WO2016108757A1

WO2016108757A1 - A prosthesis and method of manufacture

Info

Publication number: WO2016108757A1
Application number: PCT/SG2015/050512
Authority: WO
Inventors: Yin Chiang Freddy Boey; Joseph Tang
Original assignee: Medlinx Acacia Pte. Ltd.
Priority date: 2014-12-29
Filing date: 2015-12-29
Publication date: 2016-07-07
Also published as: GB201423303D0

Abstract

A method of solution dip casting to form a layered prosthesis, the method comprising the steps of: providing a polymer substrate; using a dip casting process to add first and second polymeric layers, said dip casting process comprising the steps of: performing a first casting of a first polymeric layer on the polymer substrate, the first polymeric layer having a first and second antimicrobial agent; performing a second casting of a second layer over the first polymer layer, having a third antimicrobial agent; performing a third casting of a second polymeric layer over the second on the polymer substrate; said polymer substrate with the first and second polymeric layers forming said prosthesis.

Description

A Prosthesis and Method of Manufacture

Field of Invention

The present invention relates generally to method of manufacturing processes for forming or creating medical devices that has microbial inhibition properties. In particular, the present invention relates to methods and processes for forming or adding layered substrates prosthesis, which has microbial inhibition properties on medical devices, for example hernia meshes, having various geometries that are suitable for implantation in humans.

Backeround of Invention In recent years, there has been growing interest in the use of medical devices with antimicrobial properties, particularly in devices with surface antimicrobial agents like silver salts and chlorohexidine compounds. Clinicians have been challenged in the past few years by an increasing variety of novel noninfectious and infectious complications following the widespread use of meshes after open or laparoscopic repair of hernias. Mesh-related infections are considered as possible causes of fevers of unknown origin, or symptoms and / or signs of inflammation of the abdominal wall in any patient, up to 14 days following hernia repair. The reported incidence of mesh-related infection following hernia repair has been 1 %— 20% in different series, and this incidence is influenced by underlying co-morbidities, the type of mesh, the surgical technique and the strategy used to prevent infections. While mesh, per se does not cause infection, as an implant that is recognized as a foreign body, it can potentiate infection. This process results in colonization of the mesh by bacteria. There is a need to develop a hernia mesh prosthesis with antimicrobial properties, thereby reducing the risk of mesh related infections and preventing colonization of mesh by bacteria when infection occurs.

There are currently several antimicrobial polymeric hernia mesh prostheses available in the market. These are typically woven meshes with polymer coatings incorporating antimicrobial agents. These mesh products have coatings or are impregnated with high concentrations of antimicrobial agents or salts. Due to the high antimicrobial agent loading or coating thickness, these hernia meshes have compromised mechanical properties and issues associated with surface wettability. At the same time, the high loading or concentrations of antimicrobial agents may delay the healing of the wound and induce toxicity. This translates into poor mesh handling, poor patient comfort and recovery. In addition, many existing antimicrobial hernia meshes do not have a homogeneous concentration of antimicrobial agents across the surface of the mesh. This can lead to varying levels of antimicrobial effectiveness at edges of the meshes 14 to 21 days after implantation. Usually as implantable, the loading concentration of antimicrobial agents on the meshes must be controlled to have a reduced toxicity effect.

Inflammation and swelling at the repair site is a common complication after mesh implant surgery. Antiinflammatory drugs, either steroidal or non-steroidal and through the controlled release and localized administration can reduce inflammation or pain at surgical wound site

The wettability of a hernia mesh's surface is important. It is desirable to have a hydrophobic surface as this may reduce the ability of bacteria to attach and form a biofllm on the mesh surface. At the same time, multiple layers of polymeric film can be added via solution dip casting process, which has one or multiple antimicrobial agents such as silver salts and chlorhexidine compounds. The polymeric film formation on the polymeric substrate with microbial inhibition properties added is effective up to between 14 to 21 days to reduce the ability of bacteria to attach and grow.

Accordingly, it is desirable to produce a layered hernia mesh prosthesis with controlled uptake concentration of antimicrobial agents such as silver salts and chlorhexidine compounds. The control of uptake is due to thickness formation during solution dip casting withdrawal and it is not limited to one or more layers and first polymer can be formed on or wrapped over its entire surface. This mesh should prevent or inhibit bacteria attachment effectively up to between 14 to 21 days, and has a surface wettability in the following regime of surface contact angle 40° to 95°. In addition, an anti-inflammatory drug may be incorporated within one or more layers for treatment. Summary of the Invention

In a first aspect the invention provides a method of solution dip casting to form a layered prosthesis, the method comprising the steps of: providing a polymer substrate; using a dip casting process to add first and second polymeric layers, said dip casting process comprising the steps of: performing a first casting of a first polymeric layer on the polymer substrate, the first polymeric layer having a first and second antimicrobial agent; performing a second casting of a second layer over the first polymer layer, having a third antimicrobial agent; performing a third casting of a second polymeric layer over the second on the polymer substrate; said polymer substrate with the first and second polymeric layers forming said prosthesis.

In a second aspect the invention provides a layered prosthesis comprising: a polymer substrate; a first polymeric layer on the polymer substrate, the first polymeric layer having a first and second antimicrobial agent; a second layer on the first polymeric layer having a third antimicrobial agent, said third antimicrobial agent arranged to react with the second antimicrobial agent to obtain a fourth antimicrobial agent.

The method of casting processes may be utilized to develop the layered device, for example hernia mesh prosthesis, for use as implantable medical device from a polymer substrate. The polymer substrate may be solution dip cast with a thickness formation, comprising one or more layers of first polymer, formed on or wrapped over its entire surface. The thickness formation determines the controlled uptake concentration and homogenous distribution of antimicrobial agents, such as silver salts and chlorhexidine compounds, in the first polymer solution. The polymeric substrates may be pre-dip machined or post dip machined (example, using high energy source such as laser) to create devices such as mesh having a variety of geometries for implantation in a patient, such as in hernia repair etc.

The layered device, for example hernia mesh prosthesis, may inhibit microbial growth effectively up to between 14 to 21 days if an amorphous bioabsorbable polymer, for example PDLA with intrinsic viscosity of 0.5 dl/g, is selected from the group of polymers used for first polymer solution preparation. The layered hernia mesh prosthesis may inhibit microbial growth beyond 60 days, if the first polymer layer or subsequent second polymer layer is processed from a starting semi-crystalline polymer that has molecular weight range or polymer intrinsic viscosity higher than 2.0 dl/g and the resultant layer polymer crystallinity will be greater than 30% due to method of processing.

The uptake concentrations may be a function of the following parameters, for example, chlorhexidine diacetate with effective concentrations range of 40 μg/cm² to 7 μg/cm² and silver sulfadiazine with effective concentrations range of 4 μg/cm² to 30μg/cm² which is effective for the inhibition to microbial growth on the layered prosthesis, for example hernia mesh.

Parameters such as: first polymeric solution concentration or its post mixed viscosity, first antimicrobial agent solubility in its solvent, second antimicrobial agent solubility in its solvent, rate of adding the first antimicrobial agent dissolved in its solvent to the first polymeric solution to avoid precipitation, rate of adding the second antimicrobial agent dissolved in its solvent to the first polymeric solution to avoid precipitation, the reaction time during immersion of the second antimicrobial agent with the third antimicrobial agent to form the fourth antimicrobial agent that works in synergy with the first antimicrobial agent, immersion sequence, the rate of immersion into each solution, the immersion dwell time within each solution, the withdrawal rates from the first polymeric solution which determines the uptake concentration of all antimicrobial agents due to the formation thickness of the first polymeric layer and the drying time and curing time between each immersion.

Antimicrobial agents are controlled release through the first polymer and second polymer layer and will affect the desired microbial inhibition characteristics of the layered hernia mesh prosthesis, e.g. as illustrated in Fig 16 diffusion of antimicrobial agents from the first polymer layer and second polymer layer or degradation of the first polymer layer and second polymer layer, by which antimicrobial agents are released in a controlled fashion over time, in the case of first antimicrobial agent, second antimicrobial agent, third antimicrobial agent and fourth reacted antimicrobial agent from second and third antimicrobial agent, where the individual antimicrobials can be release at the same time or at different release profiles.

A method to add layered microbial inhibition properties mesh through use of combination of various casting techniques, e.g. dip coating, spray coating, etc and scaled up manufacturing versions of such process, e.g. roll-to-roll coating etc.

The use of layered prosthesis mesh, which has microbial inhibition properties, for the repair of anatomical defects to reduce the risk of infection in potentially contaminated fields.

This layered prosthesis, for example hernia mesh, may also have anti-inflammatory drugs embedded or added on its surface which is soluble in the second polymer solution from the method of solution dip casting process.

The method of processing changes may result in device variation depending on requirements. There may be different sizes of mesh produced depending on the size of the reinforcement needed of the device implanted. Different antimicrobials agents, not limited to one or a combination of what is listed below, can be loaded via the method of processing. These include: chlorhexidine diacetate, Silver Salts e.g Silver Carbonate, Silver Sulfadiazine, silver nitrate, sodium sulfadiazine; Antiseptics e.g. Chlorhexidine, Triclosan; Antibacterial peptidesdermaseptin and lysostaphin and combinations of the above.

By way of example, chlorohexidine diacetate may be selected as the first antimicrobial agent, sodium sulfadiazine may be the second antimicrobial agent, and silver nitrate may be used for the third antimicrobial agent and the fourth reacted antimicrobial agent may be silver sulfadiazine. The second and third antimicrobial agents, which are soluble in water can be rinsed off in post processing after the solution dip casting process and it is important to keep third antimicrobial agent to be within 0.5% weight of total quantity loading.

The dip casting additive polymer layer to the polymer substrate that contains the antimicrobial agents may be made of various different bioresorbable polymers such as polylactide, polyglycolide, polylactide, and poly-co-glycolide, polylactide acid, polyglycolide acid, poly(ethylene glycolide), polyethylene glycol, polycaprolactone like poly(e-caprolactone), polydioxaneone, polygluconate,polylactide acid-polyethylene oxide copolymers, polysaccharides, cellulose derivatives, hyaluronic acid based polymers, starch, gelatin, collagen, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(amino acids) or any polymer blends, copolymers, or derivatives thereof.

Anti-microbial release may be affected by multiple factors e.g. diffusion of the antimicrobial agents through the first polymeric layer, thickness of the first polymeric layer, rate of coating breakdown, drying times and temperatures and humidity level, type of coating polymer, etc.

Different anti-inflammatory drugs that are soluble in solvents and water can be used, either steroidal or non-steroidal. These include: e.g. dexamethasone, or non-steroidal systems e.g. an indomethacin, diclofenac or ketoprofen system. Solution dip casting processes on the polymer substrate may be used. Spray coating may also be used but the relative speed (rather than uptake speed) of polymer solution release must be controlled with the polymer substrate to enable thickness formation, which carries the effective concentration for microbial growth inhibitions. In high volume preparation, roll-to-roll dip casting or spray coating techniques may be used.

Many variables within each of the processes or sub processes can be varied, e.g. coating solutions immersion sequence, rate of immersion, direction of dipping, duration of air dry, the duration dwell time of each immersion within the solution, as well as the delay time between each immersion or the drying or curing time and humidity between each dip, dipping withdrawal rates of the polymer substrate device to and/or from various coating solutions, etc. may be adjusted to control the various desired antimicrobial agent loadings, coating thickness and / or antimicrobial release profiles.

Alternative uses of the layered prosthesis mesh with microbial inhibition properties may include:

• It is possible that the device, for example hernia mesh, with antimicrobial coatings is not only used to reduce the risk of post-operative infections.

• It is also possible that the anti-microbial coated device, for example hernia mesh, be used prophylactically when repairing an anatomical defect in patients with compromised immune systems.

• It is also possible that if repair of anatomical features occur in settings where there are high rates of potential infections, e.g. in a military hospital outpost, it is likely that this antimicrobial coated device, for example hernia mesh, will be used.

• It is possible that the mesh having anti-inflammatory coatings are used to reduce the risk of postoperative inflammations at wound sites. Brief Description of the Drawings

Fig. 1 illustrates an example of method for processing such as a dip casting processes, which may be used to enable thickness formation of first polymer layer on the polymer substrate, which carries the effective concentration for microbial growth inhibitions with the controlled uptake or withdrawal speed.

Fig. 2 illustrates the addition of antimicrobial agents to first polymer solution in a drop-wise manner

Fig. 3 illustration of the dip casting process for first Layer

Fig. 4 illustration of the mechanism of thickness formation between the interface of the polymer substrate and the dip casting solution

Fig. 5 illustration of the dip casting process for second layer

Fig. 6 illustration of the dip casting process for third layer

Fig. 7 illustration of the release profile of first antimicrobial agent

Fig. 8 illustration of the release profile for the third and fourth antimicrobial agent

Fig 9. Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Staphylococcus aureus for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test

Fig 10 Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Methicillin-resistant Staphylococcus aureus (MRSA) for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test

Fig 11 Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Escherichia Coli for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test Fig 12 Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Streptococcus pyogenes for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test

Fig 13 Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Staphylococcus epidermidis for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test

Fig 14 Illustration of the Zone of Inhibition of the device which was manufactured by "method of processing B", against Pseudomonas Aeruginosa for a fresh device and a device that has been soaked in PBS for 14 days prior to placement on agar for the zone of inhibition test Fig 15. Illustration of the coating structure of the device

Fig 16. Illustration of the coating structure with the third layer as well as the release mechanism of the antimicrobial agents

Detailed Description of the Invention Method of processing parameter steps determines the microbial inhibition properties

The method of solution dip casting is described for manufacturing of implantable devices such as layered mesh prosthesis with microbial growth inhibition properties from polymeric substrate. In this example the polymeric substrate is made from a proprietary blend of non-absorbable polyvinylidene fluoride (PVDF) base material and absorbable poly 1 ,4-butylene adipate (PBA) plasticizer for improved compliance. Alternative polymer mesh can be made from other common biocompatible polymers including Polypropylene, Polyethylene, Polyvinylidene Fluoride, Polytetra Fluoroethylene or combinations thereof. The polymer substrate meshes may be fabricated by the extrusion of the polymers into a long strand and then weaving it into a mesh form. Or in this case, extruded into a flat sheet, with holes cut by high energy laser after the extrusion process. These meshes may be cut into different shapes and sizes from 10cm by 10cm dimensions to 45cm by 45cm dimensions. A typical mesh dimension for us would be 10cm by 15cm mesh.

An example of such a method of processing is to utilize a solution dip casting process to create a polymeric substrate with desirable microbial inhibition properties through a thickness formation, consisting of one or more layers, formed on or wrapped over its entire surface. The thickness formation on the polymer substrate determines the controlled uptake concentration of antimicrobial agents such as silver salts and chlorhexidine compounds mixed, miscible or dissolved in the first polymer solution. Additionally, dip casting the polymer substrate also allows for multiple layers through a thickness formation during the withdrawal from the first polymer solution which uptake desirable concentration of antimicrobial agents in each layer. Multiple layers may be formed from similar materials or a combination of materials and may include any number of antimicrobial or anti-inflammatory agents for microbial growth inhibition and/or reduce inflammatory response of the nearby tissue post implantation. Moreover, the variability of having multiple layers due to the method of processing may allow one to control other parameters, or ranges of antimicrobial concentration for example between individual layers while maintaining the intrinsic molecular weight which affects the diffusion and release mechanism of the antimicrobial agents for example to create a zone of inhibition. The zone of inhibition result is illustrated in table 1 as shown with multiple parameter changes (e.g. withdrawal speed change and concentration of first antimicrobial loaded in first polymer solution of the illustrated method of processing to yield different withdrawn loading due to thickness formation for first antimicrobial agent and fourth reacted antimicrobial agent and their Zone of inhibition results shown for "Method of processing B"

Through this method of processing, the starting molecular weight of the first polymer layer and each additional second polymer layer for example may be used to create desirable release profile of the microbial inhibition agents which is highly desirable for treatment of infections control for hernia mesh implantations. Furthermore these processes may produce high precision geometric tolerances with respect to layer thickness formation on the polymer substrate.

For example, Illustration of "Method of Processing B"

For example, Layer 1:

A polymer substrate mesh prosthesis having surface wettability or contact angle of at least 65° and above in the hydrophobic regime is prepared by its unique manufacturing processes. An example of nonabsorbable flexible polyvinylidene fluoride (PVDF) polymer substrate, which may be utilized to cast or solution dip cast is illustrated in Fig 1. Generally, the dip casting assembly 10 may be any structure, which supports the manufacture of layered mesh prosthesis with microbial inhibition properties in accordance with the description herein. A platform base 20 may support a column 30, which houses the drive mechanism 40 and an arm 50. The drive mechanism for example motor may move the arm vertically along the column 30. Polymer substrate may be attached to a bracket holder 60 and attached to the arm above the solution container 70 which may be filled for example with a first polymer with its solvent solution (e.g. PDLA, PLA, PLGA etc.), a first antimicrobial agent, such as chlorhexidine and its compound, is dissolved in a solvent for example ethanol that is miscible with the first polymeric solution for example acetone, before added slowly drip by drip by pipette or dropper 80 (as illustrated in Fig 2.) (time required for addition depending on transfer volume: 5 to 240 mins) into the first polymer solution with its solvent to form a clear solution. The solubility of the chlorhexidine and its compounds in the solvent, and consequentially its loading, can be controlled by various factors like heating the mixed solution, physical stirring etc. These factors can be adjusted to from different solutions with different levels of saturation: e.g. a saturated solution with some insoluble compounds, e.g. a clear solution with no solid compounds or e.g. a super saturated solution with no solid compounds. Different solvent types and different amounts of solvents can be also be used to dissolve both the polymer and the antimicrobial agents and they can be mixed and combined at different proportions to control the resultant concentrations and formulations, and resultantly, effect the desired antimicrobial loadings for the finished product. An example for first antimicrobial agent solubility in its solvent should be controlled by ratio of maximum 1 : 10 parts by weight for example for chlorohexidine diacetate to ethanol. A second antimicrobial agent, for example sodium sulfadiazine dissolved in HPLC grade water (or its equivalent solvent), is added drop-wise into the solution containing the first polymer, its solvent solution and the first antimicrobial agent, using a pipette or dropper 80 (as illustrated in Fig 2.) (The time required for addition depends on transfer volume: 5 to 240 mins). The second antimicrobial agent dissolved in HPLC grade water (or its equivalent solvent) is added drop-wise and mixed to prevent precipitation to form a dip solution alpha with continuous stirring. HPLC grade water is used as it is free from organic and inorganic compounds and does not have any UV absorbance. An example for second antimicrobial agent solubility in its solvent should be controlled by ratio of maximum 1 : 10 parts by weight for example for sodium sulfadiazine to HPLC water.

The polymer substrate may be dipped via a linear vertical motion into the dip solution alpha 90 (as illustrated in Fig 3 and Fig 4) for an immersion speed 100 for example 200mm/min for a dwell time of 5 mins to wet the surfaces of polymer substrate and withdraw for a controlled speed 110 for example at 360mm/min after it is mixed and stirred well for example 120mins. The first polymer solution example PDLA, thickness formation 120 from a withdrawal rate of the polymer substrate from 5mm/min to 2000mm/min in this example is between a 0.1 and 100 micrometer in thickness, commonly between 1 to 50 micrometers. This thickness formation h₀ 120 as illustrated in Fig 4 carries a precise loading amount of first antimicrobial agent and second antimicrobial agent and is achieved with competition of the solution surface tension (capillary force) due to polymer substrate's surface wettability in the following regime of surface contact angle 40° to 95°, gravity force and viscosity of dip solution alpha. Usually the gravitational force is not controllable thus the main control will be the polymer solution surface tension or polymer substrate wettability and viscosity of dip solution alpha. Generally, the faster the substrate is withdrawn, the thicker the film deposited on the polymer substrate and carrying more quantity of antimicrobial agents.

Example of mixture of Dip Solution Alpha for a 3x3cm sample with 12.022cm² geometry design.

The polymer substrate after the first dip into dip solution alpha may be dried at room temperature to elevated temperature near the boiling point of the first polymer solution solvent for example, acetone for lmin to 30mins and with environmental relative humidity level of 45% to 90% and thus induces solvent evaporation 130. It is possible that shorter or longer air-dry dwell times are used to vary the coating. It is also possible that dryer or wetter humidity levels are used as well. Another possibility is to dry the coating in inert gases like Nitrogen or argon.

For example,

Layer 2: A third antimicrobial agent for example silver nitrate dissolved in HPLC grade water (or its equivalent solvent) is stirred well to achieve a clear solution e.g with no solid compounds for dip solution beta 140 (as illustrated in Fig 5). The polymer substrate after the first dip into dip solution alpha and post air dried for lmin to 30mins with environmental relative humidity level of 45% to 90% is dipped for example an immersion speed of 200mm/min 150 into solution beta for Layer 2 with dwell time for example zero to 5 minutes within Dip Solution Beta to control the reaction time for second antimicrobial agent and third antimicrobial agent to form fourth antimicrobial agent and withdraw for a controlled speed 160 for example 360mm/min after it is mixed and stirred well for example from 5 to 120mins. This layer via dip casting may result in varying loading of fourth antimicrobial agent for example Silver Sulfadiazine concentration within the polymer matrix depending on concentration loaded in first polymer solution with second antimicrobial agent for example sodium sulfadiazine and third antimicrobial agent for example silver nitrate. The range of dwell time control may also be adjusted to be shorter or longer than the range of zero to 5 mins to reduce or increase the concentration of Silver Sulfadiazine as required. The difference in the loading of both antimicrobial agents achieved via the dip coating process will result in different antimicrobial characteristics, which affect the ability of a medical device to create a Zone of inhibition of microbial growth of an index bacterium.

Example of Mixture of Dip Solution Beta for a 3x3cm sample with 12.022cm² geometry design.

Layer 2: Dip Material Example %wt Solvent Example %wt

solution Beta Example Example

mixture

Third Silver Nitrate 0.004% HPLC grade 0.996%

Antimicrobial water

Agent The polymer substrate after withdrawal from dip solution beta may be dried 170 at room temperature to elevated temperature near the boiling point of the solution beta solvent for example, water from lmin to 30mins and with environmental relative humidity level of 45% to 90%. It is possible that shorter or longer air-dry dwell timings are used to vary the coating. It is also possible that dryer or wetter humidity levels are used as well. Another possibility is to dry the coating in inert gases like Nitrogen or argon.

For example,

Layer 3: for control release

The polymer substrate after layer 2 dip casting may be dipped into a second polymer solution 180 for example PDLA or PLGA dissolved in its relevant solvent example acetone (or its equivalent solvent) to control the release of the first antimicrobial agent, residual second antimicrobial agent, residual antimicrobial agent and fourth antimicrobial agent resulted from reaction of second and third antimicrobial agent for its initial 48hours release and up to 14 days to any medium at pH 7.4 or equivalent environment after implantation to achieve biocompatibility and its inhibition of microbial growth properties.

Example of Mixture of second polymer Solution for a 3x3cm sample with 12.022cm² geometry design.

The polymer substrate after the Layer 2 dip coasting will dip into second polymer solution with immersion speed at controlled speed 190 for example 400mm/min and withdraw for a controlled speed 200 for example 360mm/min and left it at room temp or elevated temp for example up to 15mins 210. This is followed by drying the dip coated polymer mesh prosthesis at an elevated temperature eg. 37 to 85 deg C to reduce the residual solvent to an acceptable USP <467> level for 24 to 48 hours. Post processing, e.g. Laser cutting or stamping to its desirable geometry, can be performed on the antimicrobial film-added polymer mesh prosthesis. It is possible for these processes to be converted into a line manufacturing process, where the polymer layers or mesh are coated in a roll-to-roll process. This would involve large dipping bathes to dip the polymer mesh, followed by large ovens to dry the coatings as necessary.

The degradation of first polymer for example PDLA will begin as soon as 5 to 30 days post implantation and full degradation of the PDLA coating will occur 12-18 months with example as illustrated in Fig 7 for % release of first antimicrobial agent for example Chlorohexidine Diacetate 220 remaining on mesh released over 14 days as per method of processing B for release profile 1 and as illustrated in Fig 8 for the % amount of third antimicrobial agent and reacted fourth antimicrobial agent for example all silver compound 230 remaining on mesh. For other groups of polymer used, the degradation time might be longer depending on the initial level of molecular weight of polymer selected to control the release and its degradation. The method of solution dip casting process with the sequential steps for layer 1 , layer 2 and layer 3 but not limiting to and parameters will determine the uptake concentrations for example, chlorhexidine diacetate with effective concentrations range of 40 μg/cm² to 75 g/cm² and silver sulfadiazine with effective concentrations range of 4 μg/cm² to 30μg/cm² which is effective for the inhibition to microbial growth properties on the layered prosthesis mesh for up to 14 days. These critical parameters are controlled to result in a layered prosthesis mesh with effective antimicrobial characteristics.

Antimicrobial effectiveness or microbial inhibition for method of processing with first layer, second layer and third layer processes dip casting

Effective antimicrobial characteristics is defined as the ability for the medical device to have surfaces for microbial inhibition growth with zone of no growth around the device or create a Zone of inhibition of microbial growth of an index bacterium around the medical device or portion thereof in microbiological assays. In this case, it is shown from Fig. 9 to Fig. 14 for example through the Method of Process B, several microbial species has been inhibited to grow on the layered mesh prosthesis that may be used as medical device for hernia. The effective antimicrobial properties were shown effective after 14 days soaking in PBS buffer, to simulated degradation of the coating at 14 days after implantation as shown in Fig 9 to Fig 14.

A Zone of inhibition is a Zone in which no microbial growth is evident as assessed by the naked eye. For a serial plate transfer test, the Zone of inhibition will generally extend to a width of at least 1 mm and beyond the boundary of the test material placed on the surface of a nutrient (agar) medium, however, the ability of the test material to inhibit microbial growth beneath the test material is also taken into account (i.e. a Zone of inhibition may be observed beneath the test material). "Inhibition of resistant mutant strains" is a very different measure and in this application is to be taken to mean the absence of any visible bacterial colonies in any Zone of inhibition.

The length of time that antimicrobial activity and inhibition of resistant microbial mutations exhibited depends on the geometry of the device and its combination of antimicrobial agents loading that has been achieved by the method of processing as described for a polymer substrate mesh prosthesis.

The molecular weight of the first and second polymer casted on the polymer substrate layer is one of the factors in determining the mechanical behavior of the device layered mesh prosthesis and the degradation time of the onset of mass loss. In this case, a low molecular weight biocompatible / bioresorbable polymer may be selected to form the first polymer layer cast on the polymer substrate. In the described example, two antimicrobial agents, chlorohexidine compound and silver sulfadiazine were incorporated as illustrated in Fig 15. The range of molecular weight of the polymer was selected dependent on the desired period of time over which the antimicrobial agents are to be entrapped in the matrix and released in a controlled manner. By controlling the release of antimicrobial agents over time, this method gives the mesh an effective antimicrobial effect up to 14 days after implantation, while maintaining sufficiently low concentrations of released antimicrobial agents to not hamper the wound healing response and toxicity. Example of table below shown with multiple parameter changes (e.g. withdrawal speed change and concentration of first antimicrobial loaded in first polymer solution of the illustrated method of processing to yield different withdrawn loading due to thickness formation for first antimicrobial agent and fourth reacted antimicrobial agent and their Zone of inhibition results.

Table 1 :

Claims

What is claimed is:

1. A method of solution dip casting to form a layered prosthesis, the method comprising the steps of:

providing a polymer substrate;

using a dip casting process to add first and second polymeric layers, said dip casting process comprising the steps of

performing a first casting of a first polymeric layer on the polymer substrate, the first polymeric layer having a first and second antimicrobial agent;

performing a second casting of a second layer over the first polymer layer, having a third antimicrobial agent;

performing a third casting of a second polymeric layer over the second on the polymer substrate; said polymer substrate with the first and second polymeric layers forming said prosthesis.

2. The method according to claim 1 , wherein the second antimicrobial agent will react with the third antimicrobial agent to form a fourth antimicrobial agent but not limited to and leaving only residual second antimicrobial agent and third antimicrobial agent which is water soluble.

3. The method according to claim 1 or 2, wherein the second polymeric layer includes a plurality of antimicrobial agents.

4. The method according to claim 1 or 2, wherein the second polymeric layer includes a plurality of anti-inflammatory agent.

5. The method according to any one of claims 1 to 4, wherein the uptake concentration of antimicrobial agents cast with the film thickness formation from first polymeric solution upon the polymer substrate is a function of any one or a combination of: the polymeric substrate surface wettability, withdrawal up speed and concentration of polymer in solvent, antimicrobial agents solubility in its solvent, miscible antimicrobial solvent ratio with polymer solvent,

6. The method according to any one of claims 1 to 5, wherein the first casting step includes immersing a polymer substrate layer into at least a first polymeric solution having an intrinsic viscosity of about 0.2 to about 6.5 dl/g which contains a first antimicrobial agent dissolved in its solvent and added slowly to be miscible with the first polymeric solution and a second antimicrobial agent that is soluble in its solvent and added slowly to the first polymeric solution so as to form the first layer of polymeric layer on the polymer substrate.

7. The method according to any one of claims 1 to 6, wherein the second casting step includes immersing the polymer substrate with the first cast polymeric layer in a second solution containing a fully dissolved third antimicrobial agent compound that reacts with the second antimicrobial agent; to form a fourth antimicrobial agent compound that works.

8. The method according to claim 7, wherein the second polymeric solution having an intrinsic viscosity of 0.2 to 6.5 dl/g to control the diffusion and release of the first antimicrobial agent and the fourth antimicrobial agent

9. The method according to any one of claims 1 to 8, wherein the polymer substrate includes apertures, said apertures for example includes any one or a combination of as, but not limited to, circular holes or diamond shaped holes.

10. The method according to claim 9, wherein the dimension of each aperture is greater than 1mm and the interstices in-between each aperture should be less than 1.25mm, the combination of this arrangement facilitates incorporation of the prosthesis into the body.

1 1. The method according to any one of claims 1 to 10, wherein the polymer substrate includes a surface wettability in the range of surface contact angle of 40° to 95°.

12. The method according to any one of claims 5 to 1 1, wherein the withdrawal speed from the first polymeric solution after each immersion is in the range of lOmm/min to 2000mm/min.

13. The method according to any one of claims 1 to 12, wherein the first polymeric layer comprises a polymer having a relatively high molecular weight more than intrinsic viscosity of 2.0 dl/g if the release of the antimicrobial agents is desirable for longer periods beyond 30 days.

14. The method according to any one of claims 1 to 13, wherein the polymeric substrate is selected from the group consisting of polyvinylidene fluoride, polyamide, polyethylene, polypropylene, poly(ethylene terephthalate), polyurethane, polystyrene, polymethyacrylate, polytetrafluoroethylene, and polymers or copolymers of p-dioxanae, trimethylene carbonate (1 ,3- dioxan-2-one) and alkyl derivatives thereof, valerolactone, butyrolactone, decalactone, hydroxybutyrate, hydroxyvalerate, l,5-dioxepan-2-one, 1 ,4-dioxepan-2-one, 6,6-dimethyl-l , 4- dioxan-2-one or any polymer blend thereof.

15. The method according to any one of claims 1 to 14, wherein the first polymeric solution and the second polymeric solution is selected from the group consisting polydL-lactide, polyglycolide, polylactide, and poly-co-glycolide, polylactide acid, polyglycolide acid, poly(ethylene glycolide), polyethylene glycol, polycaprolactone like poly(e-caprolactone), polydioxaneone, polygluconate,polylactide acid-polyethylene oxide copolymers, polysaccharides, cellulose derivatives, hyaluronic acid based polymers, starch, gelatin, collagen, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(amino acids) or any polymer blends, copolymers, or derivatives thereof.

16. The method according to any one of claims 1 to 15, further including the steps of: further immersing the polymeric substrate to second polymeric solution such that a second layer of polymer is formed upon the first layer with the first antimicrobial agent, second antimicrobial agent, third antimicrobial agent and fourth reacted antimicrobial agent entrapped below the second layer of polymer.

17. The method of claim 16, wherein the second polymeric solution comprises an anti-inflammatory drug or agent selected from the group consisting of: dexamethasone, an indomethacin, diclofenac or ketoprofen system.

18. A layered prosthesis, manufactured according to any one of claims 1 to 17.

19. A layered prosthesis comprising: a polymer substrate; a first polymeric layer on the polymer substrate, the first polymeric layer having a first and second antimicrobial agent; a second layer on the first polymeric layer having a third antimicrobial agent, said third antimicrobial agent arranged to react with the second antimicrobial agent to obtain a fourth antimicrobial agent.

20. The layered prosthesis according to claim 19, further comprising a second polymeric layer on top of first polymeric layer to control the diffusion and release of first, second, third and fourth antimicrobial agent.

21. The method according to any one of claims 1 to 20, wherein an effective uptake concentration range of 40-75 g/cm² for the first antimicrobial agent and the fourth antimicrobial agent with an effective concentration range of 4-30μg/cm^2;, for the inhibition to microbial growth.