Patent Application: US-24289699-A

Abstract:
the invention provides an ocular socket prosthesis comprising a hydrogel consisting essentially of a biocompatible hydrophilic polymer onto which tissues can be directly sutured . preferably the prosthesis comprises the polymer both in its homogeneous gel form and in its sponge form , and the two forms are chemically joined at their interface via an interpenetrating polymer network . however , it is also contemplated that the prosthesis of the invention may be made predominantly or entirely from the sponge form of the polymer . methods of production of the prosthesis of the invention and of surgical implantation are also disclosed and claimed .

Description:
the invention will now be described in detail by way of example only with reference to the examples and to the figures , in which : fig1 a represents a sagittal section showing the eyeball and surrounding tissues ; fig1 b illustrates the extrinsic muscles which control eye movement , and their attachments to the eyeball ; fig2 illustrates a sagittal section of a first preferred embodiment of the invention , in which the prosthesis comprises a homogeneous gel hemisphere and a sponge hemisphere ; and fig3 illustrates a sagittal section of a second preferred embodiment of the invention , in which a homogeneous gel core is surrounded by a layer of sponge polymer . fig4 illustrates a sagittal section showing a prosthesis according to the first embodiment of the invention in situ after implantation . fig5 illustrates a sagittal section of a third preferred embodiment of the invention , in which the prosthesis comprises a homogeneous gel hemisphere and a sponge hemisphere , and in which the sponge hemisphere is strengthened by the presence of a column of gel passing through its centre . fig6 is a photograph showing an implant according to the first preferred embodiment of the invention . fig7 shows the appearance of an implant according to the first embodiment at six months after implantation into a rabbit , showing the thick , continuous conjunctival layer . fig8 is a histological section of the anterior ( sponge ) half of an implant according to the first embodiment of the invention , showing extensive infiltration of tissue into the implant . the eyeball and surrounding structures are generally illustrated in fig1 a , which represents a sagittal section through the eyeball . only the principal structures relevant to the present invention are shown . the eyeball ( 1 ) is bounded anteriorly by the cornea ( 2 ), and is separated into anterior and posterior portions by the lens ( 3 ). the optic nerve ( 4 ) carries visual impulses from the retina ( 5 ) to the brain . the posterior portion of the eyeball is surrounded by the sclera ( 6 ) and tenon &# 39 ; s capsule connective tissue ( not shown ), and the cornea ( 2 ) is covered by an epithelium which is continuous with the conjunctive ( 7 ), which is in turn continuous with the lining of the eyelids ( 8 ). movement of the eyeball is controlled by the extrinsic muscles ( 9 ), of which only two are shown in this figure . the anterior chamber of the eye between the cornea and the lens is filled with a watery fluid , the aqueous humour ( 10 ), while the posterior chamber behind the lens is filled with the vitreous humour ( vitreous body ) ( 11 ), which is a transparent gel - like material . the movements of the eyeball are controlled by three pairs of extrinsic eye muscles , which are illustrated in fig1 b . these are the superior rectus muscle ( 12 ) the inferior rectus muscle ( 13 ); the superior oblique muscle ( 14 ), which is bent about a pulley ( 15 ), and the inferior oblique muscle ( 16 ); and the lateral rectus muscle ( 17 ) and the medial rectus muscle ( 18 ). the pulley or trochlea is a fibrous loop in the orbital cavity , located near the nasal process of the frontal bone , through which the tendon of the superior oblique muscle passes . a first preferred embodiment of the invention is illustrated in fig2 . this shows a socket prosthesis ( 19 ), which is generally spherical in shape , and which comprises an anterior hemisphere ( 20 ) which consists of phema in its sponge form , and a posterior hemisphere ( 21 ) which consists of the phema polymer in its homogeneous gel form . the interface ( 22 ) between the two hemispheres constitutes an interpenetrating polymer network , which provides a permanent chemical attachment between the two hemispheres . in this embodiment the ocular extrinsic muscles are sutured directly into the sponge , so that a covering layer of sclera or dacron is not required . the fascial sheath of the eyeball ( tenon &# 39 ; s capsule ) and the conjunctiva are closed over the outside of the prosthesis . the spongy consistency of the anterior hemisphere permits cell ingrowth from the extrinsic muscles and from connective tissues . in contrast , the smooth surface of the solid polymer gel which forms the posterior hemisphere prevents direct tissue integration into the polymer , and therefore maximises the range of movement of the prosthesis . a second preferred embodiment of the invention is illustrated in fig3 . the prosthesis ( 19 ) is again generally spherical , but in this case consists of a homogeneous gel core ( 23 ) surrounded by a sponge layer ( 24 ). again the interface ( 25 ) between the core ( 23 ) and the outer layer ( 24 ) is an interpenetrating polymer network , providing a permanent chemical attachment between the two . it can be seen that in this embodiment the whole surface of the prosthesis is provided by the spongy polymer , and therefore tissue integration can take place over the entire surface . this will minimise the risk of extrusion of the prosthesis , but may not allow as much movement as in the first embodiment . fig4 is a sagittal section showing a prosthesis according to the first embodiment of the invention in situ after implantation . the prosthesis ( 19 ) lies under the sutured conjunctiva ( 7 ). the extraocular muscles , of which only the superior rectus ( 12 ) and the inferior rectus ( 13 ) are shown , and the tenon &# 39 ; s capsule connective tissue ( 6 ) are attached to and integrating with the anterior hemisphere ( 20 ) of the prosthesis ( 19 ). the externally - worn cosmetic shell ( 25 ) lies under the eyelids ( 8 ), which hold the cosmetic shell ( 25 ) in position . a third preferred embodiment of the invention is illustrated in fig4 . as in the first two embodiments , the prosthesis ( 19 ) is again generally spherical , and as in the first embodiment comprises an anterior hemisphere ( 20 ) which consists of phema in its sponge form , and a posterior hemisphere ( 21 ) which consists of phema polymer in its homogeneous gel form . again the interface ( 22 ) between the two hemispheres constitutes a interpenetrating polymer network as described in example 1 . however in this embodiment a column of the gel form of phema ( 26 ) passes from the surface of the anterior hemisphere to the centre of the prosthesis . the gel column may extend all the way to the posterior hemisphere , as illustrated in fig5 or may extend only partly through the anterior hemisphere . the gel column increases the mechanical strength of the anterior hemisphere . when the extraocular muscles are sutured to the implant , the muscles overly the anterior hemisphere , but the sutures are passed through the sponge so that they emerge through the reinforced central area . this reduces the risk of tears occurring in the sponge . such tears are detrimental , because they may allow the muscles to detach from the implant . however , once healing and tissue ingrowth into the anterior hemisphere has commenced , the muscles do not detach , even though the suture material undergoes biodegradation . while the gel cylinder provides a stronger anterior anchor area for the sutures , it is to be clearly understood that this modification is optional , and is not required if the strength of the sponge material utilised for the anterior hemisphere is increased . in all three embodiments the overall diameter of the prosthesis is preferably 14 to 22 mm , but it will be appreciated that this can be adjusted to accommodate the needs of individual patients . in the second embodiment , the outer sponge layer ( 24 ) is preferably 2 to 4 mm thick . again this will depend on the needs of the individual patient . while the figures illustrate the prostheses as perfect spheres , in both embodiments the surface of the prosthesis may comprise a means such as a point , nipple , hole or groove to permit interlocking with the externally - worn cosmetic shell . in the first preferred embodiment this will be located at the most anterior point of the anterior hemisphere . in the second embodiment , this may be located at any site , and the prosthesis rotated in order to interlock with corresponding means on the cosmetic shell . preferably the prosthesis will be soaked in antibiotic solution before use , in order to minimise the risk of infection . the person skilled in the art will be aware that a wide range of antibiotics will be suitable for this purpose , and the choice will depend in part on whether the patient suffers from any allergies to antibiotics . otherwise the choice is at the discretion of the individual surgeon . the conditions for polymerisation of the homogeneous gel polymer and the sponge polymer , and for the formation of the interpenetrating polymer network , are generally as described in australian patent no . 650156 . briefly , the gel polymer is obtained as a homogeneous hydrogel by bulk polymerisation of hema to form a non - porous polymer , and the sponge form of phema is produced by polymerisation of hema in the presence of a concentration of water higher than a critical value , usually approximately 45 % by weight of the initial monomer mixture , in order to produce a heterogeneous hydrogel with a porosity adjustable between 5 and 80 microns . in the preferred embodiments of the invention , in the situation where other monomers are to be used in conjunction with hema for the production of the sponge polymer it is important that only hydrophobic monomers should be used , since the sponge must be sufficiently strong to prevent tearing or cutting by the sutures used to attach the ocular tissues to the prosthesis . the crude prosthesis is formed within a mould or moulds of the appropriate size and shape . it is then cut by any suitable method , such as cryolathing , to the desired final size and shape required for the individual patient . in one preferred example of the process of manufacture of a prosthesis according to the invention , there are three steps involved in the casting procedures , including the optional modification in which a gel cylinder is created within the anterior hemisphere . water , hema monomer , dvg , and aps are mixed , then temed is added to the solution immediately prior to casting , as polymerisation occurs rapidly after addition of this agent . immediately after addition of the temed the solution is placed in a polypropylene tube containing a cryolathe spindle , to a depth sufficient to cover the spindle . in general approximately 7 . 3 g of solution will suffice . the tube is capped , and left on a level surface for at least two hours to allow polymerisation to take place . after polymerisation is completed , the sponge is rinsed several times with purified water while still in the tube . the spindle is gently removed , rotating it so as to cause minimal damage to the sponge . if a hole is formed in the sponge during withdrawal of the spindle , the preparation must be rejected . the tube containing the sponge is stored in a capped specimen jar or other suitable vessel , together with a small quantity of purified water to prevent dehydration of the sponge . the gel components are mixed , and sufficient of the resulting solution is added to the sponge in the tube , prepared as in step 1 , to fill the tube ; generally between 13 and 14 g will suffice . the tube is recapped and replaced in the specimen jar , again containing a small quantity of purified water to prevent dehydration . the jar is placed in an air oven at 50 ° c . for at least 5 hours to permit polymerisation , then removed and allowed to cool at room temperature . the cap of the tube is removed and a series of vertical incisions ( approximately 5 to 8 mm long ) are cut around the periphery of the top of the polypropylene cylinder using a scalpel , the number of these cuts being sufficient to enable the polypropylene between them to be easily folded outwards , thus exposing the top 5 to 8 mm of the cast gel cylinder . insertion of a sharp instrument horizontally into this to portion enables the combined gel / sponge part to be gently extracted from the mould . if the sponge and gel halves of the cylinder separate , the preparation is rejected . once the gel - sponge cylinder has been removed from the tube , the gel is cut with a scalpel about 12 mm above the gel - sponge interface , and the gel is rounded off around the top in order to facilitate lathing . the gel - sponge cylinder is now ready for its first lathing to convert it from cylindrical to spherical shape . the cylinder is mounted on the lathe spindle , using tissue - tek ™ in the hole which was created during the initial sponge casting . the mounted gel - sponge is then placed in a freezer at − 75 ° c . for at least one hour , after which it can be cryolathed under a stream of dry ice . the gel hemisphere is cut to the required radius of curvature . care should be taken not to remove too much material at a time , since this generates lateral stress , which may cause loss of adhesion to the lathe spindle . in addition to cutting the gel hemisphere , at this stage about 20 mm of the sponge is also cut beyond the gel , so that it is the same diameter as the gel hemisphere . however , at this stage no radius is cut on the sponge section . it is strongly preferable to cut the gel hemisphere in a single lathing operation , since the sponge is not very resilient ; and consequently if the sponge does not adhere sufficiently to the lathe spindle and relathing is required , it is very difficult to realign it along the axis created during the first lathing . thus asymmetry is likely to result . c ) addition of a gel reinforcement through the sponge hemisphere , and lathing the sponge if a gel reinforcement is desired , as in the third embodiment of the invention described in example 3 , the gel - sponge is thawed and placed into another polypropylene tube with the gel hemisphere facing down . the hole in the sponge is filled with the gel formulation described in step b ) above ; about 0 . 7 g is generally required . the gel is polymerised in an air oven at 50 ° c ., as described in step b ). the tube is removed from the oven , allowed to cool , and then the sponge section is cut laterally about 12 mm from the gel hemisphere . the preparation is mounted with tissue - tek ™ on the concave polytetrafluoroethylene disk which is previously mounted using tissue - tek ™ on to the appropriate lathe spindle . the preparation is frozen at − 75 ° c . as described in step b ), and the sponge hemisphere is cryolathed to yield a spherical orbital implant with equal sized gel and sponge hemispheres , and optionally comprising a gel cylinder within the centre of the sponge hemisphere . the finished prosthesis is rinsed with purified water , then subjected to continuous hot water flushing for 16 hours , for example in a soxhlet apparatus , in order to remove unreacted monomers . on removal from the soxhlet apparatus , the prosthesis is placed into sterile balanced salt solution and is autoclaved , after which it can be stored until required for implantation . the prosthesis may optionally be soaked in a variety of therapeutic agents , such as anti - inflammatory agents , antibiotics or growth factors , prior to implantation . a photograph of a finished prosthesis according to the invention is shown in fig6 . the surgical technique for implantation is the same for both embodiments of the invention . following dissection of the conjunctiva , tenon &# 39 ; s capsule and the extrinsic muscles , and removal of the eyeball , the prosthesis is placed into the eye socket , the rectus muscles are sutured anteriorly to the sponge , and tenon &# 39 ; s capsule is closed anteriorly by a purse - string suture . finally the conjunctiva is closed with a continuous suture . once the incisions have healed , an external cosmetic shell is placed in position over the anterior surface of the prosthesis under the eyelids . a pilot study has been performed in which prototype prostheses according to the first preferred embodiment have been implanted within the eye sockets of rabbits which have undergone enucleation . to date , a total of twenty implantations have been performed . all animal studies have been carried out in accordance with the australian code of practice for the care and use of animals for scientific purposes . the surgical technique is as described above in example 6 , during which the . extraocular muscles are sutured directly on to the prosthesis . the prostheses in these cases were not soaked in antibiotics before use , but per - operative antibiotics were given . the period of post - operative follow - up now ranges up to 18 months , and there have been no cases of extrusion . fig7 illustrates the appearance of the prosthesis at six months after implantation , and shows that the implant is covered with a thick , continuous conjunctival layer . although eye movements in a rabbit are hard to assess , in the rabbits which were fitted with a cosmetic shell , “ eye ” movement appears natural , and the general appearance was very satisfactory . in one rabbit , the sutures holding the muscles to the implant tore out of the sponge in the early post - operative period , allowing rotation of the implant : deep to the conjunctival flap . this caused the gel hemisphere to underlie the conjunctiva , and self - inflicted trauma to the conjunctiva over the non - vascularised , relatively unyielding gel caused the gel to tear , allowing infection to occur . this necessitated removal of the implant . this led us to adopt the reinforced prosthesis of the third embodiment of the invention described in example 3 , which reduces the risk of suture tearing and implant rotation . since adoption of this embodiment no similar complications have occurred . one rabbit was euthanased four months after implantation for reasons unrelated to the surgery , and histological examination of the implant from this animal confirmed that good tissue integration had occurred within the anterior sponge hemisphere , with ingrowth of fibroblasts and neovascularisation , and that no adhesions to the posterior hemisphere had occurred . the extensive biocolonisation is illustrated in fig8 which shows a haematoxylin and eosin - stained section of the anterior sponge half of the implant . more detailed histological studies of the healing process are being performed , and are being correlated with magnetic resonance imaging studies . the prosthesis of the invention can be produced at relatively low cost , making orbital prostheses available to patients who live in areas where the hydroxyapatite implants of the prior art are prohibitively expensive , or where eye banks for provision of donor sclera are not available . the polymer sponge used in the invention provides a cushioning effect , making mechanical erosion of the prosthesis less likely . furthermore , the porosity of the sponge permits cellular ingrowth , providing a firmer attachment of the surrounding tissues and lowering the risk of extrusion . the ability of the prosthesis of the invention to be soaked in antibiotic solution and to take up such antibiotic prior to implantation reduces the risk of infection . the ability of the invention to provide a means of interlocking with the external cosmetic shell without breaching the conjunctiva provides a significant margin of safety over hydroxyapatite implants , in many forms of which it is necessary to breach the conjunctival covering tissue by a peg placed into the prosthesis in order to couple it to the cosmetic shell . it is considered that the implant of the invention represents a significant improvement over the prior art , and has characteristics which approach the criteria of the ideal implant as set out by soll ( 1982 ). it will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding , various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification . references cited herein are listed on the following pages , and are incorporated herein by this reference . berry , f . d . “ a modified tissue expander for socket enlargement in clinical anophthalmos ” ophthalmic plast . reconstr . surg ., 1991 7 41 - 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