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Final Report Summary - OSTENT (Novel Materials and Processing Strategy for Oesophageal Stents)

Rationale
Oesophageal cancer affects almost half a million people each year, taking the lives of over 400,000 of these sufferers [1]. It is responsible for around 5% of all cancer mortalities, making it the sixth most common cause of cancer death overall. It is often diagnosed at an advanced stage meaning cure of the disease is unlikely. Hence, treatment efforts focus on palliative care to improve the quality of life of the patient. The majority of those with advanced disease suffer from some degree of dysphagia (difficulty swallowing) which can lead to problems with feeding and drinking, as well as the risk of aspiration. These issues can be alleviated by the use of oesophageal stents. The most commonly used stents in practice are made of metal (e.g. shape memory nickel-titanium alloys (Nitinol)) or plastic (polyester with silicone-coating) and have an established role in the management of both benign and malignant strictures. However, there are several limiting factors with current stent materials including migration of the device, hyperplastic/granulation tissue, tumour in-growth, and peristalsis.

The only commercially available biodegradable stent currently available in Europe and Asia for benign oesophageal strictures is the Ella-BD stent [2]. This is composed of magnesium alloy, polylactic or polyglycolic acid and polydiaxanone. It degrades over 11-12 weeks but is very much controlled by the pH levels in the oesophagus (e.g. acid reflux accelerating degradation) with difficulties associated with pre-loading the stent and radio-opacity [3]. However, they do reduce procedure related complications such as tumour in-growth and hyperplasia and are seen to be the direction in which oesophageal cancer treatment is moving. The incorporation of drugs into stents has been attempted by various research groups [4, 5], but such localised therapeutic treatment of oesophageal cancer is very much in its infancy.

Significant research is needed to improve the advantages of these new materials over currently used stents. There is also a need to optimise the physiochemical and mechanical properties of stents in terms of their design and materials selection for optimal and controlled drug release. The cardiovascular stent market has attracted and continues to stimulate much research attention allowing drug-eluting stents to be used in endovascular surgery. However, their use has not been so developed for gastrointestinal applications due in part, to the vastly different requirements of such stents [6].

The aim of this project was the development and optimisation of a biodegradable polymer stent for the palliative treatment of oesophageal cancer. The following objectives were set out to address this goal:
1. Synthesis and optimisation of mesh structures based on biodegradable polymers with shape memory properties using electrospinning technology.
2. Synthesis and optimisation of drug-encapsulation using nano-sized, bioresorbable carriers.
3. Drug carrier incorporation into shape memory degradable polymer and electrospinning of composite into nanofibres.
Results
In the framework of this Marie Curie Intra-European Fellowship (FP7-PEOPLE-2012-IEF) a biodegradable polymer stent with a drug-eluting particulate filler was created. A novel technique was set-up for the synthesis of a number of ceramic nanoparticles (hydroxyapatite and calcium carbonate) and these particles optimized according to their nanostructural and drug eluting characteristics. The fillers were used to reinforce a number of polymer matrices, including polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), using film casting, electrospinning and melt electrospinning techniques. In fact, for the first time, melt electrospinning was successfully set-up in the Institute, allowing for the creation of 2 and 3D structures (Figure 1c).


Figure 1: Currently available oesophageal stents. A selection of currently available self-expanding metal stents (SEMS) (Boston Scientific and Cook Inc.) [6] (a), the degradable polymer, SX-ELLA oesophageal stent [2] (b), the new melt electrospun prototype (c).

Blends of polymer with and without ceramic filler were produced and their in vitro degradation observed in phosphate buffer solutions (PBSs) of both acidic and neutral pHs in order to mimic the conditions of the lower oesophagus. The mechanical properties of the degraded materials were analysed as were the surfaces using Fourier Transform Infrared Spectroscopy (FTIR) and scanning electron microscopy (SEM).

The non-cytotoxicity of the melt electrospun composites and their interaction with epithelial stem cells were illustrated. The filler nanoparticles were fabricated using ultrasound techniques and the stent structure achieved using melt electrospinning and standard electrospinning.

Conclusion
The final outcome of the OSTENT project was the creation of a novel biodegradable composite stent structure for potential use in oesophageal and gastrointestinal applications.

Potential impact and use and any socio-economic impact of the project
In the past few years, the scientific development of oesophageal stents has been on an increase. It is apparent that developments are being made, however the creation of a therapeutic device rather than merely a palliative one is still not clinically available. Such an advancement would cause a major shift in the treatment of oesophageal cancer, allowing the state-of-the-art to be pushed beyond its current position.

The gap in the market for cancer treatment both commercially and in research-terms is obvious both in Europe and the World. Any advancement of these medical devices in Europe would assist in further enhancing the reputation of Europe in the localised treatment of cancers.

In Europe, around 5-10 in every 1000 men and around 1 in 1000 women will develop oesophageal cancer, and it has been demonstrated to be on the increase in Europe due to the growth in case of adenocarcinomas, which in turn can be linked to the increase in alcohol consumption and obesity in western countries [7]. Hence, there remains a very strong case for the need to accelerate the development of ‘smart’ oesophageal stents.

The present project has provided a step forward in exploring novel techniques for producing oesophageal stents as well as the filler nanoceramic. Developments achieved in both these areas will not only benefit oesophageal stent material technology, but allow the knowledge gained to be passed over into other medical areas, such as stent and graft processing for cardiovascular, vascular and even neurological applications. It is anticipated that once all the results of the present project are made public, there will be a long-term impact on the European gastrointestinal and cardiovascular healthcare systems. Successful completion of the project has allowed the first steps to be made in the evaluation of novel techniques and materials for stent applications. It will also lead to the development of collaborations among European research groups on this topic and related fields, as well as the ability for further funding to be sought for more in-depth analysis of the processing techniques performed in this work.

References
[1] http://info.cancerresearchuk.org/cancerstats/types/oesophagus/incidence/#geog
[2] www.ellacs.eu.
[3] Lam-Tsai, Y., Hindy, P. and Gress, F., ‘A review of gastrointestinal stenting’, Gastroenterology and Endoscopy News, 2011, 62, 6, 1-8.
[4] Jeon, S. R., Eun, S. H., Shim, C. S., et al.,‘Effect of drug-eluting metal stents in benign esophageal stricture: an in vivo animal study. Endoscopy, 2009, 41, 449-456.
[5] Guo, S. R., Wang, Z. M., Zhang, Y. Q., et al., ‘In vivo evaluation of 5-fluorouracil-containing self expandable nitinol stent in rabbits: efficiency in long-term local drug delivery, J. Pharmacol Sci., 2010, 99, 3009-3018.
[6] Irani, S. and Kozarek, R., ‘Esophageal stents: past, present and future’, Techniques in Gastrointestinal Endoscopy, 2010, 12, 178-190.
[7] Stahl, M., Budach, W., Meyer, H, -J., and Cervantes, A., Esophageal cancer: clinical practice guidelines for diagnosis, treatment and follow-up,’ Annal of Oncology, 2010, 21, Suppl. 5, 46-49.

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Record Number: 193095 / Last updated on: 2017-01-10
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