This invention relates, generally, to the treatment of degenerate, diseased or damaged body tissue and, more particularly, to an agent delivery system, a method of delivering an agent to a site in a patient's body and to components for the administration of an agent to a site in a patient's body tissue where the tissue pressure is such that special arrangements are required at the point of egress of the agent.

Background A major cause of joint pain in a person arises due to degeneration, disease or damage of tissue at a bony interface in the person's body. A typical example is the occurrence of back pain in a person due to degeneration, disease or damage to an intervertebral disc (referred to as a "degenerate disc") between two vertebrae in the person's spinal column. Such a degenerate disc may result in back pain, neck pain and/or referred pain in the person's arms or legs.

An intervertebral disc is an avascular structure that is viscoelastic in nature and consists of a central nucleus pulposus (referred to for brevity as the "nucleus") and an outer annulus fibrosis (referred to for brevity as the "annulus"). The nucleus performs a compressive load bearing function of the disc and the annulus serves a tensile function of the disc. The nucleus and the annulus are both cellular in nature and injury, disease or degeneration due to senescence of the cells can lead to changes in the physical characteristics of the disc which can result in the generation of pain in the person.

The disc is sandwiched between end plates of the vertebrae. The end plates have been postulated to act as a diffusion barrier, the physiological alteration of which contributes to an altered metabolism and, hence, degeneration of the disc. The present inventors have discovered that this is an over-simplification of a complex tissue interface and that the end plates are an active cell repository which have the potential for cell renewal and the supply of mature cells to the disc. The inventors also believe that the apophyseal ring-vertebral bone junction in adults continues to replenish the cellular contents of the disc. Morphogens, reagents or cells with the potential to activate and mobilise precursor cells or pre-cartilaginous cells can be made to proliferate, or mobilised and enhanced, in the area of the end plate-annulus-bone junction and the apophyseal ring. It therefore appears that the physiological attributes of the end plate are predominantly cellular functions. It is generally understood that the active ingredient necessary to encourage proliferation of precursor cells or pre-cartilaginous cells is expensive and wastage of such active ingredient is to be minimised. Also, techniques and equipment are required for delivering the active ingredient to the desired site in the patient's body in situations where tissue pressure can be significantly higher making egress of the active ingredient difficult.

Summary

According to a first aspect of the invention, there is provided an agent delivery system which includes a dispenser defining a reservoir and an outlet port in communication with the reservoir; a high density, immiscible, non-reactive, biocompatible displacement fluid contained within the reservoir; and a displacement device arranged in the reservoir for displacing the fluid through the outlet port of the dispenser. Further, the system may include a receptacle of the agent, the receptacle having a mounting formation for mounting the receptacle to the dispenser so that an interior of the receptacle is in communication with the outlet port of the dispenser. Preferably, the receptacle comprises a cannula with at least one discharge opening. The cannula may be elongate having a side wall defining a plurality of axially spaced discharge openings. It will be appreciated that the tip of the cannula could also define an opening.

Each discharge opening may include an occluding device for inhibiting back flow of the agent into the interior of the cannula. Each occluding device may be in the form of a one-way valve. Further, each of at least some of the openings may open out into a recessed region of the side wall of the cannula.

The cannula may be shaped and dimensioned to access a plurality of sites simultaneously. The cannula may also be flexible to be able to be directed to a desired location in a patient's body. Thus, in the case of the treatment of degenerate discs, the cannula may be shaped to facilitate periannular insertion, including trans-sacral epidural insertion, transforaminal epidural insertion and interlaminar periannular insertion. In addition, or instead, the cannula may be shaped to facilitate insertion into the epidural space from one side to a contralateral side within the spinal canal close to the annulus whilst still in the epidural space and/or in the extra canal space in the periannular area. The cannula may have radiological markers and be flexible to be able to be negotiated with minimum likelihood of damage to neighbouring blood vessels, the dura, or nerve tissue. The system may include a reaming tool for forming a passage through bone at a site in the patient's body into which the receptacle is to be inserted. The reaming tool may be insertable via a working cannula to the site and be manipulated through the bone to form the passage. The reaming tool may be steerable. According to a second aspect of the invention, there is provided a receptacle for delivering an agent to a site in a patient's body, the receptacle including an elongate body defining a lumen; at least one opening defined in the body through which the agent can be discharged; and an occluding device contained in the receptacle in register with the at least opening for closing off the at least one opening to inhibit back flow of the agent into the lumen of the body after being discharged through the at least one opening.

The body may have a mounting formation for mounting to a dispenser so that an interior of the body is in communication with an outlet port of the dispenser. The body may comprise a cannula having a side wall defining a plurality of axially spaced discharge openings. It will be appreciated that each opening may have an occluding device associated with it. Each of at least some of the openings may open out into a recessed region of the side wall of the cannula.

The cannula may be shaped and dimensioned to access a plurality of sites simultaneously. Further, the cannula may be flexible to be able to be directed to a desired location in a patient's body.

According to a third aspect of the invention, there is provided a reaming tool for forming a passage in bone in a patient's body, the reaming tool including a reaming head; a pivot to which the reaming head is pivotally mounted; and a steering mechanism for steering the reaming head through body tissue and bone.

The reaming head may be omni-directionally pivotally mounted relative to the pivot. According to a fourth aspect of the invention, there is provided a method of delivering an agent to a site in a patient's body, the method comprising inserting a cannula into the site, the cannula containing a quantity of the agent to be delivered and the cannula being mounted on a dispensing device; and using a high density, immiscible, non-reactive, biocompatible displacement fluid contained within a reservoir of the dispensing device to discharge the agent from the cannula. The dispensing device may be a syringe with a plunger displaceably arranged in the syringe. The arrangement may be such that there is a sufficient volume of displacement fluid in the syringe so that, when the plunger has reached its maximum point of travel, the volume of displacement fluid has been displaced into the cannula to discharge substantially all the agent from the cannula.

The method may include inserting the cannula into the patient's body percutaneously. Thus, the agent may be delivered minimally invasively.

Further, the method may include forming a passage through tissue and bone in the patient's body to enable the cannula to be delivered to the site. In one embodiment, the method is intended particularly, but not necessarily exclusively, for treating at least one degenerate disc in the patient's body and the method may include forming a passage through the vertebra on at least one side of the disc to be treated and delivering the agent to an end plate of the vertebra. The method may include delivering the agent to a number of vertebrae simultaneously. The method may include inserting the cannula trans-sacrally.

In another embodiment, the method may include manipulating the cannula about cartilaginous tissue in the patient's body. Once again, in this embodiment, the method is intended particularly, but not necessarily exclusively, for treating at least one degenerate disc in the patient's body and the method may include inserting the cannula periannularly adjacent the disc to be treated. The periannular insertion of the cannula is selected from the group consisting of trans-sacral epidural insertion, transforaminal epidural insertion, interlaminar periannular insertion, negotiation of the cannula through the epidural space from one side to a contralateral side within the spinal canal close to an annulus of the disc and negotiation of the cannula in extra canal space in the periannular area.

Brief Description of Drawings

Fig. 1 shows a schematic representation of a vertebral joint showing a pair of vertebrae sandwiching an intervertebral disc; Fig. 2 shows a schematic, sectional side view of an embodiment of an agent delivery system prior to use;

Fig. 3 shows, on an enlarged scale, a schematic, sectional side view of a part of the system of Fig. 2 encircled by Circle 'A';

Fig. 4 shows a schematic, sectional side view of the agent delivery system in use; Fig. 5 shows, on an enlarged scale, a schematic, sectional side view of a part of the system of Fig. 4 encircled by Circle ¹ B ¹ ;

Fig. 6 shows a schematic, sectional side view of the agent delivery system after discharge of the agent into a site in a patient's body; Figs. 7a - 7d show, schematically an example of steps for forming a passage in a patient's vertebrae using an embodiment of a reaming tool;

Fig. 8 shows, schematically, four different embodiments of receptacles for delivering an agent, in use;

Fig. 9 shows, schematically, two further embodiments of a method of delivering an agent to a site in a patient's body;

Fig. 10 shows a schematic side view of a distal part of a further embodiment of a cannula of the delivery system, in use;

Fig. 11 shows a schematic side view of a distal part of yet another embodiment of a cannula of the delivery system; Fig. 12 shows a schematic side view of a distal part of still a further embodiment of a cannula of the delivery system;

Fig. 13 shows a side view of yet another cannula of the delivery system; and

Fig. 14 shows a side view of a distal part of the cannula of Fig. 13.

Detailed Description of Exemplary Embodiments

An embodiment of the present system for delivering an agent is described below with reference to its application for use in the treatment of a degenerate disc in a patient's spinal column. However, it will be appreciated by those skilled in the art that the system has applications in other joints at a bony interface in a patient's body. Referring initially to Fig. 1 of the drawings, a schematic representation of a vertebral joint is illustrated and is designated generally by the reference numeral 10. The vertebral joint 10 comprises a first vertebra 12, a second vertebra 14 and an intervertebral disc 16 sandwiched between the vertebrae 12 and 14. The disc 16 comprises an annulus fibrosis, or annulus, 18 surrounding a nucleus pulposus, or nucleus 20.

Each vertebra 12, 14 includes an end plate 22 which bears against the disc 16 and serves in regulating hydration of the disc 16.An intervertebral disc 16 such as illustrated in Fig. 1 of the drawings, can degenerate due to a number of factors, including age, injury or other biological factors. A consequence of a degenerate disc 16 is the generation of back and neck pain, this pain radiating to arms and legs of the patient's body. Changes to the disc resulting in the generation of change could arise from the following:

• End plate changes - can be very subtle demonstrating only minor diffusion anomaly • Modic type changes

• Scheurmanns disease

• Black disc

• Internal disc disruption

• Annular tears • High Intensity Zone (HIZ) signal in posterior annulus

• Painful provocative discograms

• Positive functional discography, where the pain is suppressed when a local anaesthetic is applied to the pain generator.

Remedies in the treatment of degenerate disc include removal of the entire disc and replacement thereof by a prosthetic disc, removal of the disc and fusion of the vertebrae, both of which are very invasive procedures resulting in major tissue trauma, and, more recently, removal of the nucleus 20 of the disc and replacement by a prosthetic nucleus. The present inventors have determined that degenerate discs can also be treated therapeutically by the introduction of suitable active agents. Reference is made to applicant's co-pending US Provisional Patent Application Nos. 61/012,708 entitled "Agent delivery device and method" dated 10 December 2007 and 61/030,736 entitled "Bioactive fragment of BMP- 13 pathway protein" dated 22 February 2008 as well as the applicant's co-pending International Patent Application No. PCT/AU2008/000242 entitled "Composition and method for the treatment or prevention of spinal disorders" dated 22 February 2008. All of these applications are incorporated in this specification by reference in their entirety.

The inventors have now determined that each end plate of the vertebrae is a repository for stem cells which can be used in regeneration of discal cells by the injection of suitable active agents. A similar discovery has occurred in respect of the apophyseal ring-vertebral bone junction.

The list of agents to be used includes, but is not limited to, the following:

• an indigenous plant extract or an extract from animal tissue, • BMP' s super regulator or receptor modifier,

• Runx, Sox-9 or MSX modulator, • BMP 2, 4, 6, 8, 10, 12, 14 and 16, PDGF, FGF 13 and FGFl 8,

• a disc morphogeneic protein that is an extract from human or animal cartilage,

• Protein and protein complex that can induce uncommitted progenitor cells to differentiate into cells that have the potential of making parts of the intervertebral disc,

• Factors isolated from culture systems when mesenchymal stem cells are co- cultured with discal tissue (organ), the stem cells differentiating into cells exhibiting features of disc cells

• Proteins whose gene's have been identified as causative for the heterogenic condition of congenital Klippel Feil Syndrome or for the mutant type of Klippel

Feil Syndrome.

One factor which needs to be borne in mind with the delivery of such agents to a site such as the vertebral joint 10 in a patient's body is that such agents are used in extremely small quantities and are also extremely expensive. Hence, it is desirable to utilise as much of the agent as possible and to minimise wastage of the agent.

With reference to Figs. 2-6 of the drawings, an embodiment of a system for delivering an agent is designated generally by the reference number 30. The system 30 includes a dispenser in the form of a syringe 32. The syringe 32 defines a reservoir 34. A displacement device in the form of a plunger 36 is displaceably mounted in the reservoir 34 for discharging an agent 38 received in the reservoir 34 through an outlet port 40 of the syringe 32. A receptacle in the form of a cannula 42 is attachable to the outlet port 40 of the syringe 32 so that an interior 44 of the cannula 42 is in communication with the reservoir 34 of the syringe 32.

The system 30 includes a high density, immiscible non-reactive biocompatible displacement fluid 46 contained within the reservoir 34 of the syringe 32. The term

"fluid" is to be understood in a broad sense as any suitable fluent material and includes gels, etc. The displacement fluid 46 is arranged in the reservoir between the outlet port

40 and the plunger 36 of the syringe 32 so that, when the syringe 32 is primed for use by withdrawing a small quantity of active agent 38 into the reservoir 34, as shown in Fig. 2 of the drawings, the displacement fluid 46 is interposed between the active agent

38 and a downstream end of the plunger 36.

The volume of displacement fluid 46 arranged in the reservoir 34 of the syringe 32 is selected to approximate that of the volume of the interior 44 of the cannula 42.

The displacement fluid 46 is selected to have sufficiently fluent properties to be able to be displaced out of the reservoir 34 and also to be biocompatible. Importantly, the displacement fluid 46 should not mix with the active agent 38. An example of a suitable displacement fluid is a grade of cured or uncured _^ silicone as produced by Nusil Technologies.

The cannula 42 is an elongate element and, as will be described below, may, in certain circumstances, be flexible to steer through passages formed in bone of the patient's body.

An upstream end of the cannula 42 has a mounting formation, such as a Luer lock, 48 for mounting to the outlet port 40 of the syringe 32.

The cannula 42 has a plurality of axially spaced, circumferentially distributed openings 50 defined in a sidewall 52 of the cannula. The mounting formation 48 is arranged at an upstream end of the sidewall 52 of the cannula.

Each opening 50 is closed off by an occluding device in the form of a one-way valve 54. This inhibits backflow of the agent 52 into the interior 44 of the cannula 42 after having been discharged through the relevant opening 50 of the cannula 42.

Further, to inhibit tissue pressure preventing discharge of the agent 38, each opening 50 opens out into a recess 56 defined in the sidewall 52 of the cannula 42.

As described above, the volume of displacement fluid 46 selected equates to the volume of the interior 44 of the cannula 42. Thus, in use, to prime the syringe 32, the plunger 36 is withdrawn in the direction of arrow 58 (Fig. 2) after the cannula 42 has been attached to the outlet port 40 of the syringe 32. This results in a quantity of the active agent 38 being drawn into the reservoir 34 of the syringe 32 from the cannula 42 as shown in Fig. 2 of the drawings.

When the cannula 42 has been received at the site in the patient's body, the plunger 36 is urged in the direction of arrow 60 (Fig. 4 of the drawings). This causes the active agent to be discharged through the openings 50 of the cannula 42 under the action of the displacement fluid 46 being expelled from the reservoir 34 into the interior 44 of the cannula 42.

When the plunger 36 has been fully displaced to the position shown in Fig. 6 of the drawings, the arrangement is such that substantially all of the active agent 38 has been discharged through the openings 50 of the cannula 42 and the interior 44 of the cannula 42 now contains the displacement fluid 46. The one-way valves 52 inhibit backflow of the active agent 38 into the interior 44 of the cannula 42. Also, the provision of the recesses 56 facilitates discharge of the active agent 38 through the openings 50 and the likelihood of surrounding tissue inhibiting discharge of the active agent 38 is reduced. Once the active agent 38 has been discharged from the openings 50, the cannula

42 can be removed from the site in the patient's body. Referring now to Figs. 7a-7d of the drawings, use of an embodiment of a reaming tool is illustrated. The reaming tool is designated generally by the reference numeral 70. The reaming tool 70 comprises a reaming head 72 which is used to form an access opening 74 and a passage 76 (Figs. 7c and 7d) in the vertebrae 12, 14 of the patient's body.

The reaming head 72 is a rotatable drill head mounted on an omnidirectional pivot 78. The pivot 78 is, in turn, carried on a flexible shaft 80. The reaming tool 70 is steerable. More particularly, the reaming head 72 is able to be steered to form curved passages (as shown, for example, in Fig. 7c of the drawings) in bone. The steerability of the reaming tool 70 is provided by a steering mechanism comprising a pair of pull wires 82 mounted on opposite sides of the flexible shaft 80 to facilitate steering of the pivot 78 and, hence, the reaming head 72.

In use, the vertebra 14 on which the procedure is to be performed is accessed in a minimally invasive manner. A working cannula 84 is inserted percutaneously to abut against the vertebra 14. The reaming tool 70 is received within the cannula 84 and is operated to form the access opening 74 and the passage 76. The reaming head 72 of the tool 70 is steered through the bone of the vertebra 14 under control of the steering mechanism 82.

It is to be noted, as shown in Fig. 7d of the drawings, that the passage 76 can extend through the intervertebral disc (not shown in Fig. 7 of the drawings) from the vertebra 14 into the vertebra 12 so that the end plates (once again, not shown in Fig. 7 of the drawings) of both vertebrae 12 and 14 can be accessed simultaneously by the cannula 42 of the system 10 subsequently inserted into the working cannula 74 as shown in Fig. 7d of the drawings. Referring now to Fig. 8 of the drawings, various examples of cannulas 42 for use with the system 10 are shown. Hence, as shown at 90 in Fig. 8 of the drawings, a straight cannula 42 is used which accesses only a single vertebra of a patient's spinal column 92 in a direction parallel to a plane in which the end plate of the vertebra lies. As shown at 100 in Fig. 8 of the drawings, the cannula 42 is flexible and its tip 42.1 is able to be bent through a suitable angle, which may be up to approximately 90° or greater, to access the vertebra along an axis substantially perpendicular to a plane in which the end plate of the vertebra lies. In this example, only a single vertebra of the spinal column 92 is accessed.

At 110, a further example of a cannula 42 is shown. In this example, the sidewall 52 of the cannula 42 is flexible and the cannula 42 is of sufficient length to enable a plurality of vertebrae of the spinal column 92 to be accessed simultaneously. Reference numeral 120 shows a similar system where a longer cannula 42 is used and accesses the spinal column 92 trans-sacrally through the sacrum 94 of the spinal column 92 via an access opening 74 formed in the sacrum 94. A downstream end of the cannula 42 can, from the sacrum, access all or some of the lumber vertebrae 96 of the spinal column 92.

In all of the above examples, instead of the active agent 38 being injected directly into the bone of the vertebra, the agent can in addition, or instead, be inserted into the venous sinusoids of the vertebral bodies 12, 14.

With reference to Fig. 9 of the drawings, other methods of delivering the active agent to the site in the patient's body are illustrated. Thus, instead of delivering the active agent to the end plates 22 through the bone of the vertebrae 12, 14, the cannula 42 of the system 30 is inserted peri-annularly. This can be done by trans-sacral epidural access, transforaminal epidural access, interlaminar periannular access or, as shown in Fig. 9 of the drawings at 130, the cannula 42 can be negotiated through the epidural space 132 between the disc 16 and the spinal cord 134 of the spinal column 92. The cannula 42 is inserted from one side of the epidural space 132 to a contralateral side within the canal close to the annulus 18 of the disc 16.

In addition, or instead, as shown at 140, a cannula 42 of the system 30 can be introduced into peri-annulus space 142 adjacent the annulus 18 of the disc 16. Still other methods of delivering active agent may include continuous discharge of active ingredient by means of a controlled release discharge pump or a long acting deposit preparation to be implanted into the disc or adjacent vertebral bone. Through dermal patches, transcutaneous delivery of the active ingredient can be effected. Still further, the active ingredient could be taken orally together with an inactive ingredient or can be delivered parenterally.

Fig. 10 shows another embodiment of a distal part 144 of the receptacle in the form of the cannula 42. In this embodiment, at least the distal part 144 of the cannula 42 is formed of a shape memory alloy, such as, for example, Nitinol, and is pre-set into a bent shape as shown. For delivery to the site, a stylet (not shown) is introduced into the interior 44 of the cannula 42 to cause the distal part 144 of the cannula 42 to straighten. At the site, the stylet is removed so that the distal part 144 of the cannula 42 adopts its, pre-set, bent shape for delivery of the agent 38. To reposition the cannula 42, the stylet is reinserted, the cannula 42 moved to the new location and the stylet is withdrawn to cause the distal part 144 of the cannula 42 again to adopt its pre-set, bent shape as shown in dotted lines in Fig. 10 of the drawings. Fig. 11 shows a further embodiment of a distal part of the cannula 42. With reference to previous drawings, like reference numerals refer to like parts unless otherwise specified.

In this embodiment, each opening 50 is closed off by a one-way valve 54 in the form of a flap valve. A flap 146 of each flap valve 54 is hinged at a leading end of its associated opening 50 to facilitate ejection of the agent 38 as shown by arrows 148.

Fig. 12 shows still another embodiment of a distal part of the cannula 42. Once again, with reference to the previous drawings, like reference numerals refer to like parts unless otherwise specified. The cannula 42 includes an occluding device in the form of a sleeve 150 which occludes the openings 50 of the cannula during delivery of the cannula 42 to the site. At the site, the sleeve 150 is withdrawn proximally in the direction of arrow 152 to expose the openings 50 and to allow the agent 38 to be discharged through the openings 50. After discharge of the agent 38, the sleeve 150 is then repositioned over the openings 50 to inhibit back-flow of the agent into the interior 44 of the cannula 42.

Referring now to Figs. 13 and 14, still a further embodiment of a cannula 42 is shown. As is the case with the other embodiments previously described, like reference numerals refer to like parts unless otherwise specified.

In this embodiment, the cannula 42 has two lumens, one defining the interior 44 of the cannula 42 and which has at least one opening 50 in communication with the interior 44. A second lumen 154 runs parallel to the lumen 44 and a steering stylet 156 is contained in the lumen 154 for steering the distal part of the cannula 42 to the site and to position the distal part of the cannula 42 at the desired location at the site.

It is to be noted that the occluding device 54 is, in this embodiment, an axially displaceable piston which closes off the opening 50 prior to use and is moved proximally to expose the opening 50 to allow discharge of the agent 38 at the site. It will be appreciated that the piston has a shape to permit passage of the agent 38 past it in the interior 44 of the cannula 42.

It is a particular advantage of embodiments of the invention that systems are provided which assist in delivery of an active agent to a joint in a patient's body where it is desired to stimulate the growth of tissue such as tissue of an intervertebral disc in a vertebral joint. The system 30, in particular, minimises wastage of the active agent through the use of an immiscible, biocompatible displacement fluid. It is a further advantage of embodiments of the invention that devices are provided which assist in the delivery of the agent to the desired site in the patient's body a minimally invasive manner. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the scope of the invention as broadly described.

The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.