Final Report Summary - BIO-POLYTEC (Enhanced Process Monitoring and Control Technology to Accelerate Development of Bioresorbable Polymeric Medical Devices)
Executive Summary:
The Bio-PolyTec project aimed to deliver process monitoring and control technology for the manufacturing of bioresorbable medical devices and to utilise this technology to enhance the manufacturing processes of the medical sector SMEs within the consortium. Bioresorbable devices are made from bio-polymers which breakdown inside the body into harmless, non-toxic products. Ideally, they provide a temporary function for as long as they are needed and breakdown at the same rate at which the patient's own tissue regenerates. Typical uses include bone fixation screws and plates; sutures; tissue scaffolds and stents. Increasingly bioactive particles are added to the polymer to enhance healing, prevent wound-site infection, or to enable drug delivery to a specific location in the body.
Bioresorbable devices have many patient benefits over traditional devices however they are complex to manufacture. In order to form into the required implant shape they must generally be processed at elevated temperatures and undergo mechanical shearing in an extruder or injection moulding machine. Such conditions tend to thermally degrade the polymer which can result in inferior performance of the product. Addition of filler particles further complicates the manufacture, agglomeration of particles is a particular issue which can lead to mechanical weaknesses, aesthetic defects and a poor release profile. The testing of polymer degradation and filler dispersion within a product must currently be completed after the production of a batch and can take several hours in a laboratory. As a result the industry currently suffers from long and expensive process development and scale-up, long lead times and high scrap rates.
The Bio-PolyTec project aimed to address these issues through the development of novel sensor technology for real-time, in-process monitoring of polymer degradation and filler dispersion. Throughout extensive extrusion processing trials with PLA (Polylactide) and calcium phosphate powders (fillers widely used in orthopaedic devices), significant process knowledge in the processing of these materials was generated. A new high-speed process was developed for the production of PLA fibres for the Scaffdex RegJoint product at six times the production rate of the existing process. An NIR spectroscopy system (hardware: FOS Messtechnik) was developed for real-time monitoring of the Molecular Weight of the PLA in this process. It was shown that it was possible to predict the Molecular weight of the product with high accuracy via real-time multivariate analysis of the NIR spectra of the melt acquired continuously during processing.
A UV-Vis spectroscopy system (hardware: FOS Messtechnik) was developed for the monitoring of particle size/particle agglomeration in the compounding of PLA with beta-TCP (a form of calcium phosphate). Multivariate analysis techniques were applied which were able to classify the size of particles within the melt during compounding with excellent accuracy. The method was shown to be robust to different days of processing; different processing temperatures and even different grades of PLA. The system was shown to be suitable for any polymer system provided it had sufficient transparency to allow transmission of the UV-Vis light. This was demonstrated at the industrial compounding facilities of Innovative Polymer Compounds Ltd during the production of a different medical compound - Pebax with Barium Sulphate. The system could differentiate between very small differences in the level of agglomeration (average particle sizes differing by only a few micron) and unlike the current QA system enables 100% continuous sampling of the product.
Project Context and Objectives:
Bio-PolyTec aimed to enhance the manufacturing of bioresorbable medical devices - to reduce product cost and accelerate the development of novel bioresorbable implants. The manufacture of such devices for temporary implantation inside the human body is growing into a high-value industry with many benefits over traditional devices. Bioresorbable devices breakdown inside the body over time into safe, non-toxic products, ideally at the same rate the body's own tissue regenerates and the device is no longer needed. Such devices have better biocompatability than traditional devices and do not require a removal operation, reducing patient trauma and significant healthcare costs. Due to the ability to add antibacterial or antibiotic drugs and to control the release rate at the implant site, such devices can reduce the number of post-operative complications and open up possibilities for new pharmaceutical therapies.
However, development times for new devices can be lengthy and extremely expensive. Bioresorbable materials have a high cost and are difficult to process, resulting in high scrap rates. The addition of fillers such as bioactive particles further complicate the manufacture. In Bio-PolyTec, sensor technology - centering on optical and vibrational spectroscopic techniques - will be developed for in-process monitoring of the key quality measures of polymer degradation and additive dispersion.
The availability of this information in real-time rather than after time-consuming and expensive laboratory testing represents a significant improvement in Quality Control for bioresorbable devices as well as enabling better process control. The influence of typical processing procedures (particularly extrusion) on the degradation and mixing and hence subsequent bioresorption/release behaviour and mechanical properties have been investigated for the commercial products of the consortium SMEs to optimise their processes to achieve specific and consistent product requirements. In particular the project addressed the ability to produce the Scaffdex 'RegJoint' product at high throughput with significantly lower scrap rates. The processing of Polylactide (PLA) and dispersion of bioactive Calcium Phosphate particles for orthopaedic implants has been investigated among other polymer/filler systems. It has been shown to be possible to monitor PLA molecular weight on-line during extrusion processing via an NIR spectrometer system and also to monitor changes in filler particle size/agglomeration in a compounding process in real-time with a UV-Vis system.
Project Results:
1) The effect or process conditions, particle size and filler loading on the mechanical and degradation properties of pure PLA and compounds of PLA filled with beta-TCP (a common additive in orthopaedic implants) has been thoroughly investigated. This has led to new knowledge on the optimum process conditions, filler loading and particle size to produce a bioresorbable compound with specific properties depending on the requirements of the application.
2) The use of UV-Vis spectrometry (hardware by FOS Messtechnik) in tandem with multivariate analysis to monitor particle size or percentage loading has been validated in an extrusion processing environment. This has been thoroughly investigated with different grades of PLA and different grades and sizes of HA and beta-TCP particles. Models developed for classification of particle size have been shown to be robust to different days of processing; to different grades of polymer and to different processing conditions (e.g. changes in temperature). Further the system has been applied in the industrial compounding of a Pebax: Barium Sulphate compound at Innovative Polymer Compounds Ltd. The hardware proved to be robust to the industrial environment and also the system was sensitive enough to differentiate between levels of agglomeration in the product where the average particle size varied by only a few micron.
3) A new high-speed process has been developed for the manufacture of medical grade PLA fibres for use in the Scaffdex RegJoint product. Achieving high quality fibres required extensive optimisation of process set-up and processing parameters. FOS Messtechnik precision pressure and temperature sensors were integrated into the process line for all trials together with a fibre-optic NIR spectrometer system.
3) A method of monitoring the Molecular Weight of the produced fibre in-process was investigated using pressure drop measurements to infer changes in shear viscosity of the polymer and also using the NIR spectra and multivariate analysis. Both methods showed potential, however the NIR method had better accuracy and was more robust. This was developed into a strategy for instant classification of the state of degradation of the polymer (acceptable/unacceptable) giving an operator immediate feedback on the product and an opportunity to retune the process settings without having to wait for detailed information on the Molecular weight following laboratory analysis.
4) Fibre-spinning of PLA and beta-TCP compounds was attempted with subsequent analysis of the fibre properties. It was shown that compound fibres could be achieved which had suitable properties for post-processing (in this case 'knitting' into a joint implant). These implants were cheaper to produce than pure PLA implants and offer a potential future product for Scaffdex.
Potential Impact:
The final results and impacts include:
1) Novel Sensor technology for monitoring key product quality indicators during bioresorbable and medical polymer processing: i) The ability of fibre optic probes together with NIR spectroscopy and analysis to predict degradation in a PLA product has been demonstrated in an industrial manufacturing environment, and ii) The ability of fibre optic probes together with UV-Vis spectroscopy and analysis to predict filler dispersion in a polymer compound has also been demonstrated in an industrial manufacturing environment. The method has been shown to be robust to changes in polymer grade, melt temperature and the time of processing.
This result provides a 'tried and tested' application of the FOS hardware products to open up new sales markets.
2) Improved Manufacturing Process for 'RegJoint' bioresorbable fibers (Scaffdex)
A new manufacturing process set-up for RegJoint fibres involved replacing the existing single-screw extruder and drawing line consisting of several ovens and conveyors with a twin-screw extruder and drawing line consisting of heated godet rolls. The new set-up was capable of an over six times increase in fibre production rate while maintaining or improving the required fibre properties. Further the new process set-up produced more consistent fibres with few issues of process-induced degradation compared to the existing manufacturing process. This result provides a more efficient and cost-effective manufacturing route for Scaffdex's RegJoint fibres for the scale-up of the business. It also allows the launch of a new larger implant model which was not previously commercially viable with the old manufacturing process.
3)Enhanced processing knowledge for processing of bioresorbable polymer compounds
i) IPC now have a tested method for determining the acceptability or otherwise of filler dispersion in any polymer compound with sufficient transparency for the UV-Vis transmission probes. This is a significant improvement on their current test method which involves sampling of material; compression of sample into a thin film; optical microscopy analysis of the film. The ability to monitor filler dispersion in real-time saves money, energy and raw material as less off-spec product is produced while waiting for the analysis to be carried out.
ii) Scaffdex have tested new compound formulations for possible future generations of the RegJoint product which have the benefits of being significantly cheaper to produce
iii) PBL have increased knowledge on how to process their products which they can use to advise their customers and hence promote uptake.
4) New knowledge on optimum sizing of Calcium Phosphate powders for bioresorbable implants in order to achieve specific end properties for a particular application – this will enable PBL to develop new products (e.g. specifically for bioresorbable fibres using the outputs from Task 3.4) and allow them to better advise their customers on particle size and processing.and hence improve uptake and use of their powder products.
The innovations in sensor technology and material supply and compounding services will extend outside the consortium to enable other device manufacturers to reduce scrap rates and hence production costs for bioresorbable devices. The Bio-PolyTec project will accelerate the commercial availability of bioresorbable medical devices in Europe, at more affordable prices. In the immediate term, Scaffdex will be able to bring a new implant to market for treatment of osteo- and rheumatoid arthritis. Future Scaffdex products can incorporate bioactive particles, such as β-TCP particles to aid regeneration of host bone tissue, with obvious patient benefits in accelerating the healing process. As a result of the uptake of Bio-PolyTec sensor technology by other companies, many more bioresorbable products will be brought to market cheaper and more quickly than would otherwise be possible. This will bring a host of patient benefits - including elimination of a removal operation for implants, lower risk of infection at the implant site, faster healing at the wound site and will open up new therapies with targeted localised drug delivery. The effect on healthcare systems across the EU will be significant - offering new improved medical devices with better clinical outcomes and significantly lower costs than traditional therapies.
The technology developed in Bio-PolyTec will increase the competitiveness of the EU medical device sector, which at present is largely dominated by US companies. Although the consortium includes only one medical device SME, the sensor technology and IPC processing services will be available to many more SMEs and multinationals across Europe (in non-competitive markets to Scaffdex). As well as helping eliminate current financial barriers to SMEs in bringing bioresorbable devices to market it will also increase the competitiveness of the EU as a manufacturing base for multinationals with a positive impact on employment. Further the world’s leading bioresorbable supplier, consortium End-User member Corbion/Purac, based in the Netherlands will benefit from increased uptake of their materials with an associated increase in turnover and employment.
List of Websites:
www.biopolytec.eu
The Bio-PolyTec project aimed to deliver process monitoring and control technology for the manufacturing of bioresorbable medical devices and to utilise this technology to enhance the manufacturing processes of the medical sector SMEs within the consortium. Bioresorbable devices are made from bio-polymers which breakdown inside the body into harmless, non-toxic products. Ideally, they provide a temporary function for as long as they are needed and breakdown at the same rate at which the patient's own tissue regenerates. Typical uses include bone fixation screws and plates; sutures; tissue scaffolds and stents. Increasingly bioactive particles are added to the polymer to enhance healing, prevent wound-site infection, or to enable drug delivery to a specific location in the body.
Bioresorbable devices have many patient benefits over traditional devices however they are complex to manufacture. In order to form into the required implant shape they must generally be processed at elevated temperatures and undergo mechanical shearing in an extruder or injection moulding machine. Such conditions tend to thermally degrade the polymer which can result in inferior performance of the product. Addition of filler particles further complicates the manufacture, agglomeration of particles is a particular issue which can lead to mechanical weaknesses, aesthetic defects and a poor release profile. The testing of polymer degradation and filler dispersion within a product must currently be completed after the production of a batch and can take several hours in a laboratory. As a result the industry currently suffers from long and expensive process development and scale-up, long lead times and high scrap rates.
The Bio-PolyTec project aimed to address these issues through the development of novel sensor technology for real-time, in-process monitoring of polymer degradation and filler dispersion. Throughout extensive extrusion processing trials with PLA (Polylactide) and calcium phosphate powders (fillers widely used in orthopaedic devices), significant process knowledge in the processing of these materials was generated. A new high-speed process was developed for the production of PLA fibres for the Scaffdex RegJoint product at six times the production rate of the existing process. An NIR spectroscopy system (hardware: FOS Messtechnik) was developed for real-time monitoring of the Molecular Weight of the PLA in this process. It was shown that it was possible to predict the Molecular weight of the product with high accuracy via real-time multivariate analysis of the NIR spectra of the melt acquired continuously during processing.
A UV-Vis spectroscopy system (hardware: FOS Messtechnik) was developed for the monitoring of particle size/particle agglomeration in the compounding of PLA with beta-TCP (a form of calcium phosphate). Multivariate analysis techniques were applied which were able to classify the size of particles within the melt during compounding with excellent accuracy. The method was shown to be robust to different days of processing; different processing temperatures and even different grades of PLA. The system was shown to be suitable for any polymer system provided it had sufficient transparency to allow transmission of the UV-Vis light. This was demonstrated at the industrial compounding facilities of Innovative Polymer Compounds Ltd during the production of a different medical compound - Pebax with Barium Sulphate. The system could differentiate between very small differences in the level of agglomeration (average particle sizes differing by only a few micron) and unlike the current QA system enables 100% continuous sampling of the product.
Project Context and Objectives:
Bio-PolyTec aimed to enhance the manufacturing of bioresorbable medical devices - to reduce product cost and accelerate the development of novel bioresorbable implants. The manufacture of such devices for temporary implantation inside the human body is growing into a high-value industry with many benefits over traditional devices. Bioresorbable devices breakdown inside the body over time into safe, non-toxic products, ideally at the same rate the body's own tissue regenerates and the device is no longer needed. Such devices have better biocompatability than traditional devices and do not require a removal operation, reducing patient trauma and significant healthcare costs. Due to the ability to add antibacterial or antibiotic drugs and to control the release rate at the implant site, such devices can reduce the number of post-operative complications and open up possibilities for new pharmaceutical therapies.
However, development times for new devices can be lengthy and extremely expensive. Bioresorbable materials have a high cost and are difficult to process, resulting in high scrap rates. The addition of fillers such as bioactive particles further complicate the manufacture. In Bio-PolyTec, sensor technology - centering on optical and vibrational spectroscopic techniques - will be developed for in-process monitoring of the key quality measures of polymer degradation and additive dispersion.
The availability of this information in real-time rather than after time-consuming and expensive laboratory testing represents a significant improvement in Quality Control for bioresorbable devices as well as enabling better process control. The influence of typical processing procedures (particularly extrusion) on the degradation and mixing and hence subsequent bioresorption/release behaviour and mechanical properties have been investigated for the commercial products of the consortium SMEs to optimise their processes to achieve specific and consistent product requirements. In particular the project addressed the ability to produce the Scaffdex 'RegJoint' product at high throughput with significantly lower scrap rates. The processing of Polylactide (PLA) and dispersion of bioactive Calcium Phosphate particles for orthopaedic implants has been investigated among other polymer/filler systems. It has been shown to be possible to monitor PLA molecular weight on-line during extrusion processing via an NIR spectrometer system and also to monitor changes in filler particle size/agglomeration in a compounding process in real-time with a UV-Vis system.
Project Results:
1) The effect or process conditions, particle size and filler loading on the mechanical and degradation properties of pure PLA and compounds of PLA filled with beta-TCP (a common additive in orthopaedic implants) has been thoroughly investigated. This has led to new knowledge on the optimum process conditions, filler loading and particle size to produce a bioresorbable compound with specific properties depending on the requirements of the application.
2) The use of UV-Vis spectrometry (hardware by FOS Messtechnik) in tandem with multivariate analysis to monitor particle size or percentage loading has been validated in an extrusion processing environment. This has been thoroughly investigated with different grades of PLA and different grades and sizes of HA and beta-TCP particles. Models developed for classification of particle size have been shown to be robust to different days of processing; to different grades of polymer and to different processing conditions (e.g. changes in temperature). Further the system has been applied in the industrial compounding of a Pebax: Barium Sulphate compound at Innovative Polymer Compounds Ltd. The hardware proved to be robust to the industrial environment and also the system was sensitive enough to differentiate between levels of agglomeration in the product where the average particle size varied by only a few micron.
3) A new high-speed process has been developed for the manufacture of medical grade PLA fibres for use in the Scaffdex RegJoint product. Achieving high quality fibres required extensive optimisation of process set-up and processing parameters. FOS Messtechnik precision pressure and temperature sensors were integrated into the process line for all trials together with a fibre-optic NIR spectrometer system.
3) A method of monitoring the Molecular Weight of the produced fibre in-process was investigated using pressure drop measurements to infer changes in shear viscosity of the polymer and also using the NIR spectra and multivariate analysis. Both methods showed potential, however the NIR method had better accuracy and was more robust. This was developed into a strategy for instant classification of the state of degradation of the polymer (acceptable/unacceptable) giving an operator immediate feedback on the product and an opportunity to retune the process settings without having to wait for detailed information on the Molecular weight following laboratory analysis.
4) Fibre-spinning of PLA and beta-TCP compounds was attempted with subsequent analysis of the fibre properties. It was shown that compound fibres could be achieved which had suitable properties for post-processing (in this case 'knitting' into a joint implant). These implants were cheaper to produce than pure PLA implants and offer a potential future product for Scaffdex.
Potential Impact:
The final results and impacts include:
1) Novel Sensor technology for monitoring key product quality indicators during bioresorbable and medical polymer processing: i) The ability of fibre optic probes together with NIR spectroscopy and analysis to predict degradation in a PLA product has been demonstrated in an industrial manufacturing environment, and ii) The ability of fibre optic probes together with UV-Vis spectroscopy and analysis to predict filler dispersion in a polymer compound has also been demonstrated in an industrial manufacturing environment. The method has been shown to be robust to changes in polymer grade, melt temperature and the time of processing.
This result provides a 'tried and tested' application of the FOS hardware products to open up new sales markets.
2) Improved Manufacturing Process for 'RegJoint' bioresorbable fibers (Scaffdex)
A new manufacturing process set-up for RegJoint fibres involved replacing the existing single-screw extruder and drawing line consisting of several ovens and conveyors with a twin-screw extruder and drawing line consisting of heated godet rolls. The new set-up was capable of an over six times increase in fibre production rate while maintaining or improving the required fibre properties. Further the new process set-up produced more consistent fibres with few issues of process-induced degradation compared to the existing manufacturing process. This result provides a more efficient and cost-effective manufacturing route for Scaffdex's RegJoint fibres for the scale-up of the business. It also allows the launch of a new larger implant model which was not previously commercially viable with the old manufacturing process.
3)Enhanced processing knowledge for processing of bioresorbable polymer compounds
i) IPC now have a tested method for determining the acceptability or otherwise of filler dispersion in any polymer compound with sufficient transparency for the UV-Vis transmission probes. This is a significant improvement on their current test method which involves sampling of material; compression of sample into a thin film; optical microscopy analysis of the film. The ability to monitor filler dispersion in real-time saves money, energy and raw material as less off-spec product is produced while waiting for the analysis to be carried out.
ii) Scaffdex have tested new compound formulations for possible future generations of the RegJoint product which have the benefits of being significantly cheaper to produce
iii) PBL have increased knowledge on how to process their products which they can use to advise their customers and hence promote uptake.
4) New knowledge on optimum sizing of Calcium Phosphate powders for bioresorbable implants in order to achieve specific end properties for a particular application – this will enable PBL to develop new products (e.g. specifically for bioresorbable fibres using the outputs from Task 3.4) and allow them to better advise their customers on particle size and processing.and hence improve uptake and use of their powder products.
The innovations in sensor technology and material supply and compounding services will extend outside the consortium to enable other device manufacturers to reduce scrap rates and hence production costs for bioresorbable devices. The Bio-PolyTec project will accelerate the commercial availability of bioresorbable medical devices in Europe, at more affordable prices. In the immediate term, Scaffdex will be able to bring a new implant to market for treatment of osteo- and rheumatoid arthritis. Future Scaffdex products can incorporate bioactive particles, such as β-TCP particles to aid regeneration of host bone tissue, with obvious patient benefits in accelerating the healing process. As a result of the uptake of Bio-PolyTec sensor technology by other companies, many more bioresorbable products will be brought to market cheaper and more quickly than would otherwise be possible. This will bring a host of patient benefits - including elimination of a removal operation for implants, lower risk of infection at the implant site, faster healing at the wound site and will open up new therapies with targeted localised drug delivery. The effect on healthcare systems across the EU will be significant - offering new improved medical devices with better clinical outcomes and significantly lower costs than traditional therapies.
The technology developed in Bio-PolyTec will increase the competitiveness of the EU medical device sector, which at present is largely dominated by US companies. Although the consortium includes only one medical device SME, the sensor technology and IPC processing services will be available to many more SMEs and multinationals across Europe (in non-competitive markets to Scaffdex). As well as helping eliminate current financial barriers to SMEs in bringing bioresorbable devices to market it will also increase the competitiveness of the EU as a manufacturing base for multinationals with a positive impact on employment. Further the world’s leading bioresorbable supplier, consortium End-User member Corbion/Purac, based in the Netherlands will benefit from increased uptake of their materials with an associated increase in turnover and employment.
List of Websites:
www.biopolytec.eu