X1is oriented substantially perpendicular to the direction of muscle fiber extension M1, which can therefore provide for the fluid injection to be distributed along a greater number of individual muscle fiber striations. Such selective orientations and usages of the array615can be further tailored by the application of the pulsing pattern with respect to specific sub-sets of dual-purpose electrodes, which pulsing patterns can be adapted to focus the EP field along the direction of muscle fiber extension M1. These is configurations and usages can also take advantage of the fact that, during EP electrical current flow, the impedance is reduced when directed in the same direction as the muscle fibers. Moreover, the direction of fluid ejection from the injection needles20,625can also be expected to experience less mechanical impedance to fluid flow, which can allow for beneficial drug distribution along the electroporation field.

Referring now toFIGS.6A-6B, an example embodiment of an array assembly712is shown having a matrix electrode array715coupled to a support member716. In this example embodiment, the matrix array715includes a plurality of needle electrodes14arranged in rows717and columns719and having injection channels736located between the needle electrodes14, generally similar to the embodiments described above with reference toFIGS.1C-3B and4-5C. However, in the present embodiment, one or more and up to all of the injection channels736is eccentrically offset from adjacent rows717and/or adjacent columns719. As used herein with respect to an injection channel736and an adjacent row717and/or adjacent column719, the phrase “eccentrically offset” means that the injection channel736is spaced from the nearest row717and/or column719along a respective direction and at a respective offset distance that is less than a distance along the respective direction between the injection channel736and the next nearest row717and/or column719.

In the illustrated embodiment, each of the injection channels736is eccentrically offset from the respective nearest row717along the longitudinal direction X1. In particular, each injection channel736of the illustrated embodiment is longitudinally spaced from the nearest row717at an offset distance X4that is less than a secondary offset distance X5between the injection channel736and the next nearest row717. The offset distance X4and the secondary offset distance X5are measured between the central axis755of the injection channel736and the nearest electrode row axis747and the next nearest electrode row axis747, respectively. The offset distance X4can be quantified as a factor (i.e., multiple) of the secondary offset distance X5. For example, the offset distance X4can range from a factor of about 0.001 to a factor of about 0.999 of the secondary offset distance X5.

According to a non-limiting example of the illustrated embodiment, the matrix array715has six (6) electrodes14arranged in a 3×2 matrix (i.e., three (3) rows717and two (2) columns719), with equidistant row and column spacing X2, Y2. The injection channels736are arranged in a 3×1 channel array (i.e., three (3) rows740and one column742of channels136) such that each injection channel736is eccentrically offset from the nearest row717of electrodes14at equidistance offset distances X4. In this example, each offset distance X4is a factor of about 0.25 of the respective secondary offset distance X5. In particular, in this example the electrode row spacing X2, electrode column spacing Y2, and the channel row spacing X3are each about 10 mm, with the injection channels eccentrically offset at an offset distance X4of about 2.5 mm along the longitudinal direction X1. It should be appreciated that any of these spacing distances X2, Y2, and offsets X4, X5can be adjusted as needed.

It should also be appreciated that, in other embodiments, the injection channels736can be eccentrically offset from one of the electrode columns719along the lateral direction Y1. It should yet also be appreciated that the number of electrodes14and/or injection channels736in the matrix array715can be reduced or increased as needed based on various factors, such as the target treatment location, target tissue, and injection volume, by way of non-limiting examples. For example, the matrix array715can be increased to include one or more additional rows717and/or columns719of electrodes14and/or one or more additional rows740and/or columns742of injection channels736, such that the injection channels736are eccentrically offset from the electrode rows717. It should further be appreciated that the matrix array715can employ a combination of eccentrically offset injection channels717and injection channels717that are not eccentrically offset (such as by being located equidistantly between respective electrodes14or by being aligned with a respective electrode row717). The matrix array715of the present embodiment provides significant advantages for electroporation treatment. One such advantage is that by employing multiple injection channels736within the electrode array715, the agent dosage can be fractionated among multiple injection sites. This is expected to enhance fluid dispersion in target tissue.

Referring now toFIGS.7A-7B, in another example embodiment, an array assembly812has a support member816that includes a matrix array815configured similar to the embodiment described above with reference toFIGS.6A-6B. As with the aforementioned embodiment, the matrix array815has six (6) electrodes14arranged in a 3×2 matrix, with equidistant electrode row and column spacing X2, Y2, and three (3) injection channels836arranged in a 3×1 channel array. In the present embodiment, however, the injection channels836are aligned with the rows817of electrodes14, such that the injection channels836are intersected by the respective electrode row axes847. In one non-limiting example of the matrix array815, the array815can employ an electrode row spacing X2, electrode column spacing Y2, and channel row spacing X3that are each about 10 mm. It should be appreciated that any of these spacing distances X2, Y2, X3can be adjusted as needed.

The matrix array815of the present embodiment provides significant advantages for electroporation treatment. As with the matrix arrays described above, the array815employs multiple injection channels836that allows fractionating the agent dosage among multiple injection sites. Moreover, the dispersed injectate at the multiple injection sites can be targeted with respective electroporation fields delivered by respective subsets of electrodes14in the array815. Another advantage is that the matrix array815can employ a pulse pattern that enhances co-localization of the electroporation fields with the delivered fluid dispersions from the injection channels836aligned with the electrode rows817. In particular, the matrix array815can employ a pulse pattern that delivers pulses between electrode pairs in each row817, thereby directing the pulses across the area underneath the injection channels836. This better co-localizes the electroporation fields with the fluid dispersions emanating from injection needles14extending through the injection channels836, as described in more detail below.

Referring now toFIG.8A, an example pulse pattern will be described for the matrix array81shown inFIGS.7A-7B. For purposes of illustrating the pulse pattern, the electrodes14of the matrix array815will be referred to by electrode positions E1-E6, in which electrode positions E1and E2are on a first electrode row817, electrode positions E3and E4are on a second electrode row817, and electrode positions E5and E6are on a third electrode row817. In this example, the pulse pattern includes three (3) pulses, of which the first pulse P1is delivered between E1and E2, the second pulse P2is delivered between E3and E4, and the third pulse P3is delivered between E5and E6. In another example, the pulse pattern shown inFIG.8Acan be repeated, providing a pulse pattern having two identical pulse trains and a total of six (6) pulses. Such a repeated pulse pattern provides two pulses per electrode pair, which can facilitate enhanced electroporation results.

Referring now toFIG.8B, in an additional example, a pulse pattern can employ the three pulses P1-P3shown inFIG.8A, plus four (4) additional pulses P4-P7delivered diagonally between adjacent electrode rows817and columns819. In this particular example, the fourth pulse P4is delivered between E1and E4, the fifth pulse P5is delivered between E4and E5, the sixth pulse P6is delivered between E2and E3, and the seventh pulse P7is delivered between E3and E6. The four (4) diagonal pulses P4-P7can be beneficial for co-localizing the electroporation fields with any injectate that dispersed between the electrode rows817along the longitudinal direction X1.

Referring now toFIG.8C, in a further example for co-localizing the electroporation fields with injectate that dispersed longitudinally between the electrode rows817, a pulse pattern can effectively replace pulses P4-P7shown inFIG.8Bwith two (2) alternative pulses P4-P5that each split the current diagonally from the center row817to the first and third rows817. In particular, in this example the fourth pulse P5is delivered from E3to both E2and E6, and the fifth pulse P5is delivered from E4to both E1and E5. This pulse pattern can effectively target injectate dispersed between the electrode rows817using fewer total pulses than the pattern shown inFIG.8B.

It should be appreciated that the example pulse patterns described above with reference toFIGS.8A-8Crepresent non-limiting examples of pulse patterns that can be employed with the matrix array815. It should also be appreciated that the foregoing pulse patterns can also be employed with the matrix array715shown inFIGS.6A-6B. Furthermore, these pulse patterns can be adjusted as needed based on the particular factors involved.

Referring now toFIG.9A-9C, an additional advantage of the matrix array815described above with reference toFIGS.7A-7Binvolves its particular effectiveness in tissues that influence fluid dispersion along specific directions. One such tissue is muscle tissue675. As described above, intramuscular (IM) tissue tends to influence injected fluid7(e.g., the injectate) to disperse predominantly along the direction of muscle fiber extension M1. One particular advantage of the matrix array815is that its design allows favorable IM electroporation results regardless of its orientation relative to the direction of muscle fiber extension M1. In this manner, the matrix array815can be said to be more robust against mis-orientation in muscle.

As shown inFIG.9A, the matrix array815can be inserted into muscle tissue675at an orientation whereby the electrode rows817align with the direction of muscle fiber extension M1. This orientation can be characterized as a “parallel” or “0-degree” orientation. In this orientation, each electrode row817and the associated injection channel836generally extends alongside and/or in-between the same muscle fibers677. The three (3) fluid injections (utilizing the injection channels836) disperse predominantly along the direction of muscle fiber extension M1, resulting generally in three side-by-side fluid dispersions7. In this manner, each of electroporation pulses P1-P3can effectively target the respective fluid dispersion7so that the high-magnitude portions of the electroporation fields co-localize with the respective fluid dispersions7.

As shown inFIG.9B, the matrix array815can alternatively be inserted into muscle tissue675at an orientation whereby the electrode rows817are oriented perpendicular to the direction of muscle fiber extension M1. This orientation can be characterized as a “perpendicular” or “90-degree” orientation. In this orientation, each electrode row817can traverse multiple muscle fibers677. The three (3) fluid injections (utilizing the injection channels836) disperse predominantly along the direction of muscle fiber extension M1, resulting generally in longitudinally overlapping fluid dispersions7having a maximum concentration between electrodes E3and E4. In this manner, electroporation pulses P1-P3can effectively target more muscle fibers and encompass more of the injected fluid than at the 0-degree orientation. Thus, a physician can employ the matrix array815at the 90-degree orientation to target more injectate with a more homogeneous electrical field, which can lead to transfecting more myocyte cells.

Referring now toFIG.9C, each electrode pair (i.e., the electrodes in a single row817) demonstrate strong co-localization of the electroporation field and the fluid dispersion regardless of the array orientation relative to the direction of muscle fiber extension M1. For example, at the 0-degree orientation, the high-magnitude portion of the electrical field aligns with the high-concentration portion of the fluid dispersion7. One reason for this result is because the muscle fibers677demonstrate anisotropic electrical conductivity that is highest along the direction of muscle fiber extension M1. Thus, electrical impedance is minimized along direction M1. Additionally, muscle fibers provide a lower mechanical fluid impedance along the direction of muscle fiber extension M1, as discussed above. However, even when the orientation rotates toward higher angles, the injectate still disperses along the direction of muscle fiber extension M1while the electrical field deforms (due to electrical conductivity being anisotropic and highest along the fiber axis) to somewhat match. Even at a 90-degree orientation, the electrical field is effectively “stretched” in direction M1, resulting in an electrical field that bulges out in the middle, where injectate is located. Thus, regardless of the array815orientation relative to muscle fibers, the array815beneficially co-localizes the electrical field with the injectate.

In other embodiments of the matrix array815, the number of electrode rows817and/or columns819and/or the number of injection channel rows840and/or columns842of the matrix array815can be reduced or increased as needed based on various factors, such as the target treatment location, target tissue, and injection volume, by way of non-limiting examples. For example, the matrix array815can be increased to include one or more additional rows817and/or columns819of electrodes and/or one or more additional rows840and/or columns842of injection channels836, such that the rows840of injection channels836are aligned with the rows817of electrodes14. It should also be appreciated that the matrix array815can employ a combination of one or more injection channels836that are aligned with respective electrode rows817and one or more injection channels836that are offset from respective electrode rows817(including eccentrically offset or equidistantly offset).

It should be appreciated that the various parameters of the injection needles20,625and associated array assemblies212,312,412,612,712,812and/or electrode arrays215,315,415,615,715,815described above are provided as exemplary features, such as for enhancing injection volumes within an expanded electroporation field and thereby enhancing electroporative transfection. These parameters can be adjusted as needed without departing from the scope of the present disclosure. For example, the illustrated electrode arrays and chimney arrays represent non-limiting examples of the array sizes and designs possible according to the embodiments herein. The electrode arrays and chimney arrays can be employed at virtually any array respective size (e.g., 15×15, 50×50, 100×100, and more than 100× more than 100). Moreover, the array assemblies disclosed herein can be adapted so that their electrode arrays and chimney arrays can approximate a shape of a patient's entire muscle or a portion thereof, including an entire length of a patient's muscle, including a long muscle, such as the sartorius muscle, by way of non-limiting examples. It should also be appreciated that the electrode arrays and/or chimney arrays can be arranged in various patterns, including staggered patterns, curved patterns, and irregular patterns, with can involve various spacing distances and/or non-uniform spacing distances.

It should be understood that when a numerical preposition (e.g., “first”, “second”, “third”) is used herein with reference to an element, component, dimension, or a feature thereof (e.g., “first” electrode, “second” electrode, “third” electrode), such numerical preposition is used to distinguish said element, component, dimension, and/or feature from another such element, component, dimension and/or feature, and is not to be limited to the specific numerical preposition used in that instance. For example, a “first” electrode, direction, or support member, by way of non-limiting examples, can also be referred to as a “second” electrode, direction, or support member in a different context without departing from the scope of the present disclosure, so long as said elements, components, dimensions and/or features remain properly distinguished in the context in which the numerical prepositions are used.