A ME DICAL IMP LANT AND A ME TH OD OF C OATING A ME DICAL IMP LANT TE C H NICAL FIE L D

[001 ] The present disclosure relates to a medical implant and a method of coating a medical implant.

BAC K G R OUND

[002] Any discussion of the prior art throughout the specification s hould in no way be considered as an admission that such prior art is widely known or forms pa rt of the common general knowledge in the field.

[003] Infection in surgery has always been a concern. The surgeon must cut through the protective barrier of the skin to get to the site requiring intervention. This exposes the patient a nd places them at risk of a deep seated infection. The incidence of infection is dependent on numerous factors from the patient s demogra phics and medical history, reason for the surgery a nd the local environment.

[004] The complications of a surgica l infection can be significant. Orthopaedic periprosthetic joint infection can be a devastating, limb and life threatening condition.

[005] The cause of infection can vary from contamination, systemic spread or emergence from a n existing condition. Once bacterial colonisation in the operative site is esta blished, the pathological process follows a fairly consistent course. The bacteria multiply using various virulent attributes to capita lise on the traumatised and poorly perfused environment, fixating on the adjacent foreign object which is the implant. T he body s immune system tries to prevent this a nd local cells also attempt to reach the implanted material. This has been referred to as the :race to the surface ^" a nd is the focus of much resea rch around infection control.

[006] If the infection is identified a nd managed early enough, the bacteria fail to reach significant numbers a nd fail to develop an enveloping biofilm. If the biofilm is established, the infection has reached a chronic state which limits the treatment modalities available. The effect of systemic a ntibiotics is greatly reduced and often the only method for successful management is further surgery that involves the removal of the implant and the radical debridement of infected a nd devascula rised tissue.

[007] The management of bacteria l infection has long focussed on the administration of effective a ntibiotics. In the surgical patient the specific species of bacteria and their susceptibility to a ntibiotics is often unknown. It is suggested that the antibiotic used should have a broad a ntibacterial spectrum (including gram positive and gram negative cover) a nd a low percentage of resistant species. The most commonly mixed a ntibiotics are gentamicin, tobramycin (aminoglycosides with pa rticula r effectiveness against gram-negative bacteria) and vancomycin (glycopeptide active mainly on gram-positive bacteria e.g. S taphylococcus aureus).

[008] A crucial requirement for effective delivery of these a ntibiotics is reaching a concentration that can overcome the relevant bacterial ^' break point sensitivity limits .. This is the concentration that facilitates the eradication of the colony without inducing resistance to the a ntibiotic. One must a lso avoid reaching dose levels which are systemically toxic- not only eradicating the bacteria but concurrently poisoning the patient and causing cell death.

[009] The management of infections in surgica l patients, especia lly those with an impla nted device is a specific challenge due to the added complexity of antibiotic penetration into the operative site. Antibiotic penetration is hindered by the local devascularisation and the retention of foreign material that ca n occur post-operative intervention. S car creation a nd the formation of a new cavity can dis rupt local a ntibiotic delivery and foreign material can facilitate the formation of a residual biofilm that can shield bacteria from antibiotics.

[010] C urrent preventative options for minimising the incidence of infection associated with orthopaedic implants a re associated with the impla ntation of antibiotic integrated composites in the space around the definitive implant. These composites come in the form of poly methyl methacrylate (medical cement), a ntibiotic eluting biodegradable beads or antibiotic laden polymer coatings. The limitations of these options are the structura l compromise that can occur due to the presence of the beads and a limited ability to control antibiotic dosing. Dosing is compromised by the rate of dispersion either being too rapid, leading to cytotoxic concentrations or being too slow, leading to sub therapeutic doses that breed resistance.

[01 1 ] The most common treatment approach is the use of antibiotic laden cement. The antibiotic powder is mixed into the poly methyl methacrylate (cement) manua lly before use. For this treatment to work the antibiotic relies on the a bility to diffuse out from cracks and voids in the cement itself. The pharmacologica l effects of the composite are dependent on the persistence of structural defects, the viscosity of the cement, the contact surface a nd the concentration of a ntibiotic. S tudies on the impact of the required voids to facilitate functional dispersion have shown a weakening of up to 36% of the structural integrity of the cement, compromising the quality of the surgery. F urthermore, even with the creation of optima l defects, due to the polymer structure a nd the hydrophobicity of the cement a significant portion of the a ntibiotic is retained a nd is unavailable for use. Often levels of less than 10% of the mixed a ntibiotic are released into the surrounding tissue and this release of drug may conclude within hours (or a few days) after surgery. S tudies into the effects of dosage have shown that even with the optima l selection of cement (Palacos) a nd antibiotic (gentamicin and teicoplanin), at low doses very little elution occurs a nd at high concentrations there are local cytotoxic effects.

[012] S tudies on antibiotic effects on osteoblasts derived from trabecular bone showed that increasing gentamicin concentrations effects the function of the cells. Increasing levels of gentamicin decreased the osteoblast activity of alka line phosphates (0 to 100¾/mL), impeding 3H-thymidine levels (>100¾/mL), a nd eventua lly inhibiting total DNA production (fi700¾/mL). Tobramycin at low levels (<200¾/mL) had no effect on the replication of osteoblasts, however at higher concentrations (>400¾¾/mL) replication decreases a nd eventually cell death occurs. With vancomycin, at low levels (<1 .000¾/mL) there is little effect on replication, but at high concentrations (10,000¾/mL) cell death of osteoblasts occurs.

[013] The use of a ntibiotic beads ca n be broken into the use of the traditional non-dissolvable a ntibiotic cement beads a nd the use of the newer biodegradable calcium based compounds. C ement beads function with the same mechanism as the antibiotic laden cement above, but with the added benefit of greater surface area a nd not being utilised for a functional role. T he drawbacks of such beads is the added volume they take up in the operative cavity, the added pressure exerted by the beads within the site, and the need for remova l of the beads once the infection has cleared. There is also a high potential for a locally toxic pea k a nd a short effective time of a ntibiotic release. Due to these drawbacks the use of beads is also not suitable for a primary procedure or for prophylactic use. They fulfil the role of providing a first stage therapy, sterilising the field before a second stage definitive procedure. The added issue specifically with cement beads is the difficultly in locating them at the time of reconstruction and the potentia l for impacting mecha nica l performance of the definitive surgery.

[014] The use of the dissolvable ca lcium sulfate beads needs special mention as they have developed a niche role in the ma nagement of infection. Calcium sulfate beads are synthetic hemihydrate calcium sulphate compounds that, like cement equivalents, are mixed with the desired antibiotic at the time of use. These calcium sulfate beads are composed of hydrophilic crystals. T he hydration of these crysta ls from biological fluids results in the breakdown and elution of the stored antibiotic over a 2-to-3-week period. Whilst the complete breakdown of calcium sulfate beads overcomes the recollection issue of the cement alternatives they still possess the volume filling issues previously mentioned, with little data on the local concentrations or cellular effects of this method. [015] Therefore, there is at least a need for providing an improved way of addressing the issue of bacterial infections by preventing bacterial growth when impla nts are surgica lly placed in patients.

S UMMARY OF TH E INVE NTION

[016] In one aspect, the invention provides a medical implant comprising an implant surface, the surface comprising: an inner layer comprising a first bioceramic material and a first therapeutic agent; and an outer layer comprising a biodegradable polymer and a second therapeutic agent.

[017] In an embodiment, the outer layer further comprises a second bioceramic material. P referably, the second bioceramic material is dispersed throughout the matrix of the biodegrada ble polymer.

[018] In an embodiment, the biocompatible polymer is selected from the group comprising: Poly lactic acid (P LA), poly glycolic acid (PGA), Poly lactic co-glycolic acid (P LGA), and copolymers with polyethylene glycol (P E G); polya nhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone) a nd trimethylene carbonate a nd combinations and co-polymers thereof.

[019] In an embodiment, the bioceramic material is selected from the group comprising of hydroxyapatite, tricalcium phosphate, bioglass, calcium phosphate or bone or a combination thereof.

[020] P referably, the bioceramic material is hydroxyapatite and wherein the hydroxyapatite comprises one or more of the following ions selected from the group consisting of ca lcium, phosphates, fluorine, strontium, silicon and magnesium.

[021 ] In an embodiment, the first therapeutic agent is adsorbed on a surface of the inner layer.

[022] In an embodiment, the second therapeutic agent is dispersed throughout the matrix of the biodegrada ble polymer forming the outer layer.

[023] In an embodiment, the first and second thera peutic agents a re the same. [024] In an embodiment, the thickness of the outer layer is configured such that a substa ntial portion of the outer layer degrades under physiological conditions within a time period of 3 to 10 weeks and more preferably within a time period of 4 to 6 weeks.

[025] P referably, the first or second therapeutic agent is selected from the group comprising a ntibiotics, vitamins, chemotherapy drugs, bisphosphonates, osteoporotic drugs, growth factors, or a combination thereof.

[026] In an embodiment, the inner layer and the outer layer is applied on the implant surface, wherein the implant preferably comprises one or materials from the group of titanium, nickel- titanium alloys, platinum-iridium alloys, gold, magnesium, stainless steel, chromo-coba lt alloys, ceramics, biocompatible plastics or polymers a nd combinations thereof.

[027] In another as pect, the invention provides a synthetic bead for implantation within the body of a n animal or huma n body, the bead comprising a surface defining a s hape having a bulk volume of the bead, the bead being coated with at least a first thera peutic agent to form an inner layer; a nd an outer layer comprising a biodegradable polymer and a second therapeutic agent positioned above the inner layer.

[028] In an embodiment, at least the surface of bead comprises a bioceramic material such that the first therapeutic agent is coated on the bioceramic material and wherein the bioceramic materia l in combination with the first therapeutic agent forms the inner layer.

[029] In an embodiment, the outer layer further comprises a second bioceramic material.

[030] In an embodiment, the biodegradable polymer may be selected from the group comprising: Poly lactic acid (P LA), poly glycolic acid (P GA), Poly lactic co-glycolic acid (P LGA), a nd copolymers with polyethylene glycol (P E G); polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(va leric acid), poly(lactide-co-caprolactone) and trimethylene carbonate and combinations and co-polymers thereof.

[031 ] In an embodiment, the bioceramic material is selected from the group comprising of hydroxyapatite, tricalcium phosphate, bioglass, calcium phosphate or bone or a combination thereof. [032] In an embodiment, the bioceramic material is hydroxya patite and wherein the hydroxyapatite comprises one or more of the following ions selected from the group consisting of calcium, phosphates, fluorine, strontium, silicon and magnesium.

[033] In an embodiment, the first therapeutic agent is adsorbed on the surface of the synthetic bead to form the inner layer thereon.

[034] In an embodiment, the first or second therapeutic agent is selected from the group comprising antibiotics, vitamins, chemotherapy drugs, bisphosphonates, osteoporotic drugs, growth factors, or a combination thereof.

[035] In a n embodiment, the inner layer comprises a biomimetic material with the first therapeutic agent being adsorbed on the surface of the biomimetic material.

[036] In yet a nother as pect, the invention provides a bone cement for cemented arthroplasty or in the form of a drug eluting spacer impla nt, the bone cement comprising:

a powder component comprising:

(a) an acrylic polymer;

(b) a radical initiator; and

(c) one or more synthetic beads as described herein; and

a liquid monomer component, wherein a reaction of the powder polymer component and liquid monomer component provides the bone cement composition.

[037] In yet another aspect, the invention provides a bone void filler material for sustained release of one or more therapeutic agents, the bone void filler material comprising a biodegrada ble matrix having ceramic particles and synthetic beads as described herein dis posed within the matrix.

[038] In another aspect the invention provides a method of coating a medica l implant, the method comprising the steps of: (1 ) applying a bioceramic coating on a surface of an implant and contacting the bioceramic coating with a first thera peutic agent to form an inner layer; and (2) a pplying a biodegradable polymer a nd a second therapeutic agent to form an outer layer.

[039] In a n embodiment step (2) comprises applying the biodegradable polymer and the second therapeutic agent on the inner layer to form a n outer layer.

[040] P referably, step (2) further comprises applying the biodegrada ble polymer in combination with a bioceramic material. [041 ] In an embodiment, step (1 ) comprises adsorbing the first therapeutic agent onto a surface of the bioceramic coating.

[042] In an embodiment, a cold plasma is disposed on the surface of the inner layer before deposition of the first thera peutic agent.

[043] In an embodiment, the first therapeutic agent is electrostatically bonded to the bioceramic coating.

[044] In an embodiment, formation of the inner layer in step (1 ) is carried out under vacuum.

[045] In another embodiment, formation of the inner layer in step (1 ) is carried out under sonication, preferably pulsed-ultra-sonication.

[046] In a n embodiment, the step of a pplying the biodegradable polymer and the second therapeutic agent in step (2) comprises a pplying a solution comprising said biodegradable polymer and the second therapeutic agent.

[047] P referably, the solution comprises the bioceramic material, said bioceramic material being preferably dispersed in the solution.

[048] In an embodiment, the solution is prepared by dissolving the biodegreadable polymer in the solvent, the solvent preferably being selected from acetonitrile or ethyl acetate.

[049] In an embodiment, the second therapeutic agent is initially dissolved to form a therapeutic solution, said therapeutic solution being added to the biodegradable polymer solution.

[050] In an embodiment of the method, the biodegradable polymer is selected from the group comprising: Poly lactic acid (P LA), poly glycolic acid (P GA), Poly lactic co-glycolic acid (P LGA), a nd copolymers with polyethylene glycol (P E G); polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(va leric acid), poly(lactide-co-caprolactone) and trimethylene carbonate and combinations and co-polymers thereof.

[051 ] In an embodiment, the biodegradable polymer is a poly(lactic-co-glycolic acid) (P LGA), molar ratio 50:50, or P LGA, molar ratio 75:25, or P LGA with a free carboxyl group (P LGA-C OOH), molar ratio 50:50. [052] In an embodiment of the method, the bioceramic material is selected from the group comprising of hydroxya patite, tricalcium phosphate, bioglass, calcium phosphate or bone or a combination thereof.

[053] In a preferred embodiment, the biodegradable polymer is a poly (lactic-co-glycolic acid) (P LGA) and wherein the bioceramic material is hydroxyapatite (HA).

[054] P referably, the P LGA is dissolved in the solvent at a concentration in the range of 0.5w/v(%) to 40w/v(%), more preferably 1 w/v(%) to 20w/v(%).

[055] In an embodiment, the HA is dis persed in the solvent at a concentration in the ra nge of 0.1 w/v(%) to 20w/v(%), more preferably 0.5w/v(%) to 10w/v(%).

[056] In an embodiment, volumetric ratio (R) between the volume of the thera peutic solution (T) to the volume of the P LGA solution comprising dispersed HA and R ranges from about 2:8 to 5:8.

[057] In a n embodiment of the method, the solution is applied on the inner layer by air-s praying or by dip coating.

[058] In another aspect, the invention provides a method of treating a patient in need of a medical implant, the method comprising the step of surgically placing the medica l implant, as described herein, into said patent.

[059] In another aspect, the invention provides a method of coating a synthetic bead, the synthetic bead comprising a biomimetic surface defining a shape having a bulk volume of the bead, the method comprising the following steps:

(1 ) coating a first therapeutic agent on the biomimetic surface to form an inner layer; a nd

(2) a pplying a biodegradable polymer a nd a second thera peutic agent on the inner layer to form an outer layer.

[060] In yet another aspect, the invention also provides a method of coating a synthetic bead, the synthetic bead comprising an outer surface defining a sha pe having a bulk volume of the bead, the method comprising the following steps:

(1 ) coating a biomimetic materia l on the outer surface a nd applying a first therapeutic agent onto the biomimetic material;

(2) a pplying a biodegradable polymer a nd a second thera peutic agent on the inner layer to form an outer layer. [061 ] In a n embodiment, the step (2) further comprises applying the biodegrada ble polymer in combination with a bioceramic material.

[062] In an embodiment, step (1 ) comprises adsorbing the first thera peutic agent onto a surface of the biomimetic surface.

[063] In an embodiment, step (1 ) further comprises the following steps:

(a) soa king or immersing the synthetic bead in a solution comprising said first therapeutic agent for a pre-determined time period for coating the surface of the bead; and

(b) retrieving the coated synthetic beads and freeze drying said coated beads.

[064] In an embodiment, step (2) comprises the following steps:

(c) soa king or immersing the coated beads obtained from step (1 ) in a solution comprising said biodegrada ble polymer, the second therapeutic agent a nd an orga nic solvent ;

(d) evaporating the solvent from step (c) under stirring to obtain the said outer layer.

[065] In an embodiment, step (1 ) comprises dissolving said first therapeutic agent in a solvent.

[066] In an embodiment, formation of the inner layer in step (1 ) is carried out under vacuum.

[067] In an embodiment, the biodegradable polymer is selected from the group comprising: Poly lactic acid (P LA), poly glycolic acid (PGA), Poly lactic co-glycolic acid (P LGA), and copolymers with polyethylene glycol (P E G); polya nhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone) a nd trimethylene carbonate a nd combinations and co-polymers thereof.

[068] In a n embodiment, the biodegradable polymer is a poly(lactic-co-glycolic acid) (P LGA), molar ratio 100:0 or 90:10 or 80:20 or 75:25 or 70:30 or 65:35 or 60:40 or 50:50 or 40:60, 30:70 or 20:80 or 10:90; or P LGA, molar ratio 100:0 or 90:10 or 80:20 or 75:25 or 70:30 or 65:35 or 60:40 or 50:50 or 40:60, 30:70 or 20:80 or 10:90; or P LGA with a free carboxyl group (P LGA- C OOH), molar ratio 100:0 or 90:10 or 80:20 or 75:25 or 70:30 or 65:35 or 60:40 or 50:50 or 40:60, 30:70 or 20:80 or 10:90.

[069] In an embodiment, the bioceramic materia l is selected from the group comprising of hydroxyapatite, tricalcium phosphate, bioglass, calcium phosphate or bone or a combination thereof. [070] In an embodiment, the biodegradable polymer is a poly(lactic-co-glycolic acid) (P LGA) a nd wherein the bioceramic material is hydroxya patite (HA).

[071 ] In an embodiment, the P LGA is dissolved in the solvent at a concentration in the range of 0.5w/v(%) to 40w v(%). nnore preferably 1 w/v(%) to 20w v(%) and more preferably 1 w/v(%) to 10w v(%).

[072] In an embodiment, the bioceramic material is dispersed in the solvent at a concentration in the range of 0.1 w/v(%) to 20w v(%), nnore preferably 0.5w/v(%) to 10w v(%)-

[073] In an embodiment, the first therapeutic agent is an a ntibiotic agent and wherein the solution in step (1 ) comprises a n antibiotic concentration in the range of 10%w v to 30%w/v and more preferably in the range of 10%w v to 25%w v.

[074] In a n embodiment, the second therapeutic agent is an antibiotic agent and wherein the solution in step (2) comprises a n antibiotic concentration in the range of 10%w v to 30%w/v and more preferably in the range of 10%w v to 25%w v.

[075] In an embodiment, a bioceramic material is dispersed in the solvent of step (c).

[076] In an embodiment, the bioceramic material comprises one or more of the following: hydroxyapatite, tricalcium phosphate, bioglass, calcium phosphate or bone or a combination thereof.

[077] In an embodiment, the outer layer comprises a thickness in the range of 10i m to 150i m a nd more preferably in the range of 20i m to 100i m.

B RIE F DE S C R IPTION OF FIG UR E S

Figure 1 is a first sectiona l view of a medical implant 100 in accordance with a first embodiment of the present invention.

Figure 2 is an enla rged sectiona l view of the medical implant 100 in accordance with the first embodiment of the present invention.

Figure 3 is a schematic view of the medica l implant 100 in accordance with the first embodiment of the present invention.

Figure 4 is a graphical illustration showing the relationship between antibiotic elution from the medical implant 100 a nd time.

Figure 5 depict results of drug elution from example 1. Figure 6 depicts a schematic view of a coated synthetic bead 200.

Figure 7 depicts a schematic illustration depicting a method of coating a synthetic bead 200. Figure 8 depicts an enlarged schematic view of the coated synthetic bead 200.

D ETAIL E D DE S C RIPTION

[078] Referring to F igures 1 to 3, a first embodiment of a medical implant 100 in accordance with the present invention is illustrated. The impla nt body 10 may be formed from one or more materia ls from the group of titanium, nickel-tita nium a lloys, platinum-iridium a lloys, gold, magnesium, stainless steel, chromo-cobalt alloys. The implant body 10 may a lso be formed from ceramic materials or polymeric materials.

[079] In the preferred embodiment, the medical impla nt 100 comprises a metallic body 10 having a n implant surface 12. The implant surface 12 is coated with an inner Iayer 20 and a second outer layer 60.

[080] The inner layer 20 comprises a sub-layer or base layer 22 comprising biomimetic hydroxyapatite (HA) that is directly coated onto the implant surface 12 a nd an antibiotic coating 24 that is adsorbed on the surface of the biomimetic HA layer 22.

[081 ] The outer layer 60 comprises a polymeric matrix comprising a biodegradable polymer provided by Poly lactic co-glycolic acid (P LGA) that substantially forms the outer layer 60. T he outer layer 60 also comprises antibiotic particles 64 and bioceramic particles, preferably hydroxyapatite pa rticles 62 dispersed uniformly across the matrix of the P LGA in the outer layer 60.

[082] The medical implant 100 provides an improved coating system based on hydroxya patite (HA) a nd poly (lactic-co-glycolic acid) (P LGA) that is adapted for carrying antibiotics (such as vancomycin, gentamycin). Without wishing to be bound by theory, the applicants have theorized that a coating system, in accordance with a n embodiment, comprising the combination of the inner Iayer 20 a nd the outer Iayer 60 provides sustained elution of a ntibiotics over a period of 4-6 weeks and superior osteoinductivity due to the presence of biomimetic HA component in combination with the antibiotics in the inner layer 20 and the outer layer 60 in the aforementioned configuration. [083] Without wishing to be bound by theory, the applicants also believe thatthe medical implant 100 provides an improvement over previous ly known medical implants a nd coating methods for the following reasons.

[084] The medical implant 100 having the combination of the inner layer 20 and the outer layer 60 on the impla nt surface 12 provides an increased a ntibiotic loading capacity for the medical implant 100 as will be demonstrated in the foregoing sections. S pecifically, the HA layer 22 provided on the implant s surface 12 is likely to adsorb a ntibiotic agents 24 through physica l adsorption and ionic bonding as a result of the high surface area of the HA particles on the HA Iayer 22 and the intrinsically high negative cha rge densities of the HA particles in the HA Iayer 22. At least some antibiotic agents such as vancomycin and gentamycin have partial positive charges under physiological pH conditions. Therefore, it is hypothesized that such positively charged a ntiobiotic agents are likely to be electrostatically bonded to the HA particles in the HA layer 22. The inner layer 20 is then covered by a biodegrada ble polymer such as P LGA to form the outer layer 60. The a pplicants have hypothesized that providing a biodegradable polymeric layer 60 directly a bove the inner layer 20 slows down drug elution, specifically elution of antibiotic agents adsorbed on the HA layer 22. Importa ntly, the polymer matrix of the P LGA layer 60 is formulated to contain additional dispersed antibiotic particles to provide additional loading and release during use. The co-polymer ration in the P LGA forming the P LGA layer 60 is selected such that this protective coating formed by the outer layer 60 completely degrades after 4-6 weeks in vivo. The a ntibiotic payload dispersed in the P LGA layer 60 is exhausted within the 4-6 weeks and biomimetic HA coating underneath is exposed to further accelerate new bone formation.

[085] The applica nts have hypothesized that the elution of antibiotic agents in the inner Iayer 20 a nd the outer P LGA layer 60 is regulated by 3 mechanisms that work together to provide sustained release of the antibiotic agent at a level above the recommended minimum inhibitory concentration (MIC) for a period of 4-6 weeks:

(a) diffusion of antibiotics agents/molecules dispersed in the outer layer 60, specifically the matrix of the P LGA 62.

(b) diffusion of antibiotics agents/molecules that are adsorbed on the HA layer 22 through the polymeric coating forming the outer layer 60 a nd

(c) biodegradation of the P LGA coating 62 of the outer layer 60 which takes ~ 4-6 weeks for P LGA of 50% lactic and 50%glycolic (i.e., P LGA 50:50).

[086] The applicants have hypothesized, as shown in F igure 4, that the combined effects of surface diffusion, bulk diffusion and matrix erosion processes may result in antibiotic elution kinetics of desirable properties: quickly (-2-3 hours) and loca lly reach therapeutic level (above MIC), remain above the MIC for extended periods of time (4-6 weeks) followed by a sharp release of the antibiotic agents (-10-12 hrs-referred to as a ^' tail J when drug release is completed (to avoid drug resistance development).

[087] The a pplicants also believe that the medical implant 100 with the inner Iayer 20 and outer layer 60 provides improved osteoinductive (i.e., inducing bone formation) properties. S pecifically, the outer layer 60 having the P LGA polymer matrix is formulated to contain amorphous hydroxyapatite HA particles 64 to provide additiona l osteoinductivity to the medica l implant 100. It is understood by the applica nts that that the dissolution and re-precipitation of Ca a nd P from HA particles in the outer layer 60 and the inner layer 20 after implantation in vivo is a major mechanism for HA to form new bone. The incorporation of amorphous HA in the outer layer 60 by incorporating HA particles 62 in the P LGA matrix of the outer layer 60. The a pplicants have found that higher (faster) degradation kinetics of amorphous HA particles 62 in the outer P LGA layer 60 is more favourable for bone formation.

[088] The medical implant 100 having the combination of the inner layer 20 and the outer layer 60 on the implant surface 12 also provides increased bone ingrowth capability. Bone ingrowth largely depends on the presence of macropores. The applicants envision that, during use, bone ingrowth will not be affected by the provision of the inner layer 20 and the outer layer 60 of the medical impla nt 100. P referably, the combined thickness of the inner Iayer 20 and the outer layer 60 will a pproximately be in the range of 1 5i m to 25i m. As a result, the combined thickness of the inner and outer layers 20 and 60 is approximately 10 times smaller than the average size of the macropores commonly found on medica l impla nt surfaces (~ 200-300um). In addition, the amorphous HA particles 62 in the polymeric coating forming the outer layer 64 provides osteoinductivity that promote new bone formation.

[089] The polymer coating forming the outer layer 64 a lso effectively shields the a ntibiotic agents adsorbed on the inner layer 20, specifica lly the antibiotic agents 24 adsorbed on the HA pa rticles forming the HA layer 22, against excessive friction forces which may occur during insertion of certain implants.

[090] The applica nts also believe that there is a n unexpected and surprising synergistic effect between the osteoinductive and biomimetic properties of the HA (provided in the first layer 20 a nd the second Iayer 60), controlled release of the antibiotic agents (24 and 64) a nd the biodegradable properties of P LGA in the outer layer 60. Therefore, the applicants expect that the combination of the inner layer 20 and the outer layer 60 on a medical impla nt is likely to provide protective effects against infection during the first critical 4-6 weeks after implant insertion and at the same time promote new bone formation and bone ingrowth into the impla nt surface 12 to achieve superior implant integration and reduced infection rates. [091 ] The presently described embodiment refers to antibiotic agents 24 a nd 64 being incorporated into the inner layer 20 and the outer layer 60. However, it is expected in alternative embodiments, therapeutic agents such as a nticancer drugs (e.g., doxorubicin) or bioactive agents (e.g., BMP2) may be incorporated into the inner layer 20 or outer layer 60 without departing from the scope of the invention described herein.

[092] A method for forming a coated medical impla nt 100, in accordance with a nother embodiment of the present invention, is described in the following sections.

[093] In a first step, the process of forming the inner layer 20 comprises the loading of antibiotic agents 24 upon the implant surface 12 of the implant 10 coated with HA forming the HA Iayer 22. In a first step, a medical impla nt 10 is provided. In a second step, the implant 10 may be immersed in a simulated body fluid, such as a phosphate buffer saline (P BS ) solution. T he P BS solution may be prepared at various ion concentrations to mimic the chemical composition of human body fluids, such as blood plasma. The impla nt 10 may be initially soaked in the P BS solution and the HA coating 22 be grown biomimetically. It should be a ppreciated that other methods for forming the HA coating 22 may also be used in alternative embodiments.

[094] P rior to a pplying the HA coating 22, a surface 12 of the implant 10 may also be coated with for example, a crystalline Ti02 coating through, for example, cathodic a rc eva poration. It should be appreciated that other methods can be used to deposit a volume of the coating. The surface metal coating can be selected from the group of T 1O2, TiO, TiC rCh, T 12O3, T 13O5, S 1O2, Mg0 ₂ , AI0 ₂ , and C r0 ₂ . In the preferred embodiment, the impla nt 10 may have an implant body with the impla nt surface 12 comprising a base metal of Ti a nd S S T alloys. The provision of the crystalline T 1O2 coating provides a bioactive underlying surface so as to nucleate the HA crysta ls of the HA layer 22 on the metal base provided on the implant body 12.

[095] The next step involves adsorbing antibiotics onto the HA-coated impla nt 10 obtained in the previous step.

[096] Antibiotic powder (such as gentamycin powder) may be dissolved in aqueous solution having a pH 4.5 to 7. The HA coated implant 10 may be coated with the aqueous solution of the a ntibiotic powder. Before forming the a ntibiotic coating on the HA Iayer 22 of the impla nt 10, the HA coated implant 10 may be plasma-treated to achieve a desired charge polarization. For example, Ar-gas cold plasma may be applied for 10 minutes to create surface negative charge of a bout -35 mV. After the plasma treatment has created surface charge polarization desirable for strong electrostatic binding with a ntibiotic agents, the plasma treated implant may be immersed in the antibiotic solution. [097] The immersion of the plasma treated implant 10 may be followed by application of a low vacuum for 10 to 30 mins or by pulsed ultra-sonication applied for 2-5 mins to facilitate better contact between the HA coated implant 10 and the antibiotic solution to preferably achieve homogeneous antibiotic adsorption and adsorb antibiotic particles 24 on the HA layer 22. The implant 10 may be removed from the a ntibiotic solution and air-dried for 12 to 24 hours in the dark at room temperature. T he inner layer 20 comprising the HA layer 22 with the adsorbed antibiotic particles 24 is thereby formed.

[098] The next step involves the formation of the outer layer 60. The outer layer 60 may be formed by at least two different coating methods.

[099] In a first alternative embodiment, the outer layer 60 comprising P LGA may be formed by way of air-drying.

[100] S pecifically, P LGA (50:50 or 75:25; MW=106 kDa) may be dissolved in a solvent such as acetonitrile or ethyl acetate at concentrations of from 1 w v % to 20 w/v % with slight heating at 37 to 50 degree C for 10 to 30 minutes. Amorphous hydroxyapatite (HA) powder may be dis persed into the P LGA polymer solution at a concentration from 0.5 w/v % to 10 w/v %. The P LGA solution with the HA particles dispersed in the solution may be ultrasonicated for about 30 mins to 60 mins to uniformly dis perse the amorphous HA in the P LGA solution.

[101 ] An a ntibiotic solution may be prepa red by introducing antibiotic powder in an appropriate solvent (such as water, sa line, P BS) at a relatively high concentration. The a ntibiotic solution is mixed with the P LGA solution (containing the dispersed HA particles). S pecifically, the a ntibiotic solution is added and mixed to the HA-P LGA solution at volume ratios ranging from 2:8 to 5:8 (vol. antibiotic solution: volume HA-P LGA solution). The a ntibiotic HA ^" P LGA solution is air- sprayed using air pressure from 1 -3 ba rs at distance from 3.5 to 21 cm for a period of 30 seconds to 2 minutes on to the HA-coated implant rotating at speed of from 0 rpm to 60 rpm. The coated implant is air-dried at temperature from 20 to 100 degree C for a period of 30 mins to 2 days when complete evaporation of solvents is achieved. The coated implant 10 may then be treated by a cold plasma-treatment again (for example 10 mins under Argon gas plasma) to increase hydrophilicity of the surface of the coated implant 10.

[102] In a second alternative embodiment, the outer layer 60 comprising P LGA may be formed by way of dip-coating.

[103] An a ntibiotic solution may be prepa red by introducing antibiotic powder in an appropriate solvent (such as water, sa line, P BS) at a relatively high concentration. The a ntibiotic solution is mixed with the P LGA solution (containing the dispersed HA particles). S pecifically, the a ntibiotic solution is added and mixed to the HA-P LGA solution at volume ratios ranging from 2:8 to 5:8 (vol. antibiotic solution: volume HA-P LGA solution). The initially coated implant 10 may be dipped in the antibiotic ^" HA ^' P LGA solution. T he immersion of the implant 10 may be followed by a pplication of a low vacuum for 10 to 30 mins or by pulsed ultra-sonication applied for 2-5 mins to facilitate better contact between the inner layer 20 of the implant 10 and the a ntibiotic ^" HA ^" P LGA solution to form a homogeneous outer layer 60 coated on the inner layer 20. The implant 10 may be removed from the a ntibiotic ^" HA ^' P LGA solution and air-dried for 12 to 24 hours in the dark at room temperature.

[104] The coated implant 100 with the outer layer 60 may once again be treated by a cold plasma-treatment again (for example 10 mins under Argon gas plasma) to increase hydrophilicity of the surface of the outer layer 60 provided on the coated implant 100.

[105] Referring to F igures 6 to 8, a second embodiment of a coated synthetic bead 200 in accordance with the present invention is illustrated. Synthetic beads in the form of uniform tricalcium phosphate (TC P) porous beads 205 having a n average pa rticle size in the range of 10i m to 100 I m with micro and macro pores having an outer surface 210 may be obtained or fabricated by any conventional means. In other embodiments, the synthetic beads 205 may be formed using other bio-ceramic or biomimetic materials. The outer surface 210 is coated with a base layer 215 of a ntibiotic solution. The porous nature of the outer surface 210 allows the a ntibiotic solution to be adsorbed a nd/or absorbed into the synthetic bead 205 thereby forming a base anti-biotic layer 215. Once the inner anti-biotic layer 215 has been formed, an outer layer 260 comprising a polymeric matrix having a biodegradable polymer provided by Poly lactic co- glycolic acid (P LGA) is formed on the base layer 215. T he outer layer 260 also comprises a ntibiotic particles 264 and bio-ceramic particles 263 that are dispersed throughout the polymer matrix of the P LGA in the outer layer 260.

[106] In order to form the base layer 21 5, as shown in S tep 1 in Figure 7, powdered antibiotic materia l 267 is dissolved in a n appropriate solvent (e.g., water) or co-solvent a nd stabilizer (e.g., polyvinyl alcohol) at approximately 10-30% (w v). T he TC P beads 205 are then immersed in the a ntibiotic solution for a period of 2-6 hours under vacuum (10 ¹ -10 ³ Torr.) to achieve a n antibiotic coating 215 on the synthetic bead 205. It is important to appreciate that the material cha racteristics may vary a nd such characteristics a re expected to impact the manner in which the a ntibiotic material is coated on the bead 205. As shown in Figures 6 to 8, the porous (micro- porous or macroporous) nature of the TC P beads allows the antibiotic particles 267 to be coated not only on the outer surface 210 of the bead 205 but to also be received in the porous interna l volume of the bead 205. [107] The method of forming the outer layer 260 once the initia l a ntibiotic base layer 21 5 has been coated is illustrated in S tep of Figure 7 a nd explained in further detail. An antibiotic solution is formed by dissolving powdered a ntibiotic in a n a ppropriate solvent (e.g., water) or co-solvent a nd stabilizer (e.g., polyvinyl a lcohol) at approximately 10-30% (w/v). The antibiotic solution is then added into a P LGA solution (prepared at concentration of 1 -10%w/v) to achieve a final a ntibiotic concentration in the ra nge of 5-20% w/v.

[108] The coated beads 205 having a n initial base layer 215 are immersed in P LGA solution of 1 -10% (w/v) in appropriate solvents) (acetone or acetonitrile or a ny other appropriate organic solvent) with the anti-biotic concentration of 5-20% w/v continuous stirring under low vacuum until complete evaporation of solvent(s) to form the outer layer 260 on the beads 205. In some embodiments, the outer layer 260 may be dried further by e.g., repeated spreading on glass disk with a stainless steel s patula to prevent coa lescing. The thickness of the outer layer 260 may be controlled to be in the range of 20i m-100i m. The coating of the outer P LGA layer allows antibiotic particles 264 to be dispersed through the polymer matrix of the P LGA in the outer layer 260. Bioceramic material such as hydroxya patite or TC P particles 263 are also dispersed through the P LGA matrix of the outer layer 260.

[109] Depending on the ratio of lactide to glycoiide used for the polymerization, different forms of P LGA can be obtained: these are usually identified in regard to the molar ratio of the monomers used (e.g. P LGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid). In the presently described the molar ratio in the P LGA may be 100:0, 90:10, 80:20, 75:25, 70:30, 65:35, 60:40 50:50, 40:60, 30:70, 20:80, 10:90 with molecular weight in the range of 60-134 kDa are appropriate.

[1 10] The coated beads 205 provide an improved coating system based on poly (lactic-co- glycolic acid) (P LGA) that is adapted for carrying antibiotics (such as vancomycin, gentamycin). Without wishing to be bound by theory, the applicants have theorized that a coating system, in accordance with an embodiment, comprising the combination of the inner layer 21 5 and the outer layer 260 provides sustained elution of antibiotics over a period of 4-6 weeks and superior osteoinductivity due to the presence of biomimetic TC P component on the outer surface of the beads 205 in combination with the a ntibiotics in the base Iayer 215 a nd the outer Iayer 260 in the aforementioned configuration.

[1 1 1 ] Without wishing to be bound by theory, the applicants also believe that the coated beads 205 provide an improvement over previously known synthetic beads a nd coating methods for the following reasons. [1 12] The coated beads 200 having the combination of the inner base layer 21 5 and the outer layer 260 on the surface of the synthetic bead 205 provides an increased a ntibiotic loading capacity for the coated synthetic beads 205 as will be demonstrated in the foregoing sections. S pecifically, the outer surface of the uncoated bead comprises micorpores and/or macropores that are likely to adsorb or absorb antibiotic agents 224 through physical adsorption and ionic bonding as a result of the high surface area of the outer surface of the uncoated beads and the intrinsically high negative cha rge densities of the outer surface of the uncoated TC P beads. At least some antibiotic agents such as vancomycin and gentamycin have partial positive charges under physiological pH conditions. Therefore, it is hypothesized that such positively charged a ntiobiotic agents are likely to be electrostatically bonded to the outer surface of the TC P beads thereby forming the base layer 215. T he inner base layer 215 is then covered by a biodegradable polymer such as P LGA to form the outer layer 260. The applicants have hypothesized that providing a biodegradable polymeric layer 260 directly above the inner layer 215 slows down drug elution, specifically elution of antibiotic agents adsorbed on the surface 210 of the bead.

[1 13] Importa ntly, the polymer matrix of the P LGA layer 260 is formulated to contain additional dis persed antibiotic pa rticles to provide additional loading and release during use. The co-polymer ration in the P LGA forming the P LGA layer 260 is selected such that this protective coating formed by the outer layer 260 completely degrades after 4-6 weeks in vivo. The antibiotic payload dis persed in the P LGA layer 260 is exhausted within the 4-6 weeks and biomimetic TC P surface having adsorbed anti-biotics in the base layer 215 is exposed to further accelerate new bone formation.

[1 14] The applicants have hypothesized that the elution of a ntibiotic agents in the inner base layer 21 5 and the outer P LGA layer 260 is regulated by 3 mechanisms that work together to provide sustained release of the antibiotic agent at a level above the recommended minimum inhibitory concentration (MIC) for a period of 4-6 weeks:

(a) diffusion of antibiotics agents/molecules dispersed in the outer layer 260, specifically the matrix of the P LGA 262.

(b) diffusion of antibiotics agents/molecules in the inner base layer 215 that are adsorbed on the TC P outer surface 210 layer 22 through the polymeric coating forming the outer layer 60 and

(c) biodegradation of the P LGA coating in the outer layer 260 which takes ~ 4-6 weeks for P LGA of 50% lactic and 50%glycolic (i.e., P LGA 50:50).

[1 15] The applicants have hypothesized, that the combined effects of surface diffusion, bulk diffusion and matrix erosion processes may result in antibiotic elution kinetics in the coated synthetic beads 200 to have desirable properties: quickly (-2-3 hours) and loca lly reach therapeutic level (above MIC), remain above the MIC for extended periods of time (4-6 weeks) followed by a sharp release of the antibiotic agents (-10-12 hrs-referred to as a ^' tail J when drug release is completed (to avoid drug resistance development).

[1 16] The applica nts also believe that the use of the coated beads 200 with the inner base layer 215 and outer layer 260 provides improved osteo-inductive (i.e., inducing bone formation) properties. S pecifically, the outer layer 260 having the P LGA polymer matrix in some embodiments may be formulated to contain amorphous hydroxyapatite bioceramic or biomimetic particles to provide additional osteoinductivity. It is understood by the applicants that that the dissolution and re-precipitation of ions such as Ca and P from bioceramic particles such as HA particles in the outer layer 260 a nd the inner base layer 21 5 after implantation in vivo is a major mechanism for to form new bone. The applicants have found that higher (faster) degradation kinetics of amorphous HA particles in the outer P LGA layer 260 is more favoura ble for bone formation.

[1 17] The coated beads 200 may be utilised as an added constituent in bone cement or void fillers. By way of example, the coated beads 200 may be added to a bone cement for use as a drug eluting cement in cemented arthroplasty or in the forming of a temporary drug eluting spacer implant. A typical bone cement comprises a powder component comprising: an acrylic polymer (such as P MMA) a nd a radica l initiator. The coated beads 205 may be added to the powder component of the bonce cement, before adding a liquid monomer component. T he reaction of the powder component (specifica lly the polymer in combination with initiator) and the liquid monomer component, is accompanied by curing which provides the bone cement composition. The drug elution cha racteristics of the coated beads 205 are useful when use in conjunction with bone cement.

[1 18] S imilarly, the coated beads 200 may also be utilised for use as a constituent in bone void fillers. Typically, bone void fillers comprise a biodegradable matrix having cera mic particles. The coated beads 200 may be added to the bone void fillers to derive benefit from the improved drug elution cha racteristics of the aforementioned coated beads 200.

E xample 1

[1 19] In an exemplary embodiment, the drug elution characteristics of the coated medical implant 100 were investigated. S pecifica lly, elution of vancomycin a nd cefazolin was investigated in a dynamic, physiological resembling condition (phosphate buffer saline pH 7.4, shaking, 37 degree C) a nd eluted a mounts of vancomycin and cefazolin over time were quantified using UV- visible spectrophotometry. P reliminary results have indicated eluted doses of vancomycin a nd cefazolin above the MIC (>0.5 microgram per ml) for 5 -7 days in impla nt samples without coatings. P roviding the inner coating 20 and the outer coating 60 is likely to extend to a bove 4 weeks with a ppropriate and thick P LGA material forming the outer coating 60.

[120] C ulture S . aureus with eluted drug showed that the drug bioactivity is preserved during preparation, loading a nd releasing processes. P revious in house work has shown that the binding a nd release of a ntimicrobial silver on Ti, P C L and P E E K demonstrated similar release kinetics of a ntimicrobial Ag for 40 days above 1 ug/mL MIC based on same release mechanisms (diffusion, degradation, erosion).

[121 ] Throughout the specification, biodegrada ble polymers a re ones which degrade to smaller fragments by enzymes present in the body. The terms ^' medical implant., Implant _, and the like a re used synonymously to refer to any object that is designed to be placed partially or wholly within a patient's body for one or more therapeutic purposes such as for restoring physiologica l function, alleviating symptoms associated with disease, delivering therapeutic agents, and/or repairing or replacing or augmenting etc. damaged or diseased organs and tissues.

[122] Representative examples of medica l implants/devices include pins, fixation pins and other orthopaedic devices, dental implants, stents, ba lloons, drug delivery devices, sheets, films and meshes, soft tissue implants, implantable electrodes, implantable sensors, drug delivery pumps, tissue ba rriers a nd s hunts. It should be a ppreciated that other devices listed herein are contemplated by the present disclosure.

[123] In compliance with the statute, the invention has been described in language more or less specific to structural or methodical features. The term comprises _, and its variations, such as comprising _, and comprised of. is used throughout in an inclusive sense and not to the exclusion of a ny additional features. It is to be understood that the invention is not limited to specific features shown or described since the means herein described comprises preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims a ppropriately interpreted by those skilled in the art.

[124] Any embodiment of the invention is meant to be illustrative only and is not meant to be limiting to the invention. Therefore, it should be appreciated that various other cha nges and modifications can be made to a ny embodiment described without departing from the spirit and scope of the invention.