Various forms of therapeutic implant are known.

Some of these are bulk inserts, which may be cast or otherwise formed to a particular shape, and are intended to fill a volume within the body, for example after tissue has been removed in surgery. Other inserts are intended to have negligible bulk, and may be used as a means for providing a particular therapeutic function at a specific location.

One known example of a small insert is a seed for localised radiotherapy. These seeds are cylinders of titanium or stainless steel, normally 0.8mm diameter and 4.5mm long, containing a small amount of radioactive material (normally iodine-125) together with another material such as silver or gold which renders the seeds radio-opaque. The radio-opacity enables the seeds easily to be located with known medical imaging systems. The radioactive material and the radio-opaque material may be provided in ceramic or resin beads packed into the seed. Various packing patterns are used, and internal arrangements to hold components in the correct location, in order to ensure the required performance.

These seeds allow small doses of radiation to be applied over a period to a precisely located small part of the body. The titanium or stainless steel shell is not biodegradable, and ensures that the radioactive

material does not migrate around the body. However, it also means that the seed continues to exist in the body long after its radioactivity has decayed to a negligible level, so that either the seeds must be left permanently in the body or further surgery is required to remove them. Each seed needs to contain a relatively large amount of radioactive material in order to compensate for the radioactive shielding of the titanium or stainless steel shell. The shell construction makes it difficult to reduce the diameter of the seeds below 0.8mm.

An implant for localised radiotherapy is also known in the form of a wire. This has a platinum/iridium alloy core, containing iridium-192 as a radioactive isotope.

To reduce the toxicity of the wire due to the iridium, it is coated with a thin layer of platinum. In use, the wire is cut to length. The iridium-192 provides an implant for relatively high dose radiotherapy. Low dose wire implants using radioactive iodine-125 cannot easily be provided because the open ends of the implant following cutting would allow the radioactive iodine to escape with consequent danger to the thyroid.

Wire implants have the advantage over seed implants that they can be threaded through tissue and tied in order to ensure that they are securely held in place, and consequently there is less risk of undesirable migration of the implant after insertion as compared with the use of seeds.

In order to provide a medically appropriate period of radiotherapy at an appropriate dose, short half-life radioactive isotopes have to be used. This means that these known forms of implant need to be manufactured shortly before use and ideally on-demand. However, it

is awkward and expensive to manufacture them on demand because of the complexity of their design and the process involved.

A radioactive gel or tissue glue is known from WO-A-96/03112. This is a flowable congealing material which contains minute radioactive ferrite particles suspended in it. It may be used to coat the cut surface after surgery. For example, following surgery to remove a glioma (a form of brain tumour) the excision surface may be coated with this material to provide localised radiotherapy in order to kill tumour cells which may have been left behind. The gel material can be biodegradable or absorbable, and the ferrite particles themselves are also biodegradable, so that after the localised radiotherapy has ceased as the radioactivity level decays, the inserted material is gradually eliminated from the body. The radioactive ferrite particles may contain palladium-103 or yttrium-90. The use of iodine-125 is not proposed.

WO-A-96/03112 also proposed that the radiotherapeutic particles can be dissolved in aqueous- based plastic polymers which can then be caused to polymerise, which would allow for casting of a salable shaped radiation carrier prior to surgery or during surgery.

The ferrite particles themselves and a method of making them, both with and without radioactivity, are known from WO-A-93/05815 and EP-A-0640350, as well as WO- A-96/03112. As disclosed in those documents, the particles will typically have a size in the range of 5 to 100nm in diameter, and may include a coating such as dextran, to enable various molecules to be bound to the

particle.

WO-A-96/03112, WO-A-93/05815 and EP-A-0640350 are all incorporated herein by reference. It should particularly be noted that the example given near the end of the description in WO-A-96/03112 and the example given at the end of the description in EP-A-064035 provide methods of making the ferrite particles.

In one aspect, the present invention relates to a therapeutic implant (of the small volume type rather than bulk type), containing minute solid particles, comprising a polymeric material at least at its surface. The implant, or at least its polymeric component, is cast or set, in the sense that a flowable or mouldable material has become solid. The implant is typically less than one millimetre thick, and may be a sheet of indefinite size, a filament or ribbon of indefinite length, or a small nugget or rod less than 10mm long. In one form, it is a seed having substantially the dimensions of the known seeds (0.8mm across and 4.5mm long), so that it is compatible with existing apparatus and methods for handling seed implants. However, unlike the known titanium or stainless steel shell seed, the seed of the present invention can easily be made smaller than this so that they are less intrusive in the body, and the minimum size of the implant is limited in practice by the need for it to be large enough to handle and to prevent migration in the body.

The particles in the implant of this aspect of the invention are typically less than one micrometre across.

They may be radioactive and/or radio-opaque and/or ferromagnetic. The usefulness of radioactive and radio- opaque inserts has been discussed above. Ferromagnetism

is useful in a therapeutic implant because it allows the implant to be heated for example by the application of an oscillating electromagnetic field, allowing localised heat therapy.

The particles are preferably but not necessarily ferrite particles, either radioactive or non-radioactive, such as those disclosed and discussed in WO-A-96/03112, WO-A-93/05815 and EP-A-0640350. These ferrite particles are preferred because ferrite is inherently radio-opaque and ferromagnetic, and the particles can easily be manufactured to be radioactive.

Most conveniently, the particles are embedded in a polymeric matrix forming all or part of the implant. Both the implant as a whole and the particles themselves may be biodegradable. Various slowly-soluble, bioabsorbable or otherwise biodegradable polymers are known for creating a biodegradable implant. One example is poly- lactic acid (PLA). The implant may include one or more further substances, such as a pharmaceutical, DNA or other genetic material, or any other desired substance.

This can be adhered to the surface of the particles, for example by use of a dextran coating as discussed above.

Alternatively, the further substance may be separately incorporated in the implant.

If desired, the implant or a part of it can be made so as not to be biodegradable. For example, the polymeric outermost part may be non-biodegradable or the particles may be embedded in a non-biodegradable matrix, so as to ensure that the particles are not released into the body, or the entire implant may be made of a non- biodegradable material.

The particles may be distributed uniformly

throughout the implant, but in most uses a non-uniform distribution will be preferable. For example the outermost layer of the implant may be free of particles.

This ensures that, during the initial stages of biodegradation, no particles escape from the implant into the body. This is particularly useful in the case of radioactive particles. On the other hand, it is also advantageous in the case of radioactive particles to place all or the majority of the particles near the surface of the implant to avoid substantial"self screening"by which some particles block the radiation emitted by other particles deeper within the implant.

Accordingly, one preferred construction comprises a central core of polymeric material not containing particles, with an outer layer on at least one side of the core which does contain the particles, and a final outermost coat which does not contain particles. In order to manufacture such an arrangement, the core is initially made from a polymeric material, having a shape according to the desired final shape of the implant.

This is then coated (e. g. by dipping or painting), either partially or completely, with a layer of a polymerisable matrix into which particles have been mixed at a desired concentration, and finally the outer layer is applied as further coat. As an alternative, the various layers may be co-extruded. As another alternative, pre-formed components, radioactive or non-radioactive, may be joined by mechanical or adhesive means.

By way of a numeric example, a seed implant having conventional dimensions (0.8mm diameter and 4.5mm length) may include up to 30 micrograms of radioactive ferrite particles, which would occupy significantly less than 1%

of the total volume of the seed. The seed could be implemented with a core, not containing particles, of about 0.75mm diameter, coated with a layer about 0.02mm thick containing 10% by volume of radioactive ferrite particles, optionally with a thin outer coating layer.

In the case of radioactive particles, a particularly useful form of implant can be manufactured by providing the radioactive particles on one side of the implant only, such as by partial coating or by co-extruding with extrusion of the particle-containing material on one side of the core only. This allows the implant to be placed in the body so as to provide radiotherapy primarily to one side of it. This directional aspect of the implant can be further enhanced by providing a layer containing a screening material on the other side of the implant, so as to reduce the amount of radioactivity leaving the implant in an undesired direction.

Where the implant has a long or indefinite extent in one or more directions (a sheet, ribbon or filament), the particles may be distributed uniformly along or across the implant, or non-uniformly as desired. Non- uniform distribution provides a surgeon with an implant which can be easily positioned or secured within the body, due to the extent of the implant, while providing the therapeutic effect of the particles only at a specified location or locations.

In the case of radiotherapy, the properties of the implant can easily be tailored to a wide variety of uses.

For example, the duration of the radiotherapy is determined by selecting a radioisotope of appropriate half life. The effective irradiated area, in terms of distance through the body from the implant, depends on

the energy of the radioactive decay and this is also determined by the selection of the radioactive isotope.

The intensity of the radiotherapy is determined by the amount of the radioisotope which is incorporated in the particles, or alternatively by the concentration of the particles in the implant. Finally, the speed at which the implant biodegrades can be controlled by appropriate choice of the polymeric material forming the insert. For example, the nature and thickness of the outer coating of the implant can be selected to ensure that the parts of the implant containing radioactive particles do not biodegrade, with consequent release of the radioactive material, until the desired period of radiotherapy is completed.

It can also be noted that, in the case of radioactive ferrite particles, the amount of radioactivity depends on the amount of the radioactive isotope incorporated in the implant whereas the amount of radio-opacity depends on the total volume of the particles. Accordingly, the balance between radioactivity and radio-opacity can be determined by selecting the concentration of the radioactive isotope in the particles, and then overall radioactivity and radio-opacity is determined by the total concentration of the particles in the implant.

The implant can also easily be made so as to give information about its orientation during imaging, for example by containing a non-uniform distribution of an appropriate material.

In one example of use, a biodegradable implant having radioactive particles concentrated on one side may be attached to the tissue to be irradiated, using a glue

resistant to degradation such as medical cyanoacrylate.

The glue is applied to the side of the implant having the radioactive particles. Because the glue is resistant to degradation, the implant biodegrades only from other side, and therefore the part of the implant carrying the radioactive particles only biodegrades after the remainder of the implant behind it has been degraded.

This provides a further way of ensuring localisation and control over the biodegradation of the implant.

In the case where drugs or other chemicals for affecting the body are included in the implant, a wide variety of effects can be obtained. For example, if the drug is bound to the surface of the particles, it is only released into the body as biodegradation of the implant releases the particles. If the drug is incorporated in the main material of the implant, it can be released during biodegradation of the implant, and the distribution of the drug within the implant can be controlled so as to control the timing of its release.

For example, if the core of the implant contains a drug and a coating contains radioactive particles, the drug will be released after the part of the implant bearing the particles has biodegraded, so that the drug is delivered to the site of the implant after the end of the radiotherapy period. Alternatively, if the radioactive particles are provided on one side of the implant and the drug is provided on the other side of the implant, protection of the radioactive side of the implant from biodegradation, such as by medical cyanoacrylate as discussed above, allows the drug to be released during the radiotherapy period before the biodegradation of the implant has the reached the radioactive particles.

Furthermore, if the drug can diffuse through the material of the implant, it can be delivered to the implant site almost immediately following insertion of the implant.

The ease with which such implants can be manufactured, and the flexibility in the choice of materials incorporated into the particles, provides significant advantages. Additionally, the ease with which radioisotopes other than iodine can be used is particularly valuable in providing a biodegradable implant. Because radioactive materials can be used which are not naturally concentrated in any particular part of the body, minute residual radioactivity released into the body during biodegradation of the implant is much less dangerous than in the case of iodine which would be retained in the body and concentrated in the thyroid.

As compared with the known titanium shell seed implants, the outer layer of the present implant can have a very low radioactive screening property, so that substantially all of the radioactivity from radioactive particles in the implant reaches the surrounding body tissue. Consequently, the amount of radioactive material required for any given radiotherapy dose can be substantially reduced as compared with the case of a titanium shell type seed.

A further advantage of the present implant is that, as compared with the known metal shell implants, the present implant has reduced weight which reduces its tendency to migrate through tissues after implantation.

As is clear from the numeric example given above, the particles (which will often provide the sole or main therapeutic effect) can be concentrated in a small proportion of the total volume of the implant.

Consequently, the implants could be formed with a hollow core, reducing their weight further without reducing therapeutic effect. Additionally, the polymeric outer surface of the implant can easily be roughened to reduce its tendency to slip through tissue, or may be provided with activated carbon, a non-allergenic polysaccharide, or a protein coating, for promoting a greater or lesser extent of adhesion to the surrounding tissue.

As mentioned above, the present implants can be made smaller than prior art ones. It is anticipated that seed type implants could be reduced to 0.5mm across. Filament type inserts, which are easier to handle and which can avoid migration problems by being tied in place, could be made thinner still, e. g. down to 0. lmm across. The limiting factor with filament inserts is probably the need to ensure that they are strong enough not to break in use.

Some examples of implants embodying the present invention will now be described with reference to the following drawings.

Figure 1 is a side view of a seed type implant embodying the present invention.

Figure 2 is a cross-section, showing a first construction example, through a seed type or filament type implant.

Figure 3 is cross-section showing a preferred construction for a seed type or filament type implant.

Figure 4 is a cross-section showing a modification of the construction of Figure 3, having particles on one side of the implant only.

Figure 5 is a cross-section showing a further modification of the construction of Figure 4, with a

layer of further material on the side opposite the particles.

Figure 6 is a cross-section showing a construction for a seed type or filament type implant having a hollow centre.

Figure 7 is a cross-section along part of the length of a filament type or ribbon type implant or part of a sheet type implant, having a first construction.

Figure 8 is a cross-section similar to the cross- section of Figure 7, showing a preferred construction with a layer of particles on one side only.

Figure 9 is a cross-section showing a modification of the construction of Figure 8, having a further layer on the other side of the implant containing particles or a further material.

Figure 10 is a cross-section showing a further modified construction, in which particles are located intermittently along or across the implant.

Figure 11 is a view of a length of a filament type implant.

Figure 12 is a view of a length of a ribbon type implant.

Figure 13 is a view of a part of a sheet type implant.

A seed type implant 1 is shown in side view in Figure 1. A simple form of implant is shown in cross- section in Figure 2. This cross-section can apply to the seed type implant 1 or to a filament type implant, In this construction, the main body 3 of the implant carries the particles, and it is coated by a thin outer layer 5 which is particle free.

A more preferred construction is shown in cross-

section in Figure 3. In this case, the main bulk of the implant is made up of a central core 7, which is particle free. This is surrounded by a thin particle-containing layer 9, which is in turn surrounded by the outer coat 5. The thickness of the particle-containing layer 9 and the outer coat 5, relative to the central core 7, is exaggerated in the figures for reasons of clarity.

Figure 4 shows a cross-section of an implant having a similar structure to that of Figure 3, but in which the particle-containing layer 9 is provided only on one side of the implant. Figure 5 shows a further modification, in which the particles are radioactive and in which a layer 11, which contains a radiation shielding material, is provided on the opposite side of the central core 7 from the particle-containing layer 9. In Figure 5 the radiation shielding layer 11 and the particle-containing layer 9 do not meet, but the radiation shielding layer can be extended around the central core 7 so that it reaches the particle-containing layer 9 on each side.

This construction provides a greater angle of shielding, and therefore provides still further directional control of radioactivity.

Figure 6 shows a further alternative cross-section structure for a seed type or filament type implant. In this construction the central core 7 is hollow, so as to reduce the weight of the implant.

Figures 7,8, 9 and 10 show cross-sections along the length of a filament or ribbon type of implant, or the cross-section of a sheet type implant.

Figure 7 shows the simplest construction, corresponding to the cross-section of Figure 2. A main body 3 containing the particles is coated by a particle

free outer layer 5.

In Figure 8, the implant has a particle free central core 7, and a particle-containing layer 9 on one side of it. A particle free outer layer 5 is provided on both sides of the implant, although it would be possible to provide this layer only on the side bearing the particle- containing layer 9.

In the cross-section of Figure 9, an additional layer is provided on both sides of the central core 7.

This additional layer can either be a further particle- containing layer 9 or a radiation shield layer 11, depending on the functionality required for the insert.

The cross-section of Figure 10 shows how the particle containing layer 9 may be provided intermittently on a filament, ribbon or sheet insert.

A radiation shield layer 11, on the other side of the central core 7, is shown extending continuously, since this will normally be the easiest way to manufacture it, although the shield layer is not needed except in the vicinity of the areas of the particle-containing layer 9.

In the cross-section of Figure 10, the particle- containing layer 9 is shown on one side of the central core 7 only. However, it can be provided on both sides of the implant (in the case of a ribbon or a sheet), or it can extend as a ring or an extended sheath entirely around the central core 7 (in a filament type implant).

In Figures 7 to 10, the thickness of the outer layer 5, the particle-containing layer 9 and the radiation shield layer 11 is exaggerated for clarity of illustration.

Figure 11 is a view of a length of filament type

implant. Figure 12 is a view of a length of a ribbon type implant. Figure 13 is a view of a region of a sheet type implant. In all three cases, the implant is constructed according to the cross-section of Figure 10, and the outer layer 5 has been omitted in these views so that the particle-containing layer 9 is visible. These views show how the particle-containing layer 9 may be arranged intermittently along the length of the implant (in the case of a filament or ribbon) or across its surface (in the case of a sheet).

According to another aspect of the present invention there is provided a method of applying localised heat treatment to the human or animal body by magnetic or electromagnetic excitation of ferrite particles while the particles are in the body. The ferrite particles discussed above, and disclosed in WO-A-93/05815, EP-A-0640350 and WO-A-96/03112 are suitable. The particles can be inserted into the body as an injectable gel or setting mixture as disclosed in WO 96/03112. They can be injected in liquid suspension, and if desired can be injected into the blood stream and then concentrated at the desired location for heat therapy by generating a suitably shaped magnet field in the body at the relevant location so as to cause the particles to congregate there. The particles can also be surgically implanted directly to the therapy site. If a settable mixture is used, it can be spread over a surgically exposed surface, for example using the syringe applicator disclosed in WO-A-96/03112.

Heat treatment with the ferrite particles may be conducted on its own, or it may be combined with radiotherapy or chemical therapy, or both. For example,

some or all of the particles may be made radioactive as discussed above, additionally the particles may be inserted in association with any desired chemicals, and chemicals can be adhered to the surface of the particles, for example using a dextran coat as discussed above. In this way, the ferrite particles enable a combination of therapies all highly localised within the body. The particles may be encased in further material, both for ease of handling and to provide additional function as discussed below.

In this kind of heat treatment, the applied magnetic or electromagnetic field causes alternating magnetisation in the particles, and hysteresis losses within the particles cause them to heat up. An advantage of using ferrite particles is that ferrites can be made with relatively low Curie temperatures, and the Curie temperature can be adjusted by adjusting the ferrite composition. This provides a heat therapy system with an inherent temperature self regulation.

Below the Curie temperature, the particle is ferromagnetic and responds strongly to the applied field, so that it heats up. At the Curie temperature, the material loses its ferromagnetic properties and becomes merely paramagnetic. Consequently its response to the applied field is dramatically reduced and further heating of the ferrite becomes negligible. Accordingly, when the field is applied the ferrite particles will heat up to the Curie temperature but will not exceed it. By selecting a ferrite composition with an appropriate Curie temperature, it is possible to provide a self regulating system which will provide local heat therapy at a temperature sufficient to kill tissue in the immediate

vicinity of the particle without any danger of inadvertent large scale internal burns.

Coating or containment of the particles can provide useful modification of their properties. For example, a thermally insulating coating may cause the temperature applied to the surrounding tissue to be less than the Curie temperature of the ferrite used. A coating may also be used to moderate the energy of radiation escaping from the particle. This can have various effects, such as reducing the momentum of radiation used to induce positron emission in imaging applications, which in turn can assist in the imaging process, for example by reducing the divergence angle of the positron pair and increasing imaging resolution.

In a further aspect, the present invention provides ferrite particles for use in localised heat therapy, coated or contained in a material having a thermal or radiation shielding property.

When the particles are to be inserted in solid form, the therapeutic implant discussed above can be used, provided that the other materials of the implant, in addition to the ferrite particles, are chosen so that they can sufficiently withstand the heat to which they will be subjected during the heat therapy.

The preformed therapeutic implant, heat therapy method and heat therapy particles of the present invention are expected to find application especially in the treatment of prostate cancer, lung cancer, breast cancer, glioma (a form of brain cancer) and synovitis.