WO2009009520A2

WO2009009520A2 - Nanoparticulate fillers

Info

Publication number: WO2009009520A2
Application number: PCT/US2008/069391
Authority: WO
Inventors: David Franklin Farrar; Marcia Elizabeth Clark; Colin Anthony Scotchford; David Malcolm Grant; Gavin Walker
Original assignee: Smith & Nephew, Inc.
Priority date: 2007-07-10
Filing date: 2008-07-08
Publication date: 2009-01-15
Also published as: AU2008275226A1; EP2170983A2; JP2011506619A; AU2008275226B2; WO2009009520A3; JP5753687B2; GB0713351D0

Abstract

The present invention relates to the use of nanoparticles comprising a neutralising agent for incorporation within a bioresorbable polymer to neutralise the acidic degradation products of said bioresorbable polymer. Composites and a method of making the composites are also disclosed.

Description

NANOPARTICULATE FILLERS

CROSS REFERENCE TO RELATED APPLICATION

This application is a PCT International Application of provisional application no. GB0713351.5, filed on 10 July 2007, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to orthopaedic implants and more particularly to bioresorbable polymer composites comprising nanoparticles, wherein the nanoparticles are capable of buffering the acidic degradation products of the polymer.

BACKGROUND TO THE INVENTION

Fracture fixation plates are the most commonly employed devices for surgical support of fractured bone. The plates are placed across the site of fractures bones and exert pressure on the fractured ends of the bone, thereby improving the rigidity until unity of the fracture is complete. Currently, the plates are manufactured of a rigid metal, such as stainless steel, cobalt chrome alloys and titanium alloys. However, as described in Ramakrishna et al., Composite Science and Technology, Vol. 61 , pp. 1189-1224 (2001 ), the large difference in elastic modulus between the underlying bone (14-24 GPa) and the metallic implants (100-240 GPa) causes a majority of the load of the body to be carried by the implant while fracture healing is taking place. This leads to callus formation, ossification and delays in bone union due to the lack of strain and bone resorption, resulting in an osteoporotic structure. These side effects are further described in Woo et a L₁ Journal of Biomedical Materials Research, Vol. 17, pp. 427-439 (1983). Clinically known as the stress-shielding effect, refracture of the bone often occurs once the implant has been removed. This effect is further described in Shikinami et al., Biomaterials, Vol. 20, pp. 859-877 (1999).

Other drawbacks to metallic fixation plates include: (a) a second operation is sometimes required to remove it, (b) toxicity problems caused by corrosion by-products, (c) production of artifacts in the areas surrounding the implant and (d) production of a distorted image when using magnetic resonance imaging, due to the metallic paramagnetic properties. These drawbacks are further described in Woo et a), and Shikinami et al., as noted above, and Weiler et al., Journal of Arthroscopic and Related Surgery, Vol. 16, pp. 305-321 (2000).

A solution to these drawbacks is through the use of bioresorbable polymers such as polylactide (PLA), polyglycolide (PGA) and their copolymers. However, the potential of bioresorbable plates produced by polymers such as PLA and PGA is limited by the modest initial mechanical properties with respect to bone, the rate of loss of these polymers, and the evolution of acidic degradation products on hydrolytic cleavage of the polymer backbone, as detailed in Pietrzak et al., Bone, Vol. 19, pp. 109S-

1 19S (1996). Such degradation products have been associated with foreign body immune responses in the vicinity of the implant. In a study where 282 patients over a three year time period had fractures treated with PGA rods, 6% were found to exhibit some form of foreign body inflammatory response. This study is further described in Bostman, Journal of Bone and Joint Surgery, Vol. 73, pp. 679-682 (1991 ). Generally this is found to only last as long as the time taken for the polymer to degrade, but has been reported to vary from a mild swelling reaction to the formation of a painful papule, which usually bursts releasing a sinus discharge of disintegrated implant, as further described in Gogolewski, Injury, Vol. 31 , pp. S-D 28-32 (2000) and Bostman et al., Clinical Orthopaedics, Vol. 371 , (2000).

CaCO₃, β-tricalcium phosphate and hydroxyapatite exhibit a buffering capability when used to reinforce bioresorbable polymers derived from glycolide and lactide, as further described in Agrawal et al., Journal of Biomedicals Material Research, Vol. 38, pp105-114 (1997).

The mechanical properties of a composite are dependent on the strength of the interface between the two different phases, i.e. the matrix and the reinforcement. Strong adhesion between the two phases is often difficult to achieve when microparticles are used as the reinforcing element, as further described in Gasser, Injury International Journal of the Care of the Injured, Vol. 31 , pp. S-D48-53 (2000) and Liu et al., Biomaterials, Vol. 18, 1263-1270 (1997). In Uecla et al, Biomaterials, Vol. 24, pp. 3247-3253 (2003), the disclosure of which is incorporated herein by reference in its entirety, it was demonstrated that the incorporation of calcium carbonate nanoparticles into a poly(-L-lactic acid) (PLA) biomaterial improves the mechanical properties of the biomaterial, for example increasing the modulus of elasticity, reducing the brittle fracture behaviour, and improving the bending strength. Nanoparticles of basic fillers have not been incorporated into polymer biomateriais to neutralise the acidic degradation products.

We have found that the incorporation of nanoparticles of basic fillers into polymer biomaterials buffers the acidic degradation products. Auto- catalytic degradation and any inflammatory reaction would thereby be minimised, with the fabrication of a composite potentially resulting in an improvement in the mechanical properties.

SUMMARY OF THE INVENTION

There is provided the use of nanoparticles comprising a neutralising agent for incorporation within a bioresorbable polymer to neutralise the acidic degradation products of said bioresorbable polymer.

The neutralising agent is typically a basic nanoparticulate filler.

In embodiments of the invention the neutralising agent is a salt capable of neutralising the acidic degradation products. Examples of suitable salts include, but are not limited to, a carbonate, a bicarbonate, or a phosphate salt.

In embodiments of the invention the neutralising agent is a hydroxide.

A particularly advantageous neutralising agent is one which is also a source of free calcium ions. Calcium ions are known to be osteogenic and therefore their release from the bioresorbable polymer can also promote osteogenesis. For example, the neutralising agent is a calcium carbonate (CaCO₃) or a calcium phosphate. An example of a suitable calcium phosphate is apatite. Apatite is a group of phosphate minerals, usually referring to hydroxylapatite, fluorapatite, and chlorapatite, named for high concentrations of OH^", F^", or Cl^" ions, respectively, in the crystal. The formula of the admixture of the three most common species is written as Ca₅(PO₄)₃(OH, F, Cl), and the formulae of the individual minerals are written as Ca₅(PO₄)S(OH), Ca₅(PO₄)₃F and Ca₅(PO₄J₃CI, respectively.

In a specific embodiment of the invention, the apatite is hydroxyapatite.

The concentration of the neutralising agent within the polymer is from between about 5-20 wt %, specifically from about 7-15 wt %.

In embodiments of the invention the diameter of the nanoparticle is less than about 100nm. The larger surface area to volume ratio of the nanoparticles improves the bonding between the matrix and reinforcement phase when compared to microparticfes of the basic fillers.

The larger surface area to volume ratio of the nanoparticles also significantly reduces the concentration of the basic fillers required to provide the same buffering capability as microparticlulate fillers. This has a two-fold advantage. Firstly, this allows for an improvement to the composite's mechanical properties since the incorporation of high concentrations of fillers into bioresorbable polymers results in a substantial amount of the composite being composed of the filler which has the tendency to make the polymer more brittle, have a lower fracture toughness, and lead to failure. Secondly, large quantities of filler particles within a composite can result in particle agglomeration due to the attractive van der Waals forces [13]. Lower concentrations of particles, optionally with the use of a surfactant allow these forces to be overcome by the repulsive forces, resulting in a composite with the filler homogenously dispersed within the polymer matrix.

The incorporation of the nanoparticles of the neutralising agent, for example calcium carbonate, into a bioresorbable polymer have been shown not only to have a buffering capability but they are effective in reinforcing the polymer and improving its mechanical properties. For the purposes of this invention, a bioresorbable polymer includes all bioresorbable polymers except poly-L-lactic acid (PLLA). This includes, without limitation, the following:

Polyglycolide Polylactide

Copolymers of glycolide and lactide

Polycaprolactone

Glycolide/trimethylene carbonate copolymers

Poly-DL-lactic acid (PDLLA) Poly-D-lactic acid (PDLA)

Lactide/tetramethylglycolide copolymers

Lactide/trimethylene carbonate copolymers

Lactide/d-valerolactone copolymers

Lactide/e-caprolactone copolymers PLA/polyethylene oxide copolymers

Polydepsipeptides

Unsymmetrically 3,6-substituted poly-1 ,4-dioxane-2, 5-diones

Poly-b-hydroxybutyrate

PHB/b-hydroxyvalerate copolymers Poly-b-hydroxypropionate

Poly-p-dioxanone

Poly-d-valerolactone

Methylmethacrylate-N-vinyl pyrrolidone copolymers

Polyesteramides Polyesters of oxalic acid

Polydihydropyrans Polyalkyl-2-cyanocrylates Polyurethanes (PU) Polyvinylalcohol (PVA) Polypeptides Poly-b-malic acid (PM LA)

Poly-b-alkanoic acids polycarbonates

Polymers comprising nanoparticles of a neutralising agent can be manufactured in a similar way to their micron-sized equivalents, through dissolution of the polymer in a solvent followed by the addition of the nanoparticles.

The addition of nCaCO₃ to D-L lactide prior to polymerisation has been shown to cause a decrease in the resultant polymer molecular weight. This can have a significant impact of the mechanical properties of the polymeric composite. Composites containing 30 wt % nCaCOβ have a significantly lower M_n and M_w than those produced with 14 wt % nCaCO₃. When CaCO₃ZPDLLA composites are combined with higher molecular weight PDLLA and polymerised, the resulting composite powder has bimodal molecular weight distribution. As a result of this no significant differences in M_n or M_w occur in the subsequent extrusion and injection moulding processes.

There is provided a polymeric composite comprising a first polymer and a second polymer, wherein the first polymer has a molecular weight less than the second polymer, and wherein nanoparticles of a neutralising agent are distributed throughout at least the first polymer.

In one embodiment of the polymeric composite both the first polymer and the second polymer is poly-DL-lactic acid (PDLLA) or copolymers thereof and the first polymer comprises nanoparticles of calcium carbonate.

There is also provided a method of manufacturing a composite comprising a first polymer including a nanoparticulate neutralising agent distributed throughout and a second polymer, the method comprising the steps of; a) polymerising the first polymer with the nanoparticulate agent to form a combination; and b) blending the combination produced in a) with the second polymer, the second polymer having a high molecular weight than the first polymer.

In an embodiment, the first polymer is PDLLA or copolymers thereof and the nanoparticulate agent is calcium carbonate.

Additionally, there is provided a composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material consists of PDLLA or copolymers thereof.

Also, there is provided a composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material is any polymer material other than PLLA.

For the purposes of this invention, the polymer included in the polymer/nanoparticulate neutralising agent composite is a polymer having a molecular weight of less than 20 kD. Similarly, the higher molecular weight polymer that the composite is blended with is a polymer having a molecular weight of greater than 20 kD.

Further areas of applicability of the present invention will become apparent from the detailed description provided hereafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purpose of illustration only and are not intended to limit the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and form part of the specification, illustrate the embodiments of the present invention and together with the written description serve to explain the principles, characteristics, and features of the invention. In the drawings:

FIG.1 Transmission electron micrograph of nano-particulate calcium carbonate. FIG.2 Variation in pH of the solution holding the composites with degradation time. Values are mean ± standard error for triplicate samples.

FIG.3 Variation in number average molecular weight (M_n) and weight average molecular weight (M_w) of nCaCOyPDLLA composites polymerised for 5 days at 130 ⁰C using 0.01 wt % SnOCt₂. The resultant samples were then utilised for melt processing. Values are mean ± standard error for repeated duplicate samples.

FiG.4 Variation in time with the response of the GPC detector for (a) 100 wt % PDLLA, (b) 30 wt % PDLLAAiCaCO₃ composite and <c) 15 wt % PDLLAZnCaCO₃ composite, produced by melt processing equal quantities of PDLLA and 30 wt % PDLLA/nCaCO₃ composite.

FIG.5 Difference in number average molecular weight (M_n) and weight average molecular weight (M_w) of nCaCOs/PDLLA composites following extrusion and injection moulding. Values are mean ± standard error for repeated duplicate samples.

FIG.βi SEM micrographs (a-f) illustrating the melt processed composites containing varying concentrations of CaCO₃. Those images taken in back- scattered electron mode are indicated with BS. FIG.6U SEM micrographs (g-j) illustrating the melt processed composites containing varying concentrations of CaCO₃. Those images taken in back- scattered electron mode are indicated with BS.

FIG.7 Change in pH of the starting solution holding the PDLLMiCaCO₃ composites versus degradation time. Values are mean + standard error for repeated triplicate samples.

FIG.8 Variation in mass lass of the composites as they degrade. Values are mean + standard error for repeated triplicate samples.

FIG.9 Change in (a) number average molecular weight and (b) percentage reduction in number average molecular weight (M_n) with composite degradation time. Values are mean ± standard error for repeated duplicate samples

FIG.10 Change in the concentration of calcium ions present within the composites. Values are mean for repeated ± standard error for repeated triplicate samples.

FIG.11 Change in elastic modulus with nCaCO₃ content within PDLLA and processing condition, as determined using dynamic mechanical analysis. Values are calculated at 25 ⁰C and are mean ± standard error for a minimum of 5 sampfes. FIG.12 Variation in storage modulus with nCaCO₃ content within PDLLA and processing condition, as determined using dynamic mechanical analysis. Values were calculated at 37 ⁰C and are mean ± standard error for a minimum of 5 samples.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Nano-particulate calcium carbonate (nCaCOa) with a narrow particle size distribution (all particles less than 100 nm) and a low tendency to agglomerate (Figure 1) was precipitated through carbonation of an aqueous solution of calcium hydroxide (Ca(OH)₂) in methanol. This was achieved through the use of the following processing parameters: an initial temperature of -93 ⁰C, initial Ca(OH)₂ concentration of 0.04 g cm^'3, CO₂ flow rate of 300 cm³ rnin^'1, initial pH of 8.5 (achieved through the addition of hydrochloric acid), addition of 1 wt % ethylenediaminetetraacetic acid (EDTA) prior to commencing precipitation and the use of 9.5 wt % Dispex A40 (25 wt % aqueous solution of ammonium polymethylmethacrylate) on completion to curb the effects of agglomeration.

The nCaCO₃ was dried thoroughly overnight prior to use and ground together with the monomer before being placed in borosilicate glass boiling tubes. D-L lactide, 0.01 wt % Snθct₂ and precipitated nCaCO₃ (14, 17, 20, 25 and 30 wt %) were added to borosilicate glass boiling tubes and polymerised at 130 ⁰C for 5 days within an inert nitrogen atmosphere. Table 1 : Molecular weights of the PDLLA/nCaCO₃ composites prior to processing with a higher molecular weight polymer

Pure PDLLA (Mn = 42 kDaltons; Mw = 81 kDaltons) was produced by polymerising D-L lactide in a microwave oven (Panasonic NN-T553) at 440 W for 15 minutes. Both the pure polymer and composites were removed from the borosilicate glass boiling tubes by subjecting them to a freeze/thaw cycle. The samples were then ground to an even particle size distribution using a coffee grinder and the composite mixed in equal quantities (50:50) with the pure PDLLA, resulting in a nCaCCVPDLLA composite powder of 7, 8.5, 10, 12.5 and 15 wt % nCaCO₃.

This was then dried thoroughly overnight and melt processed. Melt processing was achieved by feeding the dried powder into a micro- compounder (Haake) heated to 130 ⁰C and subsequently extruded through a 0.75 mm diameter die. The resultant fibres were then broken up and fed directly into a piston injection moulding system (Haake), which injected the composite at 140 ⁰C and 840 bar into a stainless steel die (held at room temperature for 5 seconds). Prior to injection the two halves of the mould were coated with dry PTFE mould release spray to facilitate easy removal.

Structural examination of the melt processed composite samples was performed using scanning electron microscopy (SEM; Philips XL-30). Samples were mounted onto carbon coated tabs and sputtered with gold/palladium. These were than examined using an accelerating voltage of 15 kV, working distance of approximately 10 mm and spot size of 4 under secondary electron mode. Analysis was also performed in backscattered electron mode with an increased spot size of 5.

The number average molecular weight (M_n) and weight average molecular weight (M_w) of pure PDLLA and the composites were determined using gel permeation chromatography (GPC) (see Table 2). Approximately 0.1 g of the samples were dissolved in 5 ml chloroform and GPC analysis (Polymer

Labs; PL Rl 800) run in chloroform using a rate of 1 ml min^"1 at 35 ⁰C

(calibrated against polystyrene, narrow standard).

Table 2: Molecular weights of the PDLLAAiCaCO₃ composites following blending (i.e. extrusion)

Pure PDLLA samples were also fabricated in this manner. A composite containing 10 wt % analytical grade calcium carbonate (fCaCO₃) with particle sizes all greater than 1 μm was also polymerised in borosilicate glass boiling tubes as described above. However, as a result of the heating process altering the physical properties of the material it was necessary to fabricate the fCaCCVPDLLA composite samples from pressed sheets. This was performed in a hot press at 160 ⁰C, the powder preheated in the press for 30 seconds and pressed at 50 kN for 1 minute.

Composite degradation was measured in terms of mass loss and water absorption, change in polymer molecular weight, pH of the surrounding solution and change in calcium concentration of the solution with time. Rectangles approximately 12 x 4 x 2 mm in size were cut from the injection moulded nCaCCVPDLLA samples using a heated scalpel, the mass recorded and placed individually in a 24 well plate. Samples (10 x 10 x 0.5 mm) were also cut from the pressed 10 wt % fCaCCVPDLLA sheet. They were then sterilised on both sides with UV light prior to the addition of phenol red free Dulbecco's Modified Eagle's Medium (DMEM) and 10 % foetal bovine serum (FBS) (10 ml g^"1 of composite). DMEM was also added to empty wells within the well plate in order to act as blanks. The well plates were then placed in an incubator at 37 ⁰C and 5 % CO₂ for 10 weeks. At pre-determined time points (4, 7, 14, 21 , 35, 42, 49, 56, and 70 days) these were removed and the mass recorded. Hydrolysed samples were also dried under vacuum at 10^~1-10^~2 mbar for 48 hours and the dry mass measured, allowing determination of percentage weight loss and water absorption. Following removal of the composites from the well plates, the pH was determined, the solutions removed, 0.5 ml of concentrated hydrochloric acid added and the subsequent solution filtered. The calcium ion concentration in the solution was then determined by titrating with EDTA. A buffer solution of ammonium chloride-ammonium hydroxide (NH₂OH I-ICI) was prepared by dissolving 67.6 g ammonium chloride (NH₄CI) in 200 ml dH₂O, followed by the addition of 570 ml concentrated ammonium hydroxide (NH₄OH). To this 5.0O g of magnesium salt of EDTA was added, diluted to 1000 ml with dH₂O and stored in a tightly stoppered vessel. A standard 0.01 IvI EDTA solution was produced by dissolving 3.72 g disodium ethylenediaminetetraacetic acid (Na₂EDTA; Fisher Scientific) dihydrate (dried overnight) in dH₂O and diluted to 1000 ml in a volumetric flask. The molarity of this solution was verified by titrating 25.0 ml of CaCO₃ standard solution. This was created by suspending 1.000 g CaCO₃ which was dried prior to weighing for 1 h at 180 ⁰C, in approximately 600 ml dH₂O and dissolving with a minimal amount of dilute HCI. The resultant solution was diluted to 1000 ml in a volumetric flask. Ammonium purpurate (1.0 g) was mixed thoroughly with 200 g sucrose in a sealed vessel and subsequently used in 0.2 g quantities as an indicator. An aliquot of known volume of solution with unknown calcium ion concentration was placed in a volumetric flask, 1 ml NH₂OH HCI, 1 ml NaOH (80 g I^"1) and ammonium purpurate added, and titrated with EDTA until a colour change from pink to purple was achieved. The EDTA volume was recorded and the calcium concentration determined. The change in molecular weight of the dried samples was also established through the use of GPC.

The mechanical properties of the nCaCOa/PDLLA composites and pure PDLLA, produced as described above were determined using dynamic mechanical analysis (DMA; TA Instruments). The DMA was used in the tensile mode, testing both the extruded fibres and the central long axis of the injection moulded tensile test specimens (ends were removed using a hot scalpel). Two different tests were used; a strain sweep and a temperature sweep. The strain sweep was carried out at 25 ⁰C, using a pre-load force of 0.01 N and the amplitude gradually increased from 0.5 to 6 μm. A stress versus strain graph was then plotted and the elastic modulus determined from the gradient. For the temperature sweep the temperature was gradually increased from 25 to 70 ⁰C at a rate of 3 ⁰C min^'1 with a constant frequency and amplitude of 1 Hz and 6 μm respectively. The resultant graphs were used to establish the storage modulus at 37 ⁰C.

It should be noted that an accelerated degradation study (performed using lower molecular weight PDLLA and at an elevated temperature of 45 ⁰C) of the nCaCOyPDLLA composites indicated that an nCaCO₃ concentration of 7 wt % was required in order to buffer the acidic degradation products of PDLLA (Figure 2). Additionally, preliminary mechanical analysis showed that the addition of 20 wt % nCaC0₃ to PDLLA resulted in brittle failure of the composite. Therefore it was concluded that it was undesirable to fabricate nCaCOyPDLLA composites outside the range of 7-15 wt % nCaCO₃.

As previously found with hydroxyapatite, the addition of nCaCO₃ to D-L lactide prior to polymerisation decreases the resultant polymer molecular weight (Figure 3). Those composites containing 30 wt % nCaCO₃ had a significantly lower M_n and M_w than those produced with 14 wt % nCaCO₃. The CaCO₃ZPDLLA composites (molecular weight distribution shown in Figure 4b) were then combined with higher molecular weight PDLLA (molecular weight distribution shown in Figure 4a), polymerised in the microwave oven, resulting in a composite powder with a bimodal molecular weight distribution (Figure 4c). In the case of the nano-composites, no significant differences in M_n or M_w occurred in the subsequent extrusion and injection moulding processes (Figure 5). The latter observation is as a result of the bimodal molecular weight distribution. SEM examination of the composites demonstrated that the CaCO₃ was evenly distributed throughout the polymer matrix (Figures 6i & 6ii).

Measurement of the pH of the solutions (serum based DMEM) in which PDLLA and the composites were degrading clearly demonstrated the significantly lower pH of the PDLLA solution compared to those which held the composites (Figure 7). The dramatic decrease seen over 14 and 21 days with PDLLA did not occur for the composites. In a manner similar to the change in pH over the degradation time, measurement of the sample mass showed the significantly higher mass reduction of the PDLLA samples compared to the composite samples (Figure 8). However, the initial increase in mass reduction of PDLLA did not occur until day 14 of the study (7 days later than the pH decrease), which was followed by a 20 % reduction the proceeding week. In support of both the change in pH and mass reduction, the Mn of pure PDLLA decreased at a significantly faster rate than that of the composite samples, with a reduction of 72 % over the first 14 days (Figures 9a & 9b). Additionally, after 21 days of degrading the 10 wt % fCaCCVPDLLA composite had a significantly higher rate of M_n reduction than the nano-composites, reaching 84 % on completion of the study. Throughout the entire degradation period, the concentration of calcium ions within the solutions in which the composite samples were degrading was significantly higher for those containing 15 wt % nCaCO₃ in comparison to the other samples (Figure 10). The results clearly showed that the composites degraded at a slower rate than the homogeneous polymer. In addition, no sudden decrease in pH of the solutions holding the composites was seen over the 70 day degradation period, together with a significantly less rapid reduction of mass and M_n. It is thought that the decrease in the polymer hydrolysis rate with the composites is as a result of the free calcium ions buffering the acidic degradation products of PDLLA, thereby minimising the occurrence of autocatalytic degradation.

The elastic and storage moduli of nCaCCVPDLLA composites, when determined with DMA, increased with the addition of nCaCO₃ and reached a maximum with 12.5 wt % nCaCO₃ (Figures 1 1 and 12). Both were significantly higher than pure PDLLA and this was the case for both the extruded and injection moulded samples. However, values were significantly lower for the injection moulded samples in comparison to those which were extruded. These results indicate that nCaCO₃ is effective in reinforcing PDLLA.

Claims

1. The use of nanoparticles comprising a neutralising agent for incorporation within a bioresorbable polymer to neutralise the acidic degradation products of said bioresorbable polymer.

2. The use according to claim 1 , wherein the neutralising agent is a salt capable of neutralising the acidic degradation products selected from the group consisting of a carbonate, a bicarbonate or a phosphate salt.

3. The use of nanoparticles according to claim 1 or 2, wherein the neutralising agent is a source of free calcium ions.

4. The use according to any of claims 1 to 3, wherein the neutralising agent is a calcium carbonate or a calcium phosphate.

5. The use according to claim 4, wherein the calcium phosphate is an apatite.

6. The use according to claim 5, wherein the apatite is hydroxyapatite.

7. The use according to any of claims 1 to 6, wherein the concentration of the neutralising agent within the polymer is from between about 5-20 wt %.

8. The use according to claim 6 or 7, wherein the concentration is from about 7-15 wt %,

9. The use according to any of claims 1 to 8, wherein the diameter of the nanoparticle is less than 100nm.

10. A polymeric composite comprising a first polymer and a second polymer, wherein the first polymer has a molecular weight less than the second polymer, and wherein nanoparticles of a neutralising agent are distributed throughout at least the first polymer.

11. A polymeric composite according to claim 10, wherein both the first polymer and the second polymer is PDLLA or copolymers thereof and the first polymer comprises nanoparticles of calcium carbonate.

12. A method of manufacturing a composite comprising a first polymer including a nanoparticulate neutralising agent distributed throughout and a second polymer, the method comprising the steps of; a) polymerising the first polymer with the nanoparticulate agent to form a combination; and b) blending the combination produced in a) with the second polymer to form the composite, the second polymer having a high molecular weight than the first polymer.

13. A method according to claim 12, wherein the first polymer is PDLLA or copolymers thereof and the nanoparticulate agent is calcium carbonate.

14. A composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material consists of PDLLA or copolymers thereof.

15. A composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material is any polymer material other than PLLA.