WO2022047543A1

WO2022047543A1 - "bone implant"

Info

Publication number: WO2022047543A1
Application number: PCT/AU2021/051027
Authority: WO
Inventors: Michael Jeremy McAuliffe; Ming Hao Zheng; Benjamin Samuel DALBY; Timothy Hughes; Johan Sebastian Basuki; Michael Müller; Ben Cao
Original assignee: Captix Biomedical Pty Ltd
Priority date: 2020-09-04
Filing date: 2021-09-03
Publication date: 2022-03-10

Abstract

An intramedullary device for transplanting cells into a medullary cavity of a bone having an elongate shaft defining an internal lumen and a perforated region. The device further includes a semipermeable immuno-isolation housing within the lumen to house the cells and a port fluidly connected to the housing. A method of implanting cells into a bone of a subject includes implanting the intramedullary device into a medullary cavity of the bone and inserting cells into the device after implantation of the device.

Description

"Bone Implant"

Technical Field

[0001] The present disclosure relates to devices for implanting in living mammals and more specifically to devices for the implantation of cells into a medullary cavity of a bone.

Background

[0002] Implantation of cells into a target area of the body has been trialled in the treatment of several diseases.

[0003] There are several factors for consideration in matching a cell with an optimal implantation site. For example, for non-auto- or allogeneic cells, the site of implantation has a significant impact on cell viability due to the body’s acute and chronic response to foreign bodies.

[0004] Sustained viability post implantation is key to a successful transplant and there remains a need for methods and devices for implantation of cells into patients to both provide an access vehicle for implantation as well as an optimal environment for these cells when implanted.

[0005] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

Summary

[0006] According to one aspect of the present disclosure, there is provided an intramedullary device for transplanting cells into a medullary cavity of a bone, the device comprising: an elongate shaft extending from a proximal end to a distal end, the shaft having a sidewall defining an internal lumen to house the cells, wherein the shaft comprises a perforated region, the perforated region comprising a plurality of apertures extending through the sidewall and in fluid connection with the lumen; and a port fluidly connected to the lumen.

[0007] According to another aspect of the present disclosure, there is provided an intramedullary device for transplanting cells into a medullary cavity of a bone, the device comprising: an elongate shaft extending from a proximal end to a distal end, the shaft having a sidewall defining an internal lumen, wherein the shaft comprises a perforated region, the perforated region comprising a plurality of apertures extending through the sidewall and in fluid connection with the lumen; a semipermeable immuno-isolation housing disposed within the lumen to house the cells; and a port fluidly connected to the housing.

[0008] The apertures of the perforated region may be sized and/or configured to allow vascular growth into the lumen. For example, the apertures may facilitate generation of a vascular bed within the lumen in place of hypoxic fatty bone marrow. The apertures may be further configured to limit repopulation of fatty marrow cells and/or growth of vascular vessels which do not allow oxygen exchange. For example, the apertures of the perforated region may have a size (for example, a diameter) of between about 25 microns to about 2000 microns. In some embodiments, the apertures of the perforated region may have a size (for example, a diameter) of between about 100 microns to about 200 microns. For example, the apertures of the perforated region may have a size of about 25 microns, about 50 microns, about 75 microns, about 100 microns, about 125 microns, about 150 microns, about 175 microns, about 200 microns, about 250 microns, about 300 microns, about 400 microns, about 500 microns, about 1000 microns, about 1500 microns, about 2000 microns, or otherwise. [0009] The immuno-isolation housing may be generally configured to have a high surface area to volume ratio. In some embodiments, the housing may comprise at least one tube extending from a first end to a second end, wherein the first end is in fluid engagement with an inlet of the port and the second end is in fluid engagement with an outlet of the port. In some embodiments, the immuno-isolation comprises a plurality of tubes, each extending from a first end in fluid engagement with an inlet of the port to a second end is in fluid engagement with an outlet of the port.

[0010] The tube may be coiled within the lumen. For example, the tube may be arranged in at least one helical coil within the lumen. In some embodiments, the tube may be arranged in two or more concentric helical coils within the lumen, such as in a series of nested concentric coils. Alternatively, two or more tubes may be arranged in a corresponding series of two or more concentric coils within the lumen. The concentric helical coils may be configured such that fluid passing from the inlet to the outlet travels through an outermost coil first.

[0011] The tube may have an internal diameter in the range of between about 100 microns and about 800 microns. In some embodiments, the tube may have an internal diameter in the range of between about 400 microns and about 600 microns. For example, the tube may have an internal diameter of about 100 microns, about 200 microns, about 300 microns, about 400 microns, about 450 microns, about 500 microns, about 600 microns, about 700 microns, about 800 microns, or otherwise.

[0012] The tube or multiple tubes may comprise an overall tubing length. The tubing length may be in the range of between about 5 metres and about 60 metres. For example, the tubing length may be in the range of about 5 metres, about 10 metres, about 15 metres, about 20 metres, about 25 metres, about 30 metres, about 35 metres, about 40 metres, about 45 metres, about 50 metres, about 60 metres or otherwise.

[0013] The tube may have a wall thickness of between about 25 microns and about 500 microns. For example, the tube may have a wall thickness of about 25 microns, about 40 microns, about 50 microns, about 60 microns, about 75 microns, about 100 microns, about 200 microns, about 300 microns, about 400 microns, about 500 microns or otherwise.

[0014] In some embodiments, at least a portion of the housing includes a porous membrane. In some embodiments, the tube is formed at least partially, (in some embodiments, substantially or, in some embodiments, wholly) from a porous membrane. The membrane may be an immuno-isolating membrane. The membrane may be configured to retain implanted cells within the housing and substantially prevent interaction between the implanted cells and the immune system of the subject, whilst allowing exchange of beneficial molecules across the membrane.

[0015] The membrane may be formed from a suitable material, such as a biocompatible polymer or biopolymer. For example, suitable materials may include, but are not limited to silicone, PTFE, PDMS or PFPE.

[0016] The housing may be at least partially pre-filled with a cytocompatible carrier solution. The cytocompatible carrier solution may include, for example, one or more of saline, phosphate-buffered saline (PBS), patient serum, transplant media, human serum albumin or other suitable buffer fluid. In other embodiments, the cytocompatible solution may include Ringer’s solution, Hartmann’s solution (that is, lactated Ringer’s solution) or an iso-osmotic combination of Ringer’s and Hartmann’s solutions.

[0017] The port is longitudinally slideable in the lumen, and wherein the sidewall of the shaft comprises a protrusion extending into the lumen and engageable with the port to limit travel of the port within the lumen in a distal direction.

[0018] The port may include at least one seal which is penetrable to allow insertion of the cells into the device. In some embodiments, the port may have an inlet and an outlet. For example, the port may have an inlet for inserting cells into the device and an outlet for facilitating cell removal from the device. In such embodiments, the port may have an inlet seal and an outlet seal. The inlet seal may be penetrable to allow insertion of the cells into the device and the outlet seal may be penetrable to facilitate cell removal from the device.

[0019] In some embodiments, the inlet may comprise a manifold adapted for connection to the first ends of two or more tubes of the housing. Similarly, in such embodiments, the outlet may comprise a manifold adapted for connection to the second end of the two or more tubes of the housing.

[0020] The at least one seal may be penetrable by a needle. For example, the seal may be penetrable by a non-coring needle. The at least one seal may be self-sealing after penetration to re-close the port. The seal may be formed from a suitable polymeric material, such as silicone, for example.

[0021] In some embodiments, the port may be disposed within the lumen towards the proximal end of the shaft. The port may be removable from the lumen. For example, in some embodiments, the port is longitudinally slideable in the lumen. The sidewall of the shaft may comprise a protrusion extending into the lumen and engageable with the port to limit travel of the port within the lumen in a distal direction.

[0022] In other embodiments, the port may be remote from the shaft. For example, the port may be connected to the lumen of the shaft via one or more connecting catheters. In some embodiments, a dual lumen catheter connects the port to the inlet and outlet of the housing. In such embodiments, the port may be positioned proximal to the subject’s skin to allow insertion of cells to the inlet percutaneously.

[0023] The device may further comprise a bone fixation region. The bone fixation region may be provided at or adjacent to the distal end of the shaft. The bone fixation region includes an opening configured to receive a locking member to secure the device to the surrounding bone. In other embodiments, a shape of the device may ensure stable fixation in the medullary cavity without requiring a locking member to secure the device. [0024] The shaft may comprise a distal end portion. In some embodiments, the distal end portion may be in releasable engagement with the perforated region. For example, the distal end portion may comprise a thread engageable with a corresponding distal end thread of the perforated region. In some embodiments, the thread of the distal end portion may comprise a first stop member and the distal end thread of the perforated region may comprise a second stop member, wherein the first and second stop members are mutually engageable to align the perforated region with the distal end portion.

[0025] The shaft may comprise a proximal shaft region devoid of apertures in the sidewall. In some embodiments, a longitudinal axis of the proximal shaft region may be offset from a longitudinal axis of the perforated region in a first plane, for example, by between about 10 degrees and about 20 degrees. In some embodiments, the longitudinal axis of the proximal shaft region may be offset from the longitudinal axis of the perforated region 15 degrees. The angle of offset between the longitudinal axis of the proximal shaft region and the longitudinal axis of the perforated region may be configured to match an anatomical angle in the subject into which the device is to be implanted. For example, the angle may be substantially match an angle between the greater trochanter and the femoral shaft of the subject.

[0026] The perforated region may be curved in a second plane, wherein the second plane is orthogonal to the first plane. A curvature of the distal end portion may substantially match the curvature of the perforated region in the second plane.

[0027] A maximum external width of the proximal shaft region may be greater than a maximum external width of the perforated region.

[0028] In some embodiments, the proximal shaft region is in releasable engagement with the perforated region. For example, a distal end thread of the proximal shaft region may be engageable with a corresponding proximal end thread of the perforated region. The proximal end thread of the perforated region and the distal end thread of the proximal shaft region may comprise respective third and fourth stop members, mutually engageable to align the proximal shaft region with the perforated region.

[0029] In some embodiments, the device further comprises a proximal end cap releasably engageable with the proximal end of the shaft to close the lumen. The end cap may be engageable with the shaft by a screw thread, for example.

[0030] In some embodiments, the port may form part of the end cap. In such embodiments, the lumen may be fluidly accessible through the end cap by penetration of one or more seals of the port. The end cap, port and/or shaft may comprise an anti- fibrotic coating to inhibit fibrotic growth across the port. In other embodiments, the lumen may be sealed or protected with a penetrable material, such as bone wax, or alternatives. In other embodiments, the penetrable material may include one or more of fatty acid salts, fibrin/collagen paste, gelatin paste, glycolic or lactic acid/glycerol oligomers, partially deacetylated chitin hydrochloride, PEG/microfibrillar collagen paste, polydioxanone/natural oils, polyorthoester, or other penetrable, haemostatic composites suitable for use in surgical procedures, for example. The penetrable material may provide a secondary seal to the lumen in addition to one or more seals of the port.

[0031] In other embodiments, the proximal end of the shaft may be closed, and the lumen accessible via a cannulated screw inserted to the shaft. The screw may be inserted substantially perpendicularly to an axis of the shaft.

[0032] In some embodiments, the device may be coated, impregnated or at least partially filled with an agent that stimulates cell growth and/or vascularisation. For example, the lumen of the shaft may be at least partially filled with fibrin. Alternatively or additionally, the device may be coated, impregnated or at least partially filled with an agent that inhibits bone integration.

[0033] In some embodiments, the cells may be endocrine cells. In some embodiments, the cells may be insulin producing cells. In some embodiments, the cells may be pancreatic islet cells. In some embodiments, the cells may be derived from stem cells.

[0034] According to another aspect of the present disclosure, there is provided use of an intramedullary device according to embodiments of the disclosure for implanting cells into a bone of a subject.

[0035] In some embodiments, the bone may be a femur. In some embodiments, the cells may be insulin producing cells.

[0036] According to another aspect of the present disclosure, there is provided a method of implanting cells into a bone of a subject, the method comprising: implanting a device according to embodiments of the disclosure into a medullary cavity of the bone; and inserting cells into the device after implantation of the device.

[0037] In some embodiments, the method may comprise fixing the intramedullary device to the bone of the subject with a locking member.

[0038] In some embodiments, the bone may be a femur and the intramedullary device may be implanted into the medullary cavity of the femur via the greater trochanter. In other embodiments, the device may be implanted into a different long bone of a subject. In still further embodiments, the device may be implanted into soft tissue of a subject. For example, the device may be implanted into the peritoneal cavity or the omentum.

[0039] According to another aspect of the present disclosure, there is provided a method of treating diabetes in a subject, the method comprising performing the method of implanting cells into a bone of a subject according to embodiments of the disclosure, wherein the cells are insulin producing cells. [0040] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Brief Description of Drawings

[0041] By way of example only, embodiments are now described with reference to the accompanying drawings, in which:

[0042] Figure 1A is a top view of an intramedullary device according to one aspect of the present disclosure;

[0043] Figure IB is a cross section of the device of Figure 1 A taken along line A.

[0044] Figure 2A is a front view of the device of Figure 1 A;

[0045] Figure 2B is a cross section of the device of Figure 2A taken along line B;

[0046] Figure 2C is a cross section of the device of Figure 2A taken along line C;

[0047] Figure 3A is a front view of the device of Figure 1 A;

[0048] Figure 3B is a cross section of the device shown in Figure 3A taken along line D;

[0049] Figure 4A is a perspective view of a proximal end cap of the device of Figure 1A;

[0050] Figure 4B is a left-side view of the end cap shown in Figure 4A;

[0051] Figure 4C is a right-side view of the end cap shown in Figure 4A; [0052] Figure 4D is a front view of the end cap shown in Figure 4A;

[0053] Figure 4E is a cross section of the end cap shown in Figure 4D taken along line F;

[0054] Figure 5 is a partially exploded perspective cutaway view of an intramedullary device according to another embodiment of the present disclosure;

[0055] Figure 6A is a front view the device of Figure 5;

[0056] Figure 6B is a cross section of the device shown in Figure 6A taken alone line E;

[0057] Figure 7A is a front view of a distal end portion of the device of Figure 5;

[0058] Figure 7B is a perspective view of the distal end portion shown in Figure 7A;

[0059] Figure 8A is a cross section of a perforated region of the device of Figure 5;

[0060] Figure 8B is an expanded partial view of the proximal end of the perforated region shown in Figure 8A;

[0061] Figure 8C is an expanded partial view of the distal end of the perforated region shown in Figure 8A;

[0062] Figures 9A and 9B are cross sections of a proximal shaft portion of the device of Figure 5;

[0063] Figure 10A is a perspective view of a port of the device of Figure 5;

[0064] Figure 10B is a cross section of the port shown in Figure 10A; [0065] Figure IOC shows left-side, front, right-side, front perspective, cross-section, and rear perspective views of a retaining member of the port shown in Figure 10A;

[0066] Figure 10D shows left-side, front, right-side, front perspective, and rear perspective views of a pair of port closures of the port shown in Figure 10A;

[0067] Figure 11 is a partial perspective cut-away view of a connection region between the proximal shaft portion and the perforated region of the device of Figure 5;

[0068] Figure 12 is a partial exploded perspective cut-away view of the proximal end of the device of Figure 5;

[0069] Figure 13 is a partial perspective cut-away view of the distal end of the device of Figure 5;

[0070] .Figure 14 is a perspective view of a series of tubes arranged in concentric helical coils according to another embodiment of the present disclosure;

[0071] Figure 15 is a partial exploded perspective cut-away view the proximal end of an intramedullary device according to another embodiment of the present disclosure;

[0072] Figure 16 is a partial perspective cut-away view of a connection region between the proximal shaft portion and the perforated region of the device of Figure 15;

[0073] Figure 17 A is a perspective view of a port of the device of Figure 15;

[0074] Figure 17B is a cross section of the port shown in Figure 17A; and

[0075] Figure 17C is a perspective view of a port of the device of Figure 15. Description of Embodiments

[0076] An intramedullary device according to embodiments of the present disclosure is generally shown as 100 in the drawings. The intramedullary device may be used for implanting cells into a medullary cavity of a bone, as discussed further below. The intramedullary vascular supply directly drains to the vascular tree and so hormones and/or drugs delivered in the intramedullary cavity may be distributed throughout the body.

[0077] In some embodiments, the device may be used to generate a vascular bed in place of the hypoxic fatty bone marrow. The device may provide a suitable implant site for autologous cells.

[0078] The device may be used as a macro-encapsulation protective device for the implantation of cells. Particularly, the device may be a macro-encapsulation device for cells in the treatment of an endocrine or metabolic condition.

[0079] Figure 1A shows one embodiment of an intramedullary device 100 adapted to be implanted into the medullary cavity of a femur of a subject. The intramedullary device 100 includes an elongate shaft 110 extending from a proximal end 111 to a distal end 112. The shaft has a substantially cylindrical sidewall 113, which defines an internal lumen 114. A distal end portion 140 of the shaft may be closed.

[0080] The shaft has a perforated region 120 and an un-perforated proximal shaft region 130. As shown in Figure IB, a longitudinal axis of the proximal shaft region 130 is offset from a longitudinal axis of the perforated region 120 in a first plane.

[0081] In some embodiments, a thickness of the sidewall 113 in the perforated region 120 may be, for example, between about 0.25 mm and about 0.75 mm. In some embodiments, an outer diameter of the perforated region 120 may be, for example, about 10 mm. In other embodiments, the perforated region 120 may have alternative dimensions. [0082] Referring to Figure 2A, the perforated region 120 comprises a plurality of apertures 121. As shown in Figures 2B and 2C, the apertures 121 extend through the sidewall 113 and are in fluid communication with the lumen 114. The apertures 121 may be generally configured to allow for vascular growth into the lumen 114. As such, after the intramedullary device 100 has been implanted for a sufficient time for such vascular growth to occur, the intramedullary device 100 may be considered at least partially vascularised. To facilitate this, the apertures may have a size between about 25 microns to about 2000 microns. In some embodiments, the apertures have a size of about 150 microns.

[0083] In the embodiments shown in the Figures, the apertures are generally circular. The apertures 121 are arranged in rows extending radially around the circumference of the sidewall 113. In the illustrated embodiment, the apertures 121 have a diameter of about 400 microns are spaced at intervals of about 15°. In other embodiments, the apertures 121 may be spaced at other intervals. The spacing of the apertures 121 may be selected based on one or more of the aperture diameter, the thickness of the sidewall 113 and an outer diameter of the shaft 110 at the perforated region 120. For example, the spacing of the aperture 121 may be chosen to avoid the apertures merging on the inner surface of the sidewall 113. Alternatively, the apertures 121 may be spaced such that the linear distance (or, in some embodiments, the arc length) between the apertures on the inner surface of the sidewall 113 is substantially equal to the aperture diameter.

[0084] Adjacent rows of apertures 121 are spaced longitudinally along the perforated region 120, and are radially offset, or staggered relative to each other. In the illustrated embodiment, the offset is substantially equal to half the radial distance between adjacent apertures 121. Further, as illustrated, the distance between adjacent rows is configured such that the distances between any given aperture 121 and each surrounding aperture 121 are substantially equal. As such, the apertures 121 may be considered to form a pattern of equilateral triangles. In other embodiments, the rows may offset and spaced in other configurations. [0085] The aperture density (that is, the number of apertures per mm² on the external surface of the sidewall 113, not including the area of the struts) is necessarily determined by the aperture size and spacing.

[0086] The staggered pattern of apertures 121 repeats longitudinally along the perforated region 120. In some embodiments, the staggered pattern of apertures 121 repeats longitudinally along the perforated region 120 for a distance of about 150 mm or more. Other embodiments may have apertures of other shapes, sizes and/or apertures arranged in other patterns or configurations, or with other aperture densities.

[0087] As another example, in one embodiment, the apertures may have a diameter of about 150 microns and be radially spaced at intervals of between about 3° and about 5°. In this embodiment, the aperture density may be between about 4 and about 7. In this embodiment, the proportion of surface area of the perforated region covered by the apertures 121 may be between about 40% and about 70%.

[0088] As shown in Figures 2A to 2C, the perforated region 120 includes unperforated longitudinal struts 122 which are devoid of apertures 121. The longitudinal struts 122 may provide rigidity to the perforated region 120. In this embodiment, the perforated region 122 includes three unperforated longitudinal struts 122 radially spaced around the circumference of the sidewall 113. The struts each have a width of approximately 1/12 of the circumference of the sidewall 113. The number and size of the struts 122 may be generally configured in conjunction with the thickness of the sidewall 113 and the size and spacing of the apertures 121 to impart a desired rigidity to the perforated region 120. In other embodiments, other configurations of struts may be used.

[0089] The intramedullary device 100 further includes a proximal end cap 150, which is shown in detail in Figures 4A to 4E. The end cap 150 is releasably engageable with the proximal end 111 of the shaft 100 to close the lumen 114. As shown in Figures 3A and 3B, the shaft 100 includes an internal threaded portion 115 at the proximal end 111 for engaging a corresponding threaded portion 151 of the end cap 150. The cap 150 may comprise a socket 152 configured to receive a correspondingly shaped head on a drive device for inserting and/or removing the end cap 150. As shown, for example, in Figure 4A, the socket 152 has a 6-pointed star shape. In other embodiments, other shaped sockets suitable for transmission of torque may be used.

[0090] Referring now to Figures 5 to 9, in some embodiments, the shaft 110 may be formed in multiple parts. For example, as shown in Figure 5, the perforated region 120 may be separable from the distal end potion 140 and/or from the proximal shaft region 130. The perforated region 120, proximal shaft region 130 and distal end portion 140 may be formed from different materials. For example, in one embodiment, the proximal shaft region 120 and the distal end portion 140 may be formed from a metal, such as titanium, while the perforated region 120 may be formed from a polymer. For example, the perforated region 120 may be formed from a biocompatible, radio-lucent, non-osteogenic polymer, such as PEEK. Providing separable components may allow for greater flexibility in sizing of the device, while minimising manufacturing costs. In such embodiments, the perforated region 120 may be of a fixed size, while the distal end portion 140 and proximal shaft region 130 may be of variable size to allow for patient specific sizing. Variable sizing of the distal end portion 140 may allow the device to be custom fit to an individual subject by ensuring that the perforated region 120 is aligned with the nutrient artery in the medullary cavity. Additionally, variable sizing of the proximal shaft region 130 may provide a custom fit to the subject’s anatomy and allow easy access to the proximal end of the device.

[0091] The sidewall 113 of the lumen 114 at the perforated region 120 may be thinner than at the proximal shaft region 130. In some embodiments, the sidewall 113 at the perforated region 120 has a thickness of between about 250 microns to about 750 microns. In some embodiments the sidewall 113 at the perforated region 120 has a thickness of about 500 microns. A thin sidewall 113 at the perforated region 120 may provide for increased vascularisation of the lumen 114. Further, a thin sidewall 113 at the perforated region 120 may allow for viability monitoring to be undertaken using standard imaging techniques. [0092] Figures 6A and 6B show a front view and cross section, respectively of the device of Figure 5 in an assembled configuration. Note that, although these Figures (and, similarly, Figures 8A-C) show the apertures 121 as covering a reduced portion of the perforated region 120, the apertures 121, the apertures may also extend substantially along the entire length of the perforated region 120 as shown in Figures 1- 4. In this embodiment, the proximal shaft region 130 has a larger maximum outer diameter than the perforated region 120 and comprises a taper 133 adjacent its distal end.

[0093] Figures 7, 8 and 9 show the distal end portion 140, perforated region 120 and proximal shaft region 130 of Figure 5, respectively, in a disassembled configuration.

[0094] Referring first to Figure 8A, the perforated region 120 includes a proximal-end thread 123 and a distal-end thread 124 for engaging corresponding threads on the proximal shaft region 130 and distal end portion 140, respectively. In this embodiment, the perforated region 120 has a slight curvature. In some embodiments, the perforated region may have a length of 150mm or more and an internal diameter of about 10mm.

[0095] Figures 7A and 7B show the distal end portion 140 of the device of Figure 5. The distal end portion 140 includes a thread 141 engageable with the distal end thread 124 of the perforated region 120. As can be seen in Figure 7A, in this embodiment, the distal end portion tapers towards its distal end and has a curvature matching that of the perforated region. The threads 141 and 124 comprise respective first and second stop members 142, 126. The first and second stop members 142 and 126 are mutually engageable, and configured to abut one another when the threads 124 and 141 are fully threaded, to align the curvatures of the distal end portion 140 and the perforated region 120 in the same plane.

[0096] The distal end portion 140 also comprises an opening 143 configured to receive a locking member to secure the distal end portion 140 (and thus the intramedullary device 100) to the surrounding bone. The locking member may be, for example, a locking pin, screw, bolt, blade, fin or wire. [0097] Figure 9 shows the proximal shaft region 130 of the device of Figure 5. The proximal shaft region 130 includes a thread 131 engageable with the proximal-end thread 123 of the perforated region 120. The threads 123, 131 comprise respective third and fourth stop members 125, 132. The third and fourth stop members 125, 132 are mutually engageable, and configured to abut one another when the threads 123 and 131 are fully threaded, to align the proximal shaft region 130 and the perforated region 120. When properly aligned, the curvature of the perforated region lies in a second plane orthogonal to the first plane in which the longitudinal axes of the proximal shaft region 130 and perforated region 120 are offset.

[0098] In some embodiments, for example as shown in Figure 5, the intramedullary device 100 may further comprise a semipermeable immuno-isolation housing 500 disposed within the lumen 114 to house the cells. Implanting cells within an immuno- isolation housing typically excludes large molecular weight immune system constituents such as antibodies and immune cells from interacting with the implanted cells, while at the same time allowing beneficial molecules such as low molecular weight oxygen, insulin, nutrients, and hormones to pass into the housing. As will be appreciated by the person skilled in the art, encapsulation is applicable to other endocrine cells in addition to pancreatic beta-cells/islets.

[0099] In some embodiments, the housing may be formed at least partially from a porous membrane material. The membrane may be configured to retain implanted cells (e.g. islet cells) within the housing and substantially prevent interaction between the implanted cells and the immune system of the subject, whilst allowing exchange of beneficial molecules as described above across the membrane.

[0100] As can be seen in Figure 5, and in greater detail in Figure 11, the housing 500 may be tubular and is arranged within the lumen 114 in two concentric helical coils. In other embodiments, the housing may be arranged in three, four, five or more concentric helical coils. The coils extend substantially along the length of the perforated region 120, within the lumen 114. The coils are arranged such that fluid flowing from the inlet 501 travels first in a distal direction through the outermost coil then returns in a proximal direction through the inner coil to the outlet 502.

[0101] The housing may be configured to have a high surface area to volume ratio. In the illustrated embodiment, the housing 500 is in the form of an elongate tube extending from a first end 501 to a second end 502, each disposed adjacent the proximal end 111 of the shaft 110. In this embodiment, the tube of the housing 500 has an internal diameter of about 400 microns to about 600 microns and a length of about 15 metres. The tubular housing 500 may have a wall thickness of about 25 to 500 microns. As shown in Figure 5, the intramedullary device 100 comprises a port 600. The port 600 is fluidly connected to the housing. In this embodiment, the port 600 includes an inlet 610 and an outlet 620, fluidly connected to the first end 501 and the second end 502 of the housing, respectively.

[0102] As shown in Figures 10A to 10D, the port 600 includes seals 611 and 621. Seal 611 is penetrable to insert cells (or other fluid material) into the first end 501 of the housing. Seal 620 is penetrable to retrieve cells (or other fluid material) from the second end 502 of the housing. As shown in Figure 10A, the tube ends 501 and 502 may be adapted to wrap around seals 611, 621.

[0103] The port 600 is sized to be slidably received in the proximal end of the lumen 114. As shown in Figure 9A, the sidewall 113 comprises a protrusion 117 extending into the lumen 114 and engageable with the port 600 to limit travel of the port within the lumen 114 in a distal direction. Figure 14 shows the port 600 assembled in the lumen 114 of the shaft 110.

[0104] In alternative embodiments, the housing 500 may comprise more than one tube. In such embodiments, the inlet 610 may comprise an inlet manifold adapted for connection to the first end of two or more tubes. For example, in the embodiment illustrated in Figures 15 and 17A-17C, the inlet 610 comprises an inlet manifold 615 adapted for connection to the first ends 501 of two tubes of the housing 500. Similarly, the outlet 620 comprises an outlet manifold 625 adapted for connection to the second ends 502 of the two tubes of the housing 500. The tubes are arranged in the lumen 114 a series of concentric helical coils. As in previous embodiments, the coils extend substantially along the length of the perforated region 120, within the lumen 114. Although the illustrated embodiment shows manifolds 615, 625 adapted for connection to two tubes, manifolds of other embodiments may be adapted to connect to more than two tubes.

[0105] Figure 14 shows a further embodiment having a housing 500 comprising four tubes arranged in a series of concentric helical coils. In this embodiment, the diameter of each coil is configured such that the coils nest within one another with a gap between adjacent coils. As shown, the coil diameters are stepped by 2mm, with the innermost coil having a diameter of 4mm and the outermost coil having a diameter of 10mm. Other arrangements of coil diameters are also contemplated.

[0106] In any embodiment described above, the device may be coated, impregnated or filled with an agent that stimulates cell growth and/or vascularisation, and/or an agent that inhibits bone growth. For example, in some embodiments the lumen 114 may be at least partially filled with a pro-vascular matrix, for example, fibrin, to encourage and support vascularisation of the lumen 114.

[0107] In use, the device 100 is first implanted into the medullary cavity of the subject’s femur of the subject through the greater trochanter and fixed to the surrounding bone by securing a locking member through opening 143.

[0108] The tubular housing 500 may be pre-filled with a suitable, cytocompatible, buffer prior to implantation of the device 100. The buffer may include, for example, one or more of saline, phosphate-buffered saline (PBS), patient serum and transplant media. In other embodiments, the cytocompatible solution may include Ringer’s solution, Hartmann’s solution (that is, lactated Ringer’s solution) or an iso-osmotic combination of Ringer’s and Hartmann’s solutions. Pre-filling the housing 500 with a buffer material may assist in maintaining the structural integrity of the housing, for example, by substantially preventing collapse of the tube prior to insertion of the cells. [0109] After implantation of the intramedullary device 100, sufficient time is allowed for vascular ingrowth to the lumen 114 to occur such that the device 100 is at least partially vascularised. Vascularisation of the device may provide increased nutrient supply to the cells.

[0110] Cells are then inserted into first end 501 of the housing 500. Fluid may be simultaneously withdrawn from the second end 502.

[0111] In some embodiments, the cells may be autologous cells, for example, pancreatic islet cells obtained from the subject’s own pancreas. In such embodiments, the immuno-isolation housing 500 may not be required as the subject’s immune system will not attack the transplanted cells. In other embodiments, however, the cells may be donor cells. In such embodiments, the immuno-isolation housing protects the donor cells from immune attack.

[0112] In some embodiments, the device and methods described herein are directed to the treatment of a pancreatic dysfunction. As understood in the art, pancreatic dysfunction may be associated with or cause aberrant levels of insulin, glucagon, somatostatin, and/or pancreatic polypeptide. Thus, as used herein, the term "pancreatic dysfunction" shall be taken to mean any condition in which one or more of the functions of a pancreas in a subject is/are different to the same function in a normal and/or healthy individual. For example, the term "pancreatic dysfunction" encompasses conditions in which an endocrine function of a pancreas in a subject is reduced compared to a normal and/or healthy individual. For example, "pancreatic dysfunction" may be characterized by, associated with or caused by aberrant levels of insulin, glucagon, somatostatin, and/or pancreatic polypeptide. It will be apparent to the skilled artisan from the foregoing that the term "treating pancreatic dysfunction" encompasses normalizing a function of the pancreas (e.g., treating a subject such that one or more functions of the pancreas that are abnormal are enhanced such that they are more similar to the same function in a normal and/or healthy individual). For example, such treatment may result in increased insulin levels and/or increased numbers of pancreatic beta cells and/or pancreatic islets in a subject having aberrantly reduced levels of insulin and/or beta cells and/or islets.

[0113] "Pancreatic endocrine cells," as used herein, refer to cells capable of expressing at least one of the following hormones: insulin, glucagon, somatostatin, ghrelin, and pancreatic polypeptide. In addition to these hormones, markers characteristic of pancreatic endocrine cells may include one or more of NGN3, NeuroDl, ISL1, PDX1, NKX6.1, PAX4, ARX, NKX2.2, and PAX6. Pancreatic endocrine cells expressing markers characteristic of beta-cells can be characterized by their expression of insulin and at least one of the following transcription factors: PDX1, NKX2.2, NKX6.1, NeuroDl, ISL1, HNF30, MAFA and PAX6.

[0114] The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone -producing) cells. The pancreatic islets constitute 1 to 2% of the pancreas volume and receive 10-15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

[0115] Thus, in some embodiments, the device and method described herein comprise implanting insulin producing beta-cells into the intramedullary cavity of a long bone of a subject. Implanting insulin producing beta-cells into a subject may be useful for treating type 1 diabetes, and/or for treating obesity, glucose intolerance or insulin resistance in a subject with type 2 diabetes.

[0116] The skilled person will appreciate that implanting endocrine cells, particularly hormone producing cells such as insulin producing beta-cells, into a subject may comprise implanting a relatively pure population of cells, for example a relatively pure population of beta-cells, or alternatively implanting a heterogeneous population of cells into the subject. In some embodiments, the heterogeneous population of cells comprises beta-cells or pancreatic islets. [0117] In some embodiments, the heterogeneous population of cells comprises cells that may enhance function, viability and/or engraftment of the implanted cells.

Examples of cells that may enhance function, viability and/or engraftment of implanted cells include endothelial cells and mesenchymal stem cells (MSC).

[0118] One source of transplantable allogeneic islets is cadaveric human donor pancreas, although it is a limited source because of the limited number of organs available. Cadaveric islets are obtained by the extraction of insulin-producing islet cells from the pancreas of a deceased organ donor through the use of both mechanical and enzymatic manipulation. Following extraction, the islet cells are cultured and resuspended prior to their transplantation into the recipient patient.

[0119] Alternative sources of islets include animals (i.e. xenotransplantation), especially the pig, and human pluripotent stem cells. While islets may be isolated from adult pigs, this is technically more difficult than isolating islets, or islet-like cell cluster from neonatal pigs. Clinical trials of xenotransplantation in humans have demonstrated functional implanted islets, with viable encapsulated islets found 9 years after transplantation.

[0120] Another source of endocrine cells, including insulin producing beta-cells, is pluripotent stem cells. Such stem cells have unlimited replicative capacity and potential to differentiate into different cell types. For example, the differentiation of pluripotent stem cells into insulin-producing endocrine cells can be achieved in vitro using a multi- step protocol that mimics pancreas development.

[0121] The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. The adrenal cortex produces three main types of steroid hormones: mineralocorticoids, glucocorticoids, and androgens. Mineralocorticoids (such as aldosterone) produced in the zona glomerulosa help in the regulation of blood pressure and electrolyte balance. The glucocorticoids cortisol and corticosterone are synthesized in the zona fasciculata; their functions include the regulation of metabolism and immune system suppression. The innermost layer of the cortex, the zona reticularis, produces androgens that are converted to fully functional sex hormones in the gonads and other target organs. The production of steroid hormones is called steroidogenesis, and involves a number of reactions and processes that take place in cortical cells. The medulla produces the catecholamines adrenaline and noradrenaline, which function to produce a rapid response throughout the body in stress situations.

[0122] Insufficient production of steroid hormones is associated with Addison's disease. Addison's disease refers to primary hypoadrenalism, which is a deficiency in glucocorticoid and mineralocorticoid production by the adrenal gland. Addison's disease may be caused by an autoimmune condition, in which the body produces antibodies against cells of the adrenal cortex, or it may be caused by infection, especially by tuberculosis. A distinctive feature of Addison's disease is hyperpigmentation of the skin, which presents with other nonspecific symptoms such as fatigue. A complication seen in untreated Addison's disease and other types of primary adrenal insufficiency is the adrenal crisis, a medical emergency in which low glucocorticoid and mineralocorticoid levels result in hypovolemic shock and symptoms such as vomiting and fever. An adrenal crisis can progressively lead to stupor and coma. The management of adrenal crises includes the application of hydrocortisone injections. Accordingly, in some embodiments, the present disclosure provides a method of treating adrenal insufficiency in a subject by transplanting adrenal hormone producing cells into the subject using the device described herein.

[0123] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

24 CLAIMS:

1. An intramedullary device for transplanting cells into a medullary cavity of a bone, the device comprising: an elongate shaft extending from a proximal end to a distal end, the shaft having a sidewall defining an internal lumen, wherein the shaft comprises a perforated region, the perforated region comprising a plurality of apertures extending through the sidewall and in fluid connection with the lumen; a semipermeable immuno-isolation housing disposed within the lumen to house the cells; and a port fluidly connected to the housing.

2. The device of claim 1, wherein the port has an inlet and an outlet.

3. The device of claim 2, wherein the immuno-isolation housing comprises at least one tube extending from a first end to a second end, wherein the first end is in fluid engagement with the inlet and the second end is in fluid engagement with the outlet.

4. The device of claim 3, wherein the at least one tube is coiled within the lumen.

5. The device of claim 4, wherein the at least one tube is arranged in two or more concentric helical coils within the lumen.

6. The device of claim 5, wherein the helical coils are configured such that fluid passing from the inlet to the outlet travels through an outermost coil first.

7. The device of any one of claims 3 to 6, wherein the at least one tube has an internal diameter in range of between 100 microns and 800 microns.

8. The device of claim 7, wherein the at least one tube has an internal diameter in the range of between 400 microns and 600 microns.

9. The device of any one of claims 3 to 8, wherein the at least one tube has a length in the range of between 5 metres and 25 metres

10. The device of claim 9, wherein the at least one tube has a length of approximately 15 metres.

11. The device of any one of claims 3 to 10, wherein the at least one tube has a wall thickness of between 25 microns and 500 microns.

12. The device of claim 11, wherein the wall thickness is approximately 50 microns.

13. The device of any one claims 1 to 12, wherein at least a portion of the immuno-isolation housing includes a porous membrane.

14. The device of any one claims 1 to 13, wherein the immuno-isolation housing is at least partially prefilled with a buffer fluid.

15. The device of any one of the preceding claims, wherein the port includes at least one seal which is penetrable to allow insertion of the cells therethrough.

16. The device of claim 15 wherein the port includes an inlet seal and an outlet seal.

17. The device of any one of the preceding claims, wherein the port is disposed within the lumen towards the proximal end of the shaft.

18. The device of claim 17, wherein the port is longitudinally slideable in the lumen, and wherein the sidewall of the shaft comprises a protrusion extending into the lumen and engageable with the port to limit travel of the port within the lumen in a distal direction.

19. The device of any one of the preceding claims wherein the apertures of the perforated region are sized to allow vascular growth into the lumen.

20. The device of any one of the preceding claims wherein the apertures of the perforated region have a size of between about 25 microns to about 2000 microns.

21. The device of any one of the preceding claims further comprising a bone fixation region.

22. The device of claim 21, wherein the bone fixation region is provided at or adjacent to the distal end of the shaft.

23. The device of claim 21 or claim 22, wherein the bone fixation region includes an opening configured to receive a locking member to secure the device to the surrounding bone.

24. The device of any one of the preceding claims, wherein the shaft comprises a distal end portion in releasable engagement with the perforated region.

25. The device of claim 24, wherein the distal end portion comprises a thread engageable with a corresponding distal end thread of the perforated region.

26. The device of claim 25, wherein the thread of the distal end portion comprises a first stop member and the distal end thread of the perforated region comprises a second stop member, wherein the first and second stop members are mutually engageable to align the perforated region with the distal end portion.

27. The device of any one of the preceding claims, wherein the shaft comprises a proximal shaft region devoid of apertures in the sidewall.

28. The device of claim 27, wherein a longitudinal axis of the proximal shaft region is offset from a longitudinal axis of the perforated region in a first plane. 27

29. The device of claim 28, wherein the longitudinal axis of the proximal shaft region is offset from the longitudinal axis of the perforated region by between about 10 degrees and about 20 degrees.

30. The device of any one claim 28 or claim 29, wherein the perforated region is curved in a second plane, wherein the second plane is orthogonal to the first plane.

31. The device of claim 30, wherein a curvature of the distal end portion matches the curvature of the perforated region in the second plane.

32. The device of any one of claims 27 to 31, wherein a maximum external width of the proximal shaft region is greater than a maximum external width of the perforated region.

33. The device of any one of claims 27 to 32, wherein the proximal shaft region is in releasable engagement with the perforated region.

34. The device of claim 33, wherein a distal end thread of the proximal shaft region is engageable with a corresponding proximal end thread of the perforated region.

35. The device of claim 34, wherein the proximal end thread of the perforated region and the distal end thread of the proximal shaft region comprise respective third and fourth stop members mutually engageable to align the proximal shaft region with the perforated region.

36. The device of any one of the preceding claims, further comprising a proximal end cap releasably engageable with the proximal end of the shaft to close the lumen.

37. The device of any one of the preceding claims, wherein the cells are endocrine cells.

38. The device of claim 37, wherein the cells are insulin producing cells. 28

39. The device of claim 38, wherein the cells are pancreatic islet cells.

40. The device of any one of the preceding claims, wherein the device is coated, impregnated or at least partially filled with an agent that stimulates cell growth and/or vascularisation, and/or an agent that inhibits bone growth.

41. Use of the intramedullary device of any one of the preceding claims for implanting cells into a bone of a subject.

42. The use of claim 41, wherein the bone is a femur.

43. The use of claim 41 or claim 42, wherein the cells are insulin producing cells.

44. A method of implanting cells into a bone of a subject, the method comprising: implanting a device according to any one of claims 1 to 40 into a medullary cavity of the bone; and inserting cells into the device after implantation of the device.

45. The method of claim 44, further comprising: allowing sufficient time after implantation of the intramedullary device for vascularisation of at least a portion of the perforated region such that the device is at least partially vascularised; inserting the cells into the at least partially vascularised device.

46. The method of claim 44 or claim 45, further comprising fixing the intramedullary device to the bone of the subject with a locking member.

47. The method of any one of claims 44 to 46, wherein the bone is a femur and the intramedullary device is implanted into the medullary cavity of the femur via the greater trochanter. 29

48. A method of treating diabetes in a subject, the method comprising performing the method of implanting cells into a bone of a subject according to any one of claims 44 to 47, wherein the cells are insulin producing cells.

49. An intramedullary device for transplanting cells into a medullary cavity of a bone, the device comprising: an elongate shaft extending from a proximal end to a distal end, the shaft having a sidewall defining an internal lumen to house the cells, wherein the shaft comprises a perforated region, the perforated region comprising a plurality of apertures extending through the sidewall and in fluid connection with the lumen; and a port fluidly connected to the lumen.