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Craniomaxillofacial Bone Tissue Engineering – a Translational Approach

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Craniomaxillofacial Bone Tissue Engineering – a Translational Approach Craniomaxillofacial Bone Tissue Engineering – A Translational Approach by Ahmed Abushahba Clinicum, Faculty of Medicine, University of Helsinki, Finland Doctoral Programme in Oral Sciences (FINDOS) Doctoral School in Health Sciences University of Helsinki ACADEMIC DISSERTATION Doctoral thesis, to be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination in Lecture Hall 2, Biomedicum Helsinki 1, Haartmaninkatu 8, Helsinki, on July 23rd 2021, at 12:00 pm The research was conducted at The Department of Oral and Maxillofacial Diseases Clinicum, Faculty of Medicine University of Helsinki, Finland Doctoral Programme in Oral Sciences (FINDOS), Helsinki SUPERVISORS Professor Riitta Seppänen-Kaijansinkko Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital Helsinki, Finland Docent Bettina Mannerström Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital Helsinki, Finland REVIEWERS Professor Sean Peter Edwards Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry Michigan, USA Adjunct Professor Niko Moritz Department of Clinical Medicine, Institute of Dentistry, University of Turku Turku, Finland OPPONENT Professor Dr. Dr. Henning Schliephake Department of Oral and Maxillofacial Surgery, the Georg August University of Göttingen Göttingen, Germany The Faculty of Medicine uses the Urkund system (plagiarism recognition) to examine all doctoral dissertations. Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis, series No. 40/2021 ISBN 978-951-51-7406-2 (paperback) ISBN 978-951-51-7407-9 (PDF) ISSN 2342-3161 (print) ISSN 2342-317X (online) http://ethesis.helsinki.fi Unigrafia Helsinki 2021 In memory of my beloved Father, to Gamal Taha Abushahba, I dedicate this work, ABSTRACT Bone tissue engineering (BTE) has shown a great promise in providing the next generation medical bioimplants for treating bone defects. However, BTE faces many obstacles which need to be addressed for promoting translatability. The objective of this thesis work was to explore clinically translatable tissue engineering approaches for the management of craniomaxillofacial bone defects. The role of the employed cells has witnessed a critical turning point towards an increased appreciation of the cellular paracrine effects. This paracrine effect is mediated via secreted proteins and released membrane-bound vesicles called extracellular vesicles (EVs). For advancing our knowledge about the biological roles of EVs, we employed RNA sequencing to provide a comprehensive overview of the expression profiles of small non-coding transcripts carried by the EVs derived from human adipose tissue stromal/stem cells (AT-MSCs) and human pluripotent stem cells (hPSCs). Our findings revealed distinctive small non-coding RNA profiles from hPSCs and AT-MSCs EVs. The regulatory miRNAs of stem cells at cellular level are also present in their EVs, indicating an important regulatory role which is mediated via EVs. Vascularization is the key challenge for BTE applications in large bone defects. The local delivery of growth factors leads to short lived effects. Small molecule chemicals feature alternative cost-effective bioactive agents with better stability. We assessed the ability of two small molecules; DMOG and baicalein, in triggering the proangiogenic secretome of AT-MSCs in vitro. Additionally, other effects, such as proliferation and osteogenic differentiation of AT-MSCs were assessed. DMOG and baicalein efficiently stabilized the hypoxia-inducible factor (HIF-ϭɲͿ and upregulated proangiogenic cytokines, e.g., vascular endothelial growth factor (VEGF) and platelet- derived growth factor-BB (PDGF-BB) of AT-MSCs in normoxic conditions. These effects were further associated with upregulated stemness-related gene expression, slowed proliferation, and reduced osteogenic potential. Chemically-induced hypoxia maintained the stemness and self-renewal properties of AT-MSCs, while enhancing their proangiogenic potential. The in vivo bioreactor (IVB) concept combines the potential of BTE and reconstructive surgery by employing the patient body for prefabricating new prevascularized tissues. Ideally, IVB should minimize the need for exogenous growth factors or cells and harness the native regenerative potential of employed tissues. Using acellular alloplastic bone blocks, we compared muscle-IVB with and without periosteal/pericranial grafts and flaps for prefabricating tissue engineered bone (TEB) flaps. We also assessed their functional outcomes in reconstructing a mandibular defect in an ovine model. The employment of vascularized periosteal flaps did result in more robust vascularization as compared to other IVB techniques. Both the periosteal grafts and periosteal flaps enhanced the performance of the prefabricated TEB flaps after transplantation into a mechanically stimulated bony microenvironment. However, more new bone formation and biomaterial remodeling was associated with the vascularized periosteal flaps. iv ABSTRAKTI Luukudosteknologiasta (BTE) odotetaan uuden sukupolven kudossiirteitä luukudosvaurioiden hoitoon. Tämän väitöskirjan tavoitteena oli tutkia kliinisesti sovellettavia kudosteknologisia lähestymistapoja kallon ja kasvojen luuvaurioiden korjaamiseksi. Solujen rooli kudosteknologiassa on muuttunut merkittävästi viime vuosikymmenellä kohdistaen tutkimuksen yhä enemmän solujen parakriinivaikutukseen, joka välittyy erittyvien proteiinien ja ekstrasellulaarivesikkelien (EV) kautta. Ymmärtääksemme ihmisen kantasoluista peräisin olevien EV:en roolin kudosteknologiassa, sekvensoimme näiden sisältämien pienten ei-koodaavien RNA-molekyylien ilmentymisprofiilit rasvakudoksen strooma- /kantasoluista (AT-MSC) ja pluripotenteista kantasoluista (hPSC). Totesimme selvät eroavaisuudet näiden välillä, osoittaen solukommunikaation etenevän myös EV- välitteisesti. Vaskularisaatio on keskeinen haaste BTE-sovelluksissa suurissa luukudosvaurioissa ja on todettu, että paikallinen kasvutekijöiden annostelu vaikuttaa vain lyhytaikaisesti. Pienimolekyylisissä yhdisteissä on tarjolla vaihtoehtoisia kustannustehokkaita bioaktiivisia aineita, joista tutkimme kahden, dimetyylioksalyyliglysiinin (DMOG) ja baikaleiinin, vaikutusta AT-MSC:n proangiogeenisen sekretomiin. DMOG ja baikaleiini stabiloivat tehokkaasti hypoksiaa indusoivaa tekijää (HIF-1a) ja säätelivät proangiogeenisia sytokiineja, kuten verisuonen endoteelikasvutekijää (VEGF) ja verihiutalekasvutekijää (PDGF-BB), mikä osoitti kemiallisesti indusoidun hypoksian edistävän AT-MSC:n proangiogeenista potentiaalia. In vivo bioreaktorikonseptin (IVB) tarkoituksena on hyödyntää potilaan omaa kehoa uudiskudosten verisuonittumisessa, poistaen paikallisesti annettujen kasvutekijöiden tai -solujen tarpeen hyödyntämällä kudosten luontaista uusiutumiskykyä. Tutkimuksessa testattiin lammasmallissa tehostetun luutumisen ja verisuonittumisen aikaansaamiseksi lihas- ja luukalvosiirteitä sekä -kielekkeitä alloplastisilla luusiirteillä. IVB-rakenteiden toiminnallisuus arvioitiin rekonstruoimalla näiden avulla leukakulman luuvaurioita. Verisuonittunut luukalvokieleke-IVB johti voimakkaimpaan verisuonittumiseen ja tehostettuun luuvaurion korjaantumiseen leukakulmassa verrattuna muihin IVB-tekniikoihin. v TABLE OF CONTENTS ABSTRACT ................................................................................................................. iv ABSTRAKTI .................................................................................................................. v TABLE OF CONTENTS ................................................................................................. vi LIST OF ORIGINAL PUBLICATIONS ........................................................................... viii PERSONAL CONTRIBUTION ........................................................................................ x ABBREVIATIONS ........................................................................................................ xi 1 INTRODUCTION .................................................................................................. 1 2 REVIEW OF THE LITERATURE .............................................................................. 3 2.1 Bone organ/tissue ................................................................................................... 3 2.2 Bone remodeling ..................................................................................................... 3 2.3 Bone regeneration ................................................................................................... 5 2.3.1 Mechanisms of clinical bone healing ............................................................... 5 2.3.2 Vascularization and bone healing .................................................................... 6 2.3.3 Periosteum-Sharpey’s fiber-endosteum system ............................................. 7 2.3.4 The critical critical-size bone defect ................................................................ 7 2.3.5 Osteoconduction, osteoinduction, and osteogenesis ..................................... 9 2.4 Bone cells ............................................................................................................... 10 2.4.1 MSCs, preosteoblasts, and osteoblasts ......................................................... 10 2.4.2 Bone lining cells ............................................................................................
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