WO2014113576A1

WO2014113576A1 - Needleless injection device and methods of administering one or more needleless injections to an organ of interest

Info

Publication number: WO2014113576A1
Application number: PCT/US2014/011865
Authority: WO
Inventors: Charles R. Bridges; Anthony S. FARGNOLI
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-01-16
Filing date: 2014-01-16
Publication date: 2014-07-24
Anticipated expiration: 2015-07-16
Also published as: WO2014113576A9

Abstract

The present invention provides devices for administering one or more needleless injections to an organ of interest. The devices can include a jacket comprising a flexible material and sized to circumferentially surround and contact the organ of interest. The jacket includes one or more needleless injection heads and a fluid distribution network. The fluid distribution network can include one or more fluid inlets that can enable connection with a fluid administering or discharging device and one or more conduits configured to operatively connect each of the one or more needleless injection heads to at least one of the one or more fluid inlets. The one or more needleless injection heads, therefore, can be in fluid communication with a fluid administering or discharging device such that a plurality of needleless injections can be administered to a subject.

Description

NEEDLELESS INJECTION DEVICE AND METHODS OF ADMINISTERING ONE OR MORE NEEDLELESS INJECTIONS TO AN ORGAN OF INTEREST

FIELD

The present invention pertains generally to devices for delivery of fluid

medicaments (e.g., gene therapies) to a patient's organ of interest, preferably an internal organ (e.g., heart, liver, etc.). More specifically, the present invention relates to devices including a jacket carrying one or more (preferably a plurality) needleless injection heads for providing a plurality of liquid jets that penetrate the tissue of the organ of interest to deliver the fluid medicament. BACKGROUND

The delivery of medicaments, such as cell and gene therapeutics, to a variety of mammalian organs in a manner that avoids a large systemic effect is an on-going challenge. For instance, delivery of cell and gene therapeutics to the cardiac system is a rate limiting problem in translating success in early pre-clinical models toward the clinic. This is of particular emphasis to certain cell and gene based therapies since they often times can pose significant risks if exposed systemically as well as the challenge of larger, more complex anatomical barriers in larger species. However, such therapies could provide significant relief or progress in the treatment of a variety of medical conditions.

For example, ischemic heart disease is one of the most prevalent burdens on our global healthcare system, resulting in approximately 22 million diagnosed end stage heart failure patients annually. The range of treatment options for this population is limiting as destination assist devices and the best pharmacologic interventions fail to limit mortality. Chronic end stage heart failure represents one of the most troubling conditions in medicine, where the majority of patients succumb to complete failure either of natural cause or failed ventricular assist devices. Currently, the gold standard therapy for this condition is heart transplant. However, less than 2300 are performed annually which clearly demonstrates supply will never meet the demand. The best present methods to deliver desirable therapies to the heart, for example, efficiently at the large model/human scale are via access through the transvascular system. In such approaches, infusions of therapeutics are administered in the veins and or arteries to permeate across the vessels for subsequent cell target uptake. These systems, unless incorporating the use of complete cardiac isolation via cardiopulmonary bypass, are very inefficient due to their inability to transfer the therapeutic across tight endothelial cell barriers which line the tract of the vessels and rest in dense capillary networks. Targeted myocytes are nested behind these barriers. An alternative approach to cardiac therapeutic transfer explored extensively in small animals has been direct intramuscular injection into the heart. This approach, in effect, bypasses the barrier problem since the therapies would become immediately available for uptake. This approach is feasible at the small animal scale and, in fact, is particularly successful in transferring gene and cell therapies for efficacy. Direct intramuscular injections, however, is not a viable option in large animal and human applications due to both injury

associated with requiring 100+ injection sites and the resulting chronic inflammation.

Accordingly there remains a need for devices and methods for delivering desired medicaments to a patient's organ of interest (e.g., heart, liver, etc.), particularly in large mammals including humans. SUMMARY

One or more embodiments of the present invention may address one or more of the aforementioned problems. Certain embodiments according to the present invention devices for administering one or more needleless injections to a patient's organ of interest (heart, liver, etc.). In certain embodiments, the device can include a jacket comprising a flexible material and sized to circumferentially surround and contact the organ of interest. The jacket can include one or more needleless injection heads and a fluid distribution network. The fluid distribution network can include one or more fluid inlets that can enable connection with a fluid administering or fluid discharging device and one or more conduits configured to operatively connect each of the one or more needleless injection heads to at least one of the one or more fluid inlets. The one or more needleless injection heads, therefore, can be in fluid communication with a fluid administering or discharging device such that a plurality of needleless injections can be administered to a subject. In accordance with certain preferred embodiments, the devices provide a plurality of liquid jets that penetrate the tissue of the organ of interest to deliver a fluid medicament (e.g., a gene therapy) discharged from a fluid administering or fluid discharging device (e.g., pump). In another aspect, the present invention provides an apparatus for administering one or more needleless injections comprising the combination of a needleless injector device (e.g., pump) and a needleless injection jacket carrying one or more needleless injection heads. The needleless injection device (e.g., pump) can, preferably, be loaded with a fluid medicament and discharged at a desirable pressure sufficient to convey the fluid medicament through a fluid distribution network and one or more needleless injection heads to facilitate needleless injection of the fluid medicament into a desired tissue of a subject (e.g., penetration of the tissue with a liquid jet comprising the fluid medicament). Preferably, the pressure at which the fluid medicament is discharged from the needleless injector device can be adjusted prior to or during administration of the injections. In certain embodiments, the apparatus includes one or more coupling conduits. The coupling conduit(s) are preferably flexible. The coupling conduit(s) can be connected to and positioned between the needleless injector device and the needleless jacket device. Preferably, the coupling conduits are releasably attached to the needleless injection device, the needleless jacket, or both.

In yet another aspect, the present invention provides systems and kits for administering one or more needleless injections to a patient's organ of interest (e.g., heart, liver, etc.). Systems and kits according to certain embodiments of the present invention can include a needleless injector device (e.g., pump), a needleless jacket device, and a cannula. Preferably, the needleless jacket device is configured for insertion into a body of a patient through the cannula. For instance, the needleless jacket device can comprise a collapsed position that facilitates passage of the device through the cannula into a patient's body. In this regard, the needleless jacket device can be delivered and positioned onto or around an organ of interest via a minimally invasive technique (e.g., small incision and/or a few resected ribs through which the cannula can be inserted). In certain embodiments, the systems also include one or more coupling conduits. The coupling conduit(s) are preferably flexible. The coupling conduit(s) can be connected to and positioned between the needleless injector device and the needleless jacket device. Preferably, the coupling conduits are releasably attached to the needleless injection device, the needleless jacket, or both.

In yet another aspect, the present invention provides methods of providing one or more needleless injections to an organ of interest (e.g., internal organ - heart, liver, etc.). In certain embodiments, the methods comprise providing a needleless injector device including a fluid outlet through which a fluid medicament can be expelled for discharged, providing a needleless jacket device in fluid communication with the fluid outlet of the needleless injector device. Preferably, the needleless jacket device can be in fluid communication with the fluid outlet of the needleless injector device via one or more coupling conduits to define at least one fluid pathway from the needleless injector device through the fluid distribution network and the one or more needleless injection heads. The needleless jacket device can be positioned over (e.g., proximate to or contacting the organ of interest) at least a portion of the organ of interest. In accordance with certain embodiments of the present invention, the needleless jacket device and the needleless injector device can be operatively connected (e.g., in fluid communication) to each other via the coupling conduit(s) either before or after that needleless jacket device has been positioned onto (e.g., over, around, etc.) the organ of interest. After the needleless jacket device is in place, the methods comprise a step of injecting a fluid medicament into one or more tissue locations of the organ of interest. For instance, the fluid medicament can be delivered to and penetrate a plurality of tissue locations that are aligned with the respective outlet orifices of the needleless injection heads housed or carried in the needleless jacket device. In certain embodiments, for example, the methods provide a plurality of liquid jets comprising the fluid medicament that penetrate the tissue of the organ of interest to deliver the fluid medicament directly to said organ.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

Having described the invention in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein:

Figure 1 illustrates a needleless jacket having a closed bottom end and housing a plurality of needleless injection heads according to certain embodiments of the present invention;

Figure 2 illustrates a needleless jacket having an open bottom end and housing a plurality of needleless injection heads according to certain embodiments of the present invention;

Figure 3 illustrates a cross-sectional view of a needleless injection head according to certain embodiments of the present invention;

Figure 4 illustrates a fluid distribution network including control valves and pressure sensors according to certain embodiments of the present invention;

Figure 5 illustrates collapsible and expandable needleless jacket positioned over a heart according to certain embodiments of the present invention;

Figures 6A-6B illustrate a delivery tool suitable for use with the embodiments illustrated in Figure 5;

Figure 7 shows a schematic of a system according to certain embodiments of the present invention; Figure 8 shows a left thoracotomy chest window that was implemented to access the heart of a rodent;

Figure 9 shows a rodent's heart injected with methylene blue dye; and

Figure 10 shows an experimental set up of a liquid needless injection device; Figure 1 1 is shows the dispersion of a liquid into tissue using the device of Figure

10; and

Figure 12 is a chart comparing the retention of the therapeutic agent in the heart tissue of rats using the liquid needless injection device of Figure 10 in comparison to a direct injection via a needle.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, this invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these

embodiments are provided so that this disclosure will satisfy applicable legal

requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly dictates otherwise.

Needleless injection or liquid jet injection technology has been in development since 1947 for various skin and vaccination applications; whereby an accelerated jet of fluid containing drug penetrates the target with a very small puncture. Embodiments of the present invention utilize a needleless injection approach to provide one or more (preferably multiple) injections of a desired medicament to a patient's organ (preferably an internal organ such as the heart or liver) of interest. In accordance with certain embodiments of the present invention, subsequent injury at site of injection as well as inflammation is significantly and beneficially reduced. Another advantage of liquid jet injections according to embodiments of the present invention rests in the reduced likelihood of infection and/or inflammation at the injection site as compared to traditional needle injections. Furthermore, another notable advantage of certain embodiments of the present invention utilizing needleless injection is the spread or delivery profile of the therapeutic. In particular, the spread or delivery profile of the injected medicament according to certain embodiments of the present invention can be more evenly distributed per injection. Accordingly, the more even distribution profile with many multiple needleless injections according to certain embodiments of the present invention can offer significant benefit over deeper, more inflammatory needle based injections and allows needleless cardiac injection (for example) of a variety of medicaments including efficacious cardiac transgenes presently past Phase II clinical trials for an effective means of heart disease treatment.

In one aspect, the present invention provides devices for administering one or more needleless injections to a patient's organ of interest (heart, liver, etc.). In certain embodiments, the device can include a jacket comprising a flexible material and sized to circumferentially surround and contact the organ of interest. The jacket can include one or more needleless injection heads and a fluid distribution network. In accordance with certain embodiments of the present invention, the one or more needleless injection heads can be securely fastened into the jacket (e.g., a jacket mesh material) via stitching, a sealant mechanism, or both such that the outlet orifice of the respective needleless injector heads can be positioned generally normal to the external surface of an organ of interest when positioned over the organ of interest (e.g., heart, liver, etc.). The fluid distribution network can include one or more fluid inlets that can enable connection with a fluid administering or fluid discharging device and one or more conduits configured to operatively connect each of the one or more needleless injection heads to at least one of the one or more fluid inlets. The one or more needleless injection heads, therefore, can be in fluid communication with a fluid administering or discharging device such that a plurality of needleless injections can be administered to a subject. In accordance with certain preferred embodiments, the devices provide a plurality of liquid jets that penetrate the tissue of the organ of interest to deliver a fluid medicament (e.g., a gene therapy) discharged from a fluid administering or fluid discharging device (e.g., pump).

Accordingly, the device according to certain embodiments of the present invention containing one or more (preferably multiple) liquid jet injection ports / needleless injection heads can deliver controlled and precise boluses of jet injections comprising a

medicament of choice in precise locations of interest or all around an area of both diseased and healthy tissue (e.g., myocardium) in, for example, one to two treatments in a reasonably short period of time (e.g., under a few minutes).

Although devices according to embodiments of the present invention can be sized or configured to snugly conform to a variety of internal organs, certain embodiments of the present invention are particularly adapted for application to a heart of a patient (e.g., human or other large animal). In certain embodiments, for instance, the needleless jacket housing one or more needleless injector heads defines an internal volume between an open upper end and a lower end and is dimensioned for housing an apex of a heart to be inserted into the internal volume through the open upper end. The bottom end of the needleless jacket device can either be open or closed (resembling the form of a sock or sack). The generally flexible nature of the jacket according to certain embodiments of the present invention can beneficially enable the internal volume defined by the jacket to be adjustable. For instance, after the jacket is positioned over the apex of the heart (for example) the flexible nature of the jacket can be manipulated to conform to an external geometry of the apex of the heart (for example). By way of example, excess material can be gathered and clinched together to provide a more intimate spatial relationship between the jacket and the organ of interest (e.g., heart, liver, etc.). The flexible nature of the jacket also allows for some expansion if the organ of interest is slightly larger than the "un-stretched" open jacket. In certain embodiments, for example, the jacket can comprise a knit construction of fibers defining open cells. The respective sizes of the open cells can vary in response to adjustment/positioning of the jacket on (e.g., on, over, around, etc.) the organ of interest. In certain embodiments of the present invention, the material of construction of the jacket can comprise a variety of materials such as biocompatible polymers and elastomers (e.g., preferably medical grade), shape memory materials (e.g., shape memory polymers), spring-steel, or combinations thereof. Preferably, the jacket material exhibits a low coefficient of friction (e.g., mitigates any tendency of the jacket to stick or adhere to the organ of interest) with the organ of interest and/or exhibits excellent wear and chemical resistance properties. In certain embodiments, the jacket material itself may not exhibit these properties per se, but the jacket material can be coated with a coating layer of a material that provides the jacket with these desirably properties. For instance, the jacket material can be selected for achieving a strong retention of the needleless injector heads without major concern for adherence to the organ of interest when the jacket material is coated with a suitable coating layer that can provide the jacket with at least some of the desired properties (e.g., low coefficient of friction - "non-stick", wear resistance, chemical resistance, etc.).

As illustrated by the particular embodiments shown in Figure 1 , the needleless jacket device 10 can comprise a lower end 14 that is closed and having a length L sized for the apex of a heart to be received within the lower end 14 when the upper end 12 is placed at the atrioventricular groove. The needleless jacked device defines an internal volume 16 between the upper end 12 and lower end 14, preferably, dimensioned for receiving and/or housing the apex of a heart. In the embodiment illustrated in Figure 1 , the jacket comprises a flexible material to allow the jacket to be freely bent, folded, collapsed, or expanded. For instance, the device in Figure 1 is comprises a knit construction of fibers 20 defining a plurality of open cells 18. The respective sizes of the open cells can vary in response to adjustment/positioning of the jacket on (e.g., on, over, around, etc.) the organ of interest. The needleless jacket 16 also comprises a fluid distribution network 22. The fluid distribution network 22 can include one or more fluid inlets 23 that can enable connection with a fluid administering or fluid discharging device and one or more conduits 25 configured to operatively connect each of the one or more needleless injection heads 28 to at least one of the one or more fluid inlets 23. The fluid inlet 23 can also include a connector component 24 either integral or releasably attached to the fluid inlet such that the needleless jacket device 16 can be coupled to a fluid administration device, whereby the fluid administration device is in fluid communication with each of the needleless injection heads 28. The embodiment shown in Figure 1 also includes an exhaust port or line 29 that can be opened or closed to facilitate priming for needleless injections. In certain embodiments, multiple exhaust ports or lines 29 can be included. As shown in Figure 1 , the exhaust port or line 29 is operatively connected with the fluid distribution network 22.

Figure 2 illustrates similar embodiments to those exemplified by Figure 1 . In the embodiments illustrated by Figure 2, however, the lower end 14 is open. In this particular embodiment, the needleless jacket device 10 includes two fluid inlets 23 to enable fluid administered or discharged from a fluid administering device to enter the plurality of conduits 25 and ultimately pass through the needleless injection heads 25. Moreover, the embodiment shown in Figure 2 includes a length L and is sized for the apex of a heart to protrude beyond the lower end 14 when the upper end 12 is placed at the atrioventricular groove.

After the needleless jacket 10 is positioned on the organ of interest (e.g., heart) as described above, the needleless jacket can preferably be secured to the heart.

Preferably, the needleless jacket 10 can be secured to the organ (e.g., heart) using sutures, staples, or releasable straps. For example, the needleless jacket 10 can be sutured or strapped to the organ at suture locations circumferentially spaced along the upper end 12. If straps are used to maintain the positioning of the needleless jacket 10, a strap can be circumferentially positioned and fastened around the upper end 12 and lower end 14 of the needleless jacket.

In accordance with certain embodiments of the present invention, the needleless jacket is further dimensioned to include a longitudinal dimension L between the upper and lower ends of the jacket sufficient to overlie a lower portion of a heart between a valvular annulus and ventricular lower extremities and/or configured to have portions disposed on opposite sides of a heart between a valvular annulus and ventricular lower extremities.

Although not illustrated in Figures 1 and 2, the conduits fluid distribution network 22 preferably comprises flexible materials such that the conduits 25 can be freely bent. The flexibility or bendability of the conduits 25 facilitate easy delivery and positioning of the needleless device 16 to an organ of interest. In accordance with certain

embodiments of the present invention, the materials of construction for the conduits and fluid inlets can comprise a variety of materials that provide the desired degree of flexibility so as to not significantly restrain the flexible nature of the jacket. For example, suitable materials of construction can comprise, according to certain embodiments, stainless steel, nitinol (e.g., nickel-titanium alloy), polymeric materials, spring-steel, or combinations thereof. In certain embodiments of the present invention, for instance, the conduits can comprise spring-steel. Spring-steel, for example, can beneficially provide a flexible yet firm positioning (e.g., fluid path to the needleless injector heads) once optimal placement is achieved by the clinician. In certain embodiments, the lining of the conduits and/or the lining of the needleless injection inlets can comprise a surface modification of the conduit materials, or preferably an ultra-high-molecular-weight polyethylene flow liner

(UHMWPE). UHMWPE beneficially resists mechanical wear and fatigue, is temperature resistant, possesses a particularly low coefficient of friction, and can prevent blockages of the conduits and/or needleless injector heads by reducing medicinal aggregation. Such a lining, for instance, is particularly ideal for delivering a variety of biopharmaceuticals to the targeted organ of interest (e.g., heart, liver, etc.).

Needleless jacket devices according to certain embodiments of the present invention can include one or more needleless injection heads, preferably multiple needleless injection heads to enable a plurality of liquid jets that can penetrate the organ tissue of interest in a variety of selected configurations. For instance, needleless jackets according to certain embodiments of the present invention can include at least any of the following: 1 , 2, 3, 5, 10 , 15, 20, 25, 20 and 30 needleless injection heads; and /or at most about any of the following: 20, 25, 30, 40, 50 , and 60 injection heads (e.g., 1 -50, 2-25, 10-50).

The particular construction or geometrical configuration of the needleless injector heads is not particularly limited as long as liquid jet is produced that can penetrate a tissue of choice. For instance, a variety of commercially available needleless injector heads can be accommodated into the structure of the jacket if so desired. In general, however, the at least one of the one or more needleless injection heads in the jacket includes an outlet orifice having a diameter smaller than the diameter of the one or more conduits of the fluid distribution network. In certain embodiments, at least one of the one or more needleless injection heads comprises a capillary jet. Preferably, each of the one or more needleless injection heads (or at least those intended to be utilized in a procedure of choice) comprises an outlet orifice at least one of proximate to or contacting a tissue location of the organ of interest when the jacket is positioned over the organ of interest. In some applications, for instance the outlet orifices of the needleless injector heads can be in direct contact with the tissue of choice while in other applications it may be desirable to have a less intimate spatial relationship between the tissue and the outlet orifices.

In certain embodiments of the present invention, the needleless injection heads can incorporate a slight vacuum assist feature to facilitate positioning of the needleless injector heads onto the tissue. That is, the vacuum feature can gently "pull" the adjacent or proximately located tissue towards or into contact with the needleless injector heads. Figure 3, for instance, illustrates a cross sectional view of one such needleless injector head.

As shown in Figure 3, one embodiment of a needleless injector head 28 in contact with tissue 50 of an organ of interest. When viewing Figure 3, it should be appreciated that the tissue 50 of organ of interest (e.g., patient's organ) is illustrated as if the syringe 56 is engaged with an activated suction pump via vacuum conduit 51 . With such engagement the vacuum line 51 is placed in fluid communication with a vacuum compartment 40 via the aperture 53. Vacuum compartment 40 can be defined by a skirt 45 provided circumferentially around the needleless injection tube 42. Preferably the skirt 45 includes an integral rim portion 38 at the end of the skirt for abutment with a tissue. The spatial relation between the rim 46 of skirt 45, the abutment 48 and the tip 44 of the injection tube 42 can be varied somewhat depending on the application (e.g., heart tissue, liver tissue, healthy or diseased tissue, etc.). In certain application, for example, it can be preferable that the rim 46 of skirt 45, the forward edge 60 of abutment 48 and the tip 44 of the injection tube 42 all lie substantially in the same plane. However, this particular orientation can be modified as desired.

With the vacuum feature engaged, a partial vacuum in a range of around six to twelve inches of mercury (6-12 inches of Hg), for example, can be created inside the compartment 40. Due to this partial vacuum, the tissue 50 can be partially drawn into the compartment 40. Specifically, as shown, the tissue 50 is drawn into the compartment 40 until it comes into contact with an abutment section 48. As such, this places the tissue 50 into a state of tension at the point where a tip 44 of the needleless injection tube 42 is positioned against the tissue 50.

As shown in Figure 3, prior to an injection an air pocket 52 can be formed in the injection tube 42 between the tip 44 of the injection tube 42 and the fluid medicament 54 in a fluid chamber 24. The air pocket 52 can be formed in any manner well known in the art, and it can be of any desired volume. The importance of an air pocket 52 can be related to the initial acceleration of the fluid medicament 54 through the needleless injection head 28. For instance, when the device is first activated to effect an injection, the fluid medicament 54 will be accelerated through the injection tube 42. Due to the presence of an air pocket 52, the initial acceleration of the fluid medicament 54 through the injection tube 42 will be relatively rapid. The result of this rapid acceleration is a pressure spike in the fluid medicament which effectively causes the initially expelled fluid medicament 54 to create a hole in the tissue 50. The duration of this pressure spike, can vary but often comprises about one millisecond (1 ms). Once a hole has been created, and there is no longer an air pocket 52 in the injection tube 42, infusion of any fluid medicament 54 that is remaining in the fluid chamber 24 will be accomplished at a reduced infusion pressure.

In certain embodiments, the needleless jacket device includes one or more pressure sensors configured for monitoring the pressure within the fluid distribution network. The signals from respective pressure sensors can be used to monitor and provide a basis for adjusting the fluid pressure throughout the entire device or locally (e.g., discrete sections). In such embodiments, the at least one pressure sensor can preferably be located at least one of adjacent or proximate to at least one of said one or more needleless injection heads. Most preferably, a fluid pressure at or near each of the needleless injection heads can be monitored.

In accordance with embodiments of the present invention, the fluid distribution network can also include at least one adjustable control valve disposed therein. The valve can be opened and closed to varying degrees (e.g., 0-100% closed) at the will of a physician or operator. In certain embodiments, at least one adjustable control valve is disposed at least one of adjacent or proximate to at least one of said one or more needleless injection heads. Preferably, an adjustable control valve is positioned near each needleless injection head to enable individual control over every needleless injection head.

For instance, Figure 4 illustrates a fluid distribution network 22 including multiple adjustable control valves 26 and pressure sensors 27 disposed within or on conduits 25 connecting the needleless injector heads 28 to the fluid distribution network. For ease of reference, the fluid distribution network is illustrated without being embedded in the jacket. As shown in Figure 4, the flow and pressure of a fluid medicament to be administered (or in the process of being administered) to an organ of interest can be controlled at each of the needleless injector heads 28 independently of other needleless injection heads. Such embodiments facilitate the ability to provide tailored administration profiles of a fluid medicament. For example, a first needleless injector head can be operated at a higher pressure relative to others so that a deeper penetration of the fluid medicament into that tissue region can be realized or a second needleless injector head can be operated at a reduced pressure to limit or reduce the penetration depth of the fluid medicament into a particular region of the target organ. As shown in Figure 7, the adjustable control valves 26 and pressure sensors 27 can be monitored and adjusted using a central processing unit.

In certain preferred embodiments, the needleless jacket can be configured to collapse and expand to facilitate delivery of the jacket into a patient's body (e.g., via a variety of minimally invasive surgical techniques). For instance, the needleless jacket can include a variety of connection components configured for engaging with a variety of delivery tools, which can be used by a physician to manipulate the degree to which the jacket is expanded (e.g., opened) or collapsed (e.g., closed/folded). Such features are not particularly limited, but preferably enable insertion of the needleless jacket into the inside of a patient's body through a typical cannula that can provide a pathway through an incision or the like. For instance, the needleless jacket can be provided in a collapsed position and fed through a cannula into the inside of a patient's body. Once the needleless jacket is at or near the organ of interest (e.g., heart, liver, etc.), the needleless jacket can be expanded and positioned (and preferably releasably secured) over the organ of interest.

Although the configuration of needleless jackets according to certain

embodiments of the present invention configured to collapse and expand to facilitate delivery of the jacket into a patient's body via a cannula are not particularly limited, Figure 5 illustrates one exemplary embodiment of a needleless jacket 10 in accordance with certain embodiments of the present invention being engaged by a delivery tool 30 and positioned over and in contact with a patient's heart (H). Such embodiments facilitate delivery and/or application of a needleless jacket 10 through procedures which are less invasive and less traumatic as compared to full sternotomy approaches. In general, such needleless jackets can be compacted or collapsed and passed through a minimally invasive opening into a patient's thorax and subsequently opening the upper end 12 of the jacket for passing over the heart. In certain embodiments, the needleless jacket can include arrangements to facilitate securing the jacket to the heart prior to removal of the apparatus from the thorax (for example). As illustrated in Figure 5, the needleless jackets according to certain embodiments of the present invention can be configured to engage with a delivery tool 30. In the particular embodiment shown in Figure 5, the delivery took comprises a biasing member which provides for collapsing and opening the upper end of the jacket through the use of components which permit selective alteration of

configurational states such as hinges, shape memory materials, elastic materials, springsteel, etc.

One exemplary delivery tool 30 suitable for engaging needleless jackets in accordance with certain embodiments of the present invention is illustrated in Figures 5 and 6A-6B. In particular, Figures 6A and 6B are schematic representations of the tool 30 in longitudinal cross-section and showing only two diametrically opposed spacing arms (as will be described) and showing the tool 30 in open (Figure 6A) and closed/collapsed (Figure 6B) positions (also, as will be described). As noted previously, Figure 5 shows a distal end of the tool 30 with attached needleless jacket 10 placed on a heart H.

In this particular embodiment, the delivery tool 30 includes a proximal handle 32 for hand-held manipulation by a physician. A plurality of attachment locations 34 are secured to the handle 32 at a distal end of the tool 30. The attachment locations 34 are preferably blunt, non-piercing and smooth, such as smooth plastic knobs, to avoid trauma to the patient as the attachment locations 34 are advanced toward the heart H as will be described.

Preferably, each of the attachment locations 34 can be individually attached to the handle 32 by a plurality of spacing arms 36. The spacing arms 36 can be strips of flexible, elongated shape memory materials having straight portions 36a and outwardly curved portions 36b. In this particular embodiment, the spacing arms 36 comprise flat, narrow sheets of spring metal having curved portions 36b configured for selective flexing toward and away from axis X-X. The proximal ends of the straight portions 36a can be secured to the handle 32. The attachment locations 34 can be secured to distal ends of the curved portions 36b.

The spacing arms 36 can be secured to the handle 32 for the straight portions 36a to be arranged in a closely compact cylindrical array around the longitudinal axis X-X of the tool 30. In the open position, the curved portions 36b curve outwardly from the axis X-X. Thus, the attachment locations 34 are disposed in a circular array around the axis X-X. In the embodiment shown in Figures 5 and 6A-6B, all spacing arms 36 are of equal length. As a result the circular array of the attachment locations 34 is in a plane perpendicular to the axis X-X. In an alternative embodiment, the lengths of the spacing arms 36 can independently vary. The curved portions 36b provide for attachment locations 34 to expand into an open configuration for attachment locations 34 to be spaced from axis X-X by a distance substantially greater than the spacing of the straight portions 36a from the axis X-X.

Figures 6A-6B also show one embodiment of a control arrangement 38 for controlling the position of the attachment locations 34. The control arrangement 38 shown here is a tube 39 which surrounds the straight portions 36a of spacing arms 36. The control arrangement 38 is axially slidable along spacing arms 36 toward and away from the distal end of the tool 30. As the tube 39 is moved distally, the tube 39 slides over the curved portions 36b urging the curved portions 36b and the connected attachment locations 34 toward axis X-X. When the tube 39 is moved proximally (i.e., the "open position"), the tube 39 is not covering the curved portions 36b. With the tube 39 in the open position, the shape memory biases the spacing arms 36 to urge the attachment locations 34 to the spaced-apart open array. When the tube 39 is moved distally to cover and compress the curved portions 36b (i.e., the "closed position"), the attachment locations 34 are urged to a compact array.

Such embodiments in which the needleless jacket can be opened and closed at the will of the physician are particularly desirable for application of the needleless device through minimally invasive techniques.

In another aspect, the present invention provides an apparatus for administering one or more needleless injections comprising the combination of a needleless injector device (e.g., pump) and a needleless injection jacket carrying one or more needleless injection heads. The needleless injection device (e.g., pump) can, preferably, be loaded with a fluid medicament and discharged at a desirable pressure sufficient to convey the fluid medicament through a fluid distribution network and one or more needleless injection heads to facilitate needleless injection of the fluid medicament into a desired tissue of a subject (e.g., penetration of the tissue with a liquid jet comprising the fluid medicament). Preferably, the pressure at which the fluid medicament is discharged from the needleless injector device can be adjusted prior to or during administration of the injections. In certain embodiments, the apparatus includes one or more coupling conduits. The coupling conduit(s) are preferably flexible. The coupling conduit(s) can be connected to and positioned between the needleless injector device and the needleless jacket device. Preferably, the coupling conduits are releasably attached to the needleless injection device, the needleless jacket, or both.

In accordance with certain embodiments of the present invention, the needleless injector device comprises either a mechanically actuated injection device or a gas actuated injection device. In accordance with certain embodiments, for instance, the injection device can comprise a gas powered device utilizing carbon dioxide or other similarly used medical gas lines that can be readily accessible in healthcare systems. Such embodiments beneficially provide a safe, clean, and economically sustainable option. Preferably, the needleless injector device (e.g., pump) includes a delivery chamber for containing a fluid medicament for delivery to a patient's organ of interest.

The apparatuses according to certain embodiments of the present invention can include a needleless injector device (e.g., pump) that has a pressure control mechanism for selecting the pressure at which the fluid medicament will be discharged from the injector device. Controlling the discharge pressure from the needleless injector device, in some instances, can simplify any downstream pressure control scheme employed at the fluid distribution network and/or needleless injector heads disposed in or on the needleless jacket. In this regard, apparatuses according to certain embodiments can deliver a plurality of liquid jets that penetrate the tissue of the organ of interest. Moreover, the depth of penetration can be tailored for specific applications (e.g., differing organs and healthy vs. diseased tissue can warrant utilization of different pressures).

In yet another aspect, the present invention provides systems and kits for administering one or more needleless injections to a patient's organ of interest (e.g., heart, liver, etc.). Systems and kits according to certain embodiments of the present invention can include, as shown in Figure 7, a needleless injector device (e.g., pump) 102, a needleless jacket device 10, and a cannula. Preferably, the needleless jacket device is configured for insertion into a body of a patient through the cannula. For instance, the needleless jacket device can comprise a collapsed position that facilitates passage of the device through the cannula into a patient's body. In this regard, the needleless jacket device can be delivered and positioned onto or around an organ of interest via a minimally invasive technique (e.g., small incision and/or a few resected ribs through which the cannula can be inserted). In certain embodiments, the systems and/or kits also include one or more coupling conduits. The coupling conduit(s) are preferably flexible. The coupling conduit(s) can be connected to and positioned between the needleless injector device and the needleless jacket device. Preferably, the coupling conduits are releasably attached to the needleless injection device (at a discharge end of the injection device), the needleless jacket, or both.

Systems and/or kits according to certain embodiments of the present invention can include monitoring and/or control software. The software can be configured for monitoring pressure readings from the respective pressure sensors, valve positions of the adjustable control valves, providing target pressure values for multiple locations within the fluid distribution network, and/or adjusting valve position values (e.g., 0-100% closed) for each of the adjustable control valves. As shown in Figure 7, the software can be executed by a central processing unit 100.

Although not shown in Figure 7, certain embodiments of the invention comprise a system and/or kit in which the needleless jacket device 10 is configured for delivery through the cannula and for releasable attachment around an internal organ of interest. In such embodiments, the system and/or kit can also include a delivery tool configured to engage and guide the needleless jacket through the cannula and into a patient's body.

Kits according to certain embodiments of the present invention can include written instructions (e.g., electronic or printed) for assembling and/or coupling each of the individual components together in to provide a working apparatus for delivering a fluid medicament to a patient's organ of interest. For instance, the written instructions can outline proper assembly and/or guidelines for use of the assembled components. In certain preferred embodiments, the written instructions outline how to position and/or secure the needleless jacket onto or over the patient's organ of interest, load the medicament of choice in the needleless injector device, priming of the assembled apparatus (e.g., fluid distribution network, conduits, etc.), and triggering of the needleless injection device to provide one or more needleless injections of the fluid medicament to the patient's organ of interest.

In yet another aspect, the present invention provides methods of providing one or more needleless injections to an organ of interest (e.g., internal organ - heart, liver, etc.). In certain embodiments, the methods comprise providing a needleless injector device including a fluid outlet through which a fluid medicament can be expelled for discharged, providing a needleless jacket device in fluid communication with the fluid outlet of the needleless injector device. Preferably, the needleless jacket device can be in fluid communication with the fluid outlet of the needleless injector device via one or more coupling conduits to define at least one fluid pathway from the needleless injector device through the fluid distribution network and the one or more needleless injection heads. The needleless jacket device can be positioned over (e.g., proximate to or contacting the organ of interest) at least a portion of the organ of interest. In accordance with certain embodiments of the present invention, the needleless jacket device and the needleless injector device can be operatively connected (e.g., in fluid communication) to each other via the coupling conduit(s) either before or after that needleless jacket device has been positioned onto (e.g., over, around, etc.) the organ of interest. After the needleless jacket device is in place, the methods comprise a step of injecting a fluid medicament into one or more tissue locations of the organ of interest. For instance, the fluid medicament can be delivered to and penetrate a plurality of tissue locations that are aligned with the respective outlet orifices of the needleless injection heads housed or carried in the needleless jacket device. In certain embodiments, for example, the methods provide a plurality of liquid jets comprising the fluid medicament that penetrate the tissue of the organ of interest to deliver the fluid medicament directly to said organ. In this regard, a systemic effect can be greatly reduced or avoided all together as is desirable with a variety of therapeutic agents.

In certain embodiments, the organ of interest (e.g., heart, liver, etc.) can be scanned to identify regions of diseased and/or healthy tissue locations. Based at least in part on this information, the penetration depth of respective liquid jets of said fluid medicament can be tailored. For instance, diseased tissue in several instances will be easier to penetrate so the pressure at which the liquid jets exit the needleless injection heads overlying or contacting such regions can be reduced relative the pressure at which the liquid jets exit the needleless injection heads overlying or contacting regions of healthy tissue. In this regard, the step of injecting can comprise penetrating the tissue of an organ of interest at a uniform (e.g., same) depth throughout the exterior surface of the organ or the penetration depth can be varied depending on a determination of the healthiness of tissue at respective tissue locations.

As noted above, the penetration depth associated with each respective needleless injector head can be individually varied or identified regions can provide a first penetration depth while a second region can provide a second and different penetration depth (e.g., a first penetration depth can be reduced and associated with a region of diseased tissue while the second penetration depth can be associated with healthy tissue). According to certain embodiments of the present invention, for instance, the penetration depth associated with a needleless injector head can include at least any of the following: 1 , 2, 3, 5, 10 , 15, 20, and 25 mm; and /or at most about any of the following: 10, 15, 18, 20, 25, and 30 mm (e.g., 5-30, 10-25, 15-18, 15-25 mm, etc.).

In accordance with certain embodiments of the present invention, the step of positioning the needleless jacket comprises surgically placing the needleless jacket over and/or in contact with the organ of interest in a manner so that the outlet orifices of the one or more needleless injection heads are positioned one of proximate to or in contact with an exterior surface of the organ of interest. In certain embodiments, the step of positioning the needleless jacket also comprises delivering the needleless jacket to the organ of interest through a cannula inserted through an orifice (e.g., incision) of a patient. As discussed earlier, the needleless jacket can be provided in a closed or collapsed configuration and passed through the cannula into the patient's body. Once inside the patient's body, the needleless jacket can be positioned at or near the organ of interest and expanded as needed to accommodate the particular size of the organ of interest. Preferably, the organ of interest comprises a heart.

The fluid medicament according to certain embodiments of the present invention can comprise a wide variety of therapeutic agents or drugs ranging from active compounds to markers to gene therapy compounds. The terms "therapeutic agents" and "drugs" are used interchangeably herein and include pharmaceutically active compounds, cells, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus, polymers, proteins, and the like, with or without targeting sequences.

In certain embodiments, the therapeutic agents penetrated into the tissue of the organ on interest can comprise vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (aFGF, bFGF), angiogenin, nitric oxide, prostaglandin, prostaglandin synthase and other prostaglandin synthetic enzymes and isoforms of superoxide dismutase and other antioxidant proteins. Specific examples of therapeutic agents that can be used in conjunction with certain embodiments of the present invention include, for example, proteins,

oligonucleotides, ribozymes, anti-sense genes, DNA compacting agents, gene/vector systems (i.e., anything that allows for the uptake and expression of nucleic acids), nucleic acids (including, for example, recombinant nucleic acids; naked DNA, cDNA, RNA;

genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector which may have attached peptide targeting sequences; antisense nucleic acid (RNA or DNA); and DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences ("MTS") and herpes simplex virus-1 ("VP22")), and viral, liposomes and cationic polymers that are selected from a number of types depending on the desired application. Other pharmaceutically active materials include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPACK (dextrophenylalanine proline arginine chloromethylketone); antioxidants such as probucol and retinoic acid; angiogenic and anti-angiogenic agents; agents blocking smooth muscle cell proliferation such as rapamycin, angiopeptin, and monoclonal antibodies capable of blocking smooth muscle cell proliferation; anti-inflammatory agents such as

dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylic acid, and mesalamine; calcium entry blockers such as verapamil, diltiazem and nifedipine; antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel, 5- fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors;

antimicrobials such as triclosan, cephalosporins, aminoglycosides, and nitorfurantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine, NO-protein adducts, NO- carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D- Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, antiplatelet receptor antibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet factors; vascular cell growth promotors such as growth factors, growth factor receptor antagonists,

transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol- lowering agents; vasodilating agents; agents which interfere with endogeneus vascoactive mechanisms; survival genes which protect against cell death, such as anti- apoptotic Bcl-2 family factors and Akt kinase; and combinations thereof

Examples of polynucleotide sequences useful in accordance with certain embodiments of the present invention can comprise DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The

polynucleotides can also code for therapeutic proteins or polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic proteins and polypeptides include as a primary example, those proteins or polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body. In addition, the polypeptides or proteins useful in the present invention include, without limitation, angiogenic factors and other molecules competent to induce angiogenesis, including acidic and basic fibroblast growth factors, vascular endothelial growth factor, hif-1 , epidermal growth factor, transforming growth factor a and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor .alpha., hepatocyte growth factor and insulin like growth factor; growth factors; cell cycle inhibitors including CDK inhibitors; anti-restenosis agents, including p15, p16, p18, p19, p21 , p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase ("TK") and combinations thereof and other agents useful for interfering with cell proliferation, including agents for treating malignancies; and combinations thereof. Still other useful factors, which can be provided as polypeptides or as DNA encoding these polypeptides, include monocyte chemoattractant protein ("MCP-1 "), and the family of bone

morphogenic proteins ("BMP's"). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1 ), BMP-7 (OP-1 ), BMP-8, BMP-9, BMP-10, BMP-1 1 , BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively or, in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the

"hedgehog" proteins, or the DNA's encoding them.

A wide variety of different agents may be used for delivering therapeutic agents in accordance with embodiments of the invention. For example, viral vectors may be used to deliver therapeutic agents in accordance with invention. Examples of viral vectors include retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, and the like. In certain embodiments according to the present invention, the fluid medicament can comprise cells as the therapeutic agent. Cells can be of human origin (autologous or allogeneic) or from an animal source (xenogeneic), genetically engineered if desired to deliver proteins of interest at a delivery or transplant site. The delivery media can formulated as needed to maintain cell function and viability.

In certain preferred embodiments, the fluid medicament comprising at least one therapeutic agent is injected into the tissue of the organ of interest in a generally uniform distribution of injection sites about the entire external surface of the organ covered by the needleless jacket. In this regard, both diseased and healthy tissues are injected with the fluid medicament as a means of treated a particular medical disorder or condition. For instance, when subjecting a diseased heart (e.g., congestive heart failure) to methods according to embodiments of the present invention both healthy and diseased tissue locations are subjected to needleless injections. In certain embodiments, for instance, as much of the jacketed organ is subjected to needleless injection as possible.

Injection of such therapeutic agents according to certain embodiments of the present invention can beneficially deliver the desired therapeutic agent(s) locally to the organ or interest (e.g., heart), while providing a greater retention and distribution of the therapeutic agent in the targeted tissue. Furthermore, methods according to certain embodiments of the present invention also greatly reduce the risk of perforation (as compared to direct needle injection techniques) and undesirable systemic exposure of therapeutic agents that may be harmful to organs other than the targeted organ of interest.

Other aspects of the invention are directed to methods of delivering therapeutic agents to an internal organ, such as the heart, of interest using needless liquid injection. In one embodiment, the method comprises positioning a needless injector device over at least a portion of the organ. The fluid medicament comprising a therapeutic agent is then injected into one or more tissue locations of the organ of interest. Desirably, the velocity and pressure of the fluid medicament exiting the injector device is from 50 to 150 m/s and from 100 to 250 kPa, respectively. In one embodiment, the velocity of the liquid exiting the injector device is from 75 to 125 m/s, and more typically, from about 100 to 1 15 m/s. The driving pressure of the liquid is typically between 150 to 225 kPa.

In large animal organs, such as in a human, it may be desirable to position the ending of the needless injector device from about 3 to 8 inches away from the targeted organ tissue, and in particular, from about 4 to 6 inches.

In addition, it has been found that a modification to the injection outlet of the needless injection device may also help improve dispersion of the liquid into the targeted organ. In this regard, an outlet having an inwardly disposed conical shape may help improve dispersion of the liquid.

EXAMPLES EXAMPLE 1

A test utilizing a euthanized rodent model was performed in which a small incision was made in the body of the rodent to access the rodent's heart. 2 mL of methylene blue (dye) was loaded into a DermoJet Pen Injector (Robbins Instruments, NJ) and placed on a needle stand to compensate for the distance required for ideal penetration without resulting in heart perforation. That is, this particular device is rated for human skin penetration (not heart tissue of a rodent) so the injection head of the DermoJet Pen Injector was not placed directly in contact with the exterior surface of the rodent's heart.

A left thoracotomy chest window was implemented to access the heart (see Figure 8) and 4-5 needleless injections, each containing 100 ul or 0.1 mL fixed were delivered to a fixed site on the heart for a total of about 500 ul of total injection.

After performing the needleless injections, the rodent's heart was examined for retention of the dye, distribution of the dye, and damage to the tissue at or proximate to the injection sites. Figure 9, illustrate retention of the methylene blue as evident by the "purplish color of the heart" with minimal or no observed bleeding of the injection sites.

EXAMPLE 2

In this example, the effectiveness of using needless liquid injection for delivering a therapeutic agent into heart tissue was evaluated in comparison to intramuscular injection via a needle. The Ca²⁺ sensor protein S100A1 , which is a validated, promising strategy for heart failure, was used as the therapeutic agent. By way of background, a rate limiting problem that may be associated with adeno-associated virus (AAV) therapy is the ability to achieve sufficient myocyte expression and limiting off-target expression, such as in the liver. This is a major challenge for the percutaneous intracoronary infusion (PCI) approach. PCI has two major disadvantages: one is inefficient transfer across tight barriers between the capillary and the myocyte interstitial environment, the second is with undesired systemic exposure. Direct cardiac injection methods (e.g., needle) can restrict delivery to the heart, but are limited in the clinic due to injury, inadvertent perforation to the system and a poor global distribution profile.

Methods

A liquid jet device (DermoJet Pen Injector available from Robbins Instruments) was used in the experiment. The liquid jet device as available from Robbins Instruments is designed for dermal delivery of various medicaments including vaccines, local anesthesia, and the like. The device is unsuitable for delivery of therapeutic agents into internal organs and was therefore modified for use in the present example. In particular, the distal end of the device was modified so that exit point of the liquid injector had an inverted cone shape. It was found that this shape would allow for a wider dispersion of the liquid into the tissue of the targeted organ. In addition, the device was modified so that pressure and speed of the liquid exiting the needle was between 100 to 250 kPa and 50 to 150 m/s. In this specific example, the driving pressure of the liquid was 200 kPa and the speed was 1 12 m/s. The experimental set up of the device is shown in FIG.

32 rats received a baseline echo and infarct creation via LAD ligation and were divided into 4 separate groups (n=8 ea.): 2 Control consisting of, Needle injection (NE) and Needless Liquid Jet Injection (LJ), both receiving equal amount of saline and 2 Experimental consisting of, NE and LJ each receiving 1 x10¹³ vg of ssAAV9.S100A1 .

NE was performed with three separate 100uL injections in the left ventricle with a 30G needle, while the LJ device fired three separate 100 uL injections projected at the exposed left ventricle from 25 cm above the thoracotomy. Following 10 weeks, the rats were evaluated with echo and QPCR for ssAAV9.S100A1 genome copies (GC).

Results

The needless liquid injection device resulted in a robust AAV delivery jet featuring rapid velocity and a dispersion factor for wider range injection. The dispersion of the liquid from the needless liquid injection device is shown in FIG. 1 1 .

All animals survived the procedures and there was no difference in baseline function between the groups. At 10 weeks, all groups demonstrated decline from baseline. However, the LJ S100A1 therapy group preserved the most function and demonstrated significantly higher ejection fraction [60±3] % than the NE S100A1 [47±4], and both control groups: LJ saline [42±3] and NE saline [45±3] p<0.05. The results are summarized in the chart shown in FIG. 12. Quantitative polymerase chain reaction

(QPCR) evaluation of the NE group revealed all 8 rats had robust cardiac [17982±4312] GC per 100 ng DNA, but also with significant liver exposure [91842±15517] p<0.05. Contrary in the LJ, there was cardiac detection in 5/8 LJ rats [10147±3993] but only 1 /8 of these [40] GC exhibited liver exposure. While not wishing to be bound by theory, the inventors believe an immune response attributable to inadvertent infusion by the NE method resolves the discrepancy in outcomes.

Conclusion

From the foregoing results, it can be seen that the needless liquid injection method offers a promising cardiac specific delivery profile and could become an alternative direct cardiac delivery method. With more evaluation, this could add significant value for clinical trials, especially for patients that are excluded from PCI due to pre-existing AAV immunity. Many modifications and other embodiments of the invention set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

THAT WHICH IS CLAIMED:

A device for administering one or more needleless injections, comprising:

a. a jacket comprising a flexible material and sized to circumferentially

surround and contact a mammal's organ of interest;

b. one or more needleless injection heads carried by the jacket;

c. a fluid distribution network comprising (i) one or more fluid inlets and (ii) one or more conduits, said one or more conduits being configured to operatively connect each of the one or more needleless injection heads to at least one of the one or more fluid inlets.

The device of claim 1 , wherein said jacket defines an internal volume between an open upper end and a lower end, said jacket dimensioned for housing an apex of a heart to be inserted into said internal volume through said open upper end.

The device of claim 2, wherein the lower end of the jacket is closed such that the jacket comprises the shape of a sack.

The device of claims 2 or 3, wherein the internal volume defined by the jacket is adjustable when said jacket is positioned over the apex of the heart to conform to an external geometry of the apex of the heart.

The device of any of the preceding claims, wherein the jacket comprises a knit construction of fibers defining open cells and a size of the open cells varies in response to adjustment of said jacket on said organ of interest.

The device of any of the preceding claims, further comprising one or more pressure sensors configured for monitoring the pressure within the fluid distribution network.

The device of claim 6, wherein at least one pressure sensor is located at least one of adjacent or proximate to at least one of said one or more needleless injection heads.

The device of any of the preceding claims, further comprising at least one adjustable control valve disposed within the fluid distribution network.

9. The device of claim 8, wherein at least one adjustable control valve is disposed at least one of adjacent or proximate to at least one of said one or more needleless injection heads.

10. The device of any of the preceding claims, wherein the device includes from about 1 to about 50 needleless injection heads.

1 1 . The device of claim 10, wherein the device includes from about 2 to about 25 needleless injection heads.

12. The device of any of the preceding claims, wherein at least one of said one or more needleless injection heads includes an outlet orifice having a diameter smaller than the diameter of the one or more conduits of the fluid distribution network.

13. The device of any of the preceding claims, wherein each of the one or more

needleless injection heads comprises an outlet orifice at least one of proximate to or contacting a tissue location of the organ of interest when the jacket is positioned over the organ of interest.

14. The device of any of the preceding claims, wherein at least one of the one or more needleless injection heads comprises a capillary jet.

15. The device of any of the preceding claims, wherein the fluid distribution network comprises only one fluid inlet.

16. The device of any of the preceding claims, further comprising a connector

component either integral or releasably attached to the one or more fluid inlets such that the device can be coupled to a fluid administration device, whereby the fluid administration device is in fluid communication with each of the needleless injection heads.

17. The device of any of the preceding claims, wherein said jacket is further

dimensioned to include a longitudinal dimension between said upper and lower ends of the jacket sufficient to overlie a lower portion of a heart between a valvular annulus and ventricular lower extremities.

18. The device of any of the preceding claims, wherein said jacket is configured to have portions disposed on opposite sides of a heart between a valvular annulus and ventricular lower extremities. 19. The device of any of the preceding claims, wherein the one or more conduits comprise flexible conduits.

20. The device of claim 19, wherein the flexible conduits can be freely bent. 21 . The device of any of the preceding claims, further comprising at least one exhaust line operatively connected with the fluid distribution network.

22. The device of any of the preceding claims, wherein the one or more conduits comprise spring-steel.

23. The device of any of the preceding claims, wherein said one or more needleless injection heads is fastened to the jacket via stitching.

24. The device of any of the preceding claims, wherein said jacket comprises a

biocompatible polymer or elastomer.

25. An apparatus for administering one or more needleless injections, comprising: a. a needleless injector device; and

b. a needleless jacket device, said needleless jacket device comprising a device according to any of claims 1 -24;

c. one or more coupling conduits; said needleless injector device operatively connected to said needleless jacket device via said one or more coupling conduits. 26. The apparatus of claim 25, wherein the needleless injector device comprises a mechanically actuated injection device or a gas actuated injection device.

27. The apparatus of claim 25, wherein the needleless injector device comprises a hand actuated device.

28. The apparatus of claims 25-27, wherein needleless injector device includes a delivery chamber for containing a fluid medicament for delivery to a mammal's organ of interest. 29. The apparatus of claim 28, wherein the needleless injector device includes a pressure control mechanism for selecting the pressure at which the liquid medicament will be discharged from the injector device.

30. The apparatus of claims 25-28, wherein the needleless injector device comprises a pump for discharging a liquid.

31 . The apparatus of claims 25-30, wherein the apparatus delivers a plurality of liquid jets that penetrate the tissue of the organ of interest. 32. A system for administering a one or more needleless injections, comprising: a. a needleless injector device; and

b. a needleless jacket device according to any of claims 1 -24;

c. one or more coupling conduits; said needleless injector device operatively connected to said needleless jacket device via said one or more coupling conduits;

d. a cannula, said needleless jacket device being further configured for insertion into a body of a mammal through said cannula.

33. The system of claim 32, wherein the one or more coupling conduits are releasably attached to a discharge end of the needleless injector device, the one or more fluid inlets of the needleless jacket device, or both.

34. The system claims 32-33, further comprising control software configured for monitoring pressure readings from the respective pressure sensors, adjustable control valve settings, setting target pressure values for multiple locations within the fluid distribution network, and adjusting valve positions of each of the adjustable control valves.

35. The system of claim 34, wherein the control software is executed by a computer.

36. The system of claims 32-34, wherein the needleless jacket device is configured for delivery through the cannula and for releasable attachment around an internal organ of interest.

37. The system according to claims 32-34, further comprising a delivery tool

configured to guide the needleless jacket through the cannula.

38. A method of providing one or more needleless injections to an internal organ of interest, comprising:

a. providing a needleless injector device, said needleless injector device including a fluid outlet;

b. providing a needleless jacket device according to any of claims 1 -24; said fluid outlet of said needleless injector device being in fluid communication with said needleless jacket device via one or more coupling conduits to define at least one fluid pathway from the needleless injector device through the fluid distribution network and said one or more needleless injection heads;

c. positioning the needleless jacket over at least a portion of the organ of interest;

d. injecting a fluid medicament into one or more tissue locations of the organ of interest.

39. The method of claim 38, wherein the step of injecting comprises penetrating the one or more tissue locations with a liquid jet of said fluid medicament.

40. The method of claim 38, wherein a penetration depth of respective liquid jets of said fluid medicament comprise the same depth or varied depth depending on a determination of the healthiness of tissue at respective tissue locations.

41 . The methods of claims 38-40, wherein positioning the needleless jacket

comprises surgically placing the needleless jacket with outlet orifices of said one or more needleless injection heads being positioned one of proximate to or in contact with an exterior surface of the organ of interest.

42. The method of claims 38-41 , wherein the positioning the needleless jacket further comprises delivering the needleless jacket to the organ of interest through a cannula inserted through an orifice of a patient.

43. The method of claims 38-42, wherein the needleless jacket is configured to collapse and expand.

44. The method of claim 43, wherein the needleless jacket is passed through the cannula in a collapsed position.

45. The method of claims 38-44, wherein the organ of interest comprises a heart.

46. The method of claims 38-45, wherein the fluid medicament comprises a gene therapy.

47. A kit for administering a fluid medicament, comprising:

a. a needleless injector device; and

b. a needleless jacket device, said needleless jacket device comprising a device according to any of claims 1 -24.

48. The kit of claim 47, further comprising one or more coupling conduits configured to operatively connect said needleless injector device to said needleless jacket device.

49. The kit of claim 47 or 48, further comprising at least one cannula.

50. The kit of claims 47-49, further comprising a delivery tool configured to releasably engage the needleless jacket.

51 . The kit of claims 47-50, further comprising control software configured for

monitoring pressure readings from the respective pressure sensors, adjustable control valve settings, setting target pressure values for multiple locations within the fluid distribution network, and adjusting valve positions of each of the adjustable control valves.

52. The kit of claims 47-51 , further comprising written instructions, said written

instructions comprising assembling guidelines, positioning guidelines, or both.

53. A method of delivering a therapeutic agent to an internal organ of interest,

comprising:

positioning a liquid needless injector device over at least a portion of the organ; injecting a fluid medicament comprising a therapeutic agent into one or more tissue locations of the organ of interest, wherein the velocity and pressure of the fluid medicament exiting the injector device is from 50 to 150 m/s and from 100 to 250 kPa, respectively.

54. The method of claim 53, wherein the organ is the heart and the injector device is positioned about 3 to 8 inches above the portion of the heart into which the medicament is injected.