A winning combination: How Evonik's copolymers combine mechanical strength with rapid degradation
Martin Bindl, global director of biomaterials and Cecile Boudot, head of application technology for biomaterials, both from the healthcare business line of Evonik, discusses it’s commercial line of PLA-PEG copolymers which combine mechanical strength with rapid degradation.
The global market for implantable medical devices has been transformed in recent decades by the development of functional bioresorbable polymers with well-defined mechanical properties and precise degradation times.
Poly(lactic-co-GLycolic Acid) (PGLA) polymers are 100% biodegradable, can be fully metabolised by the body, and tailored to degrade over periods of up to four years. They have helped to transition markets away from metal-based-materials to reduce surgical costs associated with post-treatment implant removal and accelerate rates of patient healing.
Recent innovations including the development of osteoconductive composites that can match bone ingrowth, or filaments and powders that enable high-resolution 3D printing of patient-specific parts are now beginning to make important contributions towards improving the safety, biocompatibility and performance of bioresorbable implantable medical devices across a range of application areas.
Finding the perfect combination
Such therapeutic benefits have to date however been largely constrained to the orthopaedic and cardiovascular markets. Within the wound healing and paediatric markets in particular, conventional bioresorbable polymers have lacked the combination of high mechanical strength and the ability to degrade rapidly. While commonly used lactide-based polymers can achieve the desired mechanical strength based on monomer selection, monomer ratio and applied processing technology, their molecular weights influence degradation time. By comparison, other polymer compositions such as Poly(DiOxanone) (PDO), which are designed for rapid degradation within six months or less, are unsuitable for applications that require high mechanical strength due to their material properties, such as having a glass transition temperature that is below room temperature.
As a result, companies seeking to develop bioresorbable wound closure devices such as stomach or ligating clips and vascular closure devices have been forced to either utilise traditional metal-based materials or make compromises in the use of polymeric-based materials that may adversely affect functional performance. If a company chooses to compromise on degradation rates and prioritise mechanical strength, then device parts may remain in the body much longer than necessary, potentially increasing the risk of patient discomfort or the need for additional surgery. However, if companies prioritise rapid degradation over strength, then device parts may not perform as intended, potentially resulting in complications of the healing process or device failures with the consequences of increased patient pain or the need for follow-up surgery. For paediatric applications with accelerated bone regeneration, such as for Cranio Maxillo-Facial (CMF) implants, imbalanced degradation times could significantly impair the ability of the device to match the natural healing process.
Evonik believes it has established a strong core competency in the production of highly pure PolyEthylene Glycol (PEG) and Poly (Ethylene Glycol) Methyl ether (mPEG) substances that have a low PolyDispersity Index (PDI) value and low diol content. These competencies have been leveraged by Evonik to supply pharmaceutical-grade PEGs and mPEGs to a range of pharmaceutical companies.
Within the pharmaceutical market for complex parenteral drug products, the hydrophilic properties of PEGs have been successfully combined with the hydrophobic properties of PLA polymers to create di-block copolymers that can be utilised with micelles and other nanoparticle-based formulations. By being able to control the extended release of Active Pharmaceutical Ingredients (APIs), these copolymers can help to improve API solubility and the overall performance of parenteral drug products.
Addressing the unmet need
Until now, there has been no equivalent and commercially available PLA-PEG copolymers suitable for use in medical device implants. Evonik recognised that it was in a unique position to develop a new polymer class to address this unmet need within the medical device market. After several years of developing and testing, Evonik recently launched the world’s first and only known commercial platform of PLA-PEG copolymers for use with implantable medical devices.
By combining the hydrophobic properties of PLA polymers with the hydrophilic properties of PEG to increase water uptake, the new platform of tri-block (PLA-PEG-PLA) copolymers is able to replicate the mechanical strength of standard, equivalent Resomer grades but degrade up to six times faster.
By modifying various factors including PEG content and the composition and molecular weight of the polymer, Evonik has developed an initial range of four standard Resomer PLA-PEG grades that can address common application requirements. Featuring either 100% L-lactide or 70% L-lactide and 30% D,L-lactide as the PLA component. Each grade provides well-defined mechanical strengths and degradation rates from 12 months to less than six months. PEG ratios for standard grades range between 1% and 4%, with the PEG segments having a molecular weight of 6000 dalton. A range of additional customisation options are available upon request, including the PEG to PLA weight ratio, the molar mass of each block, and monomer type and composition.
Like standard PLA polymers, Resomer PLA-PEG copolymers are made through Ring Opening Polymerisation (ROP), which remains the most common method to combine various monomers for polymer synthesis. In reflection of the high quality of the products, they have a high level of purity due to their production under controlled cleanroom conditions that are compliant with “Good Manufacturing Practice” (GMP) guidelines and ISO 13485 certification.
Polymer degradation for PLA-PEG copolymers takes place exclusively in the body, with materials converted into well-defined and biocompatible metabolites. Biodegradation of PLGA-based polymers occurs via the random cleavage of polymer chains through hydrolysis. Polymeric fragments are ultimately released as lactic acid and glycolic acid. These metabolites, which also occur naturally, are transformed into carbon dioxide and water via the Krebs cycle, and are eliminated from the body through the respiration system (Holland et al 1986).
Biological degradation of other polymer families, such as PDO depends largely on the hydrolysis of ester linkages. The initial degradation is an abiotic degradation at the carboxyl end-groups formed by chain cleavage. Chain cleavage is autocatalysed by hydrolytical carboxyl end-groups formation, which accelerates the hydrolytic reaction. In vivo studies have shown that unlike PGA and PLA, PDO is removed via urine suggesting other final degradation products than water and carbon dioxide.
When utilised in the form of a ligating clip, the main degradation product is 2-hydroxyacetic acid (Schaefer et al. 1982). PCL degradation starts similarly to PLA degradation with random chain scission by ester hydrolysis. However, the degradation rate is significantly lower. Intracellular degradation of PCL occurs once the molecular weight falls below 3000 (Woodward 1985). As shown in models with rodents, polymer fragments do not accumulate in the body and final products will be eliminated via the faeces (Sun et al., 2006).
Resomer PLA PEG copolymers are supplied as granular form and are designed be easily processed on standard processing equipment including injection moulding, compression moulding and extrusion without any changes to processing methods. Current data indicates a similar shelf life compared with the corresponding standard polymers. Furthermore, Evonik can support customers in the processing of these new materials. The company’s application development laboratories and competence centres around the world also enable close collaboration between implant manufacturers and materials specialists.