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정보검색

소장정보 검색

국회도서관 홈으로 정보검색 소장정보 검색
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결과 내 검색 동의어 포함

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Title Page

Abstract

Contents

Technical Terms and Abbreviations 9

1. Introduction 10

2. Materials and methods 12

2.1. Cell culture 12

2.2. Bio-inks preparation 12

2.3. 3D bioprinter and printing process 13

2.4. Compressive modulus of matrix gel bio-inks 13

2.5. Microscopy 13

2.6. Cell viability test 13

2.7. Analysis of VEGF secretion and ATP normalization 14

2.8. Subcutaneous implantation of constructs 14

2.9. Immunocytochemistry 14

2.10. Murine critical limb ischemia model establishment 14

2.11. Transplantation of constructs into hindlimb ischemia model 15

2.12. Histological Analysis and Immunohistochemistry 16

2.13. Statistical Analysis 16

3. Results 17

3.1. Fabrication of the constructs 17

3.2. Optimization of ADSC spheroid printing for enhanced secretion of angiogenic factors 17

3.2.1. Matrix gel composition 17

3.2.2. Spheroids size 19

3.3. Investigation of optimized distance between spheroids and capillary pattern 19

3.4. Spheroids number effect on neo-vascularization in fabricated constructs 20

4. Discussion 25

5. Conclusion 27

6. References 28

List of Tables

Table 1. Composition of cell-laden bio-inks 12

Table 2. Compositions of tested matrix gel bio-inks 12

List of Figures

Figure 1. Pilot study results for establishment of proper surgical model of murine critical limb ischemia model (n＝4). 15

Figure 2. Fabrication process of the pre-vascularized constructs using the 3D bioprinter for ischemia therapy 17

Figure 3. In-bath dot-printing of ADSC spheroids. (a) Schematic image illustrating the dot-printing and function of ADSC spheroid with high VEGF secretion. (b) Measured compressive modulus of each... 18

Figure 4. Spheroidal morphology and VEGF secretion differing by matrix gels. (a) Fluorescent and confocal images of ADSC spheroids stained with calcein (green, live cells) and ethidium homodimer... 18

Figure 5. Investigation of VEGF secretion ability according to dispensing time of ADSC bioink. (a) Fluorescent images of ADSC spheroids stained with calcein (green, live cells) and ethidium homodimer... 19

Figure 6. Maturation of capillary pattern with and without spheroids pattern (SP). (a) Bright-field images (upper) and fluorescent images (lower) (green, GFP-HUVEC; scale bars＝1 mm). (b) Magnified... 20

Figure 7. Investigation of neo-vascularization via subcutaneous implantation. (a) Schematic image illustrating implantation experiment. Constructs were implanted into dorsal region on the left and right... 21

Figure 8. Schematic image illustrating implantation experiment. Enhanced therapeutic effect on ischemia tissues via implantation of printed construct. Schematic image illustrating implantation... 22

Figure 9. Harvested after 2 weeks muscles analysis. Representative photographs of ischemic limbs at day 3, 7 and 14 after implantation of each construct. H&E (upper) and Masson's trichrome (lower)... 23

Figure 10. Microcapillaries formation in the harvested ischemic muscles of all groups. (a) Immunostaining for CD-31 of each group (scale bars＝100 μm). (b) Quantification of CD-31 positive... 24

Figure 11. Mature arterioles formation in the harvested ischemic muscles of all groups. (a) Immunostaining for alpha-SMA of each group (scale bars＝100 μm). (b) Quantification of alpha-... 24

초록보기

 Ischemia, characterized by restricted blood supply, leads to irreversible tissue damage and necrosis due to oxygen and nutrient insufficiency, contributing to severe conditions such as heart failure, stroke, or limb ischemia. Current approaches, relying on injection-based delivery of biomaterials (e.g., growth factors, nucleic acids, stem cells), often yield inconsistent therapeutic effects and unintended side effects due to off-target distribution.

This study proposes a novel approach through the fabrication of a pre-vascularized graft comprising capillary pattern and human mesenchymal stem cell (MSC) spheroids encapsulated in hydrogel for ischemic disease treatment. Utilizing dot-printing technology and optimizing the hydrogel composition, we fabricated hMSC spheroids with enhanced and sustained secretion of angiogenic factors. Whereas capillary pattern was patterned between spheroids for optimized intercellular interaction, the gradient of paracrine secretion promoted maturation and micro-capillary sprouting towards spheroids.

In a mouse hind limb ischemia model assay, our bioprinted constructs exhibited superior efficacy in preventing ischemic disease symptoms and demonstrated the highest percentage of limb salvage compared to other groups. This innovative construct design presents significant potential for optimized tissue regeneration in ischemic disease therapy.

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