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Title: Polydioxanone weft-knitted stents with drug delivery fuction for the treatment of colorectal cancer
Authors: Li, Gang
Degree: Ph.D.
Issue Date: 2014
Abstract: Bowel obstruction and stenosis are often appearing in colorectal cancer patients. To restore luminal patency, these patients may have to undergo emergency surgery, but this is often associated with high mortality. Furthermore, chemoradiation treatments and palliative by-pass surgeries require the patients to be in good general health condition. For patients with advanced disease and in poor general health, stent insertion to broaden the lumen at the site of the stricture is often used to restore the intestinal lumen through palliative therapy. However ingrowth of the tumour or granulation tissue within the lumen stent was still found in all patients with uncovered stents and in 53% of patients with common covered stents. Owing to a lack of the antitumour capability, restenosis caused by tumour ingrowth is still a major problem. Therefore a stent with both a lumen restoring capability and an intraluminal antitumour capability is important in the treatment of these patients. The stenosis site can be expanded and the tumour site can be locally treated by the drugs loaded into the membrane coated onto the stents. This work started with understanding the physical, mechanical and physiological mechanisms in the human intestines that is required to achieve good interaction between intestines and stents. The intra-abdominal and intra-intestinal pressures of the human intestine were investigated through an intestine physical model; then identify the effect of weft-knitting parameters on the mechanical properties of stents and propose optimum parameter settings by statistical modeling method. Stents were knitted on a small diameter, circular weft knitting machine using polydioxanone biodegradable monofilament. Subsequently, a seamless polyurethane membrane was spun onto the inner surface of the weft-knitted stents. Finally, an antitumour drug, 5-Fluorouracil (5-FU) added to a bio-based poly(L-lactic acid), was electrospun onto the outer surface of the stents to create a drug delivery layer. The mechanical properties of the stents were characterized, and their thermal stability following the heat-setting process was evaluated. Owing to the importance on understanding of the physical and mechanical changes of stents during degradation process, this study investigated the changes of the radial compression strength and circumferential expansion strength, the degradation mechanism and their correlations in a phosphate buffer solution (pH = 6.8 ± 0.2, 37 ± 0.5 ℃). The physical and mechanical properties were evaluated according to British standard BS EN 13895:2003 and ISO 7198:1998. In order to determine the most suitable drug concentration, the 5-FU safe concentration in vivo and appropriate loading percentage in the membranes was investigated; and then 5-FU-loaded poly(L-lactic acid) membranes at concentration of 1.6%, 3.2%, 6.4% and 12.8% were electrospun onto the stent surface respectively. The morphology, chemical structure and in vitro drug release property of the coating membranes were studied separately. Also their antitumour activity and mechanism were assessed in vitro and in vivo using a human colorectal cancer cell line HCT-116 and tumour-bearing BALB/c nude mice.
The results from the experimental investigations revealed that optimum stents with radial compression strength in the range of 1.3 - 2.5 cN/mm and circumferential expansion strength in the range of 20 - 50 cN/mm could be obtained at a 29 mm diameter, 7 gauge, 22 needles small circular weft-knitted machine ST-06SL of stitch cam setting ranging from 3.2 to 3.4 mm, with fabric tension in the range of 140 - 160 cN if the yarn tension and yarn linear density were held at 1.2 cN and 150 tex, respectively. The model validation results showed that stents with different mechanical properties could be tailored through the statistical method and proposed model. The in vitro degradation results showed that stent maintained more than 60% of its original radial compression strength above 12 weeks. The chemical structure of polydioxanone polymer was integrated during the in vitro degradation up to 16 weeks. The characterization results for the drug-loaded coating membrane of the stent showed that the chemical structure of the drug in the coating membranes was completed through electrospinning process. The drug release behavior was enhanced when the drug loading percentage increased. The half maximal inhibitory concentration (IC50) and the median lethal dose (LD50) demonstrated that the 6.4% and 12.8% membranes had better antitumour effects than pure 5-FU due to the sustainable drug releasing property of the coated membranes on the stent. The membranes possessing appropriate drug loading doses, such as 6.4% or 12.8% also provided better anti-in-stent restenosis effects than other groups tested. Therefore, it is concluded that the drug loaded stents have great potential for the use in the treatment of intestinal cancers in the future.
Subjects: Stents (Surgery)
Drug delivery systems.
Colon (Anatomy) -- Cancer -- Treatment.
Hong Kong Polytechnic University -- Dissertations
Pages: xxviii, 195 leaves : ill. (some col.) ; 30 cm.
Appears in Collections:Thesis

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