In vitro and in vivo studies are critical for the preclinical efficacy assessment of novel therapies targeting musculoskeletal infections (MSKI). Many preclinical models have been developed and applied as a prelude to evaluating safety and efficacy in human clinical trials. In performing these studies, there is both a requirement for a robust assessment of efficacy, as well as a parallel responsibility to consider the burden on experimental animals used in such studies. Since MSKI is a broad term encompassing infections varying in pathogen, anatomical location, and implants used, there are also a wide range of animal models described modeling these disparate infections. Although some of these variations are required to adequately evaluate specific interventions, there would be enormous value in creating a unified and standardized criteria to animal testing in the treatment of MSKI. The Treatment Workgroup of the 2023 International Consensus Meeting on Musculoskeletal Infection was responsible for questions related to preclinical models for treatment of MSKI. The main objective was to review the literature related to priority questions and estimate consensus opinion after voting. This document presents that process and results for preclinical models related to (1) animal model considerations, (2) outcome measurements, and (3) imaging.

Surgical site infections after orthopaedic surgery using fracture fixation devices or endosseous implants create major surgical challenges with severe adverse effects, such as osteomyelitis. These infections are frequently caused by Staphylococcus aureus, often with high resistance to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). Due to the formation of impenetrable biofilms on implant surfaces, systemic antibiotic treatment has become exceedingly difficult. New solutions are pursued by combining several drugs using a controlled delivery system from specifically engineered implant surfaces. A sol-gel coating on titanium implants was previously developed with 20 wt % vancomycin and 30 wt % farnesol, with suppression of MRSA in vitro. The present study investigated the efficacy of sol-gel film coatings for controlled dual local delivery over 4 weeks utilising a rat infection model. The findings confirmed the viability of this new concept in vivo based on the differences observed between coatings containing vancomycin alone (SGV) and the dual-drug-containing coating with vancomycin and farnesol (SGVF). While both the SGVF and SGV coatings facilitated excellent preservation of the osseous microarchitecture, SGVF coating displayed a slightly higher potency for suppressing MRSA infiltration than SGV, in combination with a lower reactive bone remodelling activity, most likely by disturbing biofilm formation. The next step for advancing the concept of dual-drug delivery from sol-gel coatings to the clinic and confirming the promising effect of the SGVF coatings on reactive bone remodelling and suppressing MRSA infiltration is a study in a larger animal species with longer time points.

Since the independent discovery of the formation of mesostructured silica using surfactants as structure directing agents by several groups in the early 1990s, these materials have found important application in the area of catalysis, separation technology and, most recently, as biomaterials. Among all the silica based materials that have been investigated, mesoporous silica nanospheres with well-defined structures and surface properties are very promising for various biomedical applications. In this chapter we first provide a brief history along with the general synthesis procedure of mesoporous silica materials. This is followed by a description of the synthesis to obtain the mesoporous silica based microspheres and nanospheres. We also discuss the physical and chemical properties along with the general characterization techniques used for these materials. Particular attention is paid towards the applications as biomaterials.

Biodegradable polymers and bioactive ceramics are being combined in a variety of composite materials for tissue-engineering scaffolds. Materials and fabrication routes for three-dimensional (3D) scaffolds with interconnected high porosities suitable for bone tissue engineering are reviewed. Different polymer and ceramic compositions applied and their impact on biodegradability and bioactivity of the scaffolds are discussed, including in vitro and in vivo assessments. The mechanical properties of today's available porous scaffolds are analyzed in detail, revealing insufficient elastic stiffness and compressive strength compared to human bone. Further challenges in scaffold fabrication for tissue engineering such as biomolecules incorporation, surface functionalization, and 3D scaffold characterization are discussed, giving possible solution strategies. Stem cell incorporation into scaffolds as a future trend is addressed briefly, highlighting the immense potential for creating next-generation synthetic/living composite biomaterials that feature high adaptiveness to the biological environment.

Due to the significant increase in dental implants placements and in alveolar ridge augmentation procedures over the last two decades, there has been an ever increasing demand for adequate bone grafting materials. Consequently, numerous bone grafting materials have been investigated. This includes calcium phosphate-based grafting materials such as synthetic as well as corallline or bovine-derived hydroxyapatites, tricalcium phosphate ceramics, biphasic hydroxyapatite tricalcium phosphates, calcium carbonates, bioactive glasses and glass ceramics, and demineralized freeze-dried bone allografts. More recently injectable and mouldable cements, putty like materials as well as scaffolds for craniofacial bone tissue engineering have been developed. Furthermore the combination of grafting materials with growth factors has been explored. However, compared to the bone substitute materials which are currently clinically available, there is a significant need for bone substitute materials which degrade more rapidly, but still stimulate osteogenesis at the same time. This has initiated an ever increasing search for bioactive rapidly resorbable bone grafting materials, which exhibit good bone bonding behavior by stimulating enhanced bone formation at the interface in combination with a high degradation rate. A silica containing calcium alkali othophophate material, which meets these requirements, has been shown to render excellent bone regeneration results in the maxillary sinus floor 6 months after sinus floor augmentation in humans in a first clinical study. Furthermore, current research efforts include the optimization of resorbable bone grafting cements as well as of scaffolds and concepts for various tissue engineering approaches.

In this chapter, we focus extensively on sol–gel processed silica to illustrate the benefits and to elucidate the structure–property–processing relationships of sol–gel oxides as controlled release system. We discuss the general sol–gel process and the biocompatibility of the sol–gel oxides. As a control release system, the release kinetics of the incorporated molecules is discussed. Following the discussion regarding the effect of physical and chemical processing parameters of sol–gel-derived oxides on drug release kinetics, we review the applications potential of these materials in the controlled release arena. In the last section, we also summarize various applications that are being pursued with sol–gel oxides as controlled release system for pharmaceutics and biological molecules.

NASA-designed rotating-wall vessels (RWVs) can simulate microgravity and therefore have been used to investigate the effect of microgravity on cellular function in ground-based studies. In addition, because they support three-dimensional (3D) cell culture, they have also been used for 3D cell cultures and tissue engineering. This chapter analyzes the factors associated with the fluid mechanics and microcarrier dynamics that affect cell culture in an RWV. The focus is on factors that affect shear stress, microcarrier trajectory and collisions, and mass transfer in the RWV. On the basis of the fluid flow analysis, the criteria for microcarrier and scaffold selection are described. This chapter also provides a summary of the scaffolds and microcarriers that have been used for different cell cultures and tissue engineering employing RWVs. The advantages and disadvantages of using these carrier materials are discussed. Finally, a brief review on 3D cultures of different cell types, tissue engineering, and space biology research with use of RWVs is included in the chapter. The tissue engineering section primarily includes the 3D tissue-like assemblies that have many characteristics of the functional tissue, whereas the cell culture section contains 3D cell cultures that have not yet reached the stage of functional tissue formation.

Event Abstract Back to Event Micron-thin bactericidal sol-gel coated intramedullary nails for the prevention and treatment of infection Haibo Qu1, Christine Knabe2, Zosia Zawacki3, Thomas Schaer3 and Paul Ducheyne1 1 University of Pennsylvania, Bioengineering, United States 2 Philipps University, Department of Experimental Orofacial Medicine, Germany 3 University of Pennsylvania School of Veterinary Medicine, Comparative Orthopaedic Research Laboratory, United States Introduction: Implant associated infections continue to result in increased morbidity, pain and suffering to the patient and are linked to substantial cost to the health care system. A major factor contributing to the development of implant associated infections is rapid bacterial adherence resulting in biofilm formation on the implant surface[1]. The biofilm-embedded bacteria are up to 1000 times more resistant to antibiotics. In our program we pursue the use of a novel, controlled release sol-gel nanotechnology for the continuous delivery of bactericidal molecules. These films are firmly adherent and the release of bactericidal molecules can be easily adjusted for different applications[2]. Herein, we report on the prevention of infection using micron-thin bactericidal sol-gel films on intramedullary (IM) nails in a sheep osteomyelitis model. Methods: Custom-made IM nails (Ti6Al4V, length of 140mm and diameter of 6mm) were sandblasted, cleaned and dried prior to dip-coating. IM nails were coated by dipping in a sol solution with or without vancomycin using a previously reported procedure[2],[3]. Sols with nominal vancomycin concentrations of 5wt%, 10wt%, or 20wt% were used for the vancomycin containing sol-gel film (SGV). Sol containing no vancomycin was used for control sol-gel film (SG). The micron-thin SG and SGV films consisted of 15 layers consecutively deposited. The SG coated and SGV coated implants were sterilized using STERRAD (gas plasma sterilization method, Advanced Sterilization Products). The in vitro vancomycin release was determined using a phosphate buffered saline solution at 37°C, with daily solution exchange and gentle shaking. Concentrations of released vancomycin were measured spectrophotometrically at 280 nm. To assess the vancomycin concentration in the intramedullary canal, two sheep received SGV implants were implanted with ultrafiltrate probe in the medullary cavity to collect interstitial fluid. For the infection study, total of 30 skeletally mature Dorset-cross were operated upon. To establish a model that recapitulates clinical signs of osteomyelitis, animals received one of two different doses of either 106 or 108 colony-forming units (CFU) of S. aureus, (ATCC 25923), instilled into the medullary tibial canal. Animals were sacrificed at 4 and 12 weeks postoperative. Eighteen sheep that received either SGV or SG coated nail were sacrificed at 4 weeks. Twelve sheep receiving either SGV or SG coated implants were sacrificed at 12 weeks. To determine bacterial presence, culture swabs were taken from the medullary canal. The tibiae and implants were then harvested using aseptic techniques and radiographed in µCT scanner. The histomorphologic and immunohistochemical analyses on stained thin sections were performed. Results: The time-dependent in vitro release of vancomycin from micron-thin sol-gel films is shown in Figure 1 for release duration up to 11 weeks. The release profile showed a linear release regardless of the vancomycin concentration. In addition, the vancomycin release rate increased with higher drug content. The vancomycin released from sol-gel film quickly built up a local vancomycin concentration exceeding MIC (2mg/ml, red dotted line) 24 hours after implantation. Such high concentration maintained for 384 hours (16 days) (Figure 2), the longest time point measured in both sheep. One month after surgery, the treatment SGV films, but not the control SG film, prevented intramedullary infections after challenged with S. Aureus. Discussion: The amount of vancomycin and rate of release can be adjusted by varying the vancomycin concentration of the SGV film. By optimizing the sol-gel condition and vancomycin concentration, sol-gel films can provide vancomycin exceeding MIC 24 hours after implantation, and such high concentration can be maintained for more than 16 days (Figure 2). Such high and prolonged localized vancomycin concentration in tibial medullary cavity is beneficial in preventing and treating intramedullary infections. Conclusion: This study shows vancomycin released from sol-gel film maintained a high local vancomycin concentration exceeding MIC for more than 16 days inside the sheep medullary cavity. Such high local vancomycin concentration can successfully prevent osteomyelitis development. This work is supported by the U.S. Army contract #W81XWH-10-2-0156.References:[1] Stoodley P, et al. Orthopaedic biofilm infections. Current orthopaedic practice 2011;22:558-63.[2] Radin S, et al, Biomaterials 2007;28:1721-1729.[3] Adams CS, et al, Journal of Orthopaedic Research 2009;27:701-709. Keywords: Infection, in vivo, Drug delivery, Implant Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Anti-infective biomaterials Citation: Qu H, Knabe C, Zawacki Z, Schaer T and Ducheyne P (2016). Micron-thin bactericidal sol-gel coated intramedullary nails for the prevention and treatment of infection. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02341 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Haibo Qu Christine Knabe Zosia Zawacki Thomas Schaer Paul Ducheyne Google Haibo Qu Christine Knabe Zosia Zawacki Thomas Schaer Paul Ducheyne Google Scholar Haibo Qu Christine Knabe Zosia Zawacki Thomas Schaer Paul Ducheyne PubMed Haibo Qu Christine Knabe Zosia Zawacki Thomas Schaer Paul Ducheyne Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Conventional silica xerogels prepared through sol-gel processing are regarded as suitable materials for the long-term release of proteins due to the mild processing conditions. However, they fall short of short-time release of these large molecules because of their small pore size and a slow dissolution rate. With the goal of achieving controlled release of large molecules (such as proteins) in a very short time (several days), herein we focus on the co-hydrolysis and co-condensation of different precursors to synthesize composite xerogels (co-xerogels) with adjustable degradation rates. Tetraethoxysilane and 3-(triethoxysilyl) propylsuccinic anhydride were employed to prepare the co-xerogels. Succinic anhydride was chosen due to its potential to crosslink with Si-OH and to integrate into the silica network under acidic conditions. Using the trypsin inhibitor (TI) as a model drug to characterize the release properties of co-xerogels, we obtained tailored release behavior of TI (2-7 days). It is demonstrated that the co-hydrolysis and co-condensation of different precursors is an easy technique that further expands the applicability of sol-gel materials as excellent carriers for the controlled release of a variety of drugs.

Musculoskeletal infections are a leading cause of patient morbidity and rising healthcare expenditures. The incidence of musculoskeletal infections, including soft-tissue infections, periprosthetic joint infection, and osteomyelitis, is increasing. Cases involving both drug-resistant bacterial strains and periprosthetic joint infection in total hip and total knee arthroplasty are particularly costly and represent a growing economic burden for the American healthcare system. With the institution of the Affordable Care Act, there has been an increasing drive in the United States toward rewarding healthcare organizations for their quality of care, bundling episodes of care, and capitating approaches to managing populations. In current reimbursement models, complications following the index event, including infection, are not typically reimbursed, placing the burden of caring for infections on the physician, hospital, or accountable care organization. Without the ability to risk-stratify patient outcomes based on patient comorbidities that are associated with a higher incidence of musculoskeletal infection, healthcare organizations are disincentivized to care for moderate- to high-risk patients. Reducing the cost of treating musculoskeletal infection also depends on incentivizing innovations in infection prevention.

Polymer-xerogel composite materials have been introduced to better optimize local anesthetics release kinetics for the pain management. In a previous study, it was shown that by adjusting various compositional and nano-structural properties of both inorganic xerogels and polymers, zero-order release kinetics over 7 days can be achieved in vitro. In this study, in vitro release properties are confirmed in vivo using a model that tests for actual functionality of the released local anesthetics.

By virtue of excellent tissue responses in bone tissue, silicon oxide (silica) based materials have been used for bone tissue engineering. Creating nanoscale porosity within silica based materials expands their applications into the realm of controlled release area. This additional benefit of silica based materials widens their application in the orthopedic fields in a major way. This review discusses the various chemical and physical forms of silica based controlled release materials, the release mechanisms, the applications in orthopedic procedures and their overall biocompatibility.

Risk of infection is considerable in open fractures, especially when fracture fixation devices are used to stabilize the fractured bones. Overall deep infection rates of 16.2% have been reported. The infection rate is even greater, up to 32.2%, with external fixation of femoral fractures. The use of percutaneous implants for certain clinical applications, such as percutaneous implants for external fracture fixation, still represents a challenge today. Currently, bone infections are very difficult to treat. Very potent antibiotics are needed, which creates the risk of irreversible damage to other organs, when the antibiotics are administered systemically. As such, controlled, local release is being pursued, but no such treatments are in clinical use. Herein, the use of bactericidal micron-thin sol-gel films on metallic fracture fixation pins is reported. The data demonstrates that triclosan (2,4,4'-trichloro-2'-hydroxydiphenylether), an antimicrobial agent, can be successfully incorporated into micron-thin sol-gel films deposited on percutaneous pins. The sol-gel films continuously release triclosan in vitro for durations exceeding 8 weeks (longest measured time point). The bactericidal effect of the micron-thin sol-gel films follows from both in vitro and in vivo studies. Inserting percutaneous pins in distal rabbit tibiae, there were no signs of infection around implants coated with a micron-thin sol-gel/triclosan film. Healing had progressed normally, bone tissue growth was normal and there was no epithelial downgrowth. This result was in contrast with the results in rabbits that received control, uncoated percutaneous pins, in which abundant signs of infection and epithelial downgrowth were observed. Thus, well-adherent, micron-thin sol-gel films laden with a bactericidal molecule successfully prevented pin tract infection.

Orthopedic injuries constitute the majority of wounds sustained by U.S. soldiers in recent conflicts. The risk of infection is considerable with fracture fixation devices. In this pilot study, we examined the use of unique bactericidal micron-thin sol-gel films on fracture fixation devices and their ability to prevent and eradicate infections. External fixation was studied with micron-thin sol-gel coated percutaneous pins releasing triclosan and inserted medially into rabbit tibiae. A total of 11 rabbits received percutaneous pins that were either uncoated or sol-gel/triclosan coated. Internal fracture fixation was also studied using sol-gel coated intramedullary (IM) nails releasing vancomycin in the intramedullary tibiae. Six sheep received IM nails that were coated with a sol-gel film that either contained vancomycin or did not contain vancomycin. All animals were challenged with Staphylococcus aureus around the implant. Animals were euthanized at 1 month postoperative. Rabbits receiving triclosan/sol-gel coated percutaneous pins did not show signs of infection. Uncoated percutaneous pins had a significantly higher infection rate. In the sheep study, there were no radiographic signs of osteomyelitis with vancomycin/sol-gel coated IM nails, in contrast to the observations in the control cohort. Hence, the nanostructured sol-gel controlled release technology offers the promise of a reliable and continuous delivery system of bactericidals from orthopedic devices to prevent and treat infection.

Consensus: The type of prosthesis (cemented versus uncemented) or coating with hydroxyapatite does not influence the incidence of SSI or PJI.