Nanofiber covered stent for vascular diseases

NANOFIBER COVERED STENT FOR VASCULAR DISEASES DONG YIXIANG (B.Sc. (Hons.), Tsinghua University, PRC) A THESIS SUBMITTED FOR THE DEGREE OF PHILOSOPHY GRADUATE PROGRAMME IN BIOENGINEERING SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2009 ACKNOWLEDGEMENT First of all, I would like to give my sincere thanks to my supervisor, Prof. Seeram Ramakrishna, for his guidance and support during my PhD study. His foresight of frontier science, his tender attention to students, his patience, wisdom and enthusiasm always inspires and encourages me all over my 4-year PhD life. Great appreciation would also be given to Prof. Casey Chan, my co-supervisor, who helped me develop my PhD project and guided my research direction. From patent writing to his great reference software (WizFolio), from research ideas to detailed engineering techniques, from business negotiation to entrepreneurship advice, from finding fund for my research to getting my tuition fee exempted, his guidance, supervision and inspiration came from every aspect. Full gratitude should be given to Dr. Thomas Yong and Dr. Susan Liao, who have been my supervisors, mentors and trustful friends throughout my PhD study. Their footprints could be found all over my experiments, papers and thesis. Whenever I have problems with research or daily life, they were always there to offer a hand. I must give my thanks to Nanobioengineering Labs, where I benefited a lot from the collaboration with our experienced colleagues with different backgrounds. First, I must thank Dr. Yang Fang, Dr. Ryuji Inai and Mr. Wee Eong Teo, who introduced me both basic and advanced techniques in electrospinning. Second, I would like to thank Ms. Cheng Ziyuan, Ms. Satinderpal Kaur, Ms. Karen Wang and again Mr. Wee Eong i Teo, not only for their well maintenance and great contribution to the laboratory, but also for their timely helps whenever I asked for. Third, thanks should be given to Dr. He Wei, Dr. Zhang Yanzhong, Ms. Koh Huishan and Ms. Ma Kun, who have given me a lot of advices and help in my experiments. Especially, I must thank Mr. Steffen Ng, Ms Pang Soo Hoon and Ms. Chuan Irene, for their help in all the administration work. Finally, I would like to extend my thanks to all my friends in the lab: Feng Yu, Bojun, Michelle, Luong, Yingjun, Rama, Ahbi, Liumin, Zuwei etc., for their precious friendship and help during my PhD studies. Especially I must thank my current supervisor in Imperial College, Prof. Molly Stevens, for her great understanding when I was working and writing my thesis at the same time. I would like to give the highest thanks to my wife, my parents, and parents in law for their constant love, care, and support during my PhD study. This thesis is especially dedicated to my dearest daughter, Chloe, who has been my greatest joy during the perplexing period in my PhD study. ii Publications Honors & Awards: • President Graduate Fellowship (PGF), National University of Singapore, 2005. • 3rd prize of Silicon Valley Chinese Engineers Association (SCEA) Business Plan Competition, California, US, 2007 • Research Scholarship, NUS, 2004-2008 Journal Papers: • Yixiang Dong, Thomas Yong, Susan Liao, Casey K Chan, Seeram Ramakrishna, Long term viability of coronary artery smooth muscle cells on poly(L-Lactide-co-ε-Caprolactone) nanofibrous scaffold indicates its potential for blood vessel tissue engineering, Journal of the Royal Society, Interface, Volume 5, Number 26, 1109-1118, 2008 • Yixiang Dong, Thomas Yong, Susan Liao, Casey Chan, Seeram Ramakrishna, Degradation of electrospun nanofiber scaffold by short wave-length ultraviolet radiation treatment and its potential applications in tissue engineering, Tissue Engineering: Part A, Volume 14, Number 8, 1321-1329, 2008 • Yixiang Dong, Susan Liao, Casey K Chan, Seeram Ramakrishna, Degradation behaviors of electrospun resorbable polymeric nanofibers for tissue engineering (review), Tissue Engineering: Part B, Volume 15, Number 3, 333-351, 2009 • • Wei He, Zu Wei Ma, Wee Eong Teo, Yi Xiang Dong, Peter Ashley Robless, Thiam Chye Lim, Seeram Ramakrishna. Tubular Nanofiber Scaffolds for Tissue Engineered Small-Diameter Vascular Grafts. Journal of Biomedical Materials Research: Part A. Volume 90A, Number 1, 205-216, 2009. • Yixiang Dong, Thomas Yong, Susan Liao, Casey K Chan, Seeram Ramakrishna, Distinctive degradation behaviors of electrospun PGA, PLGA and P(LLA-CL) nanofibers cultured with/without porcine smooth muscle cells, Tissue Engineering: Part A, Volume 16, Number 1, 283-298, 2010 • • Michelle Ngiam, Susan Liao, Timothy Ong, Yixiang Dong, Seeram Ramakrishna, Casey Chan, Effects of Mechanical Stimulation in Differentiation of Bone Marrow-derived Mesenchymal Stem Cells on Aligned Nanofibrous Scaffolds, Biomacromolecules, Submitted iii Patents: • Casey Chan, Yixiang Dong, Wee Eong Teo, Seeram Ramakrishna, aligned Nanofiber covered stent, PCT application, 2009 • Yixiang Dong, Ramaseshan Ramakrishnan, Yingjun Liu, Abhishek Kumar, Seeram Ramakrishna, A Portable Electrospinning Apparatus, PCT Patent Application No: PCT/SG2008/000444 , 2008 • Yingjun Liu, Ramaseshan Ramakrishnan, Yixiang Dong, Abhishek Kumar, Seeram Ramakrishna, A Coating and a Method of Coating, PCT Patent Application No: PCT/SG2008/000476, 2008 Conference Abstracts and Proceedings: • Yixiang Dong, Liao S, Ramakrishna S, et al. Distinctive degradation behaviors of electrospun PGA, PLGA and P(LLA-CL) nanofibers cultured with/without cell culture, Advanced Materials Research Volume: 47-50, 1327-1330, 2008 • Yixiang Dong; Susan Liao; S. Ramakrishna; Casey K Chan, Distinctive degradation behaviors of electrospun PGA, PLGA and P(LLA-CL) nanofibers cultured with/without cell culture, International Conference On Multifunctional Materials And Structures And Their Applications (Oral Presentation), Hong Kong, 2008 • Yixiang Dong, Teo Wee Eong, Susan Liao, Casey Chan, S. Ramakrishna, P(LLA-CL) Nanofiber Covered Stent (NCS) for vascular diseases, World Biomaterials Congress (Oral Presentation), Amsterdam, 2008 • Yixiang Dong; Thomas Yong; Casey Chan; Seeram Ramakrishna, Degradation of Electrospun Nanofiber Scaffold by Short Wave-Length Ultraviolet Radiation Treatment and Its Potential Applications in Tissue Engineering, MRS fall Meeting (Oral Presentation), Boston, 2006 iv Table of Contents Summary viii List of Tables xi List of Figures xii Chapter Introduction .1 1.1 PCI and stents. 1.2 Drug eluting stents. .3 1.3 SVG intervention and covered stents 1.3.1 Failed saphenous vein grafts 1.3.2 SVG intervention with covered stent .11 1.3.3 Prospect of SVG intervention 14 1.4 Thesis Objectives 16 Chapter Literature reviews 19 2.1 Nanofibers and Electrospinning 20 2.1.1 Tissue engineering and nanofibers .20 2.1.2 Electrospun nanofibers as tissue engineering scaffolds .22 2.2 Biodegradable polyester nanofibers and its application in tissue engineering 25 2.3 Degradation behaviors of polyester nanofibers 35 2.3.1 High surface to volume ratio greatly increases the degradation rate of PGA nanofiber .36 2.3.2 Composition of D-LA and L-LA greatly affect the degradation rate of PLA nanofibers 39 2.3.3 Controllable Degradation of PLGA nanofiber .43 2.3.4 Slow degradation of PCL nanofibers .48 2.3.5 Summary of nanofiber degradation studies. 49 2.4 Rationale of Nanofiber covered stent (NCS) 50 Chapter Fabrication of PGA, PLGA and P(LLA-CL) Nanofibers by Electrospinning .53 3.1 Materials and methods 53 3.1.1 Materials 54 3.1.2 Fabrication of PGA, PLGA and P(LLA-CL) nanofibers .54 3.1.3 Material characterization .55 3.1.4 Statistical analysis 56 3.2 Results and discussions .56 3.2.1 Morphology of electrospun PGA, PLGA and P(LLA-CL) nanofibers56 v 3.2.2 Mechanical properties of electrospun PGA, PLGA and P(LLA-CL) nanofibers .61 3.2.3 Apparent density, and porosity of PGA, PLGA and P(LLA-CL) nanofibers .64 3.3 Summary .65 Chapter Biocompatibility of PGA, PLGA and P(LLA-CL) nanofibers with Smooth Muscle Cells and Endothelial Cells 66 4.1 Materials and methods 67 4.1.1 Materials 67 4.1.2 Fabrication of PGA, PLGA and P(LLA-CL) Nanofibers by Electrospinning 68 4.1.3 Cell culture .69 4.1.4 Cell morphology confluency observed by Scanning electron microscopy (SEM). 70 4.1.5 MTS assay for PCASMC viability 71 4.1.6 Quantification of mRNA to determine gene expression 71 4.1.7 BCA protein assay .73 4.1.8 Statistical Analysis .73 4.2 Results .74 4.2.1 Morphology of the nanofibers .74 4.2.2 PCASMC Cell density and viability on nanofibers .75 4.2.3 Gene expression of PCASMC on three types of nanofibers 81 4.2.4 HCAEC cellular behaviors on P(LLA-CL) nanofibers. 83 4.2.5 ECM protein secretion of PCASMC on P(LLA-CL) nanofibers .85 4.3 Discussion .86 4.4 Summary .90 Chapter In vitro degradation behavior of electrospun PGA, PLGA and P(LLA-CL) nanofibers 91 5.1 Materials and Methods 92 5.1.1 Materials 92 5.1.2 Nanofiber fabrication by electrospinning 92 5.1.3 In vitro degradation of nanofibers with or without cell culture .92 5.1.4 Scanning electron microscopy (SEM) .93 5.1.5 Gel Permeation Chromatography (GPC) .94 5.1.6 Mechanical strength .94 5.1.7 Differential Scanning Calorimetry (DSC) and wide-angle X-ray diffraction (WXRD) .95 5.1.8 UV irradiation of scaffolds 95 5.1.9 Statistical Analysis .95 5.2 Degradation behavior of electrospun PGA, PLGA and P(LLA-CL) nanofibers with and without cell culture .95 5.2.1 Nanofiber morphology during degradation .95 5.2.2 Mass loss of nanofibers and Molecular weight change of polymers .102 vi 5.2.3 Mechanical Strength loss of the nanofibrous scaffolds .104 5.2.4 Thermo-property and crystallinity during degradation 104 5.2.5 Discussion 109 5.3 PLGA and P(LLA-CL) degradation induced by Ultraviolet irradiation .115 5.4 Summary .126 Chapter Nanofiber covered stent .127 6.1 Materials and Methods 128 6.1.1 Materials. .129 6.1.2 NCS fabrication .129 6.1.3 SEM .133 6.1.4 Mechanical characterization 133 6.1.5 Degradation study of nanofibers on the stent. .134 6.1.6 Drug loading and release .134 6.1.7 Cell culture and cytotoxicity test .136 6.2 Results .136 6.2.1 NCS fabrication .136 6.2.2 Mechanical strength of the nanofiber cover .137 6.2.3 In vitro Deployment of NCS 139 6.2.4 In vitro degradation of nanofibers on NCS 143 6.2.5 Drug release study of Paclitaxel loaded P(LLA-CL) .145 6.3 Discussions .149 6.4 Summary .153 Chapter Conclusions and Perspectives 155 7.1 Conclusions .155 7.2 Limitations and future studies .159 Bibliography 162 vii Summary A covered stent is one whose length and circumference is enclosed with a membrane or fabric like material. When implanted in an artery, the covering of the stent acts as a mechanical barrier to prevent contact between the vessel wall and the components of blood. Current covered stents have been proposed for the intervention of failed saphenous vein grafts (SVG), in the hope of reducing embolism and in-stent restenosis. However, clinical trials failed to demonstrate such benefits. The deficiencies of existing covered stent include thick stent design, non-degradable PTFE membrane with poor endothelialization, high deployment pressure and no drug loading capacity. The objective of my PhD study was to develop a new type of covered stent, nanofiber covered stent (NCS), which is thinner in wall thickness, more flexible and more biocompatible than the commercial design. Electrospinning techniques were proposed to deposit a nanofibrous membrane onto bare metal stents. The advantages of electrospun nanofiber include ease of fabrication, biomimic structure and flexibility. At a first step, Polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA) and poly(L-lactic acid)-co-poly(ε-caprolactone) [P(LLA-CL)] were electrospun into nanofibrous mesh with various electrospinning conditions. Optimized concentrations of PGA, PLGA and P(LLA-CL) electrospinning using different solvents were determined. Hexafluoroisopropanol (HFIP) was found to be a proper solvent which could be used to electrospin all three polymers while maintaining good mechanical viii strength of the resultant nanofibrous mesh. The electrospun nanofibers using HFIP can be controlled to have consistent fiber diameter and porosity. Secondly, porcine coronary artery smooth muscle cells (PCASMC) were cultured on three different polymeric nanofibers for up to 15 weeks. Cellular behaviors and nanofiber degradation were evaluated. Although PGA supported initial PCASMC growth, the rapid degradation of PGA nanofibers may limit its function as a physical barrier in NCS application. PLGA nanofibers facilitated cell growth during the first 30 days after seeding but the cell growth was slow thereafter. P(LLA-CL) facilitated long term (1-3 months) cell growth although the initial cell growth was slower than that of PLGA nanofiber. We found that cell culture significantly increased the degradation of PGA nanofibers while this effect was minor on PLGA and P(LLA-CL) nanofibers, although accelerated surface erosion was observed. The molecular weight of P(LLA-CL) and PLGA nanofibers decreased linearly during the degradation period for up to 100 days. A separate study was made to evaluate the degradation effect of UV irradiation on nanofibers. It was demonstrated that normal dosage UV sterilization induced significant damage on PLGA and P(LLA-CL) nanofiber, reducing the molecular weights and mechanical strengths, but with no obvious effects on cell proliferation. 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Biomacromolecules, (2): 416-423. 183 [...]... are covered with the low surface tension, non-degradable polymer, polytetrafluoroethylene (PTFE) Both stents use the sandwich structural design Jomed Stent employs stent- polymer -stent design while Symbiot stent employs polymer -stent- polymer 11 Chapter 1 Figure 1.4 PTFE covereds stents: Jostent (left) and Symbiot stent (right) As SVG intervention is haunted by embolism and high rate of ISR, covered stents... 2007) 1.3.2 SVG intervention with covered stent A covered stent is one whose length and circumference is enclosed in a material Therefore covered stent, after implantation, can prevent contact between the vessel wall and blood by creating a physical barrier Stents can be covered in a variety of materials There are two covered stents commercially available: Jomed Stent graft (Figure 1.4 left) and... from the unstented edges to the luminal stent surface The authors also pointed out that higher pressure (18atm for covered stents while ~12atm for bare metal stents) required to deploy covered stents may induce deeper injury to the vessel wall, leading to a higher rate of restenosis In summary, based on the available data from the prospective trials with both the Jomed and Symbiot covered stents, no... protection from distal embolization or from in -stent restenosis However, the comparable outcomes obtained also indicated that a covered stent with refinement may be able to outperform bare metal stents, the current practice in SVG intervention The potential improvement of covered stent includes an alternative covered membrane for better hemocompatibility, thinner stent design, lower deployment pressure and... outcomes In summary, a new design of covered stent with reduced thickness, better membrane material, lower deployment pressure, and drug incorporation could overcome the limitations of traditional covered stent and improve performance in SVG intervention 1.4 Thesis Objectives The objective of the research was to engineer a new type of covered stent, namely a nanofiber covered stent, with thinner wall, more... matrix formation, eventually leading to a stable in -stent restenotic lesion (weeks to months) (F G P Welt and Rogers,C., 2002) 5 Figure 1.3 Main targets of drugs in relation to the cell cycle (B.L.van der Hoeven, 2005) 6 Figure 1.4 PTFE covereds stents: Jostent (left) and Symbiot stent (right) 12 Figure 2.1 Schematic diagram showing the components of nanofiber- covered stent. .. cultured with SMCs for 1 day (a) and 20 days (b&c) 125 Figure 6.1 Three different electrospinning setups for NCS fabrication (a) Direct electrospinning, Setup for random nanofiber covered stent (b) Double-disk method and (c) Single-disk method, setups for longitudinally aligned nanofiber covered stent (d) An image of NCS 132 Figure 6.2 Diagram of setup to obtain pressure-volume curve during... wall has been proposed as a way to reduce in -stent restenosis There were four randomized clinical trials on covered stent in the SVG intervention, three of which compared Jomed stent with bare metal stents and the other studied Symbiot III covered stent The first trail was the RECOVERS trial in which patients received SVG intervention with either Jomed covered stents or Jsoflex BMS (G Stankovic et al.,... that UV radiation induces polymeric nanofiber degradation does not significantly affect cell -nanofiber interactions 4 To develop an electrospinning set-up to deposit uniformly aligned nanofibers onto the bare metal stent One mechanical challenge of covered stent fabrication is that the covered material should not only be highly elastic to withstand the expansion during stent deployment without being torn,... serve as a reference for tissue engineering, since electrospun nanofiber, whose degradation behaviors have not been adequately studied, are becoming more and more popular as tissue engineered scaffolds More importantly, the nanofiber covered stent may be a good alternative for SVG intervention This research mainly focused on the “cover” in the covered stent rather than the whole stent design Because . NANOFIBER COVERED STENT FOR VASCULAR DISEASES DONG YIXIANG (B.Sc. (Hons.), Tsinghua University, PRC) A THESIS SUBMITTED FOR THE DEGREE OF PHILOSOPHY. 2005). 6 Figure 1.4 PTFE covereds stents: Jostent (left) and Symbiot stent (right). 12 Figure 2.1 Schematic diagram showing the components of nanofiber- covered stent (NCS) 19 Figure 2.2. electrospinning, Setup for random nanofiber covered stent. (b) Double-disk method and (c) Single-disk method, setups for longitudinally aligned nanofiber covered stent. (d) An image of NCS. 132