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.

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.

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.

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.

Biodegradable polymer–ceramic composites offer significant potential advantages in biomedical applications where the properties of either polymers or ceramics alone are insufficient to meet performance requirements. Here we demonstrate the highly tunable mechanical and controlled drug delivery properties accessible with novel biodegradable nanocomposites prepared by non-covalent binding of silica xerogels and co-polymers of tyrosine–poly(ethylene glycol)-derived poly(ether carbonate). The Young’s moduli of the nanocomposites exceed by factors of 5–20 times those of the co-polymers or of composites made with micron scale silica particles. Increasing the fraction of xerogel in the nanocomposites increases the glass transition temperature and the mechanical strength, but decreases the equilibrium water content, which are all indicative of strong non-covalent interfacial interactions between the co-polymers and the silica nanoparticles. Sustained, tunable controlled release of both hydrophilic and hydrophobic therapeutic agents from the nanocomposites is demonstrated with two clinically significant drugs, rifampicin and bupivacaine. Bupivacaine exhibits an initial small burst release followed by slow release over the 7day test period. Rifampicin release fits the diffusion-controlled Higuchi model and the amount released exceeds the dosage required for treatment of clinically challenging infections. These nanocomposites are thus attractive biomaterials for applications such as wound dressings, tissue engineering substrates and stents.

Conventional sol-gel processing requires several distinct steps involving hydrolysis, condensation and drying to obtain a highly porous, glassy solid material. With the goal of achieving controlled release of small molecules, herein we focus on the acceleration of the condensation and drying steps by casting the hydrolyzed sol on a large open surface to achieve a denser 100 % silica xerogel structure. Thus, cast xerogel with a more limited porosity was prepared. The effect of synthesis parameters during sol-gel synthesis on the release kinetics of bupivacaine, vancomycin and cephalexin was investigated. The release kinetics fitted well with the Higuchi model, suggesting a diffusional release mechanism. Combining the release and nanostructure data, the formation mechanism of cast xerogel is described. Without introducing additional precursors or additives into sol-gel systems, sol-gel casting 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.

Many polymers and composites have been used to prepare active wound dressings. These materials have typically exhibited potentially toxic burst release of the drugs within the first few hours followed by a much slower, potentially ineffective drug release rate thereafter. Many of these materials also degraded to produce inflammatory and cytotoxic products. To overcome these limitations, composite active wound dressings were prepared here from two fully biodegradable and tissue compatible components, silicon oxide sol–gel (xerogel) microparticles that were embedded in tyrosine-poly(ethylene glycol)-derived poly(ether carbonate) copolymer matrices. Sustained, controlled release of drugs from these composites was demonstrated in vitro using bupivacaine and mepivacaine, two water-soluble local anesthetics commonly used in clinical applications. By systematically varying independent compositional parameters of the composites, including the hydrophilic:hydrophobic balance of the tyrosine-derived monomers and poly(ethylene glycol) in the copolymers and the porosity, weight ratio and drug content of the xerogels, drug release kinetics approaching zero-order were obtained. Composites with xerogel mass fractions up to 75% and drug payloads as high as 13% by weight in the final material were fabricated without compromising the physical integrity or the controlled release kinetics. The copolymer–xerogel composites thus provided a unique solution for the sustained delivery of therapeutic agents from tissue compatible wound dressings.

Fluorapatite/hydroxyapatite solid solution has better biological properties than other apatites, especially used as films or coatings. In this work, sol-gel preparation and in vitro behavior of fluorapatite/hydroxyapatite solid solution films on titanium alloy were investigated. Ca(NO3)(2).4H(2)O and PO(OH)(x)(OEt)(3-x) were selected as precursors, and hexafluorophosphoric acid (HPF6) was used as a fluorine containing reagent. The Ca and P precursors were mixed with HPF6 to keep the Ca/P molar ratio 1.67. The mixtures refluxed for 12 h were used as dipping sols for the preparation of the films. The phase of the films obtained at 600degreesC was apatite. The F contents in the films increased with the concentrations of HPF6 in the dipping sols. The solid solution films were shown to have better stability than hydroxyapatite films, and a reasonably good bloactivity in the in vitro evaluation.

Bovine serum albumin (BSA) was employed as a model protein to study its loading efficiency into a calcium phosphate (CaP) coating on titanium substrates. It is found that the protein loading efficiency can be adjusted by varying the specific configurations of the coating system such as simulated body fluid (SBF) volume, solution height and container selection for the SBF. A BSA loading efficiency as high as 90% was achieved when the ratio of the substrate surface area to modified SBF (m-SBF) volume was as high as 0.072. The release of BSA from the biomimetic coatings was also investigated in vitro. A sustained release was achieved although a large quantity of BSA was still trapped in the coating after 15 days of immersion in a phosphate buffer solution. A much faster release rate would be expected when the coating is implanted in vivo due to the active involvement of osteoclast cells and enzymes.

Bone-like apatite coatings were prepared using a biomimetic method in a modified simulated body fluid (m-SBF). The effect of the m-SBF volume on the apatite coating quality was studied. Three m-SBF volumes, 50, 100, and 200 mL, were employed to immerse titanium substrates in a sealed container so as to produce apatite coatings with different properties, namely types I, type II, and type III apatite coatings, respectively. The coatings were characterized using X-ray diffraction and environmental scanning electron microscope. The bonding between the coating and the Ti substrate was evaluated using an adhesive strength test. All three apatite coatings demonstrated a poorly crystallized structure, and the coatings formed exhibited a uniformed surface morphology. Further increasing the m-SBF volume, small globules of apatite started to form on the surface of the coating. The bonding strength for the three coating systems were 8.52 +/- 2.41, 10.36 +/- 2.78, and 17.23 +/- 2.55 MPa for types I, II, and III apatite coatings, respectively. The failure analyses suggested that type III coating failed mostly at the interface between the coating and the substrate, while type I and II coatings failed mostly within the apatite coating. Our study revealed that a dense, thick, well-adhered apatite coating could be achieved by carefully controlling the volume of m-SBF.

: Compartment syndrome (CS) as a result of blast or traumatic injury is a devastating problem in the battlefield. The ultimate goal of this study is to develop an integrated toolkit of novel, biodegradable wound dressing composites for early stage treatment of CS. Composites made from the tyrosine-based block copolymers and silica based sol-gels were designed as an absorbent to remove fluid from injured muscle compartments and as wound dressings to deliver therapeutic agents to the compartment. This in vitro study reports the controlled release of protein analog and antibiotics from the room temperature processed sol-gel particles. Furthermore, this study reports the fabrication of the composite wound dressings with mechanical properties for the clinical application.

Bone-like apatite coatings were prepared using a biomimetic method in a simulated body fluid (SBF). The effect of initial pH values and immersing temperatures on biomimetic apatite coating formation was studied. Three different temperatures were used in this study: 24 (room temperature), 40, and 60 degrees C. At each temperature, SBF solutions with three different initial pHs were chosen: low, medium, and high. The total inorganic carbon (TIC) content and pH-time profile of each coating system were recorded during the coating formation. The apatite coatings were characterized using X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), and Fourier transform infra-red (FTIR). It has been found that SBF temperature has a great effect on the bicarbonate decomposition rate. The bicarbonate ions tend to decompose faster as the temperature increases. The decomposition of bicarbonate ions results in a pH increase in the SBF. With different initial SBF pHs, the decomposition of different amounts of bicarbonate ions is required to reach the critical pH range of apatite formation. With different amounts of bicarbonate ions in the SBF, the surface morphology of the biomimetic apatite coating formed is different. Therefore, the initial pH of the SBF solution plays a vital role in controlling the surface morphology of the biomimetic apatite coating. Also, it was found that as the SBF temperature increased, the critical pH range at which biomimetic apatite coating forms decreased. The critical pH range for the SBF prepared at 24, 40, and 60 degrees C was 6.65-6.71, 6.55-6.65, and 6.24-6.42, respectively.

In this article we describe a simple but effective biomimetic method to prepare dense apatite/collagen nanocomposites. Collagen-containing simulated body fluid was used to mimic the natural bone formation environment. The apatite/collagen films were formed at the air–solution interface under physiological conditions (40°C and pH=6.3). Transmission electron microscopy, scanning electron microscopy, thermal gravimetric analysis, X-ray diffraction, western blot analysis, and energy-dispersive X-ray were used to characterize the apatite/collagen composites. It was revealed that the nanosized apatite particles formed into a platelet shape with 100 nm in width and length and <10 nm in thickness. The collagen existed around the apatite platelets and acted as a glue to bind these platelets together. The collagen and apatite were strongly adhered to each other and formed into dense composite.

Bone-like apatite coatings were prepared using a biomimetic method in a simulated body fluid (SBF). The effect of initial pH values on the surface morphology of biomimetic apatite coating Was Studied. The coatings were characterized using X-ray diffraction and environmental scanning electron microscope. It was revealed that the morphology of the biomimetic apatite coating could be tailored by manipulating the initial pH of the SBF solution.