New Developments in Tissue Engineering and Regeneration PDF
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Computational Methods in Applied Sciences Paulo Rui Fernandes Paulo Jorge da Silva Bartolo Editors New Developments in Tissue Engineering and Regeneration Computational Methods in Applied Sciences Volume 51 Series Editor Eugenio Oñate, Universitat Politècnica de Catalunya, Barcelona, Spain This series publishes monographs and carefully edited books inspired by the thematic conferences of ECCOMAS, the European Committee on Computational MethodsinAppliedSciences.Asaconsequence,thesevolumescoverthefieldsof Mathematical andComputationalMethodsandModellingandtheirapplicationsto major areas such as Fluid Dynamics, Structural Mechanics, Semiconductor Modelling, Electromagnetics and CAD/CAM. Multidisciplinary applications of these fields to critical societal and technological problems encountered in sectors like Aerospace, Car and Ship Industry, Electronics, Energy, Finance, Chemistry, Medicine, Biosciences, Environmental sciences are of particular interest.Theintentistoexchangeinformationandtopromotethetransferbetween the research community and industry consistent with the development and applications of computational methods in science and technology. Book proposals are welcome at Eugenio Oñate International Center for Numerical Methods in Engineering (CIMNE) Technical University of Catalunya (UPC) Edificio C-1, Campus Norte UPC Gran Capitán, s/n08034 Barcelona, Spain [email protected] or contact the publisher, Mrs Nathalie Jacobs, [email protected] Indexed in SCOPUS, Google Scholar and SpringerLink. More information about this series at http://www.springer.com/series/6899 Paulo Rui Fernandes Paulo Jorge da Silva Bartolo (cid:129) Editors New Developments in Tissue Engineering and Regeneration 123 Editors PauloRuiFernandes PauloJorgedaSilva Bartolo IDMEC-IST Schoolof Mechanical, Aerospace andCivil Lisboa, Portugal Engineering TheUniversity of Manchester Manchester, UK ISSN 1871-3033 Computational Methods inApplied Sciences ISBN978-3-030-15370-0 ISBN978-3-030-15372-4 (eBook) https://doi.org/10.1007/978-3-030-15372-4 LibraryofCongressControlNumber:2019934530 ©SpringerNatureSwitzerlandAG2019 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained hereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregard tojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface This book, New Developments in Tissue Engineering and Regeneration, is in line with the previous ones from the same editors, Advances on Modeling in Tissue Engineering (2011) and Tissue Engineering: computer modeling, biofabrication andcellbehavior(2014),anditrepresentsanewcontributionforthefieldofTissue Engineering with a focus on the development of mathematical and computational methods that are quite relevant to understand human tissues as well to model, design, and fabricate optimized and smart scaffolds. Thepresentbookencompassescontributionsfromrecognizedresearchersinthe field,who werekeynotespeakersintheFourthInternationalConferenceonTissue Engineering, held in Lisbon in 2015, and covering different aspects of Tissue Engineering. The book is strongly connected with the conference series of ECCOMAS Thematic Conferences on Tissue Engineering, an event that brings together a considerable number of researchers from all over the world, representing several fields of study related to Tissue Engineering. The editors are deeply grateful to all the contributing authors. We would also like to thank the European Community on Computational Methods in Applied Sciences (ECCOMAS), the Portuguese Association of Theoretical Applied and ComputationalMechanics(APMTAC),andthePortugueseFoundationforScience and Technology (FCT) for supporting the Conference. Lisboa, Portugal Paulo Rui Fernandes Manchester, UK Paulo Jorge da Silva Bartolo v Contents Computational Modelling of Wound Healing Insights to Develop New Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 M. J. Gómez-Benito, C. Valero, J. M. García-Aznar and E. Javierre Traction Force Microscopy in Differentiating Cells . . . . . . . . . . . . . . . . . 21 Shada Abuhattum, Amit Gefen and Daphne Weihs Adaptive Multi-resolution Volumetric Modeling of Bone Micro-structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Yizhak Ben-Shabat and Anath Fischer Low Temperature 3D Printing of Drug Loaded Bioceramic Scaffolds and Implants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Susanne Meininger, Elke Vorndran, Miguel Castilho, Paulo Rui Fernandes and Uwe Gbureck A Biomechanical Approach for Bone Regeneration Inside Scaffolds Embedded with BMP-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 C. Gorriz, F. Ribeiro, J. M. Guedes, J. Folgado and P. R. Fernandes vii Computational Modelling of Wound Healing Insights to Develop New Treatments M.J.Gómez-Benito,C.Valero,J.M.García-AznarandE.Javierre Abstract About1%ofthepopulationwillsufferaseverewoundduringtheirlife. Thus,itisreallyimportanttodevelopnewtechniquesinordertoproperlytreatthese injuries due to the high socioeconomically impact they suppose. Skin substitutes and pressure based therapies are currently the most promising techniques to heal theseinjuries.Nevertheless,wearestillfarfromfindingadefinitiveskinsubstitute for the treatment of all chronic wounds. As a first step in developing new tissue engineeringtoolsandtreatmenttechniquesforwoundhealing,insilicomodelscould helpinunderstandingthemechanismsandfactorsimplicatedinwoundhealing.Here, wereviewmathematicalmodelsofwoundhealing.Thesemodelsincludedifferent tissue and cell types involved in healing, as well as biochemical and mechanical factors which determine this process. Special attention is paid to the contraction mechanismofcellsasananswertothetissuemechanicalstate.Othercellprocesses suchasdifferentiationandproliferationarealsoincludedinthemodelstogetherwith extracellular matrix production. The results obtained show the dependency of the successofwoundhealingontissuecompositionandtheimportanceofthedifferent biomechanicalandbiochemicalfactors.Thiscouldhelptoindividuatetheadequate concentration of growth factors to accelerate healing and also the best mechanical propertiesofthenewskinsubstitutedependingonthewoundlocationinthebodyand B M.J.Gómez-Benito ( )·C.Valero·J.M.García-Aznar MultiscaleinMechanicalandBiologicalEngineering(M2BE),AragónInstitute ofEngineeringResearch(I3A),UniversityofZaragoza,Zaragoza,Spain e-mail:[email protected] C.Valero e-mail:[email protected] J.M.García-Aznar e-mail:[email protected] E.Javierre CentroUniversitariodelaDefensa,AcademiaGeneralMilitar;InstitutoUniversitariode investigaciónenMatemáticasyAplicaciones(IUMA),Zaragoza,Spain e-mail:[email protected] ©SpringerNatureSwitzerlandAG2019 1 P.R.FernandesandP.J.daSilvaBartolo(eds.),NewDevelopmentsinTissueEngineering andRegeneration,ComputationalMethodsinAppliedSciences51, https://doi.org/10.1007/978-3-030-15372-4_1 2 M.J.Gómez-Benitoetal. itssizeandshape.Thus,thefeedbackloopofcomputationalmodels,experimental worksandtissueengineeringcouldhelptoidentifythekeyfeaturesinthedesignof newtreatmentstohealseverewounds. · · · Keywords Woundhealing Mechanobiology Woundcontraction Skin substitutes 1 Introduction Skinisthelargestorganofthehumanbody.Itrepresentsthenaturalinterfacebetween thebodyandtheenvironment,actingnotonlyasaphysicalbarrierbutalsoasareg- ulatorofwaterloss.Itispartoftheimmunesystem,avoidingtheentranceofstrange particlesandpathogens.Whenskinisinjured,ithealsthroughacomplexcascadeof eventsaimedatrestoringskinintegrity.Normally,woundshealwithoutadditional complicationsinthetimecurseofafewweeks(torecoverthemainfunctionalities of skin). However, when the healing path is altered (by many pathological condi- tionsaffectingthisprocess),severeorchronicwoundsappear.Theseseverewounds include pathological scars in which there is an overexpression of collagen (hyper- tropicscarsandkeloids),contracturesinwhichthereisnotenoughscarformation, large area wounds such as burns, and chronic wounds such as pressure ulcer. The treatmentoftheseseverewoundsrepresentahighsocioeconomicalcost.Forexam- ple,ithasbeenreportedthatintheyear2000,thetreatmentofpressureulcersreached the4%oftheUnitedKingdomNationalHealthSystemexpenditure[2].Inthesame country,intheyear2011,theaveragecostofapressureulcerrangedfrom£1,214 to £14,108, attending to the severity of the case [9]. It is also important to notice thattheseinjuriesalsocauseconsiderablepaintothepatient,canaddmonthstothe hospitalstays[9],andintheworstscenariosdramaticallyreducethequalityoflife of the patients. Thus, it is really important from a societal, clinical and economic perspectivestoputoureffortsinthepreventionandreductionofthenumberofsevere woundsandimprove,intherangeofourpossibilities,theirtreatment. Serious injuries to the skin do not heal autonomously, and usually they require coverage to repair and restore skin function or other external treatments such as negativepressurewoundtherapy.Skinreplacementisnormallydonebyautologous skingraftofapatient;healthyskinisseparatedfromthedonorsiteandtransplanted into the recipient area. However, availability of sufficient healthy skin can limit this treatment, as well as the additional health risks associated with it such as the deformationofthedonor-site[39].Allogenetic,xenogenetic,syngeneicandcadaver skingraftsarealsoused;nevertheless,theypresentalsoproblemsofavailabilityand addtheproblemofrejection. Due to the above mentioned limitations of skin grafts, engineering skin substi- tutesemergeasagrowingareainbothclinicsandengineeringresearch.However, currently, no skin substitute has provided an outcome similar to an autograft [39]. Someoftheproblemswithexistingskinsubstitutesarethereducedvascularization ComputationalModellingofWoundHealingInsightstoDevelopNewTreatments 3 andscaringofthegraftmargins.Moreover,theirstructureremainstoberelatively simple (normal single layer or bilayered), and their three dimensional architecture and mechanical properties are still far from those of skin. This is in part due to theprocessesemployedtofabricatethem,beingtechnologicallyextremelydifficult toreplicatethewayhealthyskinappearsduringembryogenesisandfetaldevelop- ment [54]. In order to improve these treatments it is really important to know the mechanical behavior of healthy skin and the wound, and how they influence the cellmechanosensingcapacity.Therefore,thenextstepintissueengineeringshallbe thedesignofnewskinsubstitutesabletoreplicateskinandwoundmechanicaland functionalcharacteristics. Other treatments for chronic wound include the application of external stimu- lation. For example, negative pressure wound therapy (NPWT) has been used to promotehealingofsevereinjuries,anditiswidelyextendedinchronicwounds[22]. Thistreatmentisbasedonthepositiveeffectofmechanicalstimulationinthehealing oftissues.Thepositiveeffectoftensionstrainshasbeenobservedtoregenerateother biologicaltissuessuchasboneinthedistractionosteogenesisprocessinwhichthe rapidvascularizationisakeyfactorinthedevelopmentofnewbone[47].Oxygen- basedtherapieshavebeenexploredforthetreatmentofchronicwoundindiabetic patients.InthisrespectHyperbaricOxygenTherapies(HBOT)seekthepromotion of healing by the stimuli of the angiogenesis process [12], although the inherent negativeeffectsofthistherapyneedtobefurtherexamined. Unfortunately,wearestillfarfromdevelopingadefinitetreatmenttohealsevere wounds. The traditional approach to develop new therapies has been based on the useofanimalmodels.However,animalexperimentationisexpensiveineconomical, socialandtemporalterms.Also,thereisnoanimalmodelofskinwhichcompletely mimics all the characteristic of human skin [31]. On the other hand, the use of in silico models offers a wide (and cheap) spectrum for analyses. Consequently, it is calledtoplayaprominentroleinthedesignofnewtreatments,duetoitsintrinsic capacitytoisolatesinglefactors[18]. 2 HealthySkin Skinrepresentsa6%ofthetotalbodyweight[56],ithasavariablethicknessdepend- ingonthebodylocationfromaround1.5mminthesclapto4mmintheback.Itisa highlyorganizedstructureconsistingofthreemainlayers:theepidermis,thedermis andthehypodermis. Themostexternallayeroftheskinistheepidermiswhichiscontinuallyrenewing. Itisapproximately75–150µminthickness.Theepidermisisalsodividedintofive layers.Thestratumcorneumistheoutermostlayeroftheepidermiswhichprovides a permeability barrier and is mainly composed by a mixture of lipids and an acid mantle important to prevent infections. The other four layers which compose the epidermis are the stratum lucidum, the stratum granulosum, the sratum spinosum andthestratumgerminativumwhichareasecond-lineepidermalbarrierbetweenthe
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