Nghiên cứu phát triển cảm biến sinh học điện hóa trên cơ sở dây nano polypyrrole tích hợp hệ vi lưu1122

B GIÁO DO I HC BÁCH KHOA HÀ NI Trn Th Luyn NGHIÊN CU PHÁT TRIN CM BIN SINH HN  DÂY NANO POLYPYRROLE TÍCH HP H  LUN ÁN TI THUT HÓA HC HÀ NI - 2017 B GIÁO DO I HC BÁCH KHOA HÀ NI Trn Th Luyn NGHIÊN CU PHÁT TRIN CM BIN SINH HN  DÂY NANO POLYPYRROLE TÍCH HP H  Chuyên ngành: K thut Hóa hc Mã s: 62520301 LUN ÁN TI THUT HĨA HC NG DN KHOA HC: PGS.TS MAI ANH TUN PGS.TS HUNH  HÀ NI - 2017 L u ci s ng dn ca tp th ng dn Các s liu, kt qu nghiên cu trung thc cơng b bt k cơng trình khác Tp th ng dn PGS TS Mai Anh Tun Tác gi lun án PGS.TS Hun Th Luyn LI C Vi tm lịng kính trng bic, tơi xin gi li ct ti Thy, PGS.TS Mai Anh Tun PGS.TS Hu    i Thy tâm huyt, yêu ngh  tài tng dn tôi, ng, ng h ht   tơi có th hồn thành cơng trình nghiên cu Tôi xin chân thành c  v mt kinh phí t nguo nghiên cu sinh ca B Giáo d c),  tài nghiên cu khoa hc cp B (mã s: B2015-01-102) Qu Phát trin khoa hc công ngh Quc gia thông  tài mã s 103.99-2013.58 c gi li c c to Thng nghip ca tơi B  - n K thut Hóa hc, Vin ITIMS, Vi ti hi hc Bách Khoa Hà No tt c nhu kin thun li nh tơi có th thc hin lun án Tôi xin chân thành c tr lý, nghiên cu sinh hc viên cao hc ti PTN Vt liu sinh hc Khoa hc s sng, Vii hc Bách Khoa Hà Ni s h tr nhit tình thi gian tơi thc hin lun án Tôi xin trân trng c i hc Quc gia Hà Ni; GS i hc Tsukuba (Nht Bn) s  nhit tình nh góp chun mơn quý báu Tôi xin trân trng cm  CP công ngh sinh hc thú y BTV (Biotech-Vet)  cho phép tip cn ngun mu ti nhà máy trình thc hi cu sinh Thêm nc gi li c chân thành ti i thân bln ng viên, khích l Tôi c dành nhng li c, m, chm thơng chia s vi tơi cơng vi tơi có th tp trung hc tp nghiên cu sut nhgian kh Nghiên cu sinh Trn Th Luyn M  C L C DANH MC CÁC KÝ HIU, CH VIT TT i DANH MC CÁC BNG iii DANH MC CÁC HÌNH V TH iv M U 1 TNG QUAN 1.1 Cm bin sinh hn hóa n hóa 1.1.2 Cm bin sinh hn hóa 1.1.2.1 Nhu cu phát trin cm bin sinh hc 1.1.2.2 Khái nim cm bin sinh hc cm bin sinh hn hóa 1.1.2.3 Tình hình nghiên cu cm bin sinh hc 1.1.2.4 Tip cn phát trin cm bin sinh hn hóa 11 1.2 Bin tính b mt cm bin sinh hn hóa s dng vt liu polime dn polypyrrole 12 1.2.1 Vt liu polime dn polypyrrole ng dng ch to cm bin DNA n hóa 12 1.2.2 Tng hp vt liu polime dn polypyrrole s dng k thun hóa 13 c a q trình polime hóa pyrrole s d ng k thu 1.2.2.2 M t s k thu cs d n hóa t ng h p polime d n 1.2.2.3 Các y u t nh 1.2.2.4 Quá trình doping polypyrrole 17 1.2.2.5 Vai trò c a gelatin t ng h p dây nano polypyrrole 20 1.3 C nh phn t cm nhn sinh hc lên cm bin sinh hn hóa 21 1.3.1 DNA kháng nguyên, kháng th 21 1.3.1.1 DNA 21 1.3.1.2 Kháng nguyên, kháng th 22  nh phn t cm nhn sinh hc 24 1.3.2.1 H p ph v t lý 24 1.3.2.2 Liên k t c ng hóa tr 26 1.3.2.3 Ái l c sinh h c 28 1.4 Tích hp cm bin sinh hn hóa bình phn ng mini 32 1.5 K thun hóa nhn bit thành phn sinh hc 34  tng tr n hóa 34 1.5.1.1 Nguyên lý c a ph t ng tr n hóa 34 1.5.1.2 Bi u di n t ng tr 1.5.1.3 M m t ph ng ph c 35 t ng tr  39  vòng (Cyclic Voltammetry - CV) 40 V 40 1.5.3.1 Nguyên lý c 1.5.3.2 Quét th n c c ph ng 42 NGHIÊN CU CH TO CM BIN DNA  DÂY NANO POLYPYRROLE 45 2.1 M u 45 2.2 Thc nghim 45 2.2.1 Hóa cht 45 2.2.2 n cc tích hp 46 2.2.3 Tng hp dây nano PPy s dng k thun hóa 46 2.2.4 C nh DNA n cc Pt-PPy NWs 47  tng tr cn cc Pt-PPy NWs-DNA dò 47 2.3 Kt qu tho lun 48 2.3.1 Tng hn cc Pt 48 c n hóa c a h n c c Pt tích h p 2.3.1.2 Giá tr n th ph n 2.3.1.3 ng c a gelatin 2.3.1.4 ng c a n ng polyme hóa pyrrole 48 khuôn nano ch t o dây polyme 50 monome pyrrole 51 2.3.1.5 Th i gian polime hóa 53 2.3.1.6 Ph FT-IR 54 2.3.1.7 Ph Raman 55 u c nh DNA dò 56 u lai hóa DNA dị- DNA  57 2.4 Kt lun 60 NGHIÊN CU CH TO CM BIN DNA N HĨA TÍCH HP H  61 3.1 M u 61 3.2 Thc nghim 62 3.2.1 Hóa cht 62 3.2.2 H n cc tích hp kt ni vi bình phn ng mini 62 3.2.3 Tng h   65 3.2.4 C nh DNA n cc Pt-PPy NWs 66 3.2.5. DNA  -in Amplifier 66      3.3 Kt qu 66 3.3.1.        66 67 68 c tuyn hóa ca h n cc tích h   70      71 3.3.4 Phát hin hing lai hóa DNA 74 3.4 Kt lun 77 NGHIÊN CU CH TO CM BIN MIN DN HĨA TÍCH HP BÌNH PHN NG MINI NG DNG TRONG PHÁT HIN VIRUS NEWCASTLE 78 4.1 M u 78 4.2 Thc nghim 80 4.2.1 Hóa cht 80 4.2.2 Thit k ch to h n cc tích hp bình phn ng mini 81 4.2.3 C nh kháng th b mt cm bin 82 4.2.4 Phát hin virus (bt hot) s dng cm bin min dn hóa 83 4.2.5 Thng kê x lý s liu 83 4.3 Kt qu 84 c tuyn hóa ca h n cc s dn cc so sánh thay th  to 84 u c nh kháng th 87 - kháng th 91 4.3.4 Các yu t n tín hiu ca cm bin min dch 92 4.3.4.1 ng c a n kháng th 92 4.3.4.2 ng c a th i gian b t c p kháng th - virus 95 4.3.5 nhy ca cm bin min dch 97 4.4 Kt lun 100 KT LUN CHUNG 101 DANH M CA LUN ÁN 103 TÀI LIU THAM KHO 104  TT Vit tt T ti ng Vit Ab Antibody Kháng th DNA Deoxyribonucleic acid Axit deoxyribonucleic Ag Antigen Kháng nguyên AO Atomic Orbital Obitan nguyên t APTES 3-aminopropyltriethoxy- 3-aminopropyltriethoxy-silan silane BSA Bovine serum albumin Albumin huyt bò CE Counter Electrode n ci CV  -Ampe vòng DPV Diffirential Pulse Vi sai xung Voltammetry Voltammetry 10 EID50 50 % Empryo infective dose Liu nhim trùng phôi (gà) 11 EIS Electrochemical impedance spectroscopy Ph tng tr n hóa 12 FE-SEM Field Emision Scanning Hin t quét phát x ng Electron Microscope 13 ELISA Enzyme linked immuno K thut min dch hp ph gn sorbent assay men 14 FTIR Fourier transform infrared spectroscopy Ph hng ngoi bii Fourier 15 GA Glutaraldehyde Glutaraldehyde 16 GS Galvanostatic  i 17 HIV Human immunodeficiency virus Virus gây suy gim min dch cho i 18 HPV Human papillomavirus V t cung 19 IUPAC International Union of Pure Hip hi Hóa Tinh khit ng and Applied Chemistry dng Quc t 20 ISFET Ion sensitive field effect Transistor hiu ng nhy ion 21 ITO i tin oxide Indium Oxit thic - Indi 22 23 MO MP™S Molecular Orbital (3-Mercaptopropyl) Obitan phân t (3-Mercaptopropyl) trimethoxysilane trimethoxysilane 24 NHS N-Hydroxysuccinimide N-Hydroxysuccinimide 25 PANi Polyaniline Polyaniline 26 PBS Phosphate buffered saline Dung dch m phosphate i 27 PCR Polymerase chain reaction Phn ng chui polymerase 28 PDMS Polydimethylsiloxane Polydimethylsiloxane 29 PPy Polypyrrole Polypyrrole 30 PrA Protein A Protein A 31 PRE Psuedo reference electrode n cc so sánh thay th 32 RE Reference electrode n cc so sánh 33 SARS Severe acute respiratory Hi chng hô hp cp tính nng syndrome 34 SEM Scanning electron microscopy Hin t quét 35 SERS Surface Enhanced Raman Ph Raman Tng b mt Spectroscopy 36 SWV Square Wave Voltammetry Von-ampe sóng vng 37 UV Ultraviolet T ngoi 38 WE Working Electrode n cc làm vic 39 WHO World Health Organization T chc y t th gii ii  Bng 1.1: Mt s kt qu nghiên cu v cm bin sinh hn hóa th gii Bng 1.2: Mt s kt qu nghiên cu v cm bin sinh hc n hóa ti Vit Nam 10 Bng 1.3: S ph thuc cp i nhi 25 C E = Ep   0,5 43 Bng 2.1: Trình t chuDNA 45 Bng 2.2: Các thông s tng tr mô phng theo m 59 Bng 2.3: So sánh cm bin DNA  to vi mt s cm bin DNA nhng công b khác 59 Bng 3.1: So sánh cm bin DNA tích hp vi kênh PDMS ch to c vi mt s cm bin DNA nhng công b khác 76 Bng 4.1: S ng gia súc, gia cm 01.10.2014 78 Bng 4.2: Qui trình ch tn cc vàng WE CE tích hp 81 Bng 4.3: Các thông s c t kt qu s dng h n cc vi n cc so sánh t ch to n ci 85 Bng 4.4: Các giá tr Ip,a, I p,c , Ipeak c t kt qu i vn cc vàng (WE) sau mc c nh kháng th 89 Bng 4.5: Các giá tr Ip,a, Ip,c , Ipeak peak c t kt qu i vi n cc cm bin min dch cm bin min dch/virus Newcastle i n kháng th c c nh b mt cm bin 93 Bng 4.6: Các giá tr Ip,a, Ip,c , Ipeak peak c t kt qu i vi n cc cm bin mi n dch cm bin min dch/virus Newcastle i thi gian bt cp kháng th - virus 96 Bng 4.7: Các giá tr Ip,a, Ip,c , Ipeak peak c t kt qu i vi n cc cm bin min dch cm bin min dch/virus Newcastle   i hàm ng virus Newcastle 98 Bng 4.8: So sánh kt qu dị tìm virus gây bnh ca mt s loi cm bin min dch 99 iii tính tt khong virus Newcastle t 102 n 10 EID50/ml v liên h: Ipeak = 0,0279LogN  0,00306 R = 0,9969  Các kt qu c ca lun án m nhiu trin vng Vic tích hp cm bin sinh hn hóa h n ng mini nhm thu nh h thng phân tích, ging mu tiêu th có th s  c phát trin thêm mc nhm ti n gn kh ng dng thc tic tích hp thêm mt b phn thu thp x lý s  liu nhm 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Hun (2014), C nh tr c ti p DNA lên c m bi n sinh h dây nano polypyrrole, T chí Khoa hc Cơng ngh, 52(3B), p 166-173 Tran Thi Luyen, Huynh Dang Chinh, Pham Duc Thanh, Chu Thi Xuan, Mai Anh Tuan (2014), Label-free electrochemical biosensor based on polypyrrole nanowires, The th International Workshop on Advanced Materials Science and Nanotechnology (IWAMSN), Ha Long 2-6/11/2014, Vietnam, p 377 Luu Thi Hoai Thuong, Tran Thi Luyen, Do Phuc Quan, Pham Duc Thanh, Pham Thi Kim Thanh, Chu Thi Xuan, Mai Anh Tuan (2014), Design and fabrication of microfluidic biosensor composed of a PDMS microchannel and three electrode platform for electrochemical measurement, The nd International Conference on Advanced Materials and Nanotechnology (ICAMN), Hanoi, Vietnam, p 254-260 Thi Luyen Tran, Thi Xuan Chu, Phuc Quan Do, Duc Thanh Pham, Van Vu Quan Trieu, Dang Chinh Huynh and Anh Tuan Mai (2015), In-Channel-Grown Polypyrrole Nanowire for the Detection of DNA Hybridization in an Electrochemical Microfluidic Biosensor, Journal of Nanomaterials, vol 2015, Article ID 458629, pages (*IF 2016: 1.758*) Tran Thi Luyen, Chu Thi Xuan, Huynh Dang Chinh, Mai Anh Tuan (2015), Development of electrochemical biosensors integrated with microchambers for DNA detection, Tp chí Hóa hc, 53(6e4), p 169-173 Luu Thi Hoai Thuong, Tran Thi Luyen, Pham Duc Thanh, Trieu Van Vu Quan, Pham Van Tong, Ta Thi Nhat Anh, Chu Thi Xuan, Mai Anh Tuan (2015), Fabrication of PDMSbased Microfluidic Devices Toward Biomedical Applications             105A, p 38-42 Trn Th Luyn, Chu Th   Phúc Quân, Phc Thành, Nguyn Hi Nam, Nguyn Quang Long, Hun (2015), Thi t k ch t o c m bi n n hóa vi dịng ch y tích h p n c c so sánh thay th ch t o dây nano polypyrrole nh m c nh DNA,                 -10/11/2015, 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vi kênh PDMS; nghiên cu tng hn hóa dây nano polypyrrole bên vi bình