WO2012077102A1

WO2012077102A1 - Implant cage

Info

Publication number: WO2012077102A1
Application number: PCT/IL2011/000925
Authority: WO
Inventors: Morris Laster; Moshe Phillip; Yinnon Elisha; Rinat Bytton
Original assignee: Cgm3 Ltd.
Priority date: 2010-12-06
Filing date: 2011-12-06
Publication date: 2012-06-14
Also published as: EP2648617A4; EP2648617A1

Abstract

The present invention is directed to a rigid implant- protecting and stabilizing device comprising an elongate body perforated by a central bore, wherein said device is of a size and shape such that it is capable of completely or partially containing a sensor element within said central bore. The invention also encompasses methods of implanting sensor elements in a protected environment within bone tissue.

Description

IMPLANT CAGE

There are many medical conditions in which continuous sampling of blood analytes is required, for the purposes of monitoring disease status or progression, and also as part of a treatment regime. One example of such a condition is diabetes mellitus, in which regular or continuous monitoring of blood glucose levels is essential in order to ascertain that this parameter is being kept within acceptable levels. In addition, diabetic patients in need of insulin treatment (such as patients with type 1 diabetes) , would benefit from a treatment regime in which blood glucose levels are monitored on a continuous basis, in order to provide real-time information that can be used to determine whether the patient requires further insulin administration. In its more sophisticated form, such a system represents a type of 'artificial pancreas', in which the contimious blood glucose monitoring forms the afferent part of a closed-loop system that allows for the regulation of insulin injection in a way that does not require human intervention. In another form, continuous blood glucose monitoring may be used as part of an open-loop system in which the appropriate, response to the measured blood glucose concentration (i.e. whether to administer a further amount of insulin, and if so, how much is to be administered) is determined following consideration of the concentration data by a member of the medical team and/or the patient.

A device, system and method for continuous measurement of the concentration of blood glucose in bone marrow is described in co-pending, co-owned international patent application no. PCT/IL2008/000488 (published as WO 2008/129532) . The invention disclosed in that application is based on the use of a glucose detector inserted into bone marrow tissue, said detector being allowed to remain indwelling in the bone marrow tissue for long periods of time. The key advantages of this approach, in relation to many prior art methods, are firstly that the measured glucose concentration is numerically very close to that measured intravascularly by other conventional methods. Secondly, the inventors have found that the significant lag period (compared to direct measurement of blood glucose concentrations intravascularly) that is commonly seen in many prior art continuous glucose measurement systems is absent from their method. This is due, at least in part, to the faster response time that occurs due to the oxygen enriched environment in which the claimed device operates.

However, one potential problem associated with all continuous analyte measurement systems that utilize indwelling detectors is that the useful life of such systems is often limited due to the instability of the sensor at its site of implantation within the host, for example, by damage to the detector that is caused both by direct contact with the rapidly flowing blood stream (in the case of intravascular devices) and, more generally, by the response of the body to the presence of foreign body. Such responses include non-specific inflammatory states and the associated production of granulation tissue and fibrosis, as well as more specific immune reactions. As mentioned above, these responses can be so severe as to restrict the usefulness of implanted, indwelling electrodes and other implants. In view of the manifold advantages of the continuous glucose monitoring system disclosed in the aforementioned co-owned international patent application, as well as the advantages of many other systems that use indwelling analytical sensors, there is a clear and pressing need for a technical solution to this problem of the poor stability of the implanted sensor in the face of the various mechanisms used by the body to deal with the 'threat' posed by the presence of this* foreign body.

A further technical requirement of indwelling analyte measurement systems of this type is the need for the sensor to remain in close contact with vascular tissue (i.e. in an oxygen-rich environment) , despite the attempts of the patient's body to surround said sensor with fibrotic tissue. In view of this additional requirement, it is not possible to solve the abovementioned problem of the sensor being attacked by host defense mechanisms by means which would lead to isolation of the sensor from vascular tissue. On the contrary, an ideal solution would actually encourage the ingrowth of vascular tissue into the region occupied by the sensor.

The present invention provides a practical solution to the aforementioned technical problems. This solution is provided in the form of a rigid, cage-like implant- protecting device having a body perforated by a longitudinally-disposed central bore of a size and form that permits the insertion and retention of a sensor element such as an analyte detector or electrode . Generally (but not always) , said central bore is full- length, passing from one end of the device to the other, penetrating the distal and proximal extremities thereof. While experimenting with several implant designs the present inventors identified design parameters which enable fabrication of an implant that enables long term use of a sensor carried thereby without the aforementioned limitations .

Such parameters include, but are not limited to:

(i) an implant lumen that creates a reservoir capable of fluid communication with surrounding vascular tissue and circulation of blood therethrough;

(ii) implant lumen openings that can be covered by growth of bone marrow tissue 'which serves as a source of blood (and vascular tissue)

(iii) a central lumen which extends from an opening in the proximal end to an opening in the distal end of the implant facilitating sensor positioning and replacement following bone implantation of the implant device;

(iv) a central lumen which includes fluid communication channels preferably angled with respect to a longitudinal axis of the implant thereby increasing circulation through the reservoir;

(v) an external surface which facilitates bone anchoring while minimizing radial outward forces on the bone tissue

Several exemplary configurations of the device of the present invention designed in accordance with the parameters described above, as well as the implantation thereof into experimental animals will be described in more detail hereinbelow, with reference to the accompanying drawings, in which:

Figs. 1 to 6 depict several different preferred embodiments of the device of the present invention. Figs. 7 to 11 are histological sections of an in situ cage-like device of the present invention, eight weeks following implantation into the sternum of a pig.

- Figs. 12 to 14, 15, 17 and 19 depict some further preferred embodiments of the cage-like device of the present invention.

- Figs. 16, 18 and 20 are histological sections of the cage-like devices 15, 17 and 19 (respectively) , eight weeks following implantation into the sternum of a pig.

Preferably, the device mentioned hereinabove is elongate in form, having a longitudinal axis which is significantly longer than its width or diameter. The cross-sectional shape of the elongate body of the device is typically round, but it may also be any other suitable shape including (but not limited to) elliptical, square, rectangular, triangular and so on. The elongate body typically has either a cylindrical or slightly-tapering, conical form when viewed from the side. Generally, the elongate device bears a screw thread on its external surface. In one preferred form of the device, the external screw thread extends from the distal extremity of the device proximally, ending a short distance from the proximal extremity thereof. The non-threaded proximal portion thereby constitutes as a proximal head region. In a particularly preferable form, the cage-like device is provided in the form of an elongate screw having at least one central bore in the form of an internal passage orientated parallel to the longitudinal axis of said screw, wherein said passage (also referred to herein as the central bore) passes along the entire length of the device and penetrates both the proximal and distal tips thereof. In some particularly preferred embodiments, the device also possesses at least one lateral channel that is orientated such that it runs in a direction that is not parallel to the longitudinal axis of the device, and preferably at right angles thereto.

These channels may either be partial-depth channels (i.e. piercing the external wall of the device at one side and terminating in the longitudinal passage) or through-and- through channels that pierce the external wall on one side of the device, perforates the internal wall defining the internal longitudinal passage (central bore) and then continue to pierce the external wall on the other side.

While in some embodiments of the device, there may be only one lateral channel, in other versions, two or more such channels may be present. In one preferred embodiment, the device has two lateral channels. In the case that the device has two or more lateral channels, it has been found that it is preferable for the distance between adjacent lateral channels (i.e. measured along the longitudinal axis) to be no greater than 5 mm, and even more preferable for this distance to be no greater than 2 mm.

Typically, the internal diameter of the lateral channels is in the order of 0.15 to 5.0 mm. In another embodiment, the device may comprise a plurality of lateral channels, preferably arranged in the form of an evenly- spaced array. In such a case the internal diameter of each of said channels in the array will be substantially less than the diameters of the aforementioned channels that are present either singly or in pairs or triplets, for example, in the range of 150 to 900 μνα.

The primary function of the lateral channels is to permit blood, serum and blood-related tissue such as bone marrow to enter the internal spaces of the cage device of the present invention, thereby enabling a sensing device (such as a glucose electrode) placed within the longitudinal passage to be in contact with said blood and related tissues. In this manner, the sensing device may perform measurements of anaiyte concentrations in a way which is representative of the blood concentrations found throughout the circulatory system. The present inventors have also found that the internal diameter of the lateral channels may have a significant impact on the tissue that is capable of entering said channels thereby being accessible to the sensing device. Thus, as a general rule, small-diameter lateral channels, such as those having an internal diameter of 0.2 mm or less, do;, not permit ingress of bone marrow tissue. Rather, the internal spaces of the cage device tend to fill with blood and serum. On the other hand, lateral channels having internal diameters greater than about 0.5 mm permit the ingress of bone marrow tissue (as well as the liquid blood components) . In certain circumstances, this may be highly desirable, since the establishment of an organized bone marrow structure within the internal space of the cage-device (and in fluid contact with the blood vessels and bone marrow located outside of said device) , may permit the establishment of favorable conditions for providing blood to the sensor device, such that the latter is able to perform representative analyte assays over a long period of time.

In some embodiments, as will be described in more detail hereinbelow, the cage-like device further comprises one or more additional longitudinal channels entirely enclosed within the wall thereof. In this alternative embodiment, the additional longitudinal channel (s) may be used to house the sensor device (such as an analyte detector or electrode) .

It has also been found advantageous, in some circumstances, for the internal walls of the device that define the longitudinal internal passage and/or the lateral channels to be smooth-bored, for example polished. As will be described further hereinbelow, highly polished interior surfaces may prevent the attachment and organization of bone marrow tissue within the device, even when the lateral apertures are of a sufficiently large diameter to permit ingress of such tissue.

In other circumstances, the reverse may be true, that is the internal wall of the longitudinal passage may advantageously be roughened, for example by means of cutting grooves therein. This roughening process has the desirable effects of >^■ improving the stability of the implant, permitting full tissue- implant integration and stability. In addition, it assists in minimizing fibrous tissue formation and maintaining an oxygen- enriched environment. Such rough walls may be used, for example, when it is desired to encourage the persistence and organization of bone marrow tissue within the interior of the implanted device.

Furthermore, it has also been found advantageous to coat the internal wall of the longitudinal passage with an anti- fibrosis coating. One example of such a coating is the heparin-containing composition known commercially as Excor (Carmeda, Canada) .

The implant devices of the present invention may be constructed of one or more of the biocompatible materials selected from the group consisting of titanium, stainless steel, Nitinol or biocompatible polymers and plastics such as nylon, PEEK and polyethylene.

In a particularly preferred embodiment, the device is constructed of titanium.

The implant devices may be constructed using any of the suitable manufacturing techniques well known in the art including (but not limited to) machining, die-casting, laser cutting and etching. Polishing of the internal cavities and channels of the devices may be achieved using electro-polishing, reaming and/or brushes, with or without the use of smoothing pastes.

The length of the implant devices of the present invention is generally in the range of 10 to 25 mm, while the external diameter thereof is generally in the range of 1.5 to 10 mm. The longitudinal internal channel preferably has an internal diameter in the range of 1 to 6 mm. In one particularly preferred embodiment, the device length is 16 mm, the external diameter is 6 mm and the diameter of the central bore is 5mm.

The present invention is further directed to methods for implanting a sensor element in a protected environment within bone tissues of a subject. The term 'protected environment' refers to the manner in which the sensor element is allowed to come into contact with liquid blood and/or bone marrow tissue (in order that said sensor element may be used to make analyte concentration measurements that are representative of the concentration of said analytes within the blood stream of the subject) , while at the same time inhibiting or preventing (either fully or partially) contact of fibrous tissue with said sensor element. The cage-like devices may be used to protect implanted electrodes within bony tissue using either of the two following general approaches:

1) Surgical access to the desired implant site (e.g. iliac crest, sternum) is achieved, and a hole, of a size similar to the external diameter and length of the selected cagelike device, is drilled therein. An implant cage of the present invention having the upper (proximal) end of the central bore opening closed with a plug is then inserted into said drilled hole and retained therein by friction, by the use of laterally-placed retaining screws or by means of gluing using biocompatible adhesives . At a certain time following implantation of the cage, the central bore plug is removed and an analyte sensor device is inserted into the central bore. 2) Surgical access and drilling of the placement hole is performed as described above. The upper plug is removed from the device and an analyte sensor device is inserted into the central bore (or alternatively, in some embodiments, into one or more additional longitudinal channels formed within the device wall) . The cage-like device containing the pre-inserted sensor is then fitted into the pre-drilled hole and retained in place as indicated above .

In one preferred embodiment, the sensor element used in the methods of the present invention is a glucose-detecting sensor.

Examples of suitable analyte-measuring electrodes that may be used in conjunction with the implant -protecting cagelike device and method of the present invention include: the DexCom SEVEN PLUS sensor, the Medtronic MiniMed sensor and the Abbott Freestyle Navigator sensor.

In another aspect, the present invention is directed to a system for implanting a sensor element (including but not limited to an analyte detector or an elongate electrode) within a body tissue comprising an implant -protecting device according to any one of the preceding claims and a sensor element, wherein said sensor element is capable of being inserted, either fully or partially, within an internal channel of said implant -protecting device. In a preferred embodiment, the sensor element is a glucose - sensing device.

It is to be noted that the implant-protecting cage devices disclosed herein are not solely intended to be used as cages for enclosing and protecting indwelling sensor devices. Rather, they may be used in any circumstance in which there it is necessary to encourage and support the ingrowth of

prevent or

Many types

orthopedics

requirement, and the cage-like devices of the present invention, with the specially-designed structural features described hereinabove may be used in the place of (or in conjunction with) the conventional implants that are in current clinical use. Thus it may be appreciated that the present invention also includes within its scope an implantable device (as disclosed and described hereinabove in all of its aspects and with all of its features) that comprises a tissue anchoring element containing at least one internal lumen, wherein said internal lumen is configured (as described in detail hereinabove) such that it is capable of providing a reservoir suitable for receiving and holding a biological fluid (e.g. blood) . The boundaries of said reservoir may be defined either entirely by the walls of the internal lumen, or by at least a portion of the surface of said walls together with the cells of the tissue into which said device has been implanted. As disclosed above (and explained in more detail hereinbelow) , the various physical features of the device of the present invention (e.g. the number, dimensions and position of the lateral channels as well as the surface properties of the internal walls defining the longitudinal and lateral channels) may be altered in order to obtain a device which, upon implantation into (for example) bone tissue, functions as a semi -permeable tube thereby permitting the ingress of specific tissues into its internal channels. As a result, these internalized tissues and fluids may be used^' - together with the material of the implanted device itself - to define an internal space or reservoir. In this regard, the various structural features of the implantable device itself are selected in accordance with some or all of the functional parameters listed above. Of particular advantage are parameters that relate to:

(i) limiting migration into the internal spaces of the device of either all cell and tissue types, e.g. by limiting the size of the lateral channels or by limiting - via surface chemistry - the ingress of specific tissues

(e.g. of fibrotic tissue but not of bone-marrow tissue); and

(ii) enabling the flow of the desired biological fluid - such as blood - into said lumen, directing the flow and controlling the flow-rate and fluid pressure therein, thereby providing an optimal analyte- sensing environment. This may be achieved for example by selecting a device having two lateral channels with different internal diameters. As will described hereinbelow (with reference to the embodiment illustrated in Fig. 14) this arrangement leads to the establishment of a circulatory blood flow, whereby blood and serum enter one channel, pass through the central bore and then leave the internal spaces of the device through the other lateral channel. This arrangement may be particularly advantageous when the device of the present invention is used to sample or assay analytes within the blood circulation, for which fluid pooling may be problematic (e.g. for hemodynamic reasons such as W

14 settlement and aggregation of certain blood cells and solutes such as certain proteins and other solutes) .

The following section provides examples of some specific embodiments of the cage device of the present invention, as well as the results of studies in which some of said embodiments were implanted into experimental animals.

EXAMPLES

EXAMPLE 1

EXAMPLES OF SPECIFIC EMBODIMENTS OF THE IMPLANT DEVICE OF

THE PRESENT INVENTION

The inventors have developed several different versions of the claimed cage-like device, each of which comprise some or all of the structural features defined and described hereinabove. Several of these different embodiments are illustrated in Figs. 1 - 6. In each of these figures, the left-hand pane provides an external view of the illustrated device, while the right-hand pane shows a mid-line longitudinal section thereof. It is to be noted that these particular versions of the claimed device are shown for the purpose of illustration only, and to not limit the scope of the invention in any way.

The device shown in Fig. 1 possesses a single central bore without the addition of any lateral channels. It may be seen from the right-hand panel of this figure (and, indeed, also in Figs. 2 - 6) that the upper portion of the central bore has an enlarged internal diameter, immediately distal to which is a region fitted with an internal thread. These two features permit the proximal (upper) central bore of the device to be sealed by means of a small plug or cap (manufactured from either titanium or any other suitable material) screwed into the upper region thereof. Said plug may be used during the implantation of an empty device, and later removed prior to the insertion of an electrode or other implantable element within the central bore. It has been found that the use of this type of plug assists in preventing the undesired ingrowth of fibrotic tissue into the central bore of the device via its proximal (upper) opening .

The device shown in Fig. 2 is fitted with a single through- and-through lateral channel, which (as clearly shown in the longitudinal section) passes from one external surface of the device, through the central bore, finally piercing the external surface on the opposite side. While the specific embodiment shown in Fig. 2 possesses only one through-and- through channel, in other embodiments (not shown) , the device may be constructed with two or more such channels.

The device shown in Fig. 3 differs from that depicted in the previous figure with regard to the extent of penetration of the lateral channel. Thus, while in the case of the device of Fig. 2, the lateral channel is of the through-and-through type, the channel in the device of Fig. 3 is only partial depth, passing from one external surface of the device internally and ending in the central bore. The device shown in Fig. 4 contains two partial-depth lateral channels (of the same type as shown in the device of Fig. 3) , one above the other. In the specific embodiment shown in this figure, the two channels run parallel to each other. In other embodiments, however, the external openings of the two (or more) channels may be offset, such that said channels run in non-parallel directions .

Fig. 5 illustrates an embodiment of the device of the present invention in which the lateral wall has been perforated by an array of 150 micron diameter apertures which were formed by laser drilling. In some embodiments of this type, the micro-aperture array is formed in only a restricted segment of the device wall, thus forming partial-depth channels. In other embodiments however, the array covers the entire circumference of the device wall at a particular height, thereby forming a plurality of lateral channels of the through-and-through type. In a further variation of this embodiment type (not shown) , the perforated wall is formed by incorporating a rolled-up perforated sheet into the device (rather than perforating the wall of a pre-existing screw-like device, as shown in Fig. 5) .

Fig. 6 depicts a particularly preferred embodiment of the device of the present invention, in which said embodiment is characterized by having the following features:

The entire device is manufactured from titanium.

- The external, threaded surface of the device is roughened (either by sandblasting or by incorporation of metallic particles by means of laser welding) . - A relatively large-diameter central bore (typically 5 mm) .

- The internal wall surrounding the central bore may be either polished or coated with an inert coating (such as Excor, produced by Carmeda of Canada) , or subjected to both treatments.

- The external wall of the device may optionally be perforated by one or more lateral channels (not shown in Fig. 6) , each having an internal diameter of 1 - 2 mm. The internal surface of each of said channels is highly smooth and free of micro-irregularities. In the event that the device is fitted with two more lateral channels, the maximum separation distance between adjacent channels (measured along the external wall of the device) is in the order of 2 mm.

- Typical dimensions, of this preferred embodiment are: o Overall height: 16 mm. o External diameter at proximal (upper) end: 6 mm. o Length of central bore: 10.5 mm. o Diameter of central bore: 5 mm.

It is, of course, to be recognized that the dimensions listed above are given only for the purposes of illustrating a best mode embodiment, and do not restrict the scope of the invention in any way. Further preferred embodiments of the cage device of the present invention are illustrated in figs. 12-15, 17 and 19.

Fig. 12 depicts an alternative embodiment, generally indicated as 120 in which the device comprises four additional longitudinal channels 124 contained within the material of the cage wall. These additional channels may be use to house sensor devices such as elongate electrodes, the blood or other tissue fluid to be sampled being able to enter channels 124 via arrays of small -diameter lateral apertures 122 that connect said longitudinal channels with the exterior of the device. In the example of this embodiment depicted in Fig. 12, lateral apertures 122 each have a diameter of 0.2mm.

Fig. 13 illustrates another embodiment of the device of the present invention 130, comprising two arrays of 0.2 mm diameter lateral channels 134, in which each array is situated within an exposed slot formed on opposite sides of said device. The longitudinal channel 136 has an internal diameter of 1mm. As explained hereinabove, and exemplified hereinbelow, this type of device, when implanted within bony tissue, is capable of allowing blood and serum to enter its longitudinal channel by virtue of the restriction of the diameter of each of the lateral channels in the arrays to 0.2mm. Channels of this diameter are largely unable to permit the ingress of bone marrow tissue into the interior of the cage device . The device depicted in Fig. 14, represented generally as 140, differs both structurally and functionally from the device shown in Fig. 13. Firstly, device 140 possesses two, large diameter (greater than 0.5 mm) through-and-through lateral channels, 142a and 142b. Such large channels permit, in use, the ingress of bone marrow tissue together with a certain amount of liquid blood. A further feature of this embodiment is the difference in size between the two lateral channels, the distal channel 142a having a larger diameter than proximal channel 142b. It has been found by the present inventors that this type of arrangement is beneficial in that it permits the establishment of a circulatory blood flow, blood and serum entering the device through the large channel 142a and leaving it via the smaller channel 142b. The dynamic flow through the interior spaces of the device that is achieved in this way may prevent undesirable changes in some of the contents of the analyzed blood that may otherwise occur if the blood is allowed to pool in a static manner.

A further example of gradient flow into/out of the device is described in Example 3, hereinbelow.

EXAMPLE 2

EXPERIMENTAL STUDY I: IMPLANTATION OF A DEVICE OF THE PRESENT INVENTION INTO EXPERIMENTAL ANIMALS

The aim of this study was to histologically evaluate the host response to implantation of the cage-like devices of the present invention.

Methods :

Commercial pigs having a body weight in the range of 90 - 120 Kg were used for this study. Prior to surgery, the pigs were fasted overnight and pre-medicated using a Ketamine/Xylasine combination. The animals were anesthetized throughout the procedure. Anesthesia was induced with a Ketamine/Valium mixture and maintained by Isofluorane inhalation.: Pulse, oxygen saturation and body temperature were monitored continuously throughout the surgical procedure. The animals were placed in dorsal recumbency and the sternal region was surgically prepared. The first and second sternal bones were then located ultrasonically and marked. A 5 cm ventral midline incision was performed over the sternum, cutting through skin and subcutaneous layers . The sternal bone was then exposed by blunt dissection. Implants were inserted, 1-2 cm apart, into pre-drilled holes and (where necessary, according to the device design used),, secured by two screws, one on each side of the device. The implants were removed 8 weeks following their insertion using the following surgical procedure: The animals (anesthetized as described above) were placed in dorsal recumbency and the sternal region surgically prepared. A ventral midline incision through the skin and subcutaneous layers overlying the sternum was then performed, and the first and second sternal bones excised and removed, following which they were fixed, sectioned, stained and subjected to histological evaluation.

.Resul s:

Figs. 7 to 10 illustrate the histological changes seen in the tissues in contact with devices of the present invention eight weeks following implantation into the sternum. The devices used are of the general type illustrated in Fig. 2 and described hereinabove. In the longitudinal section shown in Fig. 7, it is possible to see the establishment of bone marrow "bridges" 70, which are formed by the ingress of vascular tissue into the central bore of the device via two lateral channels (the position of which are indicated by the black indicator lines in the figure) . Very little evidence of the presence of fibrotic tissue within the central bore or lateral channels is seen.

In a further representative longitudinal section shown in Fig. 8, a large portion of the previously empty central bore 80 is now seen to be filled with free-flowing blood.

Figs. 9 and 10 clearly illustrate the fact that, histologically, the bone marrow tissue found within the interior channels and bores of the implanted devices is identical with the bone marrow tissue surrounding said devices - both in terms of its reaction to the histological stain and in terms of the density of said tissue. Furthermore, there are no signs whatsoever of the presence of fibrotic or scar tissue within the interior channels of the devices. Both of these observations indicate that the implantation of the devices was entirely successful.

Finally, Fig. 11 presents transverse (horizontal) section views of an implanted cage device. Thus, the left-hand panel illustrates a transverse section taken at a level corresponding to the middle of the three lines indicated in the right-hand panel. This view clearly shows a dark staining central dot (an implanted sensor) surrounded on two sides by the walls of the cage device. Similarly, the central panel shows an enlarged view of this transverse section. It may be clearly seen from both the central and left-hand panels that the tissue within the interior of the implanted cage-like device appears to be histologically identical to the bone marrow tissue surrounding said device.

Conclusions:

The cage-like devices of the present invention encourage the ingrowth of vascular tissue and free-flowing blood within their central bore, thereby ensuring close contact between a sensor or other device placed therein and said vascular tissue and blood. Furthermore, the central bore is largely free from penetration by fibrotic or granulation tissue. These features,, clearly indicate the suitability of the devices of the present invention for use as protective cages for sensor devices, such as analytical electrodes, placed within their central cavity. EXAMPLE 3

EXPERIMENTAL STUDY II: IMPLANTATION OF DEVICES OF THE PRESENT INVENTION INTO EXPERIMENTAL ANIMALS

The aim of this study was to histologically evaluate the ability of different versions of the device of the present invention to permit blood and/or bone marrow tissue to enter the interior of said device.

The experimental methods used are the same as described in Example 2 , hereinabove .

Results:

(A) Small -diameter lateral apertures

Fig. 15 illustrates an embodiment of the cage device of the present invention in which a laser-cut matrix of 0.2mm lateral channels is present on the lower part of the side wall of the cage. It may be seen from the stained histological section presented in Fig. 16 that, eight weeks following implantation, only about 15% - 20% of the height of the longitudinal channel of the device is occupied by bone marrow and bone trabecula, while the remainder (>80% of the available volume) is filled with liquid (whole blood and serum) .

CONCLUSION: The small-size lateral apertures (array of 0.2mm holes) largely prevents the ingress of bone marrow tissue, while freely allowing entry of blood and serum. (B) Smooth-bored large-diameter lateral apertures

Fig. 17 illustrates a further embodiment of the present invention in which the cage- like device contains a single through-and-through lateral channel, having a diameter of 2mm, located in the lower portion of said device. The inner walls surrounding both the longitudinal and lateral channels are highly polished. As may be seen in the eight- week histological section shown in Fig. 18, the longitudinal channel of the device has become entirely filled with liquid components (whole blood and serum) .

CONCLUSION: Despite the relatively large diameter lateral aperture (2 mm) there was no ingress and/or local organization of bone marrow tissue within the internal cavity of the cage, said cavity being entirely filled with blood and serum. This is believed to be due to the highly polished nature of the walls of the longitudinal and lateral channels, which interferes with the ability of bone marrow tissue to physically adhere and establish itself and become organized within the interior of the device.

(C) Laser-drilled array drilled on the lower end of cage and four larger apertures in the middle portion thereof.

Fig. 19 illustrates an embodiment of the present invention in which four large-diameter lateral apertures are present in the upper portion of the device, while the lower portion of the device contains an array of small, laser-drilled apertures.

Fig. 20 is a histological section taken from tissue obtained eight-weeks following implantation of the device shown in Fig. 19. It may be seen from this section that 80% of the interior space of the device is filled with blood and bone marrow, while about 20% consists of bone trabecula and fibrosis. Generally, there is a homogeneous distribution of bone marrow and blood throughout the entire volume of the lumen.

CONCLUSION: The presence of large diameter lateral apertures at one end of the cage and small diameter (e.g. laser-cut array of 0.2 mm holes) at the other, leads to a favorable situation in which a pressure - and hence - flow gradient is established. Thus, in the case of this implant, blood flows into the cage implant through the upper, large diameter apertures, descends through the central cavity, and then exits the device via the lower micro-apertures. The circulatory flow that is thereby established is highly advantageous from the point of view of providing fresh blood for assay, and is clearly greatly superior to a static, potentially stagnant pool of blood that may otherwise collect in the internal cavity of the device. Furthermore, the presence of the large-diameter apertures permits the ingress of bone marrow tissue into the interior of the device, thereby providing a means for producing fresh blood components in situ.

In addition, continuous flow and high pressure of fluid, blood inhibits the establishment of tissue growth, formation of blood clots and accumulation of metabolites which influence sensor activity (e.g low oxygen tension), i.e essentially this form of implant act as a vessel by which blood, fluid or tissue, flow rate, and pressure could be altered with pores bore size, position, location, placement and the angle by which the edges of each lateral channel is cut in the implant .

Claims

1. A rigid implant-protecting and stabilizing device comprising an elongate body perforated by a longitudinally- disposed central bore, wherein said device is of a size and shape such that it is capable of completely or partially containing a sensor element within said central bore.

2. The device according to claim 1, wherein the central bore is configured such that it is capable of forming a reservoir for a biological fluid within said lumen following implantation into the tissue, said reservoir being defined at least in part by said tissue.

3. The device according to claim 1, further comprising a screw thread on its external surface.

4. The device according to claim 1, further comprising at least one lateral channel that is orientated such that it is not parallel to the longitudinal axis of said device.

5. The device according to claim 4, wherein the at least one lateral channel is orientated at approximately right angles to the longitudinal axis of said device

6. The device according to claim 4, wherein the at least one lateral channel is a partial length channel that pierces the external wall of said device at one side and terminates internally within the central bore.

7. The device according to claim 4, wherein the at least one lateral channel is a through-and-through channel that pierces the external wall of said device on side thereof, passes through the central bore and pierces the external wall of the device on the other side thereof. O 2012/077102

28

8. The device according to claim 4, wherein said device comprises at least two lateral channels, and wherein the distance between adjacent lateral channels is no greater than 5 mm.

9. The device according to claim 8, wherein the distance between adjacent lateral channels is no greater than 2 mm.

10. The device according to claim 4, wherein the internal diameter of the lateral channels is in the range of 0.25 - 5.0 mm .

11. The device according to claim 4, wherein said device comprises an array of small -diameter lateral channels, each of said channels having an internal diameter in the range of 200 to 500 μτη.

12. The device according to claim 4, wherein the internal diameter of the lateral channels is in the range of 0.25 - 5.0 mm .

13. The device according to claim 1, wherein said device further comprises one or more additional longitudinal channels .

14. The device according to claim 4, wherein the internal walls surrounding the central bore and/or lateral apertures are polished.

15. The device according to claim 4, wherein the internal walls surrounding the central bore and/or lateral apertures are roughened .

16. The device according to claim 4, wherein the internal walls surrounding the central bore and/or lateral apertures are coated with an anti-fibrotic coating. O 2012/077102

29

17. A system for implanting a sensor element within a body tissue, comprising an implant-protecting and stabilizing device according to any one of the preceding claims and a sensor element, wherein said sensor element is capable of being inserted, either fully or partially, within an internal channel of said implant-protecting device.

18. A system according to claim 17, wherein the sensor element is a glucose-sensing element.

19. A method for implanting a sensor element in a protected environment within bone tissue comprising the steps of:

a) gaining surgical access to the desired implant site;

b) positioning in the bone a tissue implant including an elongate body having a lumen of a size and shape selected for completely or partially containing a sensor element such that said lumen is in fluid communication with the tissue; and

c) inserting said sensor element into said lumen.

20. The method according to claim 19, wherein said lumen is configured such that it is capable of forming a reservoir for a biological fluid within said lumen following implantation into the tissue, said reservoir being defined at least in part by cells of the tissue.

21. A method for implanting a sensor element in a protected environment within bone tissue comprising the steps of:

a) gaining surgical access to the desired implant site;

b) drilling a hole of appropriate size in said implant site in order to accommodate an implant-protecting and stabilizing device comprising One or more longitudinal channels; 2012/077102

30 c) inserting said sensor element into a longitudinal channel of said implant-protecting device;

d) inserting the implant-protecting and stabilizing device with the pre-inserted sensor element into said drilled hole;

wherein said protected environment permits blood and bone marrow to come into contact with said sensor element, while preventing, either fully or partially, contact of said sensor device with fibrotic tissue.

22. The method according to either claim 19 or claim 21, wherein the sensor element is a glucose-detecting sensor.

23. An implantable device comprising a tissue anchoring element having at least one internal lumen configured such that it is capable of forming a reservoir for a biological fluid following implantation into the tissue, the boundaries of said reservoir being defined at least in part by the cells of said tissue.

24. The implantable device according to claim 23, wherein the at least one internal lumen is configured for:

(i) limiting migration of cells and tissue into said lumen ; and

(ii) enabling the flow of biological fluid into said lumen.