Implant‐associated osteomyelitis: Development, characterisation, and application of a porcine model

Abstract

The author would like to thank the Independent Research Fund Denmark (Technology and Production) and the EU Horizon 2020 research programme for funding the research presented in this doctoral dissertation. In particular, I would like to thank Professor in Veterinary Pathology Henrik Elvang Jensen who participated in all parts of the experimental studies. Thanks for your inspiration, guidance and enthusiasm. My thanks also go to all the staff at the Pathobiological Sciences Section for being great colleagues and for the many happy times during work and social events. A special thanks to laboratory technicians Elizabeth Petersen and Betina Andersen for all your help in the histo-lab. I apologize for all the challenging and problematic issues regarding histological preparation of bones. Many thanks also to technicians Dennis Brok and Frederik Andersen for their skilful technical support and help producing images. I would also like to thank the animal technicians at the Department of Experimental Medicine for their excellent care of the pigs and help with anaesthesia, blood sampling and inoculation procedures. Thank you to all my research assistants during the past 5 years, including Kristine Dich-Jørgensen, Anne Sofie Boym Johansen, Nicole Lind Henriksen and Amalie Blirup-Plum. Thank you for your hard work, including endless hours spent evaluating and scoring histological slides, and thank you for bringing enthusiasm and fun into our daily routine. Thanks also to Expert in Experimental Surgery Janne Koch, Associate Professor in Veterinary Microbiology Bent Aalbæk and to Professor in Chronic Infections and Biofilm Thomas Bjarnsholt. You have all been indispensable for the research described in this dissertation. Thomas, I enjoyed our biofilm discussions and I am grateful for all your support. Thanks to everyone in Professor and Orthopedic Surgeon Kjeld Søballe’s research group at Aarhus University Hospital for our collaboration on antimicrobial penetration into infected bone tissue. Mikkel Tøttrup, Pelle Hanberg and Mats Bue, it has been a pleasure to work with you. Finally, thanks to all my friends and family for their never ending support and trust, and thanks to my wonderful husband and daughters, Kim, Alberte and Frida, for your love and patience. Worldwide, there has been an ongoing increase in the number of bone infections that lead to amputations and lifelong disability, affecting millions of people every year. Therefore, research investigating the prevention, diagnosis and treatment of bone infections is vitally important. However, to develop effective new approaches and techniques for managing bone infections, preclinical testing and evaluations using reliable animal models are necessary. A novel porcine model of implant-associated in The model on and inoculation of into a a into the The 5 pigs to the and with The of the model that all the pigs with to in with in the porcine and the bone and on the of the bone a for biofilm an are to and are the for bone treatment new porcine model to develop a biofilm and The new the and to the of the and treatment with an for the The new also on bone with using the porcine that and penetration into the infected bone into bone tissue. this antimicrobial penetration with the of bone that to a of the into the bone antimicrobial The penetration to and bone and of the of antimicrobial the into the it to a also a on the of a of of to the to inoculation into the porcine to the of including and of effective at the that the of antimicrobial using in A of all animal models of bone pigs and it that experimental of and the Therefore, a for on animal models of bone that the animal of the on a that there many in using pigs for biofilm infections in infections also in there are many with who have infections, including bone the of antimicrobial that new for are The novel porcine model described is a and reliable for investigating new and treatment for bone infections in at at at at for at 5 at at at for to for at penetration I penetration at at at for at in I for at at at for for at for at for biofilm at for at Worldwide, there has been an ongoing increase in the number of bone infections that lead to amputations and lifelong disability, affecting millions of people every bone infections a in of and to the infections infections implant-associated in and is the of and it is that a is every to The number of bone infections is to an increase in the of the an of and an increase in the number of and bone being The of the and the of treatment that the and treatment are Therefore, research on prevention, diagnosis and treatment of bone However, the of effective new approaches and techniques on preclinical testing and evaluations in reliable animal In this a novel porcine model is The to the and of this Chronic infections are Therefore, it is that regarding are on in laboratory into there are many with who have infections, including bone In the of antimicrobial that new for are The porcine model has new in regarding In particular, have that the to in of a for the to Biofilm also and research into and is for evaluating bone new approaches to biofilm in research the of to of that of new and the of of new for using the porcine the past 5 years, the porcine model has been in In the model the of an EU 2020 Research and Biofilm to new in a and for in the porcine In the also in the of a new for a that and of EU on the new is and using the porcine In to the the porcine model also to the of a bone of the porcine model is also being to the of bone of porcine and infected bone have that bone and a an In research has that the of is for bone In particular, the of that the are in of regarding in on animal models of bone infections and the of using pigs for In the of the new porcine model is on a new for in of and biofilm in porcine 5 the of the porcine model in investigating antimicrobial penetration into infected bone and the of biofilm Finally, the the on this is In bone infections at a of and at a of In it that in the to of for the of infections and and infections at in the and the that is the and of a this lead to of the The to of the bone and the to of the bone including the is the and this is for bone in on the to of the are bone the and the and are a a the of an is also is a bone with that for at the of bone in an infections that to In is with for Therefore, also in the also using the with and The and are in this and the are the and of the The into is to the of the the and In this the bone and the the bone the of the with of The a and the is a with The is that the and are who are that have The of bone and on the of bone lead to a the and the of the of also to bone the bone increase the and of blood in to bone the and the and this lead to a and blood and of a bone a for an bone and in the into and a of an the bone The is and is with into the and to the a The of the increase and a new of are and and are the that are for and infections are A and The bone infections are of the bone during and during the infections to and infections are a of infections to the bone bone to and the bone are to infections the are to the bone the of the of is for and to and bone is to the to is a of procedures. to and of bone and the bone and and the a in to the the are to the bone into a biofilm However, of biofilm the also the A biofilm is a of in an is antimicrobial and of the in a biofilm to the to of biofilm is to their and their and antimicrobial Biofilm are to of their A bone biofilm also antimicrobial of this biofilm the of a bone to treatment is research has that is is in infections, to the of antimicrobial and and of bone of the infected and treatment to the bone the for of is biofilm in the bone pigs and are being in preclinical research to their are for the of many of and is also being in the of bone Therefore, a to an of on pigs and animal models of bone infections The to in for inoculation the animal The also the of the and and of and The on a of and of in a of that the experimental inoculation of in to model of bone in pigs and have been experimental to bone infections that the of and porcine models is an to models in the of models a for and in in a animal a a in the the animal inoculation inoculation to However, porcine including the model described in this regarding a number of In particular, the inoculation and the inoculation to in pigs in all of the animal the of bone the for inoculation of the a for the In on models that on inoculation into a bone using a inoculation an at the the Therefore, preclinical bone are with in who that a the number of to an of into the of in of the infected and of the being However, an and of all infected and of the infections The of animal models of bone infections that is and of bone Therefore, it is to including and histological and of using animal models of bone infections The of bone models is the bone a of the infected However, our that bone in of the on and models In histological and histological and The for the animal and are for bone infections in In the of histological the animal that of bone and in of the of the animal However, a of the in of the Many of the models to antimicrobial and the of it to also that of the investigating an antimicrobial that all the of to that regarding for in has been In many a in is the a and a in of A to the have an a biofilm is A of animal models of bone that the of in of the of In the of on animal models of bone infections and However, research has that the of lead to the of an being Therefore, of and the of animal models of bone infections that and inoculation it to and of models of the regarding and of that The of the for in preclinical bone In of and in many on animal models of bone infections and studies. for of animal models of bone infections are to the of on models and models in the to help to that bone models of bone of in the model inoculation inoculation into a of bone inoculation to of the including of the bone and including and of of in to inoculation of of into and The animal for of bone infections have and that are to of a and to that and in the model However, animal our of bone models the of an animal is important. Therefore, the on the of using pigs to model bone pigs experimental to and However, during the there has been an increase in the number of porcine models to infections in on and bone infections are experimental of their are to of including their and The of the has been and many laboratory for porcine have models of infections have been in pigs for in The pigs and is The of a is at at and to that of a at at and of Therefore, are for of However, the of pigs to model infections, including bone infections, of all porcine models of in have been on pigs is a in to that are of have been to many are to with to bone and of the of a porcine that the of bone of bone with in the The of bone with and the of porcine bone is to that of bone is the of The bone of pigs is to that of the of porcine bone is In the and of porcine and are and bone and with and that the of and porcine to that of the the of the bone and bone in pigs and are Finally, a on the porcine model with that the of and bone in bone to to that in The porcine to is also to that of that many of the and porcine are and The to the to infections in including bone infections, are However, research has that of the to infections and the and have in and are the in are in also and in to infections and are the blood A that all in of in and have been in using all regarding and the in bone infections on models However, the porcine model has been to the of and and of bone of infected bone of and is the of in to bone However, in in the and the of in to of a the on bone bone to is an that of to the on and and bone The and bone in using bone models and in investigating with However, it has been to the using with in the porcine the of to and in and bone infections that the is in pigs with bone the of models for investigating bone is A of in the porcine model and described has in The that bone an to bone for In the in for bone infections in reliable animal is new for bone infections antimicrobial also of the of bone of bone on the the in the porcine are being to and and are being on with new and in bone infections also in In pigs are at with their are and a of is to bone are in the of and in the of the of in pigs and is also in for of bone infections and However, the in the is the is are regarding bone infections in models have been experimental models in pigs to bone infections in research has that in the porcine model and in pigs with In the in experimental and infected pigs to that in with pigs with an that to the to bone A novel porcine model of and in experimental The model on pigs The and to for the procedures. to develop the pigs in the antimicrobial The porcine model with in and on inoculation of into the during a The an porcine it been effective in infections in including and in pigs and in on and have with in Therefore, infections in A is for in animal models of Therefore, the of and the to A and The has including and Biofilm using a in biofilm and to that of The of biofilm for the of of in the effective for in the porcine model pigs in the of the The porcine model on an of using a and and to the to the of into the that the of the The for into the and a the the and bone the pigs times the with daily for been with pigs pigs the and the A pigs with at and pigs to and of for and animal models of bone infections have a inoculation to the of for However, animal models of is problematic to issues to with infections, for the of with the of it to an in In the of the new porcine inoculation to the of the porcine bone to in and and all Therefore, a of 5 in The porcine model with infections during bone that is the of in an to and infections that the model in to infections and on and the pigs and the bone and using a and to the of bone In all with the the inoculation with in the and In of the infected and bone with at the the in all However, in infected the and the and the to the bone The the The of with a with of In of and bone the of with infected with the described the bone The on the the of the to bone In the inoculation in bone and the In a of in of for is with that in bone to A in infected with In a of that and bone the bone with the and in of the bone the of and and the of and of in a of in the porcine model described in lead to of and of in the and of bone in the of infected with and the of of is in the for of bone Therefore, this also in the histological of the porcine model The number of using the in at at and all In a of in this in a of The for a infected and in In the of the porcine model and the of histological with antimicrobial penetration into infected bone the histological and to an are to the for bone infections However, the scoring for this the number of Finally, the in for The of bone with of bone infections In the biofilm has been In the porcine all are with in of and However, to research has that the of and with a an a Therefore, the model also the of the of an the with the and the of all with in of with the that for the with porcine porcine of in and infected on is for bone in However, in the porcine this the of infections and the with for and of research that are in an and the is the of to an Therefore, to the number of to in the porcine model and the number of The pigs in the and the and all and in the and and for histological However, histological of the in In a for porcine to the of in of the pigs have been times for bone infections using inoculation into a in and The bone inoculation of into a model to the of a bone a The model in In this of and a bone to bone into the inoculation The in this model The model of into a using an The and the the porcine model a in the number of to the the porcine model with and the model a that all an that novel porcine model with a The of 5 in bone The an with with of the is with the the bone and an infected in with infections in with the for and the in our model would infections research has that the model in a of The porcine model to on the that is and bone in a In bone infections are and are in and the of is have of in a animal bone model The and in our porcine model are to in the in many and the bone is the that in the porcine model of to a a a However, with that to at the of in Experimental implant-associated bone infections a the preclinical a new antimicrobial regarding and are with the of the porcine the years, the model has been to develop a novel and a novel antimicrobial new approaches are to in a and of the model on of in of our regarding biofilm is on research in models However, have that in are in that in models are of In of and in a of and in are with and are to an are in an of the of the the of an in biofilm is to an in biofilm in have an is hard to in a laboratory porcine models of biofilm infections in and the in the models with of the infections in pigs at of in the pigs to described in In to the pigs have also been to model that are with biofilm in and The for the of and of the of the of the experimental and pigs with infections In the and of with and in and pigs in all the experimental models in the of the that on the of biofilm is of the models and biofilm is a new of in of Biofilm is in of porcine A in that all in a In it has been that all infections in for the of biofilm porcine infections are to described in on Therefore, the of with infections in a to in infections, are in the of biofilm on an However, biofilm also to and bone the of is in and of infections and in have been in models of infections in and and the new porcine model on the new porcine model that the in that to into the the in the porcine on the at the the and into the porcine model a are is to to the in the bone the all of of the Biofilm lead to antimicrobial treatment effective Therefore, to the is to the are of the of to infections in in and of is that all it to The of a biofilm is of the and the and and of have to and of the In are to the of for Therefore, a to the of using However, the is an of it is to the Therefore, in with techniques to to and the biofilm using A of infected bone the new porcine In a of infected bone the of a with of into the and Finally, a of infected bone a with of the to this all the for a biofilm including in to a and to In of porcine and using the in the of the and the of the biofilm the of the of the and the of the the and and with an on an in to and a The also to the The of the biofilm with to of and the and of the biofilm with and to of of and biofilm in and of the in the porcine and The to slides, and to the of and in a of with in the in the porcine models to the for Microbiology and for biofilm infections, to the of a of an the of and the that are in a is the using the new of and techniques for biofilm Surgery is to all and the of and are of is to biofilm at the for is on the of the for However, there is an of antimicrobial treatment models of bone infections are to and for managing in However, treatment using animal models of are the treatment of at are is to the and the has a treatment is preclinical treatment on the of also infections to develop treatment In a is for in approaches are with inoculation and is antimicrobial treatment of on using that the and have the bone penetration is to a at the to and the of treatment to of regarding penetration of antimicrobial many antimicrobial have been have is and and have bone penetration of that are to Therefore, antimicrobial treatment that are on of to with have blood at the and of and the penetration of the of antimicrobial to bone the of the to infected bone tissue. the of bone and on penetration in the porcine model of In pigs with for 5 and in the infected in the infected bone the and in the infected In in the bone and of the In a of and and the an antimicrobial penetration into bone has been using bone the antimicrobial and However, an to using bone it to the of is a on with at the The of the and the in the the is with an is never The of and that penetration of into the infected and penetration into infected bone also of penetration into the penetration into infected bone to penetration into bone In penetration of that of Therefore, the of the to a and the bone antimicrobial to antimicrobial treatment for bone infections and to of the of the in the porcine it to the histological with antimicrobial penetration of the all to that all in with the evaluating The of the the described in The to and with antimicrobial that is and penetration of antimicrobial into infected with the of bone In particular, that in antimicrobial penetration The a that and The of and the and of and to and and The all of and with at the of with a In In to the the the have and the the However, the of to the penetration Therefore, the to for the blood the and have the blood the the in the the Therefore, have been the the of the bone have the the that to develop antimicrobial of times the and antimicrobial have infected bone of bone and biofilm is for treatment of However, the bone with during The bone in and the in and have a an for new to the to is to a that the bone and of to the of the of using is that this the of Research has that the of the in However, the to into the bone the porcine model to the of a bone of of the of the bone with biofilm However, bone in of the bone of the bone have been to the of the the to The of in the bone this The are and The bone treatment have been in of of the antimicrobial the of the bone and the bone the The of on the the penetration and the of and antimicrobial and an on the of to the treatment The of in using the novel porcine model The of the to an in antimicrobial for biofilm of to the into the porcine to in an in using and and the for inoculation the and the a the and the and for the and the the and described for inoculation of the porcine the A of pigs in the with to of The in the model described of to the The in the and pigs 5 inoculation and using the described in The of using of the of and of the for of and In for of and A in the number of to the the group and The with the of in in the group for animal with in the in the of all and in the of and and the group and the group to of with In the of in the of the porcine model to to the However, the bone all in a to inoculation the effective in the of the However, of the and the of biofilm on the of the and and the on to a and the of in the in an the bone tissue. In inoculation to and and to the have the and the and bone the with to on to to the Therefore, to inoculation to to and bone the of biofilm have the of inoculation In would the increase the of for The in the are that the effective of antimicrobial to the of the and to of the that the in and of antimicrobial is in has been using experimental In of the in have been to on research with animal for the and treatment of using and the of and using pigs and and the of and using our of the and treatment of many research on is bone a reliable and effective porcine model for bone research and for studies. porcine model is being in ongoing and and The bone and for of bone that the model in that a new bone the of with and for infections the the of and antimicrobial the of and that bone are also in into bone infections, in with the of to and and a of to bone infections In with antimicrobial to in a has with infections The porcine model has been to novel In and have been on new of and

Topics & Concepts