Tổng hợp và nghiên cứu tính tương thích sinh học khả năng tạo mô xương của vật liệu composit poly (d, l) lactic axithydroxyapatit

B GIO DC V O TO TRNG I HC BCH KHOA H NI Trn Thanh Hoi TNG HP V NGHIấN CU TNH TNG THCH SINH HC KH NNG TO Mễ XNG CA VT LIU COMPOSIT POLY (D, L) LACTIC AXIT/HYDROXYAPATIT Chuyờn ngnh: Mó s : Húa lớ thuyt v Húa lớ 62440119 LUN N TIN S HểA HC NGI HNG DN KHOA HC PGS.TS Nguyn Kim Ng PGS.TS H Phỳ H H Ni - 2017 LI CAM OAN Tụi xin cam oan õy l cụng trỡnh nghiờn cu ca tụi v c s hng dn khoa hc ca PGS.TS Nguyn Kim Ng v PGS.TS H Phỳ H Hu ht cỏc s liu, kt qu lun ỏn l ni dung t cỏc bi bỏo ó v sp c xut bn ca tụi v cỏc thnh viờn ca th khoa hc Cỏc s liu, kt qu nghiờn cu c trỡnh by lun ỏn l trung thc v cha tng c cụng b bt k cụng trỡnh no khỏc Tỏc gi Trn Thanh Hoi LI CM N Li u tiờn, tụi xin by t lũng bit n sõu sc ti PGS.TS Nguyn Kim Ng v PGS.TS H Phỳ H ó ht lũng hng dn, giỳp v to mi iu kin thun li nht cho tụi hon thnh bn lun ỏn Tụi xin cỏm n s giỳp v khớch l ca cỏc cỏn b ng nghip v ngoi b mụn Húa lý, Húa Vụ c-i cng, Vin K thut Húa hc, H Bỏch Khoa H Ni Tụi xin cm n s giỳp v to iu kin thun li ca Vin K thut Húa hc, H Bỏch Khoa H Ni i vi tụi quỏ trỡnh thc hin lun ỏn Tụi cng xin gi li cỏm n chõn thnh n gia ỡnh v bn bố ó ng viờn, khuyn khớch tụi quỏ trỡnh lm lun ỏn Tỏc gi Trn Thanh Hoi MC LC DANH MC CC Kí HIU V CH VIT TT DANH MC CC BNG DANH MC CC HèNH NH, TH M U CHNG TNG QUAN 1.1 Xng v cỏc phng phỏp cy ghộp xng 1.2 Cỏc vt liu ch to khuụn nh dng 1.2.1 Polyme phõn hy sinh hc 10 1.2.2 Vt liu vụ c cú hot tớnh sinh hc 14 1.2.3 Composit 16 1.3 Phng phỏp tng hp bt HAp 20 1.4 Phng phỏp ch to khuụn nh dng composit 28 1.5 Phng phỏp nghiờn cu hot tớnh sinh hc ca vt liu 33 1.5.1 Phng phỏp nghiờn cu kh nng to apatit ca vt liu dung dch SBF 33 1.5.2 Phng phỏp nghiờn cu s phỏt trin, bỏm dớnh v di trỳ ca t bo trờn vt liu .34 CHNG THC NGHIM 38 2.1 Húa cht v dng c thớ nghim 38 2.1.1 Húa cht 38 2.1.2 Dng c v thit b thớ nghim 39 2.2 Tng hp bt HAp 39 2.2.1 Tng hp bt HAp s dng cht hot ng b mt P123 39 2.2.2 Tng hp bt HAp s dng cht hot ng b mt CTAB 40 2.3 Tng hp composit HAp/PDLLA 41 2.3.1 Tng hp composit HAp/PDLLA vi dung mụi l 1,4-dioxan 41 2.3.2 Tng hp composit HAp/PDLLA vi dung mụi l chloroform 42 2.4 Cỏc phng phỏp xỏc nh c trng 43 2.4.1 Phng phỏp nhiu x tia X (XRD) 43 2.4.2 Phng phỏp ph hng ngoi (FT-IR) 43 2.4.3 Phng phỏp hin vi in t quột (SEM) 43 2.4.4 Phng phỏp EDS 44 2.4.5 Phng phỏp ng nhit hp ph nit 44 2.4.6 Phng phỏp o xp ca khuụn nh dng 45 2.5 Cỏc phng phỏp xỏc nh hot tớnh ca vt liu 45 2.5.1 Xỏc nh hot tớnh sinh hc ca bt nano HAp 45 2.5.3 Phng phỏp nghiờn cu kh nng to apatit ca khuụn nh dng 47 2.5.4 Phng phỏp kim tra kh nng phỏt trin, bỏm dớnh ca t bo trờn khuụn nh dng 47 CHNG KT QU V THO LUN 50 3.1 Cỏc kt qu nghiờn cu c trng, thnh phn bt HAp tng hp 50 3.1.1 Cỏc kt qu c trng bt HAp tng hp bng phng phỏp thy nhit s dng cht hot ng b mt P123 50 3.1.2 Cỏc kt qu c trng bt HAp tng hp bng phng phỏp thy nhit s dng cht hot ng b mt CTAB 65 3.2 Cỏc kt qu nghiờn cu cỏc c trng, hot tớnh v tớnh tng thớch sinh hc ca khuụn nh dng composit HAp/PDLLA 75 3.2.1 Cỏc kt qu nghiờn cu i vi khuụn nh dng composit HAp/PDLLA tng hp vi dung mụi 1, 4-dioxan 75 3.2.2 Cỏc kt qu nghiờn cu i vi khuụn nh dng composit HAp/PDLLA tng hp vi dung mụi chloroform 92 KT LUN 100 DANH MC CC CễNG TRèNH CễNG B CA LUN N 101 TI LIU THAM KHO 102 PH LC.113 DANH MC CC Kí HIU V CC CH VIT TT Cỏc ch vit tt BMP Protein kớch thớch gen to xng- Bone morphogenetic protein CTAB Cetyltrimethyllammonium bromide DAPI 4, 6-diamidino-2-phenylindol DCPA Dicalcium phosphate EDS Ph tỏn sc nng lng tia X - Energy-dispersive X-ray spectroscopy FT-IR Ph hng ngoi bin i Fourier - Fourier Transform Infrared Spectroscopy HAp: Hydroxyapatit HT-PPFhm Poly(propylen fumarate) cao phõn t vi nhúm hydroxy cui chui PDLLA Poly (D, L) lactic axit PLA Polylactic axit PLGA Poly(lactic-co-glycolic) axit PGA Poly(glycolic axớt) PCL Poly(caprolactone) TTCP Tetracalcium phosphate SEM Hin vi in t quột - Scanning Electron Microscopy SBF Dung dch mụ phng dch c th ngi Simulated Body Fluid XRD Nhiu x tia X - X-Ray Diffraction -TCP -tricalcium phosphate Cỏc ký hiu P123: Pluronic co-polyme PEO20-PPO70-PEO20 DANH MC CC HèNH NH, TH Hỡnh 1.1.Cỏc loi vt liu dựng trongcha tr tỏi to xng [119] Hỡnh 1.2 Cỏc nguyờn tc chung ca k thut mụ[87, 88] Hỡnh 1.3 S polyme húa to polyme (D,L) lactic axit [48] 11 Hỡnh 1.4 Mi quan h gia nht ca dung dch PDLLA v lng phõn t [56] 12 Hỡnh 1.5 Mụ hỡnh cu trỳc tinh th HAp [70] 15 Hỡnh 1.6 Cỏc hỡnh thỏi tinh th HAp cú th tng hp bng phng phỏp thy nhit 22 Hỡnh 1.7 nh hng ca ch nhit n hỡnh thỏi ht HAp [112] 24 Hỡnh 1.8 S kt tinh quỏ trỡnh thy nhit bao gm bc hỡnh thnh mm v bc phỏt trin mm tinh th [36] 25 Hỡnh 1.9 nh SEM ca bt HAp tng hp vi thi gian thy nhit khỏc 200oC: 24 gi (a), 48 gi(b), 72 gi (c)[21] 25 Hỡnh 1.10 nh hng ca kớch thc ht to l parafin n kớch thc l xp ca khuụn nh dng polyme PLLA: 30 Hỡnh 1.11 Nguyờn tc ca phng phỏp AlamarBlue 35 Hỡnh 1.12 Nguyờn tc ca kớnh hin vi laze ng tiờu 36 Hỡnh 1.13 Hỡnh nh t bo gan chut qua kớnh hin vi laze ng tiờu 37 Hỡnh 2.1 Quy trỡnh tng hp bt HAp cú s dng cht hot ng b mt P123 40 Hỡnh 2.2 Quy trỡnh tng hp bt HAp cú s dng cht hot ng b mt CTAB 41 Hỡnh 2.3 Quy trỡnh tng hp khuụn nh dng composit HAp/PDLLA 42 Hỡnh 2.4 Quy trỡnh thớ nghim in-vitro th hot tớnh ca khuụn nh dng 48 Hỡnh 3.1 Cỏc nh SEM ca cỏc mu bt HAp tng hp bng phng phỏp thy nhit vi cỏc nng cht hot ng b mt P123 khỏc nhau: (a) g P123, (b) g P123, (c) g P123, (d) g P123 51 Hỡnh 3.2 S phõn b kớch thc ht nano HAp bt HAp tng hp bng phng phỏp thy nhit vi cỏc nng cht hot ng b mt P123 l g 52 Hỡnh 3.3 Gin XRD ca mu bt nano HAp tng hp bng phng phỏp thy nhit s dng cht hot ng b mt P123: (a) 0P123, (b) 1P123 v (c) 2P123 53 Hỡnh 3.4 Ph FTIR ca bt nano HAp tng hp bng phng phỏp thy nhit vi hm lng cht hot ng b mt P123 khỏc nhau: (a) 0P123, (b) 1P123, (c) 2P123 53 Hỡnh 3.5 Ph EDS ca bt nano HAp tng hp bng phng phỏp thy nhit vi hm lng cht hot ng b mt P123l g 54 Hỡnh 3.6 ng ng nhit hp ph v nh hp ph nit ca cỏc mu bt nano HAp tng hp bng phng phỏp thy nhit vi hm lng cht hot ng b mt P123 khỏc nhau: (a) 0P123, (b) 1P123, (c) 2P123 56 Hỡnh 3.7 ng phõn b kớch thc l trờn ht nano HAp ca cỏc mu tng hp bng phng phỏp thy nhit vi hm lng cht hot ng b mt P123 khỏc 56 Hỡnh 3.8 nh SEM ca mu HAp tng hp khụng qua x lý nhit 57 Hỡnh 3.9 C ch cú th xy quỏ trỡnh to nano HAp: (a) khụng cú mt cht hot ng b mt P123, (b) Cú mt cht hot ng b mt P123 58 Hỡnh 3.10 Hỡnh nh SEM (vi phúng 1000 v 10,000 ln) ca mng composit HAp/PDLLA c tng hp t cỏc mu nano HAp khỏc nhau: (a1), (a2) mu F-0P, (b1), (b2) mu F-1P, (c1), (c2) mu F-2P 59 Hỡnh 3.11 nh SEM (vi phúng i 250 v 25,000 ln) ca mng HAp/PDLLA sau ngõm SBF v ngy 62 Hỡnh 3.12 Phõn tớch EDS ca mu F-2P sau ngõm dung dch SBF: (a) sau ngy ngõm, (b) sau ngy ngõm 63 Hỡnh 3.13 nh SEM ca cỏc mu bt HAp c tng hp vi cỏc hm lng khỏc ca cht hot ng b mt CTAB 66 Hỡnh 3.14 nh SEM ca cỏc mu bt HAp c tng hp vi hm lng CTAB 0,64 gam v cỏc khong thi gian thy nhit khỏc gi (a), 12 gi (b), 18 gi (c) 67 Hỡnh 3.15 Kho sỏt s phõn b chiu di ht nano HAp tng hp vi 0,64 g CTAB v thy nhit 12 gi 68 Hỡnh 3.16 Ph EDS ca mu nano HAp tng hp vi 0,64 g CTAB v thy nhit 12 gi 68 Hỡnh 3.17 Ph FTIR ca cỏc mu HAp tng hp vi hm lng CTAB khỏc nhau: 4,64 g (a), 1,64 g (b), 0,64g (c) 70 Hỡnh 3.18 Gin XRD ca cỏc mu HAp tng hp vi hm lng CTAB khỏc nhau: 0,64 g (a), 1,64 g (b), 4,64 g (a) 70 Hỡnh 3.19 C ch cú th xy quỏ trỡnh to nano HAp: (a) Khi cú mt cht hot ng b mt CTAB, (b) S kt t ca cỏc ht mixen di tỏc ng ca nhit 71 Hỡnh 3.20 nh SEM ca mng HAp/PDLLA (c ph bt HAp cú thi gian thy nhit 12 gi) trc v sau ngõm SBF v ngy: a, c, f l phúng i 1000 ln; b, d, g, e, h l phúng i 5000, 10000, 20000, 50000 ln 74 Hỡnh 3.21 nh khuụn nh dng composit HAp/PDLLA c tng hp bng phng phỏp dung mụi ht s dng dung mụi 1,4-dioxan: (a) mu S3 cú t l HAp l 20%, (b) mu S4 cú t l HAp l 30% 75 Hỡnh 3.22 nh mu khuụn nh dng composit HAp/PDLLA (mu S3) vi phõn gii cao 200 px v 100 px 76 Hỡnh 3.23 nh SEM ca khuụn nh dng c tng hp vi cỏc t l HAp khỏc nhau: (a1, a2) mu S1, (b1, b2) mu S2, (c1, c2) mu S3, (d1, d2) mu S4 vi phúng i 200 v 2000 ln 77 Hỡnh 3.24 S phõn b kớch thc l ca cỏc mu khuụn nh dng composit HAp/PDLLA 79 Hỡnh 3.25 Ph FTIR ca cỏc mu: (a) mu bt HAp, (b) mu S3, (c) mu S4, (d) mu S1 80 Hỡnh 3.26 Mụ hỡnh liờn kt hydro gia nhúm OH ca HAp v nhúm CO ca PDLLA 81 Hỡnh 3.27 Ph EDS ca mu S4 81 Hỡnh 3.28 nh SEM ca mu khuụn nh dng S3, S4 sau ngõm SBF v ngy: a1, a3, b1 l phúng i 5000 ln, a2, a4, b2 l phúng i 50000 ln 83 Hỡnh 3.29 nh SEM ( phúng i 10000 v 15000 ln) ca mu S1, S2 sau ngõm SBF v ngy 84 Hỡnh 3.30 Ph EDS ca mu khuụn nh dng S3 sau ngy ngõm SBF 85 Hỡnh 3.31 C ch hỡnh thnh lp apatit ging xng trờn khuụn nh dng composit Hap/PDLLA dung dch SBF (quỏ trỡnh hỡnh thnh t a n f)[64] 86 Hỡnh 3.32 Kh nng phỏt trin ca t bo MG63 mụi trng cha cỏc mu khuụn nh dng c tng hp vi dung mụi 1,4-dioxan (S1, S2, S3 v S4) sau 3, v ngy 88 Hỡnh 3.33 S bỏm dớnh v phỏt trin ca t bo MG63 trờn khuụn nh dng (S1, S2, S3 v S4) sau v ngy 90 Hỡnh 3.34 nh SEM ca cỏc mu khuụn nh dng composit HAp/PDLLA c tng hp vi dung mụi chloroform (F1, F2 v F3): a1, b1, c1 l nh vi 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d =2 d =3 200 10 20 30 40 50 60 70 2-Theta - Scale File: Nga-DHBK-0gP123-HAP-500C.raw - Type: 2Th alone - Start: 10.000 - End: 70.000 - Step: 0.030 - Step time: 1.0 s - Temp.: 25.0 C (Room) - Anode: Cu - Creation: 11/12/12 15:51:03 24-0033 (D) - Hydroxylapatite - Ca5(PO4)3(OH) - Y: 54.55 % - d x by: 1.000 - WL: 1.54056 VNU-HN-SIEMENS D5005 - Mau 1gP123 - HAP - 500C 500 d =2 32 (b) d =1 53 d =1 17 d =1 99 d =1 81 d =1 14 d =1 54 d =1 12 d =1 98 d =1 63 d =1 51 d =1 95 d =2 57 d =2 83 d =2 64 d =2 46 d =3 59 d =3 14 d =3 26 d =3 02 d =5 80 100 d =2 31 d =3 25 200 d =1 20 d =1 96 300 d =1 40 d =2 78 d =2 44 400 Lin (C ps ) L in (C p s ) 300 10 20 30 40 50 2-Theta - Scale File: Nga-DHBK-1gP123-HAP-500C.raw - Type: 2Th alone - Start: 10.000 - End: 70.000 - Step: 0.030 - Step time: 1.0 s - Temp.: 25.0 C (Room) - Anode: Cu - Creation: 11/12/12 11:36:41 24-0033 (D) - Hydroxylapatite - Ca5(PO4)3(OH) - Y: 77.36 %- d x by: 1.000 - WL: 1.54056 113 60 70 VNU-HN-SIEMENS D5005 - Mau 1gP123 - HAP - 500C (c) d =2 32 500 d =1 53 d =1 14 d =1 17 d =1 99 d =1 81 d =1 12 d =1 54 d =1 63 d =1 98 d =1 95 d =2 57 d =2 83 d =2 64 d =2 46 d =3 59 d =3 14 d =3 26 d =3 02 d =5 80 100 d =2 31 d =3 25 200 d =1 20 d =1 96 d =1 51 Lin (C ps ) 300 d =1 40 d =2 78 d =2 44 400 10 20 30 40 50 60 70 2-Theta - Scale File: Nga-DHBK-1gP123-HAP-500C.raw - Type: 2Th alone - Start: 10.000 - End: 70.000 - Step: 0.030 - Step time: 1.0 s - Temp.: 25.0 C (Room) - Anode: Cu - Creation: 11/12/12 11:36:41 24-0033 (D) - Hydroxylapatite - Ca5(PO4)3(OH) - Y: 77.36 %- d x by: 1.000 - WL: 1.54056 Ph lc Ph FTIR ca mu bt nano HAp tng hp bang phng phỏp thy nhit s dng cht hot ng b mt P123: (a) 0P123, (b) 1P123, (c) 2P123 (a) 114 (b) (c) 115 Ph lc nh SEM ca mng HAp/PDLLA sau ngõm SBF ngy (a) 0P12 3 ngy 2àm (b) 1P123 ngy 2àm (c) 2P12 3 ngy 2àm 116 Ph lc S bỏm dớnh v phỏt trin ca t bo MG63 trờn khuụn nh dng HAp/PDLLA tng hp s dng 1,4-dioxan sau ngy: mu S1 (A), S2 (B), S3 (C) v S4 (D) A 3Day ngy B 100 m 100 m C 3Day ngy D Day 3 ngy DayDay 3 3ngy 100 m 100 m 117 Ph lc S bỏm dớnh v phỏt trin ca t bo MG63 trờn khuụn nh dng HAp/PDLLA tng hp s dng chloroform sau ngy: mu F1 (A), F2 (B)v F4 (C) (d) (a) ngy (b ) ngy 100 àm 100 àm ngy (c) 100 àm 118 ... chính: vật liệu polyme phân hủy sinh học; vật liệu vô có hoạt tính sinh học; vật liệu composit tổng hợp từ dạng vật liệu (polyme /vật liệu vô hoạt tính sinh học) 1.2.1 Polyme phân hủy sinh học Các polyme... thích sinh học khả tạo mô xương vật liệu composit poly (D, L) lactic axit/hydroxyapatit’’ Mục tiêu luận án: Nghiên cứu tổng hợp vật liệu composit sinh học gồm hydroxyapatit polyme sinh học (PDLLA)... mô [59,107] Khuôn định dạng chế tạo từ vật liệu polyme phân hủy sinh học, vật liệu vô có hoạt tính sinh học composit Vật liệu polyme phân hủy sinh học vật liệu vô nghiên cứu nhiều Nhưng vật liệu