6.1 Conclusion
The increasing risk of coronary heart disease throughout the global population has been of critical concern. The increasing population with a requirement for stent-based interventions will ultimately lead to a large population experiencing stent-related pathologies such as restenosis and thrombosis.
The main aim of stent manufacturers is to design a stent that eradicates these complications. This can only be achieved through a therapeutic option that promotes rapid endothelialisation whilst simultaneously supressing smooth muscle cell proliferation. This study developed and used systematic assessment techniques to identify potential therapies and coating platforms for use in drug eluting stents. A static and dynamic platform was designed and developed in order to facilitate these coatings and therapies to assess ex vivo performance.
Although initially hypothesised, not all drugs performed as expected for the purpose of dual-functional therapies for combating restenosis and stent thrombosis through in vitro assessments. Within the concentration ranges tested in vitro, magnolol and curcumin demonstrated no optimal effect on the endothelial and smooth muscle cells. Ferulic acid and exendin-4 did provide a level of suitability for this application due to an increase in endothelial cell activity relative to the maintenance of smooth muscle cells. The end goal was to have a drug that promotes endothelialisation faster than the rate of smooth muscle cell proliferation and thus inhibiting the possibility of stent thrombosis associated with current drug eluting stents. It was also observed that at the same concentration, the current commercially available drugs used in drug eluting stents demonstrate that endothelial cells show a higher sensitivity to the anti-proliferatives than the smooth muscle cells, which may contribute to the poor endothelialisation observed in a physiological setting upon insertion of a drug eluting stent. The retention of endothelial functionality and phenotype was observed upon dosage with exendin-4 and ferulic acid.
The assessment of the polymer coatings yielded several insights. It was observed that the rat tail collagen blended with PLGA provided an appropriate surface for cell seeding. The fast adhesion time of 30 minutes upon seeding shows that the hybrid blends of polymer are capable of rapid endothelial cell adhesion and can be incorporated into an aspect of in situ endothelialisation. The tobacco derived recombinant human type I collagen demonstrated a cytotoxic behaviour upon increasing concentrations of the collagen with PLGA. Upon neutralisation of the collagen within the blend, the coatings exhibited improved endothelial cell proliferation. The recombinant human collagen based blends exhibited a higher increase in cell activity as compared to the rat tail collagen and thus indicating
information of the drug which can be attributed to the low concentrations used. The improved outcome of using recombinant human type I collagen over animal-sourced type I collagen attests that the former type of collagen should be implemented into more biomaterials and coatings.
The commissioning and optimisation of the custom multi-station pulsatile flow bioreactor was achieved during this study. The bioreactor was set up in conjunction with the chemostat for optimising culture media properties whilst maintaining temperature within the tissue chamber. The user handling experience from tissue source to bioreactor was also improved by reducing the handling time of affixing the tissue to the tissue chamber. A thermal control system was employed within the device to compensate for temperature loss throughout the series of tubing from the chemostat to the bioreactor. Most importantly, the pressure waveform generated by the linear actuator based on a series of calculations did achieve near-physiological behaviour.
The newly developed custom static tissue holder and specialised electropolished stainless steel meshes allowed for a simplified planar stented artery in order to improve tissue and cell visualisation upon static culture. The observation of cell migration and proliferation from the tissue and endothelialised sheets onto the struts demonstrated proof of concept of the static system in order to identify endothelialisation rates of different coated mesh samples. The flow system demonstrated cell viability; although poor when using the endothelialised sheet and shows that optimisation of the system needs to be carried out. The preliminary tissue study phase in static indicated possibility of cold storage in tiprotec with the antibiotic solution as cell viability was observed of up to 1 week of culture.
The exemplary static assessment of the coated mesh structure affixed atop the endothelialised sheet established cell viability and the early process of cell migration/proliferation to the struts. Once the flow system is optimised, it is hypothesised that the endothelialisation procedure will occur at an improved rate.
This thesis covers the assessment of potential therapeutic drugs dosed on endothelial and smooth muscle cells in order to identify the optimal safe concentration that provides dual functionality on the respective cell types for the purpose of drug eluting stents. Different coating options were optimised and evaluated for endothelial cell interactions and the feasibility of in situ endothelialisation. The optimisation and setup of the multi-station pulsatile flow bioreactor as well as the design and setup of the static and dynamic stent testing platform was achieved. Final porcine tissue studies indicated proof of principle of these systems indicative of feasibility. This project encompasses an assortment of various critical stent-based parameters on an individual basis and developed a system to evaluate these aspects once they are to be assimilated as a final coated mesh structure.
6.2 Future Recommendations
The work reported in this thesis has paved the way as a development tool for a multitude of future research. Apart from continuing the stent focused research, the bioreactor aspect can dwell into further tissue engineering principles with regards to vascular tissue regeneration and graft synthesis.
Using the systematic assessment of drugs and polymers provides an initial indication towards its potential for use in drug eluting stents. Encompassing these two parameters requires a high degree of optimisation in order to match the drug release/polymer degradation with that of the effective drug concentration. The heterogeneity of the collagen dispersion within the PLGA might be an issue and would require verification. The use of an atomic force microscopy (AFM)-Raman system could provide a visualisation of the dispersion of collagen throughout the coating. The optimisation of the coating procedure is also a required point of study as homogenous thickness of the polymer coating would govern well dispersed drug release.
The static and flow system demonstrated a solid proof of concept and needs validation to ensure that the observable cells on the struts are in fact endothelial cells. The flow system requires further optimisation and would benefit from computation fluid dynamic assessments to identify the optimal flow required to generate physiological shear stresses. One important aspect with regards to stent development is the inhibition of smooth muscle cells and this study focused predominantly on the endothelial aspect. The next stage in the project would be to demonstrate the ability to induce observable smooth muscle cell proliferation over the struts in order to assess the efficacy of SMC inhibition of the coated meshes. It would also be of interest to utilise cobalt chromium mesh samples with thinner struts as this would increase endothelialisation time and provide a more accurate physiological representation. The observable differences of endothelialisation of different coated struts are the primary target for the future of this study.
The bioreactor, with its capability to produce near-physiological pulsatile flow conditions, can be used to house a stented artery in order to observe stent endothelialisation in an improved ex vivo format.
The bespoke multistation pulsatile flow bioreactor has the potential to assess the effects of atypical conditions on ex vivo arteries as a biophysical drug model. Conditions like arrhythmia and abnormal blood pressures can be simulated by the highly programmable system. The work presented in this thesis, indicating the possibility of rapid cell adhesion on the polymeric surface, showed that in situ endothelialisation might be a viable option.
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