Patent Description:
In particular, the invention relates to an arthroscopic extrusion device suitable for delivering such a therapeutic substance into an articular cavity for a minimally invasive treatment of an injured articular cartilage, in particular, in mild and severe osteoarthritis.

As well known, endoscopic surgery techniques offer important advantages over open surgery, in particular they are less invasive to the tissues surrounding the operation site, make it possible to shorten the treatment time and therefore cause less discomfort to the patients, shorten the length of stay in hospital and reduce the treatment costs.

These advantages are potentially important for treating an articular tissue, in particular an injured articular cartilage, typically in a phase III and IV osteoarthritis.

The partial surface cartilage wear in phase III osteoarthritis is normally treated by hyaluronic acid intra-articular injection and by chondrocyte-protective substances, and/or by autologous chondrocyte or stem cell transplantation. The latter two techniques consist in taking cartilage cells from another bone region of the patient, in vitro cultivating the cells during a few weeks and implanting them in the patient once they have differentiated. The cartilage lesion must be preliminarily cleaned and coated with a periosteum in which a hole is provided for injecting and retaining a solution of the cultivated cells, so that the latter form new cartilage in situ. This requires several treatments, and a long time is needed for both the cell cultivation and the operation itself. Moreover, the step cannot be carried arthroscopically, on the contrary, open surgery is necessary.

Phase IV osteoarthritis, when not so severe to require an articular prosthesis, are often treated arthroscopically by mosaicoplasty. This technique consists in a cartilage transplantation. A portion of cartilage is taken from a less worn region of the same joint and is then inserted under pressure in the damaged region. The limited availability of transplantable material limits this technique to small lesions. Moreover, small joints such as finger or spinal joints cannot be treated by this technique. Another drawback of this technique is that the transplantation is less effective in patients older than <NUM>-<NUM> years, because the cartilage proliferative capacity decreases with age.

Therefore, it would be desirable to carry out minimally invasive surgical treatments for treating damaged articular tissues, in order to join the above summarized general advantages of the endoscopic techniques, with such more specific benefits as avoiding multiple treatment in the time, preventing the cartilage replacement tissue detachment from the application site, overcoming age limitations and making autologous withdrawal unnecessary.

Several devices for extruding a biologic substance are known for endoscopic use, as described in <CIT>, <CIT>, <CIT>, <CIT>. These documents relate to devices for extruding biologic substances at an operation site in the body of a patient, comprising a cannula to be introduced into the body through an endoscopic access, and a device for feeding and pushing the biologic substances to be extruded at a predetermined operation site.

Moreover, if multiple biologic substances must be stratified, for example, to form a primer layers or coaxial layers, coaxial extruder are known comprising two coaxial annular ducts.

In any case, it is necessary that the biologic substances are uniformly distributed in a predetermined area, in directions laying in an angle centred about a predetermined middle direction. In the cited prior art, this is obtained by forming an endoscopic access in said middle direction, and leaving the surgeon the task of directing the extrusion mouth of the cannula within this angle during the release. However, the prior art devices provide stiff or even flexible but not orientable cannulas, which complicates such a procedure. This can be the cause of an uneven distribution of the biologic substances.

<CIT> discloses a device for endoscopically delivering at least one therapeutic substance into a knee joint.

Briefly, despite the important search efforts in this field, till now no device has been practically available to extrude in situ a biologic and/or therapeutic material fulfilling the above-mentioned requirements.

It is therefore an object of the present invention to provide a device that allows a minimally invasive delivery of therapeutic substances, in particular therapeutic substances for regenerating the cartilage, into a small articular cavity or into an articular cavity that is difficult to attain by the prior art devices, such as a knee or elbow articular cavity.

It is also an object of the invention to provide such a device that assists a uniform distribution of said therapeutic substances in such articular cavity.

It is also an object of the invention to provide such a device that encounter a negligible resistance while travelling through the biological material between the body access site and the operation site.

It is also an object of the invention to provide such a disposable device and that, to this purpose, is easy and cheap to manufacture.

These and other objects are achieved by an arthroscopic delivery device as defined in claim <NUM>. Advantageous exemplary embodiments of the device are defined by the dependent claims.

According to an aspect of the invention, a device for endoscopically delivering at least one therapeutic substance comprises:.

wherein the substantially rigid intermediate portion has a distal rigid edge from which the flexible distal portion protrudes, and wherein the distal rigid edge has a passageway exit for the actuation cable, said distal edge and said passageway exit arranged in such a way that only the flexible distal portion of the cannula can be brought, by the actuation cable, from the undeformed conformation to the deformed conformation while the intermediate portion is always undeformed.

The actuation cable allows a surgeon to accurately control the direction the flexible distal portion of the cannula, which is not possible by the known tools, such as those of the cited prior art. This way, the surgeon can modulate the bending of the flexible distal portion of the cannula and, by suitably orienting the cannula, can easily select the extrusion direction of the therapeutic substance according to the operation requirements.

This way, moreover, the actuation cable is maintained close to the flexible distal portion of the cannula, which allows a more precise bending of the same. Furthermore, the above-described arrangement makes it easier to introduce the cannula into the patient's body, preventing the actuation cable from getting caught through the various biological material that is present between the body access site and the operation site. Moreover, the guide element provides circumferential and/or radial constraint forces acting on the cannula, while the surgeon operates the tie-member, i.e., the actuation cable.

In an exemplary embodiment, the distal rigid edge can comprise at least one guide element for the actuation cable or for each actuation cable, the guide element or the guide elements arranged along an outer surface of the cannula, the passageway being made within the guide element, through which the actuation cable or a respective actuation cable is slidingly arranged.

The device also makes it possible to attain particularly extended areas of an operation site, due to the flexibility of the end portion. In particular, the device allows an easy and minimally invasive delivery of the therapeutic substance on articular cavity portions that would be difficult to attain by the current instruments, for instance, the knee or elbow articular cavities, and the like.

In a preferred exemplary embodiment of the invention, a flexible rod extends from the distal rigid edge of the intermediate portion, said rod comprising a plurality of ring portions that surround the flexible distal portion of the cannula, wherein the plurality of ring portions comprises a terminal ring to which the distal end of the actuation cable is connected. This way, by pulling the actuation cable, the flexible rod bends and the ring portions follow and guide the flexible distal portion of the cannula from the undeformed conformation to the deformed conformation, the actuation cable arranged to slide within the ring portions. This way, the distal portion of the cannula has a smaller radial overall size, in particular, at the extrusion mouth, which makes it easier to move the cannula between the body access site and the operation site.

In particular, the distal portion and the intermediate portion of the cannula comprise:.

wherein the shell element comprises the distal rigid edge and the flexible rod.

Advantageously, the flexible rod comprises an elongated support portion extending parallel to the longitudinal axis of the cannula from a sector of the distal edge, the ring portions extending transversally to the elongated support portion between two opposite lateral sides thereof.

Advantageously, the flexible distal portion of the cannula is resiliently compliant. This way, by releasing the actuation cable after stretching it, the flexible distal portion returns from the deformed conformation to the undeformed conformation, or also to an intermediate conformation between undeformed conformation And the deformed conformation.

In a possible exemplary embodiment, the at least one actuation cable is a first actuation cable, and a second actuation cable is provided configured to pull the flexible distal portion in an opposite direction with respect to the first actuation cable. This way, the first actuation cable and the second actuation cable can selectively work as an agonist actuation cable and an antagonist actuation cable, and vice-versa. This allows a more stable positioning of the extrusion mouth of the cannula in a predetermined delivery position.

In a possible exemplary embodiment, at least one further actuation cable is provided comprising a distal end connected to the flexible distal portion at the extrusion mouth, and configured to pull the flexible distal portion bring it from the undeformed conformation to a further deformed conformation in a bend plane different from a plane of the deformed conformation defined by the axis of the cannula and by the axis of the previously mentioned actuation cable. This way, the flexible distal portion of the cannula can be bent in a plane that is distinct from the plane defined by the axis of the cannula, i.e., by the axis of the proximal and intermediate rigid portions thereof, and by the axis of the first actuation cable. More in detail, it is possible this way to bend the flexible distal portion along any bending plane of the plurality of planes passing through the axis of the cannula, by suitably combining the pulling force exerted on the first actuation cable and the pulling force exerted on the further actuation cable. This makes less necessary for the surgeon to rotate the cannula about its own axis in order to bring the extrusion mouth to a predetermined position about the axis of the cannula.

Even in this case, obviously, a respective second actuation cable can be provided for the first and for the further actuation cable in a position diametrically opposite with respect to the cannula, the second actuation cable arranged to work as an antagonist cable or as an agonist cable in opposition to the first and to the further actuation cable.

In an exemplary embodiment, the extrusion channel is configured as a central extrusion channel and an annular extrusion channel coaxial to each other, and the proximal portion is configured to feed and push a first therapeutic substance into the central extrusion channel and a second therapeutic substance into the annular extrusion channel, and to deliver the therapeutic substances through the extrusion mouth with the flexible distal portion in the deformed conformation.

In an alternative exemplary embodiment, the extrusion channel is configured as a central extrusion channel, a first annular extrusion channel and a second annular extrusion channel coaxial to one another, and the proximal portion of the cannula is configured to feed and push a first therapeutic substance into the first annular extrusion channel and a second therapeutic substance into the second annular extrusion channel, or a first therapeutic substance into the central extrusion channel, a second therapeutic substance into the first annular extrusion channel and a third therapeutic substance into the second annular extrusion channel, and to deliver the therapeutic substances through the extrusion mouth with the flexible distal portion in the deformed conformation.

In another alternative exemplary embodiment, the extrusion channel is configured as a first and a second extrusion channel parallel to each other, and the proximal portion is configured to feed and push a first and a second therapeutic substance into the first and second extrusion channel, respectively, and to deliver the therapeutic substances through the extrusion mouth with the flexible distal portion in the deformed conformation.

The devices according to each of the last three exemplary embodiments allow to extrude at the same time two or three different therapeutic substances, each of them having a specific function, through respective extrusion channels. In these cases, the different therapeutic substances to be extruded are stored within different compartments of the device.

More in detail, in case of the device having a central extrusion channel and two annular extrusion channels coaxial to one another, the proximal portion is configured to extrude layers of therapeutic substances commonly indicated as "core" and "shell" in the two inner extrusion channels. The core contains cells for repairing the damaged portion of the cartilage in order to build up new tissue and a biomaterial to create an environment suitable fr the cells to proliferate and differentiate. The shell is also formed by hydrogels as well, in order to protect the core from both the shear stresses generated by the extrusion, and the free radicals that can be formed during a possible photopolymerization process to stabilize the extruded material. The proximal portion is also configured to use the outer layer to extrude a "primer" in order to assist the adhesion of the two inner layers, thus forming a core-shell structure at the site lesion site, which can consolidate even after the extrusion.

In comparison with the prior art, in which such a fluid substance as a surgical glue is delivered by different tools and in times different than the surgical operation, the invention provides a single device for depositing a plurality of therapeutic substances at the same time, thus reducing the time, the costs and the disadvantages associated with the treatment.

More in particular, the device according to this exemplary embodiment allows treating the damaged cartilage of osteoarthritis-affected joints by arthroscopically extruding in situ a combination of materials in a single surgical step. Therefore, multiple and long-lasting operations can be avoided, as currently required by conventional autologous chondrocyte and/or staminal cell implant techniques to treat joints with phase III osteoarthritis, and also the open surgery required to threat phase IV osteoarthritis extended lesions.

Advantageously, at the extrusion mouth a rigid spacer element is provided, to which it the distal end of the actuation cable is connected, and the rigid spacer element is configured to engage with and keep open the extrusion mouth when the flexible distal portion moves from the undeformed conformation to the deformed conformation. In other words, the walls of the central extrusion channel and of the annular channel or channels are constrained at predetermined points so as to maintain the extrusion channels concentrical to one another even in the deformed conformation.

The flexible distal portion can be made of a biocompatible polymeric material that also has such features as high deformability and flexibility, and low tendency to kinking.

For instance, the flexible distal portion of the cannula can be made of a heat-shrinking material, so as to anchor the flexible distal portion to the intermediate portion by introducing the intermediate portion into the distal portion and by performing a subsequent thermal cycle. This makes it possible to obtain a particularly strong connection between the flexible distal portion and the intermediate portion of the cannula.

As an alternative, the wall of the extrusion channel, i.e., the walls of the cylindrical extrusion channels of the flexible distal portion are made as a composite material in which a preferably helical compression spring having a predetermined length, a predetermined diameter and a predetermined wire thickness is incorporated in a polymeric tubular matrix. This structure can be obtained by such a prior art technique as dip-coating, in which the spring is immersed into a polymeric solution, then it is extracted and caused to dry or to crosslink. This way, composite walls are obtained that are particularly thin, but that are much more rigid and a radially resistant than they would be if they were exclusively formed by a polymeric material. Such composite walls are substantially free from occlusion issues during their use and have a good elastic recovery to their initial conformation after the use.

These composite structures, and the relative production process, can also be used also in the case of a flexible distal portion having concentric annular extrusion channels, and can be used for the walls of all the extrusion channels. The composite walls obtained this way, can be singularly connected at the distal end of the intermediate portion of the cannula and can preferably be connected to one another, in such a way to maintain the concentricity during the bending.

As an alternative, the flexible distal portion of the cannula can be connected to the intermediate portion of the cannula by a fixed joint, wherein a proximal part of the flexible distal portion and a distal part of the intermediate portion are introduced into each other forming a force-fitting connection.

In particular, the cannula can comprise a convergence chamber configured to convey two or three materials into the proximal part, and two or three concentric extrusion channels configured to keep the materials separate form one another during the extrusion through the extrusion mouth.

Preferably, the flexible distal portion has a length set between <NUM> and <NUM>, and is configured in such a way that the deformed conformation has the shape of an arc.

Concerning the size, the diameter of the cannula, possibly containing a plurality of extrusion channels, is advantageously set between <NUM> and <NUM>, preferably between <NUM> and <NUM>, while its length is preferably set between <NUM> and <NUM>.

In the case of a cannula including three concentric extrusion channels at least in the flexible distal portion, the diameter of the central extrusion channel is advantageously chosen in such a way to limit the shear stress acting on the therapeutic substance while being extruded therethrough. This is useful when the therapeutic substance comprises cells in culture. The diameter of the central extrusion channel is preferably set between <NUM> and <NUM>. This way, in normal extrusion conditions, the shear stress acting on the material being extruded is not higher than <NUM> kPa.

The walls of the single extrusion channels have thickness preferably set between <NUM> and <NUM>, in particular between <NUM> and <NUM>, according to the production process.

In any case, the size of the flexible distal portion is preferably selected in such a way to limit the extrusion pressure. Considering an extrusion channel wall thickness of about <NUM>-<NUM>, the extrusion space of the internal annular extrusion channel inner ring can range between <NUM> and <NUM>. Similarly, the internal annular extrusion channel can have an extrusion space ranging between <NUM> and <NUM>.

The rigid part of the cannula, i.e., the distal and/or intermediate portion, can be made of different materials, for instance AISI <NUM> stainless steel. The production process can be based on additive manufacturing methods such as Powder Bed Fusion Selective Laser Sintering (SLS), Direct Melting Laser Sintering (DMLS) or Electron Beam Melting (EBM).

The materials of all the parts of the cannula are selected among the biocompatible materials that are also resistant to wear and corrosion, and that can be transformed by one of the manufacturing processes mentioned above in connection with the single portions.

Advantageously, the proximal portion is associated with a handpiece configured to allow a surgeon to manipulate the whole device.

According to another aspect of the invention, the extrusion channels are provided by the lumina of a multi-lumen tube housed within a shell portion surrounding the proximal and intermediate portions of the cannula, wherein the multi-lumen tube distally protrudes out of the shell portion to form at least one part of the flexible distal portion of the cannula. In a particular exemplary embodiment, also the passageways for respective actuation cables are provided by further lumina of the multi-lumen tube.

The invention is shown hereafter by the description of some exemplary embodiments, exemplifying but not limitative, with reference to the attached drawings, in which:.

With reference to <FIG>, a device <NUM> is described <NUM>, according to the invention, for endoscopically delivering at least one therapeutic substance. Such device comprises a cannula <NUM> that defines an extrusion channel <NUM> and that comprises a proximal portion <NUM>, a flexible distal portion <NUM> with an extrusion mouth <NUM> at its own distal end, and a substantially rigid intermediate portion <NUM> between flexible distal portion <NUM> and proximal portion <NUM>.

Proximal portion <NUM> is configured to feed and push a therapeutic substance <NUM> into extrusion channel <NUM>, in cooperation with an actuation unit <NUM>, so that therapeutic substance <NUM> can pass through extrusion channel <NUM> flowing through intermediate portion <NUM> and through flexible distal portion <NUM>, and can exit from extrusion mouth <NUM>.

Device <NUM> also comprises at least one actuation cable <NUM>, a proximal end <NUM> of which can be operated, for example it can be pull, at proximal portion <NUM> of cannula <NUM>, i.e., of actuation unit <NUM>, as exemplified hereinafter.

Actuation cable <NUM> also has a distal end <NUM> connected to flexible distal portion <NUM> of cannula <NUM> at extrusion mouth <NUM>, for example, by an anchor <NUM> shown in detail in <FIG>. Anchor <NUM> comprises a distal fastening portion <NUM> configured to engage with an edge of extrusion mouth <NUM>, a proximal engagement portion <NUM> including an engagement means to engage with distal end <NUM> of actuation cable <NUM>, for example in the form of a hole <NUM> for engagement with a pin or the like, not shown, connected to distal end <NUM>, and an intermediate portion <NUM> of connection between distal fastening portion <NUM> and proximal engagement portion <NUM>.

In this way, or in other possible ways, distal end <NUM> of actuation cable <NUM> is configured to displace, in particular to pull flexible distal portion <NUM> of cannula <NUM> by a force F transversal to extrusion channel <NUM>, bringing flexible distal portion <NUM> from an undeformed conformation A, shown in <FIG> and, by dashed line, in <FIG>, to a deformed conformation B shown in <FIG>.

According to an aspect of the invention, substantially rigid intermediate portion <NUM> has a distal rigid edge <NUM> from which flexible distal portion <NUM> protrudes, and wherein distal rigid edge <NUM> has a passageway exit <NUM> of a passageway <NUM> for actuation cable <NUM>. Distal rigid edge <NUM> and passageway exit <NUM> of passageway <NUM> are arranged in such a way that only flexible distal portion <NUM> of cannula <NUM> can be brought from the undeformed conformation A to deformed conformation B by actuation cable <NUM>, while intermediate portion <NUM> remains undeformed.

<FIG> show a device <NUM> according to a possible exemplary embodiment of actuation unit <NUM> for causing the deformation of flexible distal portion <NUM> of cannula <NUM> and the delivery by extrusion of therapeutic substance <NUM> through cannula <NUM> and extrusion mouth <NUM> thereof. Actuation unit <NUM> comprises a support <NUM>, in this case in the form of a housing <NUM>, to which motor units <NUM> and <NUM> are integrally connected for causing the deformation of flexible distal portion <NUM> by actuation cable <NUM>, and the delivery of therapeutic substance <NUM>, through cannula <NUM>, respectively. Actuation unit <NUM> also comprises a control unit <NUM> functionally connected to motor units <NUM> and <NUM>.

In order to cause the deformation of flexible distal portion <NUM>, motor unit <NUM> comprises a motor <NUM> and a shaft <NUM> that can be brought into rotation by motor <NUM>. Proximal portion <NUM> is fixed to and wound about shaft <NUM>, as <FIG> and <FIG> show in detail. For this service, actuation unit <NUM> comprises an interface unit <NUM> wherein a pushbutton panel includes keys <NUM>' and <NUM>" and is configured to receive a manual deformation input through keys <NUM>',<NUM>", and to generate an actuation command signal for actuating the deformation of flexible distal portion <NUM>. A cable <NUM>' is arranged for transferring the actuation command signal to control unit <NUM>, which is in turn connected to motor <NUM> of motor unit <NUM> through a cable <NUM>". Upon receiving the deformation command signal, motor <NUM> causes shaft <NUM> to rotate, thus increasing the part of proximal portion <NUM> of actuation cable <NUM> that is wound about shaft <NUM>, as show still <FIG> and <FIG>, and so deforming, flexible distal portion <NUM> of cannula <NUM> from the undeformed conformation towards deformed conformation B, until it reaches deformed conformation B or an intermediate conformation between A and B, as required for the delivery by extrusion.

In this case, the therapeutic substance to be extruded is enclosed in a syringe device <NUM> that comprises a cylinder <NUM>' connected between two brackets <NUM>', <NUM>" protruding from housing <NUM> and also comprises a piston <NUM>" slidingly arranged in cylinder <NUM>'.

In order to cause the therapeutic substance extrusion, motor unit <NUM> comprises a motor <NUM> and a slide <NUM> connected to motor <NUM> and integral to piston <NUM>". For this service, actuation unit <NUM> comprises a gun portion <NUM> in which a lever <NUM>" is arranged to be shifted by the hand fingers of an operator by grasping the butt <NUM>' of gun portion <NUM>. Gun portion <NUM> comprises a drive module <NUM> configured to receive a manual delivery input through the movement of lever <NUM>', as indicated by arrow <NUM>, and to generate a delivery command signal. A cable <NUM>' is arranged for transferring the delivery command signal to control unit <NUM>, which is in turn connected to motor <NUM> of motor unit <NUM> through a cable <NUM>". Upon receiving the delivery command signal, motor <NUM> causes slide <NUM> and piston <NUM>" to move, thus pushing the therapeutic substance enclosed in cylinder <NUM>' into extrusion channel <NUM>, as shown in <FIG>, and finally causing the extrusion thereof through extrusion mouth <NUM>.

<FIG> refer to exemplary embodiments of the invention in which a single actuation cable <NUM> is provided for deforming flexible distal portion <NUM> of cannula <NUM>. In this case, advantageously, flexible distal portion <NUM> is resiliently compliant. This way, by releasing actuation cable <NUM> after stretching it, flexible distal portion <NUM> tends to resiliently return from deformed conformation B, or from an intermediate conformation between the configurations B and A, to undeformed conformation A.

In any case, it falls within the scope the invention also the case in which an actuation cable <NUM> is also configured to push and to pull flexible distal portion <NUM>, in order to bilaterally operate a flexible distal portion <NUM> of cannula <NUM> that is not resilient by a single cable <NUM>.

Instead, with reference to <FIG>, a device <NUM> is described comprising a first actuation cable <NUM>' and a second actuation cable <NUM>" that are arranged to pull flexible distal portion <NUM> in opposite directions with respect to each other. In this case, actuation cables <NUM>',<NUM>" are arranged along diametrically opposite generatrix lines of cannula <NUM>, in particular along diametrically opposite generatrix lines of flexible distal portion <NUM>, or in any case on opposite sides with respect to a longitudinal axis, not shown, of cannula <NUM>.

This exemplary embodiment of the device is preferred, in particular when flexible distal portion <NUM> is not resiliently compliant, or in any case is not resiliently compliant enough to bring to return to its initial or undeformed conformation A shown in <FIG> upon releasing such an actuation cable as actuation cable <NUM> of <FIG>.

In particular, <FIG> and <FIG> refer to an actuation unit <NUM> similar to a corresponding actuation unit <NUM> of device <NUM> of <FIG>, from which it differs in that motor unit <NUM> for causing the deformation of flexible distal portion <NUM> comprises two motors <NUM>', <NUM>" having respective shafts <NUM>', <NUM>" for operating tie-member <NUM>' and tie-member <NUM>", respectively. Even in this case, the proximal portions of tie members <NUM>',<NUM>" are fixed and partially wound about shafts <NUM>', <NUM>", respectively.

<FIG> shows flexible distal portion <NUM> of cannula <NUM> in a first deformed conformation B'. In order to attain first deformed conformation B', motor <NUM>' is operated, so as to cause shaft <NUM>' to rotate in such a rotation direction that tie-member <NUM>' is wound thereon, as shown in <FIG>, while a part of the proximal portion of tie-member <NUM>" wound about shaft <NUM>" connected to motor <NUM>" is unwound from shaft <NUM>", as shown in <FIG>, so as to allow the deformation of flexible distal portion <NUM>.

Similarly, <FIG> shows flexible distal portion <NUM> of cannula <NUM> in a second deformed conformation B". To attain second deformed conformation B", motor <NUM>" is operated, so as to cause shaft <NUM>" to rotate in such a rotation direction that tie-member <NUM>" is wound thereon, as shown in <FIG>, while a part of the proximal portion of tie-member <NUM>' wound about shaft <NUM>' connected to motor <NUM>' is unwound from shaft <NUM>', as shown in <FIG>, so as to allow a deformation of flexible distal portion <NUM>.

In other words, first actuation cable <NUM>' and second actuation cable <NUM>" can selectively work as an agonist actuation cable and an as antagonist actuation cable, respectively, and vice-versa, in the reverse order, as an antagonist actuation cable and as an agonist actuation cable, so as to deform flexible distal portion <NUM> in an opposite direction with respect to a longitudinal axis of cannula <NUM>, thus obtaining two opposite deformed conformations B', B" of flexible distal portion <NUM> and two deformed orientations, i.e., two orientation angularly spaced apart by <NUM>°, of extrusion mouth <NUM> of cannula <NUM>.

Both such deformations of flexible distal portion <NUM> of cannula <NUM> of device <NUM> take place in a deformation plane, not shown, defined by the longitudinal axis of cannula <NUM> and by actuation cables <NUM>',<NUM>" diametrically opposite to each other, similarly to the deformation of flexible distal portion <NUM> of cannula <NUM> of devices <NUM> and <NUM>, which takes place in a deformation plane, not shown, defined by the longitudinal axis of cannula <NUM> and by actuation cable <NUM> (<FIG>). The extrusion mouth is then oriented, and its own middle axis covers an angle, for example a <NUM>° angle, lying in this deformation plane.

The operator can obtain lateral orientations of extrusion mouth <NUM> other than the orientations corresponding to deformed conformations B,B',B" of <FIG>, <FIG>, <FIG> by rotating the deformation plane, i.e., by rotating cannula <NUM> about its own longitudinal axis, within a <NUM>° angle in the case of devices <NUM> and <NUM> having a single actuation cable <NUM>, and within a <NUM>° angle in the case of device <NUM> having two actuation cables <NUM>.

As an alternative, in order to obtain a generic lateral orientation of delivery mouth <NUM> about the axis of cannula <NUM> by a minimum rotation or by no rotation of cannula <NUM> about its own longitudinal axis, devices <NUM> and <NUM> can be used, as shown in the respective cross-sectional views of <FIG>, made by sectional planes transversally arranged to cannula <NUM>, for example, to flexible distal portion <NUM> of cannula <NUM>.

In device <NUM> of <FIG>, besides actuation cable <NUM>, at least one further actuation cable <NUM> is provided, for example a further actuation cable angularly distant by <NUM>° from actuation cable <NUM> about longitudinal axis of cannula <NUM>. Further actuation cable <NUM> has a distal end, not shown, connected to flexible distal portion <NUM> at extrusion mouth <NUM>, and configured to pull flexible distal portion <NUM> and bring it from undeformed conformation A to a further deformed conformation that lies in a plane different from the plane where deformed conformation B lies, which is defined by actuation cable <NUM> and by the longitudinal axis of cannula <NUM>.

By device <NUM>, the orientations of delivery mouth <NUM> out of the plane can be obtained by suitably combining the pulling forces acting on actuation cables <NUM> and <NUM>. Similarly to devices <NUM> and <NUM>, device <NUM> is adapted to provide an unilateral actuation that is well suited if flexible distal portion <NUM> is resiliently compliant enough to spontaneously return to undeformed conformation A upon releasing actuation cables <NUM>, <NUM>.

In device <NUM> of <FIG>, besides actuation cables <NUM>',<NUM>" of device <NUM> of <FIG>, at least two further actuation cables <NUM>',<NUM>" are provided, for example further actuation cables that are rotationally spaced apart by <NUM>° from actuation cables <NUM>',<NUM>", respectively, about the longitudinal axis of cannula <NUM>. Further actuation cables <NUM>',<NUM>" have respective distal ends, not shown, connected to flexible distal portion <NUM> at extrusion mouth <NUM>, and configured to pull flexible distal portion <NUM> and to bring it from undeformed conformation A to further deformed conformations that are diametrically opposite to each other and that can be arranged in a plane different from the deformation plane defined by actuation cables <NUM>',<NUM>" and by the longitudinal axis of cannula <NUM>.

By device <NUM>, the orientations of delivery mouth <NUM> out of the plane can be obtained by suitably combining the pulling forces acting on cables <NUM>',<NUM>" and <NUM>',<NUM>". Similarly to device <NUM>, device <NUM> is particularly suitable if the flexible distal portion is not resiliently compliant enough to spontaneously return to its own undeformed conformation A upon releasing actuation cables <NUM>',<NUM>", <NUM>',<NUM>".

As <FIG>, <FIG>, <FIG>, <FIG> show, the device preferably comprises at least one guide element <NUM> for each actuation cable <NUM>,<NUM>',<NUM>". This guide element <NUM> has preferably the shape of a cylinder and is arranged along an outer surface of intermediate portion <NUM> of cannula <NUM>;.

<FIG> is a partial view of a cannula <NUM> according to an exemplary embodiment in which extrusion channel <NUM> of an extrusion device is configured as a central extrusion channel <NUM> and an annular extrusion channel <NUM> coaxial to each other. With no purpose of limitation, this extrusion device relates to an exemplary embodiment of <FIG>, in which are provided two actuation cables <NUM>',<NUM>". Proximal portion <NUM> of cannula <NUM>, in cooperation with actuation unit <NUM>, is configured to feed and push a first therapeutic substance into central extrusion channel <NUM> and a second therapeutic substance into annular extrusion channel <NUM>, and to deliver the therapeutic substances through extrusion mouth <NUM>.

With reference to <FIG>, a device <NUM> is described according to an exemplary embodiment of the invention, in which extrusion channel <NUM> is configured as a central extrusion channel <NUM>, a first annular extrusion channel <NUM>' and a second annular extrusion channel <NUM>" coaxial to one another. Proximal portion <NUM> of cannula <NUM>, in cooperation with actuation unit <NUM>, is configured to feed and push a first therapeutic substance into first annular extrusion channel <NUM>' and a second therapeutic substance into second annular extrusion channel <NUM>", or a first therapeutic substance into central extrusion channel <NUM>, a second therapeutic substance into first annular extrusion channel <NUM>' and a third therapeutic substance into second annular extrusion channel <NUM>", and to deliver the therapeutic substances through extrusion mouth <NUM>.

More in detail, three connection ducts <NUM>, <NUM>, only two of which shown in <FIG>, are arranged at proximal portion <NUM> of cannula <NUM> for conveying the therapeutic substances from respective reservoirs, for example from respective syringe devices as syringe device <NUM> of <FIG>, to extrusion channels <NUM>, <NUM>',<NUM>" through a convergence chamber towards the axis of cannula <NUM> arranged upstream of concentric extrusion channels <NUM>, <NUM>',<NUM>".

In an advantageous modification of device <NUM>, as shown in <FIG>, at extrusion mouth <NUM>, a substantially comb-shaped rigid spacer element <NUM> is provided, comprising a support rod <NUM> and of a plurality of teeth <NUM>,<NUM> protruding from a same side of support rod <NUM>. More in detail, the teeth comprise a central tooth <NUM> to be diametrically introduced into central extrusion channel <NUM> and four teeth <NUM> to be two by two introduced into first and second annular extrusion channels <NUM>' and <NUM>", in order to keep the separation walls of extrusion channels <NUM>, <NUM>',<NUM>" and the external wall of flexible distal portion <NUM> spaced apart from one another, so as to maintain extrusion mouth <NUM> open when flexible distal portion <NUM> moves from undeformed conformation A to deformed conformation B,B'. In an advantageous modification, as shown in <FIG>, spacer element <NUM> also comprises a pair of engagement portions <NUM> to engage with the distal portions of actuation cables <NUM>',<NUM>", as well as two respective intermediate portions <NUM> connecting support rod <NUM> with engagement portions <NUM>. Distal end <NUM> of each actuation cable <NUM>',<NUM>" is connected to a respective engagement portion <NUM>.

<FIG> show a manufacturing cycle of flexible distal portion <NUM> of a cannula <NUM> by insertion of concentric cylindrical walls <NUM>, <NUM>, <NUM>. More in detail, as shown in <FIG>, rigid intermediate portion <NUM> comprises three fastening portions <NUM>, <NUM>, <NUM> for respective concentric cylindrical walls <NUM>, <NUM>, <NUM> defining extrusion channels <NUM>, <NUM>' and <NUM>". <FIG> show the result of the insertion of flexible cylindrical walls <NUM>, <NUM>, <NUM>. Moreover, <FIG> shows rigid spacer element <NUM> of <FIG> with teeth <NUM>,<NUM> inserted in extrusion channels <NUM>, <NUM>',<NUM>". Moreover, <FIG> shows actuation cables <NUM>',<NUM>" connected to engagement portions <NUM> of rigid spacer element <NUM>. Moreover, <FIG> shows a collar <NUM> inserted on flexible distal portion <NUM> at extrusion mouth <NUM>. Moreover, <FIG> shows a guide element <NUM> for each actuation cable <NUM>',<NUM>".

As an alternatively to what is shown in <FIG>, flexible distal portion <NUM> of cannula <NUM> can be manufactured in a heat-shrinking material, so that it can be fixed to intermediate portion <NUM> by an insertion step of intermediate portion <NUM> into the distal portion and by a subsequent thermal cycle configured to form a force-fitting connection between flexible distal portion <NUM> and rigid intermediate portion <NUM>.

As <FIG> and <FIG> show, according to another aspect of the invention, flexible distal portion <NUM> of cannula <NUM> can be manufactured from a multi-lumen tube <NUM> made of a flexible material and having a plurality of longitudinal channels, by at least partially arranging this multi-lumen tube <NUM> into a part of intermediate portion <NUM> of cannula <NUM>, so that a portion of the former protrudes out of the latter by predetermined length, said protruding portion forming flexible distal portion <NUM>.

Still according to this aspect of the invention, also passageways <NUM> for respective actuation cables are provided by further lumina of multi-lumen tube <NUM> as shown, for example, in <FIG>, <FIG>.

<FIG>, instead, relate to devices according to different modifications of an exemplary embodiment of the invention, in which extrusion channel <NUM> comprises a first extrusion channel <NUM>' and a second extrusion channel <NUM>" parallel to each other, and proximal portion <NUM>, in cooperation with actuation unit <NUM>, for example as shown in <FIG>, is configured to feed and push a first and a second therapeutic substance into the first and into the second extrusion channel <NUM>',<NUM>", respectively, and to cause such therapeutic substances to be delivered through extrusion mouth <NUM> when the flexible distal portion <NUM> is in deformed conformation B.

More in detail, in the embodiment modification of <FIG> first and second extrusion channels <NUM>',<NUM>" have a circular cross section. Instead, in the embodiment modification of <FIG>, first and second extrusion channels <NUM>',<NUM>" have a substantially rectangular cross section, with a ratio higher than <NUM> between adjacent sides, preferably higher than <NUM>, to obtain a laminar flow of the therapeutic substance being extruded through extrusion mouth <NUM>.

Flexible distal portion <NUM> has a length L‴ set between <NUM> and <NUM>, and is configured so that deformed conformation B has the shape of an arc.

With reference to <FIG>, a cannula <NUM> is described of a device according to an advantageous exemplary embodiment of the invention, in which a flexible rod <NUM> extends from distal rigid edge <NUM> of substantially rigid intermediate portion <NUM>, said flexible rod comprising a plurality of ring portions <NUM>,<NUM> that surround flexible distal portion <NUM> of cannula <NUM>, and within which an actuation cable <NUM> is slidingly arranged, in particular, within an annular end portion <NUM> to which distal end <NUM> of actuation cable <NUM> is connected. This way, when pulling actuation cable <NUM>, flexible rod <NUM> bends and ring portions <NUM>,<NUM> follow and guide flexible distal portion <NUM> of cannula <NUM> from undeformed conformation A (<FIG>) to deformed conformation B (<FIG>). In a shown modification of the present exemplary embodiment, shown in the figures, actuation cable <NUM> can comprise two branches parallel to each other, and distal end <NUM> has the shape of a connection loop for connection to annular end portion <NUM> (<FIG>).

In particular, in a further advantageous modification of the present exemplary embodiment, distal portion <NUM> and intermediate portion <NUM> of cannula <NUM> comprise a common tubular core element <NUM> which is made of a flexible material, typically a polymeric material, and that defines extrusion channel <NUM>, and also comprise a shell element <NUM> enclosing tubular core element <NUM>, which is also a common element of distal and intermediate portions <NUM>, <NUM> of cannula <NUM>. Shell element <NUM> is preferably made of a inherently rigid material, or in any case in a material more rigid than the material of tubular core element <NUM>, in particular it can be made of a metal material such as a nickel-titanium alloy, for instance, the Nitinol alloy. Moreover, shell element <NUM> comprises distal rigid edge <NUM> and flexible rod <NUM>.

More in particular, flexible rod <NUM> comprises an elongated support portion <NUM> extending parallel to the longitudinal axis of cannula <NUM> starting from a sector of distal edge <NUM>, and ring portions <NUM>,<NUM> extend between two opposite lateral sides <NUM>, <NUM> of elongated support portion <NUM>, transversally to elongated support portion <NUM>.

<FIG> show devices <NUM>, <NUM> and <NUM> according to further exemplary embodiments of actuation unit <NUM>, <NUM>' and <NUM>" to perform the deformation of flexible distal portion <NUM> of cannula <NUM>. In these cases, actuation unit is configured as a purely mechanical, manually operated actuation unit, as an alternative to driven actuation unit <NUM> of device <NUM> (<FIG>). Advantageous embodiment modifications of devices <NUM>, <NUM> and <NUM> (<FIG>, <FIG>) comprise a cannula <NUM> arranged for being removed from the device and replaced such as the only disposable part of devices <NUM>, <NUM> and <NUM>.

In devices <NUM>, <NUM> and <NUM>, manual actuation unit <NUM> is combined with a cannula <NUM>, as shown in <FIG>, however it is adapted to operate cannulas according to different embodiments of the invention, for instance, cannula <NUM> shown in <FIG>, as well as driven actuation unit <NUM> of <FIG> is adapted to operate cannula <NUM> of <FIG>.

Actuation unit <NUM> comprises a handle portion <NUM> and a housing <NUM> integral to each other. Housing <NUM> includes a manual actuation mechanism <NUM>, <NUM>', <NUM>" connected to proximal end <NUM> of actuation cable <NUM>, which are arranged for pull actuation cable <NUM> in order to position cannula <NUM> in device <NUM>, <NUM> and <NUM>, as described hereinafter, and to bend the end distal portion of cannula <NUM> from the undeformed configuration to of <FIG> towards / up to deformed configuration B of <FIG>, in the case of device <NUM>, and similar configurations, in the case of devices <NUM> and <NUM>.

Manual actuation mechanism <NUM>, <NUM>', <NUM>" comprises an actuation axis <NUM>, and an actuation rod <NUM> that is slidingly arranged in a linear extension <NUM> of housing <NUM> and integrally connected to actuation axis <NUM> in a way not shown but obvious for a skilled person. Proximal end <NUM> of actuation cable <NUM> is connected to distal end <NUM> of actuation rod <NUM>, for example, by a knot or by another releasable connection.

Actuation axis <NUM> of device <NUM> of <FIG> is rotatably arranged within housing <NUM>. A knob <NUM> extends radially from actuation axis <NUM> and is arranged to cause actuation axis <NUM> to rotate and therefore actuation rod <NUM> to translate, in order to pull/release actuation cable <NUM> of cannula <NUM>. Housing <NUM> has an annulus-shaped opening <NUM>, in this case a <NUM>° annulus sector, through which knob <NUM> protrudes, so that to be manipulated by an operator who grasps handle portion <NUM>.

Actuation mechanism <NUM>' of device <NUM> of <FIG> differs from actuation mechanism <NUM> of device <NUM> in that it comprises a slidable actuation axis <NUM>' with an end knob <NUM>' that protrudes out of a linear opening <NUM> of housing <NUM> and is arranged to cause actuation axis <NUM> to translate and actuation rod <NUM> to translate as well, in order to pull/release actuation cable <NUM> of cannula <NUM>.

Actuation mechanism <NUM>" of device <NUM> of <FIG> differs from actuation mechanism <NUM> of device <NUM> in that rotatable actuation axis <NUM>" is arranged in a peripheral position of housing <NUM>, and in that knob <NUM>" extends peripherally beyond the outline of housing <NUM> instead of extending centrally from a groove thereof.

<FIG>, <FIG> is an exploded view of devices <NUM>, <NUM> and <NUM>, i.e., the devices are shown in a removed configuration of cannula <NUM>. For bringing such devices by the removed configuration to the undeformed configuration of <FIG>, proximal end <NUM> is connected to proximal end <NUM> of actuation rod <NUM> as described above, by introducing proximal end <NUM> into a recess of a connection fitting <NUM> connected to distal end <NUM> of actuation rod <NUM> and by tightening actuation cable <NUM> by knob <NUM>, <NUM>', <NUM>" and by actuation axis <NUM>, <NUM>', <NUM>" as it can understood from the above description, causing knob <NUM>, <NUM>', <NUM>" to perform a first stroke. In case of device <NUM>, the first stroke extends by a portion of the angle defining annulus-shaped opening <NUM>, for example by the half of the angle, in the shown case this angle portion is <NUM>°.

In order to bring distal portion <NUM> of cannula <NUM> from the undeformed configuration A of <FIG> to the deformed configuration B of <FIG>, or to an intermediate configuration between the configurations A and B, the knob is caused to perform a second stroke towards a limit position of knob <NUM>, in this case a maximum extension of the second stroke corresponds to a remaining portion of the angle defining annulus-shaped opening <NUM>. Similar actions on knobs <NUM>' and <NUM>" of devices <NUM> and <NUM> can be easily deducted from the figures. For the sake of simplicity, devices <NUM>, <NUM> are shown in <FIG>, respectively, with distal portion <NUM> of cannula <NUM> only in the removed configuration, since undeformed configuration A and deformed configuration B of distal portion <NUM> appear to be obvious.

The foregoing description exemplary embodiments and embodiment modifications of the invention will so fully reveal the invention according to the conceptual point of view, so that others, by applying current knowledge, will be able to modify and/or adapt for various applications such embodiment without further research and without parting from the invention, and, accordingly, it is meant that such adaptations and modifications will have to be considered as equivalent to the exemplary embodiments and exemplary specific embodiments. The means and the materials to realise the different functions described herein could have a different nature without, for this reason, departing from the field of the invention. It is to be understood that the phraseology or terminology that is employed herein is for the purpose of description and not of limitation.

Claim 1:
A device for endoscopically delivering at least one therapeutic substance into a small articular cavity, said device comprising:
- a cannula (<NUM>) defining at least one extrusion channel (<NUM>) and comprising:
- a proximal portion (<NUM>);
- a flexible distal portion (<NUM>) having an extrusion mouth (<NUM>) and
- a substantially rigid intermediate portion (<NUM>) between said flexible distal portion (<NUM>) and said proximal portion (<NUM>),
wherein said proximal portion (<NUM>) is configured to feed and push a therapeutic substance into said extrusion channel (<NUM>), so that said therapeutic substance can pass through said extrusion channel (<NUM>) flowing through said intermediate portion (<NUM>) and through said flexible distal portion (<NUM>), and can then exit from said extrusion mouth (<NUM>),
further comprising:
- at least one actuation cable (<NUM>,<NUM>',<NUM>") having:
- a proximal end (<NUM>) operable at said proximal portion (<NUM>) of said cannula (<NUM>);
- a distal end (<NUM>) connected to said flexible distal portion (<NUM>) of said cannula (<NUM>) at said extrusion mouth (<NUM>), and configured to pull said flexible distal portion (<NUM>) with a force transversal to said extrusion channel (<NUM>), bringing said flexible distal portion (<NUM>) from an undeformed conformation (A) to a deformed conformation (B,B',B")
characterized in that
said substantially rigid intermediate portion (<NUM>,<NUM>) has a distal rigid edge (<NUM>) from which said flexible distal portion (<NUM>) protrudes, and wherein said distal rigid edge (<NUM>) has a passageway exit (<NUM>) of a passageway (<NUM>) for said actuation cable (<NUM>,<NUM>',<NUM>"), said distal rigid edge (<NUM>) and said passageway exit (<NUM>) of said passageway arranged in such a way that only said flexible distal portion (<NUM>) of said cannula (<NUM>) can be brought, by said actuation cable (<NUM>,<NUM>',<NUM>"), from said undeformed conformation (A) to said deformed conformation (B,B',B"), in order to reach said small articular cavity, while said intermediate portion (<NUM>) is always undeformed.