ELSEVIER Volume 55 Supplement 6, November 2024 ISSN 0020-1383 Supplement name: Fracture Related Infections An Update: OTC Supplement 2024 Supplement Guest editors: Volker Alt and Hamish Simpson
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ELSEVIER Injury is abstracted/indexed by: Current Contents, Science Citation Indexed Expanded, Index Medicus, Pubmed/Medline and EMBASE. Also covered in the abstract and citation database SCOPUS®. Contents Volume 55/S6, November 2024 Editorial Editorial: Fracture-related infections V. Alt, H. Simpson 111959 Pathophysiology and animal models Bone infection evolution L. K. Jensen, K. T. Hartmann, F. Witzmann, P. Asbach, P. S. Stewart 111826 Antimicrobial resistance: Biofi lms, small colony variants, and intracellular bacteria J. Straub, S. Baertl, M. Verheul, N. Walter, R. M. Y. Wong, V. Alt, M. Rupp 111638 In vivo models of infection: Large animals – Mini review on human-scale one-stage revision in a porcine osteomyelitis model N. L. Henriksen, H. Gottlieb, M. Bue, S. Vittrup, L. K. Jensen 111842 Prevention of Fracture-related Infection Eff ect of mechanical stability of osteosynthesis on infection rates: Timing of temporary and defi nitive fi xation E. Santolini, V. Giordano, P. V. Giannoudis 111845 Timing of debridement: When to do it, and who should perform it? M. F. Powell-Bowns, J. F. Keating 111604 Initial treatment of severe soft-tissue injuries in closed and open fractures to prevent fracture-related infection C. von Rüden, J. Wunder, C. Schirdewahn, P. Augat, S. Hackl 111935 The role of tranexamic acid for infection prevention after fracture fi xation A. Benjumea-Carrasco, M. Guembe, M. Díaz-Navarro, P. Muñoz, J. Vaquero-Martin, F. Chana-Rodriguez 111846 Vaccines: Do they have a role in orthopedic trauma? S. L. Kates, J. R. Owen, C. Xie, Y. Ren, G. Muthukrishnan, E. M. Schwarz 111631 Diagnosis of Fracture-related Infection: The value of current diagnostic techniques in the diagnosis of fracture-related infections: Serum markers, histology, and cultures K. Trenkwalder, S. Hackl, F. Weisemann, P. Augat 111862 Fracture-related infection blood-based biomarkers: Diagnostic strategies R. M. Natoli, S. Malek 111823 Assessing diagnostic accuracy: 18 F-FDG PET-CT scans in low-grade infection detection among post-traumatic long bone non-unions; a literature review and clinical data L. C. A. van der Broeck, C. Mitea, D. Loeff en , M. Poeze, S. Qiu, J. Geurts, T. J. Blokhuis 111712 New diagnostic techniques for diagnosing facturerelated infections A. Hoff mann, J. Hoff mann, T. Ruegamer, N. Jung, R. M. Y. Wong, V. Alt, P. Eysel, J. Jantsch 111898 Treatment of Fracture-related Infection: Recent advancements and future directions in fracture related infections: A scoping review N. Walter, S. Bärtl, V. Alt, M. Rupp 111902 Multidisciplinary approach and host optimization for fracture-related infection management B. Li, C. Liu, V. Alt, M. Rupp, N. Zhang, W.-H. Cheung, J. Jantsch, R. M. Y. Wong 111899 The DAIR-procedure in fracture-related infection–When and how S. Baertl, M. Rupp, V. Alt 111977 Phage therapy: A primer for orthopaedic trauma surgeons B. Chen, T. F. Moriarty, W.-J. Metsemakers, M. Chittò 111847 Supplement name: Fracture Related Infections an Update: OTC Supplement 2024 Supplement Guest editors: Volker Alt and Hamish Simpson
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Volume 55/S6, November 2024 Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis Supplement name: Fracture Related Infections An Update: OTC Supplement 2024 Supplement Guest editors: Volker Alt and Hamish Simpson This paper is part of a Supplement supported by the Osteosynthesis and Trauma Care Foundation (OTCF) through a research grant from Stryker.
Editor-in-Chief Systemic response to trauma, pediatric trauma and reviews P.V. Giannoudis, Leeds, UK Non Orthopaedic I. Civil, Auckland, New Zealand Basic Science and Biomechanics B. Norris, Tulsa, USA Z. Balogh, Newcastle, NSW, Australia Educational Section (BOTA) Ran Wei, London, UK Graham Finlayson, Belfast, NI Lower Limb Andrew Gray, Middlesbrough, UK Sharon Scott, Liverpool, UK Spine, Pelvis and Acetabulum H.C. Pape, Zurich, Switzerland Infection Volker Alt, Regensburg, Germany Upper Limb Y. Lu, Beijing, China Reviews Editor (Non-Orthopaedics) P. Cameron, Victoria, Australia Pathological Fractures P. Ruggieri, Padova, Italy Tissue Engineering and Regenerative Therapies (ESTROT) E. Guerado, Malaga, Spain Orthopaedic Trauma Guidance R. Buckley, Calgary, Canada Meta-analysis Studies C. Papakostidis, Limassol, Cyprous Editorial Board Past Editors S.J. Krikler, Coventry, UK Statistical Advisor Robin Prescott, Edinburgh, UK Administrative Editor E-mail: injury@elsevier.com; Online Submission: http://www.editorialmanager.com/jinj/ Editors Affiliated Societies AO Trauma China B. Yu, Guangzhou, China X. Wu, Beijing, China AO Trauma F. Gebhard, Ulm, Germany Australian and New Zealand Trauma Society D. Varma, Melbourne, Australia R. Ogilvie, Amaroo, Australia Brazilian Orthopaedic Trauma Association (BOTA) Vincenzo Giordano, Rio de Janeiro, Brazil William D. Belangero, Campinas, Brazil British Trauma Society S.J. Matthews, Leeds, UK A. Patel, Norwich, UK Club Italiano Osteosintesi G.M. Calori, Milan, Italy F. Benazzo, Pavia, Italy P. Maniscalco, Piacenza, Italy ESTROT Society T. Begue, Clamart, France E. Guerado, Malaga, Spain Croatian Trauma Society B. Bakota, Zagreb, Croatia M. Staresinic, Zagreb, Croatia Dutch Trauma Society I. Schipper, Leiden, Netherlands M. Verhofstad, Rotterdam, Netherlands Gerhard Küntscher Society D. Seligson, Louisville, USA J. Verbruggen, Netherlands Groupe d’Etude en Traumatologie Ostéoarticulaire P. Bonnevialle, Toulouse, France T. Begue, Clamart, France Hungarian Trauma Society E. Varga, Hungary Orthopaedic Trauma Care Foundation (OTCF) Volker Alt, Regensburg, Germany Italian Society of Orthopaedics and Traumatology G.M. Calori, Milan, Italy A. Piccioli, Rome, Italy Spanish Society Orthopaedic Surgery and Traumatology (SECOT) F. Chana, Madrid, Spain J. Cordero, Madrid, Spain Trauma Society of India S. Babhulkar, Nagpur, India S. Kulkarni, Miraj, India Turkish Orthopaedic Trauma Society Kemal Aktuˇglu, Izmir, Turkey Güvenir Okcu, Manisa, Turkey B. Bavonratanavech, Bangkok, Thailand M. Bhandari, Ontario, Canada M.D. Bircher, London, UK K. Boff ard, Johannesburg, South Africa H. Broekhuyse, Vancouver, Canada K. Brohi, London, UK T.J.S. Chesser, Bristol, UK S. D’Amours, Sydney, Australia S. Deane, Newcastle, Australia V. deRidder, Rotterdam, The Netherlands M. Dhillon, Chandighar, India J.J. Diaz, Jr., Nashville, USA A. Dilley, Sydney, Australia D. Eastwoody, London, UK D. Finlayson, Inverness, UK C.T. Frey, Gauteng, South Africa C. Gaebler, Vienna, Austria T.A. Gennarelli, Milwaukee, USA D. Gentleman, Dundee, UK C.A. Graham, Hong Kong E. Guerado, Malaga, Spain D. Hak, Denver, USA T. Hardcastle, Durban, South Africa I. Harris, Sydney, Australia A.G. Hill, Auckland, New Zealand P. Hoff meyer, Geneve, Switzerland R. Ivers, Sydney, Australia M. Joshipura, Ahmedabad, India J.B. Jupiter, Boston, USA N. Kanakaris, Leeds, UK L. Kao, Houston, USA J. Kortbeek, Alberta, Canada C. Krettek, Hannover, Germany F. Lecky, Salford, UK K.S. Leung, Hong Kong M.E. Lovell, Manchester, UK R.V. Maier, Seattle, USA E.J. MacKenzie, Baltimore, USA A. Masquelet, Paris, France B. Mitra, Melbourne, Australia K. Mizuno, Kobe, Japan C. Mock, Seattle, USA M. Morandi, Shreveport, USA K. Morikawa, Aichi, Japan M. Muller, Brisbane, Australia H.J. Oestern, Celle, Germany C.W. Oliver, Edinburgh, UK O.O.A. Oni, Leicester, UK C.G. Papakostidis, Lemessos, Cyprus M.J. Parker, Peterborough, UK R. Pavic, Osijek, Croatia D. Pennig, Koln, Germany R.W.H. Pho, Singapore P.M. Reilly, Philadelphia, USA J.V. Rosenfeld, Melbourne, Australia S. Ross, Camden, USA M.J. Seamon, Philadelphia, USA D. Shorwitz, Danville, USA R.M. Smith, Boston, USA P. Soucacos, Athens, Greece E. Steinberg, Tel-Aviv, Israel P. Ström, Uppsala, Sweden W. Taha, Riyadh, Saudi Arabia K. Taviloglu, Istanbul, Turkey P. Tranquilli-Leali, Sassari, Italy M. Bumbasirevic, Belgrade, Serbia D.J. Wiebe, Philadelphia, USA M.K. Wyse, Yelvertoft, UK H. Yamamoto, Ehime, Japan Y. Zhang, Shijiazhuang, China International Editorial Board
Editorial: Fracture-related infections Fracture-related infections (FRI) remain a threat for fracture patients despite remarkable progress in the last years, e.g. with multidisciplinary treatment strategies, including the so-called orthoplastic approach with combined early bone and soft-tissue management and the expertise of other disciplines, such as microbiology, pathohistology and infectious disease [1]. This is becoming more and more standard in high-income countries. In contrast, financial constraints in health care systems in low- and middle-income countries often limit treatment of FRIs to simple methods, such as abscess drainage and immobilization of the affected limb [2]. The high burden of disease due to the high prevalence of FRIs in these countries is a further escalation of this problem. The current OTCF INJURY Supplement is based on the content and presentations that were given at the Orthopaedic Trauma Care Foundation Workshop on FRIs, which was held between 16-17 November 2023, in Rome, Italy. The Orthopaedic Trauma Care Foundation (OTCF) is an interactive global network of surgeons and scientists, dedicated to the advancement of osteosynthesis and trauma care. At this workshop, experts on preclinical and clinical aspects of FRIs discussed current challenges in pathophysiology, diagnostics and treatment management of this complication after fracture treatment. The presenters of the workshop were asked to write narrative reviews on their expert area field that underwent the official review process in INJURY before publication in this Supplement. All these papers are now compiled in this OTCF INJURY Supplement 2024, which represents a comprehensive review on the topic of FRIs covering multiple areas, such as basic science, medical and surgical disciplines. Along side state-of-the art diagnostics and treatment approaches, a focus is given on further directions, including biomarkers and new imaging techniques, such as PET-CT, next generation sequencing and MALDI-TOF. Vaccines against orthopedic infections and bacteriophage therapy as new approaches in FRIs are also addressed. In summary, this OTCF INJURY Supplement 2024 is a comprehensive overview on the most relevant aspects of FRIs and aims to provide readers with a summary for their research and clinical practice. With this, we hope to create your interest in this important topic in order to improve patient outcomes in FRIs. The guest editors and all authors of this supplement express their appreciation to the Orthopaedic Trauma Care Foundation and the grantor Stryker for the sponsorship of the Hot Topic Workshop 2023 in Rome, Italy, and of this OTCF INJURY Supplement. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Rupp M, Walter N, Popp D, Hitzenbichler F, Heyd R, Geis S, Kandulski M, Thurn S, Betz T, Brochhausen C, Alt V. Multidisciplinary treatment of fracture-related infection has a positive impact on clinical outcome-a retrospective case control study at a tertiary referral center. Antibiotics (Basel) 2023;12(2):230. https://doi. org/10.3390/antibiotics12020230. Jan 21PMID: 36830141; PMCID: PMC9952612. [2] Loro A, Fulvio F, Alt V. Treatment of bone infections in children in low-income countries - a practical guideline based on clinical cases. Injury 2023;54(12):111066. https://doi.org/10.1016/j.injury.2023.111066. DecEpub 2023 Sep 26. PMID: 37856924. Volker Alta,*, Hamish Simpsonb a Department of Trauma Surgery, University Hospital Regensburg, Regensburg, Germany b Department of Trauma and Orthopaedics, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 4SA, UK * Corresponding author at: Department of Trauma Surgery, University Medical Centre Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. E-mail address: volker.alt@klinik.uni-regensburg.de (V. Alt). This paper is part of a Supplement supported by the Osteosynthesis and Trauma Care Foundation (OTCF) through a research grant from Stryker. Contents lists available at ScienceDirect Injury journal homepage: www.elsevier.com/locate/injury https://doi.org/10.1016/j.injury.2024.111959 Injury xxx (xxxx) xxx 0020-1383/© 2024 Published by Elsevier Ltd. Please cite this article as: Volker Alt, Hamish Simpson, Injury, https://doi.org/10.1016/j.injury.2024.111959
Bone infection evolution Louise Kruse Jensena,*, Katrine Top Hartmanna, Florian Witzmannb, Patrick Asbachc, Philip S Stewartd a Department of Veterinary and Animal Science, Faculty of Health and Medical Science, University of Copenhagen, Denmark b Museum für Naturkunde, Leibniz-Institut für Evolutions- und Biodiversit¨atsforschung, Berlin, Germany c Department of Radiology, Charit´e - Universit¨atsmedizin Berlin, Germany d Department of Chemical and Biological Engineering, Center for Biofilm Engineering, Montana State University, Bozeman, MT, USA ARTICLE INFO Keywords: Evolution Osteomyelitis Fracture-related infection A B S T R A C T The present minireview aims to provide a context for imagination of the timespan for bone infection evolution from the origin of cellular bone tissue to modern orthopedic surgery. From a phylogenetic osteomyelitis- bracketing perspective, and due to the time of osteocyte origin, bacteria might have been able to infect the skeleton for approximately 400 million years. Thereby, bone infections happened simultaneously with central expansions of the immune system and development of terrestrial bone structure. This co-evolution might aid in explaining the many immune evasion strategies seen in the field of bone infections. Bone infection patients with long disease-free periods followed by sudden recurrence and anamnesis of long-term and low-grade infections indicate that bacteria can perform silent parasitism within bone tissue (parasitism; one organism lives on another organism, the host, causing it harm and is structurally adapted to it). The silence seems to be disturbed by immunosuppression and the present minireview shows that a compromised immune system has been associated with bone infection development across all species in the phylogenetic tree. Orthopedic surgery, including arthroplasty and osteosynthesis, favor introduction of bacteria and prosthesis/implant related infections are thus anthropogenic infections (anthropogenic; resulting from the influence of human beings on nature). In that light it is important to remember that the skeleton and immune system have not evolved for millions of years to protect titanium alloys and other metals, commonly used for orthopedic devices from bacterial invasion. Therefore, these relatively new orthopedic infection types must be seen as distinct with unique implant/prosthesis related pathophysiology and immunology. Introduction The idea behind this minireview originates from reading two papers on different types of bone infections published in the New England Journal of Medicine (NEJM). The first paper (2012) describes a case report of haematogenous osteomyelitis caused by Staphylococcus aureus [1]. The disease was diagnosed in a 10-year-old girl in 1934 and because antibiotics were not available at that time, she was treated with several rounds of surgery and recovered fully [1]. However, at the age of 85 the osteomyelitis lesion came back due to reactivation of remnant bacteria [1]. The second paper is a newly published review (2023) on prosthetic joint infection (PJI)[2]. Both papers describe conditions based on bacterial entrance and residence within bone tissue, although in very different contexts. Therefore, we found it important to look on the evolutionary perspective of bone infections (Fig. 1). Skeletal housing of bacteria without causing serious systemic disease as reflected in the haematogenous osteomyelitis case, and often also in PJI and fracture related infections (FRI) indicates a long evolutionary relationship between bacteria and bone tissue [1-3]. A relationship that has enabled bacteria to perform silent parasitism within bone tissue (parasitism; one organism lives on another organism, the host, causing it harm and is structurally adapted to it). The present minireview aims to offer some new insights about this evolutionary silent parasitism (Fig. 2). Publication of this supplement is supported by the Osteosynthesis and Trauma Care Foundation (OTCF) through a research grant from Stryker. * Corresponding author at: Ridebanevej 3, 1870 Frederiksberg C. Department of Veterinary and Animal Science, Faculty of Health and Medical Science, University of Copenhagen, Denmark. E-mail address: Louise-k@sund.ku.dk (L.K. Jensen). Contents lists available at ScienceDirect Injury journal homepage: www.elsevier.com/locate/injury https://doi.org/10.1016/j.injury.2024.111826 Accepted 16 August 2024 Injury xxx (xxxx) xxx 0020-1383/© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Please cite this article as: Louise Kruse Jensen et al., Injury, https://doi.org/10.1016/j.injury.2024.111826
Fig. 1. Tree of life in a bone infection perspective. Bone infections (osteomyelitis and fracture-related infection (FRI)) have probably occurred since osteocytic bone was a reality. Several species across the phylogenetic tree have been diagnosed with osteomyelitis and FRI including several dinosaur species. All diagnosis of bone infections in fossils has been based on osseous pathologies such as sequester and involucrum formation which also are seen in present-day’s birds, reptiles, and mammals. Thus, these pathological manifestations seem highly conservative, but their evolution has never been investigated. In an evolutionary perspective bone infections related to implants and prostheses are young infection types and no evolution has occurred to protect titanium and other metals from bacterial invasion. The references relate to papers of bone infection in the family of the shown animals [31–39,42]. Red references =bone. Blue references =fossils. L.K. Jensen et al. Injury xxx (xxxx) xxx 2
Bone infections across the phylogenetic tree Bacteria have lived on Earth for billions of years, and it is tempting to consider whether they entered the skeleton as soon as bone tissue was a reality. The earliest bone of the vertebrate evolution was acellular which implies that at least bone cell and osteocyte lacuna canaliculi network (OLCN) invasion by bacteria was not an option [4]. Cellular bone (osteocytic and with canaliculi) developed around 400 million years-ago in the last common ancestor to osteostracans (derived jawless fishes) and jawed vertebrates [4] (Fig. 1). Interestingly, the largest and most derived group of osteichthyans (bony fishes), the teleosts, has secondarily lost osteocytes but do have many osteoclasts and a chondro-osseous intermediary bone tissue. The earliest known bone infection was documented in the early tetrapod Crassigyrinus (an amphibian in the broader sense) that lived about 320 million years ago in the Early Carboniferous [5]. Another well-known and well-preserved piece of evidence of bone infection (local inflammation of a fracture site) lies in the sail-backed Dimetrodon, a reptile-like forerunner of mammals, which was in existence 250 million years ago [6]. Only one fossil slightly supports bacterial bone invasion of ancient bony fishes as Rothschild & Martin in 2006 briefly mentioned bone infection (fracture with draining sinus) in a Late Carboniferous ray-finned fish [7]. However, bacterial induced osteomyelitis or trauma caused bone infections are not reported diseases of modern fish species (in comparison to osseous parasitic infections). Osteomyelitis has been reported in all modern reptiles, i.e., turtles, snakes, crocodilians, and lizard and even also briefly in amphibians (frog and toads) [8-12]. Therefore, in a phylogenetic disease-bracketing perspective, and due to the time of osteocyte origin, bacteria might have been able to infect the skeleton for approximately 400 million years causing both osteomyelitis and FRI (Fig. 1). Osteomyelitis was also diagnosed in a number of non-dinosaurian fossil reptiles like the 275-million-year-old basal form Labidosaurus or in the mosasaurs, giant marine lizards that lived 90–65 million years ago [13,14]. In recent years the field of dinosaurian paleopathology has grown significantly, expanding the breadth of taxa involved and types of pathologies reported [15]. Osteomyelitis and FRI has been identified in several fossils of different dinosaur species with reported paleopathological findings comparable to today’s findings in patients such as osteolysis, sequester, sinus, involucrum, and other periosteal bone formations [1-3]. Through this growing data set it has become clear that bone infections occurred in many dinosaur species across the phylogenetic tree and the pathogenesis includes both the hematogenous and traumatic/fracture related routes [15]. Co-evolution of bone and immune system Bacteria can enter bone tissue from a contiguous spread from surrounding soft tissue, directly by bone trauma due to injury or surgery, or hematogenously due to bacteremia [16]. Though pathogenesis is varied, bacteria have been shown to persist within bone tissue of PJI, FRI and osteomyelitis cases due to biofilm formation, bacterial persister cell formation, intracellular infection of bone cells, and invasion of the OLCN system which provide interconnectivity of the osteocytes [16]. All these situations serve as long-term immune-privileged reservoirs for disease Fig. 2. Selected evolutionary perspectives in relation to bacterial bone infections. After the water-to-land transition a dramatic co-evolution of the immune and skeletal systems occurred, respectively. The transition resulted in cortical bone and bone marrow formation and furthermore the immune system had to cope with a much more diverse pathogen population. Canaliculi connected osteocytes have developed around 400 million years ago and due to osteomyelitis being reported in amphibians and possibly also in some bony fishes, bone infection has probably occurred before or during the skeletal and immune co-evolution. This might explain the many immune evasion strategies seen in the field. The ability of mammals to form liquid pus may impact lesions of bone infections like bacterial dissemination into deeper locations, osteolysis, implant loosening, and faster sequester and involucrum formation. The figure is inspired by reference 17. L.K. Jensen et al. Injury xxx (xxxx) xxx 3
recurrence. Despite pathogeneses and bacterial localizations, the repertoire of osseous changes seems highly conserved. Involucrum, sequesters and osteolysis formation has undergone no major evolutionary changes, i.e., they are the structures used to diagnose bone infections in fossils. However, a truly detailed examination of their evolution has not been performed. A dramatic evolution of the skeletal and immune system occurred synchronously around 385 million years ago when fishes started to move on to land [17]. The skeletal system evolved terrestrial locomotor activity, cortical bone with hematopoietic bone marrow, and calcium homeostasis, respectively [17]. Ionized calcium has an essential role in muscular function, nerve impulses, cell membranes, coagulation etc. and, therefore, the calcium concentration must be strongly regulated in all animals [4,17]. Living in the sea delivers a high environmental calcium concentration whereas living on land necessitates an internal calcium reservoir with calciotropic hormones, vitamin D regulation, and osteocytic osteolysis capacity [17]. In other words, the demand of internal calcium homeostasis has resulted in development of the OLCN structure, a structure that supports bacterial invasion and thus immune evasion. Along with the skeletal evolution, the innate and adaptive immune systems also evolved dramatically shortly after the water-to-land transition [17-19]. Although, it must be acknowledged that the fishes already had a highly developed innate and adaptive immune system. The reason for this immune expansion is not clear, however, the diversity of microorganisms on land is much more complex than within aquatic environments [17]. Thus, an increased microbial complexity could have driven the emergence of higher-level immune responses including immunoglobulin class switching, and lymph node development [17]. You X et al., specifically reported that the innate immune system, Toll-like receptors (TLR) in particular, expands fast during a water-to-land transition to provide defense against terrestrial pathogens [19]. The fact that elements of innate and acquired immunity, cortical bone, and hematopoietic bone marrow evolved almost simultaneously may explain why several molecules, like for example activator of nuclear factor-κB ligand (RANKL) have key-roles in all systems (recognition of the bone cell and immune system connection has resulted in the research area named osteoimmunology) [17]. Osteoimmunology may also play a pivotal role in osteoblast internalization during bone infection. The internalization of bacteria into osteoblasts is described as a sophisticated immune-evasion mechanism, enabling pathogens to evade recognition by immune cells, antibodies, and antibiotics in the extracellular environment [20]. The presence of internalized S. aureus bacteria in osteoblasts has been demonstrated by multiple in vitro studies, and recently, the phenomenon was revealed in clinical tissue samples of chronic osteomyelitis, offering insights into the persistence and recurrence of infections [20,21]. Toll-like receptor 9 (TLR9), an intracellular receptor responsible for recognizing bacterial DNA to initiate a potent immune response, has been identified not only in immune cells such as NK cells, dendritic cells, monocytes, and B-cells but also in osteoblasts, signifying their immune cell-like properties. Stimulation of TLR9 in osteoblasts with synthetic bacterial DNA motifs induces a robust production of reactive oxygen species (ROS), which can effectively inhibit the intracellular survival of S. aureus in osteoblasts [22]. The co-evolution of the skeletal and immune system may also explain why so many immune evasion strategies exist for bacteria inside bone tissue. Bacteria might simply have been able to enter OLCN, osteoblasts, and form intraosseous biofilm before a specialized local osseous immune response was developed (Fig. 2). The general pathology of reptiles and birds shows some remarkable differences in comparison to mammals that might have had an impact on bone infection evolution. Birds and reptiles deposit high amounts of fibrin in infected areas to immobilize pathogens, but in contrast to mammals, their infiltrating heterophils (neutrophils of birds and reptiles) lack the enzyme systems that convert necrotic tissue and bacteria into a liquid exudate, i.e., pus [23,24]. In birds and reptiles, the pathway to resolution involves thickening of the necrotic heterophils into a caseous mass and the lesions are sometimes referred to as a fibricess [23]. A fibriscess is defined as the product of a localized chronic inflammatory process in reptiles and birds characterized by an incomplete elimination of the pathogens, the continuing exudation of fibrin and uninterrupted lesion growth [23,24]. The pathomorphological structures of osteomyelitis and FRI lesions in dinosaurs has often been associated with fibriscess formation [15,25]. The advantage of fibriscess formation is ascribed to the constant fibrin exudation, which prevent systemic dissemination of pathogens and secure a local contained lesion. The fibriscess is likely to persist indefinitely, but the caseous material can still discharge by sinus formation [23,24]. In terms of bone infection, the ability of mammals to create pus and thus liquify infected tissue might favor local bacterial spreading into deeper osseous locations, improve osteolysis and thus implant loosening, and stimulate faster sequester and involucrum formation (Fig. 2). However, this theory has to our knowledge never been investigated. Bone-bacteria relationship Maybe it is time to ask if the long evolutionary bone-bacteria relationship has resulted in a certain number of bacteria that the bone simply can live with? Of course, the bacterial species and its panel of virulence factors have roles to play, but several case reports on different type of bone infections, including the haematogenous osteomyelitis case report from NEJM, seem to support the assumption [1]. As reported in the NEJM PJI review, this type of bone infection is caused by bacteria accidently introduced when cutting the skin despite all preventive actions [2]. Yet 100 % of patients getting a prosthesis will invariably receive some bacterial contamination during implantation, however, as seen from the review only up to 2 % will develop PJI [2]. Recently, a review in Clinical Infectious Diseases by Philip Stewart and Thomas Bjarnsholt identified that the main risk factor for development of implant related infections in humans, including PJI and infection of osteosynthesis material, was immune suppressive medication followed by other immune compromising conditions like diabetes and a high BMI [26]. Immunosuppression has also been associated with occurrence of bone infection in both wild and captive animals (including modern production animals). Thus, examination of the Lake Callabonna fossils of the megafaunal bird Genyorins newtoni, who were stocked in the lake sediments approximately 50Kyr ago, showed many individuals with osteomyelitis lesions [27]. Only drought-driven stress and a consequent immunosuppressive effect can explain such a localized high frequency [27]. Likewise, osteomyelitis and immune suppression is described in cold stunned and immunosuppressed sea turtles [8]. In modern meat production chicken and pigs’ osteomyelitis is regularly reported at slaughter and associated with fast growth and behavioral stress due to management practice [28,29]. All together immunosuppression has been associated with bone infection development and recurrence across the phylogenetic tree. It can be reflected up on, that this immune compromised situation is somehow comparable to the relative primitive immune response which existed when bone infection fist happened. Becoming an anthropogenic infection By identifying ourselves, Homo sapiens, in the top of the Tree of life we see the peak of technological progression (Fig. 1). However, by looking at ourselves through the glasses of modern medicine we have evolved into a species that replaced or supported part of its own skeleton with artificial components either for a temporary or permanent time [2,3]. Insertion of metal devices like prostheses and screws into our bones has simply customized a new era for bone infections [5]. Orthopedic surgery, including arthroplasty and osteosynthesis, is with no doubt a massive success of modern medicine but the procedures also favor introduction of bacteria and thus bone infection development. Thus, orthopedic prosthesis/implant related infections are anthropogenic L.K. Jensen et al. Injury xxx (xxxx) xxx 4
infections (anthropogenic; resulting from the influence of human beings on nature). At first sight the reported 2 % infection rate for alloplastic procedures sounds low, but it translates into many patients and a substantial rise is expected in coming decades due to more surgery on high-risk immunocompromised patients, including older patients, patients with diabetes, and other comorbidities. Furthermore, worldwide 1–2 % of closed fracture fixations and up to 30 % of complex open tibia fractures lead to infection, resulting in about 1.8 million FRIs annually [30]. We are witnessing these predictions at a time when the world is approaching an irreversible antibiotic resistance crisis. We must remind ourselves that the world desperately needs new insight and solutions to chronic bacterial infections like orthopedic infections. One way to get new insights, is to increase the understanding of evolutionary perspectives. Due to the anthropogenic perspective of bone infections, their medical and social burden should rank substantially higher on the agenda for health care priorities – don’t we have an obligation? Final remarks Skeletal infections have occurred for hundreds of millions of years and bacteria have likely developed a silent parasitism of bones which certainly is disrupted by immunosuppression. Understanding this element of host immunosuppression, and the counteracting effect of patient host optimization, is of paramount importance to improve basic knowledge and treatment of bone infections. The Tree of life as depictured in Fig. 1 provides a context for imagination of the timespan for bone infection evolution. Fig. 2 provide a context for imagination of major relevant events in a bone infection evolution perspective. In that light we must remind ourselves that the skeleton and immune system have not evolved for millions of years to protect titanium alloys and other metals, commonly used for orthopedic devices, from bacterial invasion. In today’s patients, bone infections are a heterogeneous disease group including osteomyelitis, FRI, PJI, diabetic foot osteomyelitis, and implant associated osteomyelitis. All these different types of bone infections rest on the foundation of the same evolutionary events and include elements like biofilm growth, intracellular bacterial localization, and lacuna-canaliculi invasion and, therefore, in some ways they will be comparable to lesions seen across the Tree of life (Figs. 1,3 and 4). Fig. 3. Bone lesions in a porcine model of osteomyelitis [40]. A: Staphylococcus aureus bacteria stained red by immunohistochemistry. The bacteria, forming a large aggregate or biofilm, are located in the bone marrow adjacent to bone tissue (b). The biofilm is surrounded by a massive inflammatory response. Bar = 150μm. B: Bone fragments and bone trabecula (b) are surrounded by fibrin exudation seen as blue threads (arrow). Fibrin exudation is an innate immune mechanism that prevent bacterial spreading and support leucocyte migration. PTAH stain, bar =100μm. Fig. 4. Bone lesion in a chronic hematogenous osteomyelitis patient [41]. A: Sequester (s) with empty osteocyte lacuna surrounded by immune cells. HE, bar = 200μm. B: Immunohistochemistry (IHC) of A with an antibody towards staphylococci. Red IHC positive bacteria can be identified in the osteocyte lacuna and within canaliculi. Bar =200μm. A closeup of Figure B is also used in reference 41. L.K. Jensen et al. Injury xxx (xxxx) xxx 5
However, the relatively new orthopedic infection types must be seen as distinct with unique implant/prosthesis related pathophysiology and immunology. Likewise, the fracture pathophysiology of FRI must not be neglected. Therefore, theories about orthopedic infection or osteomyelitis in general should not always be cut from the same tree. Declaration of generative AI and AI-assisted technologies in the writing process No AI-assisted technologies have been used. CRediT authorship contribution statement Louise Kruse Jensen: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Katrine Top Hartmann: Writing – review & editing, Software, Resources, Methodology, Conceptualization. Florian Witzmann: Writing – review & editing, Methodology, Investigation, Conceptualization. Patrick Asbach: Writing – review & editing, Methodology, Investigation, Conceptualization. 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