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Mezenkimal kök hücrelerin ve kompozit iskelelerin kullanımıyla kemik doku mühendisliği

Diğer Başlık: Bone tissue engineering using mesenchymal stem cells and composite scaffolds

Oluşturulma Tarihi: 01-02-2008

Niteleme Bilgileri

Tür: Tez

Alt Tür: Doktora

Yayınlanma Durumu: Yayınlanmış

Dosya Biçimi: PDF

Dil: Türkçe

Konu(lar): BİLİM, Kimya,

Yazar(lar): KOÇ, Aysel (Yazar),

Emeği Geçen(ler): ELÇİN, Murat (Tez Danışmanı),


Yayınlayan: Fen Bilimler Enstitüsü Kimya Anabilim Dalı Yayın Yeri: Ankara Yayın Tarihi: 2008 Yayınlandığı Sayfalar: 105 s.


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Anahtar Kelimeler

Kemik doku mühendisliği,gen terapisi, mezenkimal kök hücre, MC3T3-E1, osteoblast, genle uyarılmış matriks,VEGF, Kompozit iskele, Poli(D,L-laktik-ko-glikolik asit), kitosan hidroksiapatit,biyoreaktör, bone tissue engineering, gene therapy, mesenchymal stem cell, MC3T3-E1, osteoblast, gene activated matrix, vegf, composite scaffold, poly(D,L-lactic-co-glycolic acid), chitosan, hydroxyapatite, bioreactor.  




Özet

    Bu tezçalışmasında, poli (D,L-laktik-ko-glikolik asit) (PLGA) vekitosan/hidroksiapatit (K/HA) kompozit iskeleler sırasıyla partikül uzaklaştırmave dondurarak kurutma yöntemleriyle hazırlandı. PLGA iskeleler malzemeyüzeyinde apatit oluşumu sağlamak için yapay vücut sıvısında inkübe edildi.K/HA iskelelerin bir bölümü insan vasküler endotelyal büyüme faktörü (hVEGF) veyeşil floresan protein (GFP) sentezleyen adenoviral vektörle transfekte edildi.Mezenkimal kök hücreler Wistar sıçanların kemik iliğinden izole edilerekkültüre alınıp çoğaltıldıktan sonra mineralize PLGA iskelelere statik vedinamik kültür şartlarında tohumlandı. Çalışmada, fare MC3T3-E1 hücre dizisi veinsan osteoblast hücreleri de hücre kaynağı olarak kullanıldı. MC3T3-E1hücreleri saf K/HA iskelelere tohumlanırken, hOB hücreleri saf ve transfekteedilmiş K/HA iskelelere tohumlandı. Hücre tohumlanmış iskelelerin 4 hafta boyunca kültürüsürdürüldü. Hücre canlılığı MTT testiyle, osteoblastik fenotip ise alkalenfosfataz aktivitesi, immünhistokimyasal boyamalar ve taramalı elektronmikroskopisi (SEM) ile belirlendi. hOB hücrelerinin K/HA iskele içerisindekidağılımını ve GFP salımını belirlemek için konfokal lazer mikroskopisi (KLM) kullanıldı.Transfekte edilen K/HA yüzeyindeki hOB hücreleri tarafından üretilen hVEGF, ELISAyöntemiyle belirlendi. SEM bulguları iskelelerin (PLGA ve K/HA) yüksekporözitede ve birbirleriyle bağlantılı gözeneklere sahip olduğunu gösterdi.Histolojik ve SEM bulguları hücrelerin (MKH’lerin, MC3T3-E1 ve hOBhücrelerinin) iskelelerin gözeneklerine yayıldığını ve çoğaldığını gösterdi.İmmünhistokimya çalışmaları hücre tohumlanmış iskelelerin yüksek seviyedeosteojenik markör proteinlerini sentezlediğini ortaya koydu. KLM hOB hücrelerinin iskele içerisine homojendağıldığını ve hücre proliferasyonun inkübasyon süresiyle orantılı arttığınıgösterdi. İskele yüzeyindeki hücreler tarafından üretilen hVEGF’un, uygulananviral dozla paralellik gösterdiği belirlendi. Elde edilen sonuçlar, PLGA veK/HA (saf ve genle aktive edilmiş) iskelelerin kemik doku mühendisliği içinpotansiyel taşıdıklarını gösterdi.

Abstract

    In this study, poly(D,L-lactic-co-glycolic acid) (PLGA) and chitosan/hydroxyapatite (C/HA) composite scaffolds were prepared by the particulate leaching and freeze-drying methods, respectively. PLGA scaffolds were incubated in simulated body fluid for apatite growth on the material. Some of the C/HA scaffolds were transfected with adenoviral vector encoding human vascular endothelial growth factor (hVEGF) and green fluorescent protein (GFP). Mesenchymal stem cells isolated from bone marrow of Wistar rats were cultured, expanded and seeded on mineralized PLGA scaffolds under static and dynamic culture conditions. In the study, mouse MC3T3-E1 cells and human osteoblasts (hOBs) were also used as cell source. While MC3T3-E1 cells were seeded on pure C/HA scaffolds, hOBs were seeded on pure and transfected C/HA scaffolds. The cell seeded scaffolds were cultured for upto 4 weeks. Cell viability was investigated by the MTT assay, differentiation of cells into osteoblastic phenotype were determined by alkaline phosphatase activity, immunohistochemical staining, and scanning electonic microscopy (SEM). Confocal laser microscopy (CLM) was used to investigate the distribution of hOBs inside the C/HA scaffolds and to visualize the GFP expression inside the cells. The hVEGF produced by hOBs on transfected C/HA scaffolds was measured using the ELISA method. SEM observations revealed that the scaffolds (PLGA and C/HA) had a highly porous structure, and were well-interconnected. Histological and SEM observations showed that cells (MSCs, MC3T3-E1 cells and hOBs) were widespread and had proliferated extensively within the pores of the scaffolds. Immunohistochemistry studies revealed that the cells-seeded scaffolds expressed higher levels of osteogenic marker proteins. CLM results confirmed that the distribution of hOBs inside sponges was quite uniform and the proliferation of the cells had gradually increased by incubation time. The hVEGF produced by the cells on the scaffolds increased with the increase in viral dose. Based on the results, it can be concluded that mineralized PLGA and C/HA (pure and gene-activated) scaffolds have potential in bone tissue engineering.

 



İçindekiler

ÖZET................................................................................................................................. i

ABSTRACT..................................................................................................................... ii

TEŞEKKÜR..................................................................................................................... iii

SİMGELER DİZİNİ....................................................................................................... viii

ŞEKİLLER DİZİNİ......................................................................................................... ix

ÇİZELGELER DİZİNİ.................................................................................................. xii

1.GİRİŞ.............................................................................................................................. 1

2. KURAMSAL TEMELLER........................................................................................ 5

2.1 Kemik Dokusu ........................................................................................................... 5

2.1.1 Kemik........................................................................................................................ 5

2.1.2 Kemik hücreleri....................................................................................................... 5

2.1.2.1 Osteojenik hücreler.............................................................................................. 6

2.1.2.2 Osteoblastlar.......................................................................................................... 6

2.1.2.3 Osteositler.............................................................................................................. 7

2.1.2.4 Osteoklastlar.......................................................................................................... 8

2.2 Kemik Matriksi........................................................................................................... 9

2.3 Periosteum ve Endosteum......................................................................................... 10

2.3.1 Periosteum............................................................................................................... 10

2.3.2 Endosteum............................................................................................................... 10

2.4 Kemik Tipleri............................................................................................................. 11

2.4.1 Primer kemik dokusu............................................................................................. 11

2.4.2 Sekonder kemik dokusu......................................................................................... 11

2.5 Kemik Gelişimi........................................................................................................... 13

2.5.1 İntramembranöz kemikleşme................................................................................ 13

2.5.2 Endokondral kemikleşme...................................................................................... 13

3. DOKU MÜHENDİSLİĞİ........................................................................................... 16

3.1 Kemik Doku Mühendisliği........................................................................................ 17

3.2 Kemik Doku Mühendisliğinde Kullanılan Destek Malzemeler.............................. 18

3.3 Kemik Doku Mühendisliği Çalışmalarında Kullanılan Bazı

Biyopolimerlerin, Biyoseramiklerin ve Kompozitlerin Özellikleri......................... 21

3.3.1 Biyopolimerler......................................................................................................... 22

3.3.1.1 Doğal polimerler.................................................................................................. 22

3.3.1.1.1. Kitosan................................................................................................................ 23

3.3.1.1.2 Kollajen.............................................................................................................. 25

3.3.1.2 Sentetik biyopolimerler....................................................................................... 26

3.3.1.2.1 Poli (a-hidroksi asitler)..................................................................................... 26

3.3.1.2.1.1 Poli (glikolik asit) (PGA)................................................................................ 27

3.3.1.2.1.2 Poli (L-laktik asit) (PLA)............................................................................... 27

3.3.1.2.1.3 Poli (laktik-ko-glikolik asit) (PLGA)............................................................ 27

3.3.2 Biyoseramikler........................................................................................................ 28

3.3.2.1 Hidroksiapatit (HA)............................................................................................. 28

3.3.3 Kompozit malzemeler.................................................................................................................... 29

3.3.3.1 Malzeme yüzeylerinin mineralizasyonu............................................................. 30

3.4 İskele Hazırlama Yöntemleri................................................................................................................. 31

3.4.1 Partikül uzaklaştırma (Solvent casting / Particle leaching) yöntemi................... 31

3.4.2 Dondurarak kurutma (Freeze-Drying) yöntemi................................................... 32

3.4.3 Lif bağlama (Fiber bonding) yöntemi.................................................................... 33

3.4.4 Gazla köpüklendirme (Gas foaming) yöntemi...................................................... 33

3. 5 Kemik Doku Mühendisliğinde Kullanılan Büyüme Faktörleri............................. 34

3.6 Gen Terapisi............................................................................................................... 36

3.6.1 Genlerin vücuda aktarılma yöntemleri................................................................. 36

3.6.2 Gen tedavisinde viral vektörler.............................................................................. 39

3.6.2.1 Adenovirüsler....................................................................................................... 39

3.6.2.2 Retrovirüsler........................................................................................................ 41

3.6.2.3 Herpesvirüsler...................................................................................................... 42

3.6.3 Gen tedavisinde viral olmayan vektörler.............................................................. 42

3.7 Hücre Kaynakları...................................................................................................... 43

3.7.1 Kök hücre kaynakları............................................................................................ 43

3.7.1.1 Embriyonik kök hücreler................................................................................... 43

3.7.1.2 Erişkin kök hücreler............................................................................................ 45

3.7.1.2.1 Erişkin kök hücre tipleri.................................................................................. 46

3.7.2 Kemik doku mühendisliğinde kullanılan diğer hücre kaynakları...................... 48

3.8 Hücre Kültürü Yöntemleri........................................................................................ 49

3.8.1 Döner kap (Spinner flask) reaktörler.................................................................... 49

3.8.2 Mikrotaşıyıcı-destekli reaktörler........................................................................... 50

3.8.3 Perfüzyon kültürler................................................................................................ 50

3.8.4 Döner-duvarlı biyoreaktörler (Rotating wall vessels, RWVs).............................. 51

3.9 Anjiyogenez................................................................................................................ 52

4. MATERYAL ve YÖNTEM....................................................................................... 57

4.1 Madde ve Malzeme.................................................................................................... 57

4.2 İskelelerin Hazırlanması............................................................................................ 58

4.2.1 Poli(D,L-laktik-ko-glikolik asit) (PLGA) iskelelerin hazırlanması...................... 58

4.2.2 PLGA iskelelerin mineralizasyonu........................................................................ 58

4.2.3 Kitosan/Hidroksiapatit (K/HA) iskelelerin hazırlanması..................................... 59

4.2.4 Kitosan/Hidroksiapatit iskelelerin Ad-GFP-VEGF ile aktivasyonu................... 59

4.3 Hücre Kaynakları...................................................................................................... 60

4.3.1 Kemik iliği mezenkimal kök hücrelerinin izolasyonu ve kültürü........................ 60

4.3.2 MC3T3-E1 ve hOBs hücrelerinin kültürü........................................................... 60

4.4 Polimer İskelelerin Sterilizasyonu ve Kültür İçin Hazırlanmaları ........................ 61

4.5 Hücrelerin İskelelere Tohumlanması....................................................................... 61

4.5.1 Statik tohumlama.................................................................................................... 62

4.5.2 Dinamik tohumlama............................................................................................... 62

4.6 Histoloji (Işık Mikroskobisi)...................................................................................... 63

4.6.1 Hematoksilin ve Eosin boyaması (H&E)............................................................... 63

4.6.2 Alizarin kırmızısı (AR-S)........................................................................................ 64

4.6.3 Von Kossa boyaması............................................................................................... 64

4.7 İmmünhistokimya..................................................................................................... 65

4.8 SEM............................................................................................................................ 65

4.9 MTT [3-(4,5-dimetildiyazol-2-il)-2,5-difeniltetrazolyum bromür] Testi................ 66

4.10 Konfokal Lazer Mikroskobisi (Confocal laser scanning microscopy, KLM)...... 66

4.11 VEGF Salımı ........................................................................................................... 66

5. BULGULAR................................................................................................................ 67

5.1 Mineralize PLGA İskelelerle İlgili Araştırma Bulguları (1.Grup)......................... 67

5.1.1 Faz konstrast mikroskobu bulguları..................................................................... 67

5.1.2 SEM bulguları........................................................................................................ 67

5.1.3 MTT bulguları........................................................................................................ 70

5.1.4 İmmünhistokimya bulguları.................................................................................. 70

5.1.5 Kütle artışı bulguları............................................................................................... 71

5.1.6 FTIR bulguları........................................................................................................ 72

5.1.7 Alizarin kırmızısı bulguları.................................................................................... 73

5.2. Kitosan/Hidroksiapatit İskeleleri İçin Araştırma Bulguları.................................. 74

5.2.1 Faz konstrast mikroskobu bulguları..................................................................... 74

5.2.2 SEM bulguları......................................................................................................... 75

5.2.3 Histoloji bulguları................................................................................................... 77

5.2.4 Von Kossa bulguları............................................................................................... 78

5.2.5 ALP bulguları......................................................................................................... 79

5.2.6 İmmünohistokimya bulguları................................................................................ 80

5.2.7 KLM bulguları........................................................................................................ 82

5.2.8 VEGF salım bulguları............................................................................................ 85

6. TARTIŞMA ve SONUÇ............................................................................................. 87

KAYNAKLAR................................................................................................................ 94

ÖZGEÇMİŞ.................................................................................................................... 104

 

 

ÖZET................................................................................................................................. i

ABSTRACT..................................................................................................................... ii

TEŞEKKÜR..................................................................................................................... iii

SİMGELER DİZİNİ....................................................................................................... viii

ŞEKİLLER DİZİNİ......................................................................................................... ix

ÇİZELGELER DİZİNİ.................................................................................................. xii

1.GİRİŞ.............................................................................................................................. 1

2. KURAMSAL TEMELLER........................................................................................ 5

2.1 Kemik Dokusu ........................................................................................................... 5

2.1.1 Kemik........................................................................................................................ 5

2.1.2 Kemik hücreleri....................................................................................................... 5

2.1.2.1 Osteojenik hücreler.............................................................................................. 6

2.1.2.2 Osteoblastlar.......................................................................................................... 6

2.1.2.3 Osteositler.............................................................................................................. 7

2.1.2.4 Osteoklastlar.......................................................................................................... 8

2.2 Kemik Matriksi........................................................................................................... 9

2.3 Periosteum ve Endosteum......................................................................................... 10

2.3.1 Periosteum............................................................................................................... 10

2.3.2 Endosteum............................................................................................................... 10

2.4 Kemik Tipleri............................................................................................................. 11

2.4.1 Primer kemik dokusu............................................................................................. 11

2.4.2 Sekonder kemik dokusu......................................................................................... 11

2.5 Kemik Gelişimi........................................................................................................... 13

2.5.1 İntramembranöz kemikleşme................................................................................ 13

2.5.2 Endokondral kemikleşme...................................................................................... 13

3. DOKU MÜHENDİSLİĞİ........................................................................................... 16

3.1 Kemik Doku Mühendisliği........................................................................................ 17

3.2 Kemik Doku Mühendisliğinde Kullanılan Destek Malzemeler.............................. 18

3.3 Kemik Doku Mühendisliği Çalışmalarında Kullanılan Bazı

Biyopolimerlerin, Biyoseramiklerin ve Kompozitlerin Özellikleri......................... 21

3.3.1 Biyopolimerler..................................................................................................................................................... 22

3.3.1.1 Doğal polimerler.................................................................................................. 22

3.3.1.1.1. Kitosan.......................................................................................................................................................... 23

3.3.1.1.2 Kollajen.............................................................................................................. 25

3.3.1.2 Sentetik biyopolimerler....................................................................................... 26

3.3.1.2.1 Poli (a-hidroksi asitler)..................................................................................... 26

3.3.1.2.1.1 Poli (glikolik asit) (PGA)................................................................................ 27

3.3.1.2.1.2 Poli (L-laktik asit) (PLA)............................................................................... 27

3.3.1.2.1.3 Poli (laktik-ko-glikolik asit) (PLGA)............................................................ 27

3.3.2 Biyoseramikler........................................................................................................ 28

3.3.2.1 Hidroksiapatit (HA)............................................................................................. 28

3.3.3 Kompozit malzemeler....................................................................................................................................... 29

3.3.3.1 Malzeme yüzeylerinin mineralizasyonu............................................................. 30

3.4 İskele Hazırlama Yöntemleri............................................................................................................................... 31

3.4.1 Partikül uzaklaştırma (Solvent casting / Particle leaching) yöntemi................... 31

3.4.2 Dondurarak kurutma (Freeze-Drying) yöntemi................................................... 32

3.4.3 Lif bağlama (Fiber bonding) yöntemi.................................................................... 33

3.4.4 Gazla köpüklendirme (Gas foaming) yöntemi...................................................... 33

3. 5 Kemik Doku Mühendisliğinde Kullanılan Büyüme Faktörleri............................. 34

3.6 Gen Terapisi............................................................................................................... 36

3.6.1 Genlerin vücuda aktarılma yöntemleri................................................................. 36

3.6.2 Gen tedavisinde viral vektörler.............................................................................. 39

3.6.2.1 Adenovirüsler....................................................................................................... 39

3.6.2.2 Retrovirüsler........................................................................................................ 41

3.6.2.3 Herpesvirüsler...................................................................................................... 42

3.6.3 Gen tedavisinde viral olmayan vektörler.............................................................. 42

3.7 Hücre Kaynakları...................................................................................................... 43

3.7.1 Kök hücre kaynakları............................................................................................ 43

3.7.1.1 Embriyonik kök hücreler................................................................................... 43

3.7.1.2 Erişkin kök hücreler............................................................................................ 45

3.7.1.2.1 Erişkin kök hücre tipleri.................................................................................. 46

3.7.2 Kemik doku mühendisliğinde kullanılan diğer hücre kaynakları...................... 48

3.8 Hücre Kültürü Yöntemleri........................................................................................ 49

3.8.1 Döner kap (Spinner flask) reaktörler.................................................................... 49

3.8.2 Mikrotaşıyıcı-destekli reaktörler........................................................................... 50

3.8.3 Perfüzyon kültürler................................................................................................ 50

3.8.4 Döner-duvarlı biyoreaktörler (Rotating wall vessels, RWVs).............................. 51

3.9 Anjiyogenez................................................................................................................ 52

4. MATERYAL ve YÖNTEM....................................................................................... 57

4.1 Madde ve Malzeme.................................................................................................... 57

4.2 İskelelerin Hazırlanması............................................................................................ 58

4.2.1 Poli(D,L-laktik-ko-glikolik asit) (PLGA) iskelelerin hazırlanması...................... 58

4.2.2 PLGA iskelelerin mineralizasyonu........................................................................ 58

4.2.3 Kitosan/Hidroksiapatit (K/HA) iskelelerin hazırlanması..................................... 59

4.2.4 Kitosan/Hidroksiapatit iskelelerin Ad-GFP-VEGF ile aktivasyonu................... 59

4.3 Hücre Kaynakları...................................................................................................... 60

4.3.1 Kemik iliği mezenkimal kök hücrelerinin izolasyonu ve kültürü........................ 60

4.3.2 MC3T3-E1 ve hOBs hücrelerinin kültürü........................................................... 60

4.4 Polimer İskelelerin Sterilizasyonu ve Kültür İçin Hazırlanmaları ........................ 61

4.5 Hücrelerin İskelelere Tohumlanması....................................................................... 61

4.5.1 Statik tohumlama.................................................................................................... 62

4.5.2 Dinamik tohumlama............................................................................................... 62

4.6 Histoloji (Işık Mikroskobisi)...................................................................................... 63

4.6.1 Hematoksilin ve Eosin boyaması (H&E)............................................................... 63

4.6.2 Alizarin kırmızısı (AR-S)........................................................................................ 64

4.6.3 Von Kossa boyaması............................................................................................... 64

4.7 İmmünhistokimya..................................................................................................... 65

4.8 SEM............................................................................................................................ 65

4.9 MTT [3-(4,5-dimetildiyazol-2-il)-2,5-difeniltetrazolyum bromür] Testi................ 66

4.10 Konfokal Lazer Mikroskobisi (Confocal laser scanning microscopy, KLM)...... 66

4.11 VEGF Salımı ........................................................................................................... 66

5. BULGULAR................................................................................................................ 67

5.1 Mineralize PLGA İskelelerle İlgili Araştırma Bulguları (1.Grup)......................... 67

5.1.1 Faz konstrast mikroskobu bulguları..................................................................... 67

5.1.2 SEM bulguları........................................................................................................ 67

5.1.3 MTT bulguları........................................................................................................ 70

5.1.4 İmmünhistokimya bulguları.................................................................................. 70

5.1.5 Kütle artışı bulguları............................................................................................... 71

5.1.6 FTIR bulguları........................................................................................................ 72

5.1.7 Alizarin kırmızısı bulguları.................................................................................... 73

5.2. Kitosan/Hidroksiapatit İskeleleri İçin Araştırma Bulguları.................................. 74

5.2.1 Faz konstrast mikroskobu bulguları..................................................................... 74

5.2.2 SEM bulguları......................................................................................................... 75

5.2.3 Histoloji bulguları................................................................................................... 77

5.2.4 Von Kossa bulguları............................................................................................... 78

5.2.5 ALP bulguları......................................................................................................... 79

5.2.6 İmmünohistokimya bulguları................................................................................ 80

5.2.7 KLM bulguları........................................................................................................ 82

5.2.8 VEGF salım bulguları............................................................................................ 85

6. TARTIŞMA ve SONUÇ............................................................................................. 87

KAYNAKLAR................................................................................................................ 94

ÖZGEÇMİŞ.................................................................................................................... 104

 

 


Açıklamalar



Haklar



Notlar



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