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An in Vitro Model of Tissue-Engineered Skin Substitute with Integrated Flow

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An in Vitro Model of Tissue-Engineered Skin Substitute with Integrated Flow AN IN VITRO MODEL OF TISSUE-ENGINEERED SKIN SUBSTITUTE WITH INTEGRATED FLOW NETWORKS IN A PERFUSION BIOREACTOR by WAN-HSIANG LIANG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Harihara Baskaran Department of Chemical Engineering CASE WESTERN RESERVE UNIVERSITY May, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Wan-Hsiang_____________________________________________________ Liang candidate for the ______________________ Ph.D. degree *. (signed)_______________________________________________ Prof. Harihara Baskaran (chair of the committee) ________________________________________________ Prof. Jean Welter ________________________________________________ Prof. Chung-Chiun Liu ________________________________________________ Prof. Heidi Martin ________________________________________________ ________________________________________________ (date) March_______________________ 25th, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS Table of Contents ........................................................................................ iii! List of Figures .............................................................................................. ix! Preface ........................................................................................................ xiii! Acknowldgements ....................................................................................... xv Abstract ..................................................................................................... xvii 1. Introduction ...............................................................................................1! 1.1! Purpose and Nature of the Study ............................................................1! 1.2! Significance and Justification .................................................................2! 1.2.1! Tissue Engineering ............................................................................................ 2! 1.2.2! TE Skin Substitutes ........................................................................................... 3! 1.2.3! Challenges for Tissue-Engineered (TE) Skin Substitutes ................................. 4! 1.3! Guiding Research Goals .........................................................................4! 1.4! Previous Studies ......................................................................................6! 1.4.1! Design Optimal Flow Networks for TE Skin Substitutes ................................. 6! 1.4.2! Lithography Technique for Micropatterning of Collagen Membranes ............. 8! 1.5! Summary .................................................................................................9! 1.6! References .............................................................................................10! 2. Background ..............................................................................................11! iii 2.1! Human Skin Tissue ...............................................................................11! 2.1.1! Epidermis ........................................................................................................ 13! 2.1.2! Dermis ............................................................................................................. 16! 2.1.3! Dermo-Epidermal Junction ............................................................................. 17! 2.2! Wound Healing .....................................................................................18! 2.2.1! Hemostasis ...................................................................................................... 20! 2.2.2! Inflammation ................................................................................................... 20! 2.2.3! Proliferation and Reepithelialization .............................................................. 21! 2.2.4! Remodeling ..................................................................................................... 22! 2.3! Tissue Engineering ...............................................................................23! 2.4! Skin Tissue Engineering .......................................................................27! 2.4.1! Epidermal Substitutes ..................................................................................... 29! 2.4.2! Dermal Substitutes .......................................................................................... 30! 2.4.3! Composite Substitutes ..................................................................................... 32! 2.5! Challenges in Skin Tissue Engineering ................................................34! 2.6! References .............................................................................................38! 3. Development of Concentrated Collagen-Chondroitin Sulfate Scaffolds with Tunable Properties for Tissue Engineering Applications ...............48! 3.1! Introduction ...........................................................................................48! 3.2! Materials and Methods .........................................................................53! iv 3.2.1! Preparation of CG Solution ............................................................................. 53! 3.2.2! Preparation of Concentrated CG Solution and Scaffolds ............................... 54! 3.2.3! Characterization of Concentrated CG Solution and Scaffolds ....................... 55! 3.2.3.1! Water Uptake ......................................................................................... 55! 3.2.3.2! Chondroitin Sulfate Content .................................................................. 55! 3.2.3.3! Imaging and Image Analysis ................................................................. 56! 3.2.3.4! Mechanical Strength Testing ................................................................. 57! 3.2.4! CG scaffolds for TE Skin Substitutes ............................................................. 59! 3.2.4.1! Medium Preparation: ............................................................................. 59! 3.2.4.2! Keratinocyte Isolation: ........................................................................... 59! 3.2.4.3! Skin Substitutes Preparation .................................................................. 60! 3.2.4.4! Histoloy .................................................................................................. 61! 3.2.5! Statistical Analysis .......................................................................................... 61! 3.3! Results ...................................................................................................61! 3.3.1! General Scaffold Characterization .................................................................. 62! 3.3.2! Pore Structure .................................................................................................. 67! 3.3.3! Mechanical Properties ..................................................................................... 68! 3.3.4! Tissue Engineering Potential .......................................................................... 71! 3.4! Discussion .............................................................................................72! 3.5! Conclusions ...........................................................................................78! 3.6! References .............................................................................................78! 4. Design of a Perfusion Bioreactor for Skin Tissue Engineering ...........83! v 4.1! Introduction ...........................................................................................83! 4.2! Materials and Methods .........................................................................86! 4.3! Results and Discussion .........................................................................92! 4.4! Conclusions ...........................................................................................96! 4.5! References .............................................................................................96! 5. Development of an in Vitro Tissue-Engineered Skin Substitute with Integrated Flow Networks in a Perfusion Bioreactor ............................100! 5.1! Introduction .........................................................................................100! 5.2! Materials and Methods .......................................................................104! 5.2.1! Preparation of Dermal Substitutes with Integrated Flow Networks ............. 104! 5.2.1.1! Fabrication of Silicon Substrate with Optimal Flow Network Design 106! 5.2.1.2! Fabrication of CG Scaffolds with Flow Networks .............................. 108! 5.2.1.3! Fabrication of PDMS Molds ................................................................ 110! 5.2.1.4! Submerged Culture .............................................................................. 110! 5.2.1.5! Air-liquid Interface Culture ................................................................. 111! 5.2.2! Assessment of Cell Survival on CG Scaffolds ............................................. 113! 5.2.3! Histological Analysis .................................................................................... 114! 5.2.4! Immunohistochemical Analysis ...................................................................
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