Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.821592
Title: Production and characterisation of bioresorbable polymers and polymer-glass composites for application in cardiac stents
Author: Oosterbeek, Reece
ISNI:       0000 0004 9359 8741
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Abstract:
Bioresorbable polymeric cardiac stents are a promising technology for treating cardiovascular diseases, but current poly-L-lactide (PLLA) stents have been limited by poor mechanical properties and slow degradation. Materials with increased strength and stiffness are needed, to reduce the required stent strut size and elastic recoil, so that the risk of restenosis can be minimised. Long term complications such as strut fracture and late stent thrombosis are also critical concerns, which require increased ductility and accelerated material degradation to be addressed. This work investigated new materials based on polymer blends and polymer-glass composites, for future application in an effective and safe bioresorbable cardiac stent. PLLA was combined with polyethylene-glycol functionalised poly(L-lactide-co-caprolactone) (PLCL-PEG) to form a semi-miscible set of polymer blends with increased ductility and degradation rate. To provide mechanical reinforcement to these polymers, water soluble phosphate glass (P2O5-CaO-Na2O) particles were incorporated to produce polymer-glass composites. These phosphate glasses were also studied to understand their structure and dissolution behaviour, to inform the subsequent design of composite materials. Material samples were degraded in vitro in phosphate-buffered saline (PBS) at 37°C to determine their relative rates of degradation. Mechanical testing was carried out immersed in 37°C water to simulate body conditions, and after various stages of degradation, to assess the evolution of mechanical properties. Thermal analysis (differential scanning calorimetry, ashing) and structural analysis (X-ray diffraction, scanning electron microscopy) techniques were used to study the microstructural changes and their effects on mechanical properties. To assess the long-term degradation behaviour of PLLA:PLCL-PEG blends, and the evolution of their mechanical properties during degradation, blends of PLLA with varying amounts of PLCL(80:20)-PEG or PLCL(70:30)-PEG were created by solvent casting. Tests undertaken in PBS at 37°C revealed that the addition of the faster degrading PLCL-PEG component catalysed and accelerated PLLA degradation. The onset of degradation was reduced controllably from 16 months for pure PLLA, to between 2 and 12 months for PLLA:PLCL-PEG blends. The miscibility of blend components had a strong impact on the ductility in ambient conditions and blends with low PLCL-PEG content underwent brittle failure, while samples with a higher PLCL-PEG content exhibited ductile failure, due to the formation of a PLCL-PEG-rich phase via phase separation or bulk changes. Under simulated body conditions all blend compositions exhibited significant ductility (>400%) due to the elevated temperature and hydration state. After 30 days of degradation several structural changes were observed. Moderate PLCL-PEG addition (10-30%) stabilised the structure and retained approximately 200% ductility, while other compositions displayed severe embrittlement resulting from enthalpy relaxation, or degradation-induced crystallisation. Phosphate glasses are attractive as a reinforcing phase in polymer-glass composites to improve the mechanical properties, however uncertainty remains over their dissolution mechanisms, specifically the multi-stage behaviour sometimes observed. This work aimed to understand the factors affecting the multi-stage dissolution mechanisms, and the cause of the transition between them, as well as measuring the relative dissolution rates of the glasses tested. The dissolution behaviour of (P2O5)90-x(CaO)x(Na2O)10 glasses (where x = 40, 45, 50) was assessed in water, PBS, and PBS pH-adjusted with lactic acid (to simulate polymer degradation) using mass loss and pH measurements, as well as structural analysis methods mentioned above. Dissolution was accelerated by lower CaO concentration in the glass, and lower solution pH. Two-stage dissolution was observed, and a new mechanism was proposed to explain this, where diffusion-limited conversion layer formation is followed by reaction-limited layer dissolution. The transition between these stages is a result of stabilisation of the conversion layer, which is dependent on layer composition and solution conditions. This mechanism is important for understanding and predicting glass behaviour, particularly in complex solutions such as body fluids and acidic polymer degradation products within polymer composites. Phosphate glass microparticles with d0.5 = 1.4 ±0.3 μm were incorporated into polymer-glass composites by precipitation of the polymer onto glass particles within a slurry, followed by injection moulding. This method was confirmed by electron microscopy and X-ray microtomography to give good dispersion. The polymer matrix composition (PLLA, 90PLLA:10PLCL(70:30)-PEG), glass composition (45, 50% CaO), and glass filler loading (0, 15, 30wt.%) were all varied to optimise and study their effects on mechanical and degradation behaviour. Glass particles provided significant mechanical reinforcement, increasing the modulus from 3.3 ±0.04 GPa to 5.1 ±0.2 GPa for PLLA with 30wt.% glass. Up to 15wt.% glass could be incorporated into the composites without ductility reduction, while interfacial adhesion resulted in comparable composite yield strength (41 ±2 MPa, 42 ±1 MPa) to the unfilled polymer (43 ±2 MPa), demonstrating that the composites are non-inferior to existing polymers in terms of yield strength and the resulting stent strut size required. Degradation testing revealed two-stage behaviour for composites, dominated initially by water absorption, followed by glass dissolution. The presence of glass suppressed polymer structural changes that lead to embrittlement, while also accelerating water absorption into the composite. Composite materials displayed a gradual reduction in mechanical properties during degradation. There was a decrease in elastic modulus (2.8 ±0.2 GPa to 1.4 ±0.2 GPa) and strain to failure (290 ±20% to 70 ±30%) after 4 months for the PLLA:PLCL-PEG composite with 15wt.% glass, which might allow slow transfer of loading to newly healed tissue. These results provide understanding of the evolution of composite mechanical properties during degradation, which is crucial in the design of effective bioresorbable cardiac stent devices. This work has shown the important influence that polymer matrix composition and glass filler loading have on the evolution of polymer blend and polymer-glass composite mechanical properties during degradation, and the degradation rate itself. These findings have significant implications for the design of materials for bioresorbable polymer-based cardiac stents. Although this work investigated a selected set of material compositions, the mechanisms revealed provide a broader understanding that can be applied to a range of other polymer blend and composite systems. This work has made significant advances towards improved bioresorbable polymer-based materials for cardiac stents, and has developed a theoretical framework that allows design of composite mechanical properties, and their evolution during degradation.
Supervisor: Cameron, Ruth ; Best, Serena Sponsor: Lucideon Ltd ; Woolf Fisher Trust ; New Zealand
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.821592  DOI:
Keywords: bioresorbable polymer ; polymer composite ; phosphate glass ; polymer blend
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