Publications

Examination of a first-in-class bis-dialkylnorspermidine-terphenyl antibiotic in topical formulation against mono and polymicrobial biofilms

Mariël Miller, Jeffery C. Rogers, Marissa A. Badham, Lousili Cadenas, Eian Brightwell, Jacob Adams, Cole Tyler, Paul R. Sebahar, Travis J. Haussener, Hariprassada K. Reddy, Ryan E. Looper, Dustin L. Williams
bioRxiv 2020.06.04.133934; doi: https://doi.org/10.1101/2020.06.04.133934

Abstract
Biofilm-impaired tissue is a significant factor in chronic wounds such as diabetic foot ulcers. Most, if not all, anti-biotics in clinical use have been optimized against planktonic phenotypes. In this study, an in vitro assessment was performed to determine the potential efficacy of a unique first-in-class series of antibiofilm antibiotics and compare outcomes to current clinical standards of care. The agent, CZ-01179, was formulated into a hydrogel and tested against mature biofilms of a clinical isolate of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa ATCC 27853 using two separate methods. In the first method, biofilms were grown on cellulose discs on an agar surface. Topical agents were spread on gauze and placed over the biofilms for 24 h. Biofilms were quantified and imaged with confocal and scanning electron microscopy. In the second method, biofilms were grown on bioabsorbable collagen coupons in a modified CDC biofilm reactor. Coupons were immersed in treatment for 24 h. The first method was limited in its ability to assess efficacy. Efficacy profiles against biofilms grown on collagen were more definitive, with CZ-01179 gel eradicating well-established biofilms to a greater degree compared to clinical standards. In conclusion, CZ-01179 may be a promising topical agent that targets the biofilm phenotype. Pre-clinical work is currently being performed to determine the translatable potential of CZ-01179 gel.

Histological Analysis of a Retrieved Porous Tantalum Total Ankle Replacement: A Case Report

Epperson RT, Barg A, Williams DL, Saltzman CL.
JBJS Case Connect. 2020 Jan-Mar;10(1):e0379. doi: 10.2106/JBJS.CC.19.00379.
PMID: 32224645

Abstract
Case: We present a case report documenting the retrieval and histological analysis of a porous tantalum (P-Ta) total ankle replacement (TAR) from a 50-year-old woman after a below-knee transtibial amputation. This rare opportunity to examine an intact TAR may help to better understand the implant-bone relationship because it would be in situ.

Conclusion: In this case study, we demonstrate bone ingrowth to the first layer of the P-Ta and organized trabecular orientation, suggesting that equal bone load was achieved on the base and the rails in both components using a transfibular surgical approach.

Bone ingrowth comparison of irregular titanium and cobalt-chromium coatings in a translational cancellous bone model.

Epperson RT, Mangiapani D, Bloebaum RD, Hofmann AA.
J Biomed Mater Res B Appl Biomater. 2020 May;108(4):1626-1635. doi: 10.1002/jbm.b.34509. Epub 2019 Nov 6.
PMID: 31696659

Abstract
The use of cobalt-chromium (CoCr)-bearing surfaces in total joint replacement (TJR) remains the predominate bearing surface. The conundrum with using this biomaterial has been selecting an ideal porous coating to assure reproducible skeletal attachment. There has been evidence that smooth CoCr beads may be inferior for skeletal attachment compared to identically shaped titanium (Ti) beads. Recent in vitro studies have demonstrated that an increased surface area and roughness favors osteoblast adhesion to metallic biomaterials. Therefore, we hypothesized that an irregular shape CoCr bead with an increased surface texture would help correct the negative bone responses that have been reported with smooth beaded CoCr coatings and thus allowing for bone ingrowth equivalently as an irregular commercially pure Ti porous coating with similar porosity. This investigation employed a weight-bearing translational sheep cancellous bone model to accurately simulate a cancellous bone response as it would be clinically in a human TJR. The data analyses obtained from this investigation revealed similar bone responses between the porous coatings. By 12 weeks the irregular shape CoCr coating was able to achieve similar bone ingrowth with skeletal interlock when compared to a clinically proven Ti porous coating.

Assessing the Effect of Physeal Biopsy on Angular Deformity in a Rabbit Model

Stevens P, Epperson RT, Taylor NB, Dickerson M, Williams DL.
J Pediatr Orthop B. 2019 Oct 22. doi: 10.1097/BPB.0000000000000687. Online ahead of print.
PMID: 31651751

Abstract
Obtaining a biopsy of the physis in a pediatric/juvenile could provide the ability to diagnose and manage children with physeal abnormalities. However, it has not yet been determined whether a physeal biopsy procedure affects angular deformity. We employed a rabbit model to collect biopsies of the distal femoral and proximal tibial physes on anesthetized, 8-week old New Zealand rabbits. The contralateral limb served as a control. At 8 (n = 5) and 16 (n = 5) weeks postbiopsy, animals were euthanized. Micro-computed tomography (CT) was employed to estimate percentage of the physis biopsied and assess structural abnormalities resulting from biopsy. Bone samples were embedded in polymethylmethacrylate and analyzed. The percentage of physis sampled was ≤1.5% of the total femoral physis while all but one of the tibiae had ≤2.3% removed. There were no iatrogenic clinical or radiographic deformities (frontal or sagittal). Micro-CT and histological analysis suggested that physeal defects had signs of healing that did not lead to subsequent angular deviation. A defect caused by physeal biopsy may not lead to angular deformity. Long-term data could help determine the safety and efficacy of collecting biopsies for histological analyses. Advanced imaging may demonstrate a detailed picture of anatomic or structural alteration of a given physis, but provides no functional information. The diagnostic and therapeutic information that could be gleaned from one or more serial biopsy samples could be invaluable in decision making and clinical management (e.g. skeletal dysplasias and metabolic conditions), so long as subsequent deformity is not a future possibility.

Plume Height and Surface Coverage Analysis of Methicillin-Resistant Staphylococcus aureus Isolates Grown in a CDC Biofilm Reactor

Rasmussen RM, Epperson RT, Taylor NB, Williams DL.
Biofouling. 2019 Apr;35(4):463-471. doi: 10.1080/08927014.2019.1612381. Epub 2019 May 30.
PMID: 31144524

Abstract
Biofilm formation is a dynamic process that leads to mature communities over time. Despite a general knowledge of biofilm community formation and the resultant limitations of antibiotic therapy, there is a paucity of data describing specific plume heights, surface coverage and rates of maturation. Furthermore, little is published on the effect that the broth medium might have on the degree of biofilm maturation. In this study, three strains of methicillin-resistant Staphylococcus aureus (MRSA) (USA300, USA400 and a clinical isolate) were grown in brain heart infusion broth (BHI) or tryptic soy broth (TSB). Following growth, SEM images were captured for 3-D analysis to assess plume height. TSB produced significantly higher plume heights of USA300 and USA400 compared to BHI. Broth type was less influential on the clinical isolate. The data indicate that broth type and time may be important factors to consider when assessing maturation and plume height formation of MRSA biofilms.

Growth Substrate May Influence Biofilm Susceptibility to Antibiotics

Williams DL, Smith SR, Peterson BR, Allyn G, Cadenas L, Epperson RT, Looper RE.
PLoS One. 2019 Mar 14;14(3):e0206774. doi: 10.1371/journal.pone.0206774. eCollection 2019.
PMID: 30870411

Abstract
The CDC biofilm reactor is a robust culture system with high reproducibility in which biofilms can be grown for a wide variety of analyses. Multiple material types are available as growth substrates, yet data from biofilms grown on biologically relevant materials is scarce, particularly for antibiotic efficacy against differentially supported biofilms. In this study, CDC reactor holders were modified to allow growth of biofilms on collagen, a biologically relevant substrate. Susceptibility to multiple antibiotics was compared between biofilms of varying species grown on collagen versus standard polycarbonate coupons. Data indicated that in 13/18 instances, biofilms on polycarbonate were more susceptible to antibiotics than those on collagen, suggesting that when grown on a complex substrate, biofilms may be more tolerant to antibiotics. These outcomes may influence the translatability of antibiotic susceptibility profiles that have been collected for biofilms on hard plastic materials. Data may also help to advance information on antibiotic susceptibility testing of biofilms grown on biologically relevant materials for future in vitro and in vivo applications.

System Setup to Deliver Air Impact Forces to a Sheep Limb: Preparation for Model Development of Blast-Related Heterotopic Ossification

Williams DL, Epperson RT, Taylor NB, Nielsen MB, Kawaguchi BS, Rothberg DL, Pasquina PF, Isaacson BM.
JMIR Res Protoc. 2019 Feb 22;8(2):e12107. doi: 10.2196/12107.
PMID: 30794203

Abstract
Background: Heterotopic ossification (HO) is a significant complication for wounded warriors with traumatic limb loss. Although this pathologic condition negatively impacts the general population, ectopic bone has been observed with higher frequency for service members injured in Iraq and Afghanistan due to blast injuries. Several factors, including a traumatic insult, bioburden, tourniquet and wound vacuum usage, and bone fractures or fragments have been associated with increased HO for service members. A large combat-relevant animal model is needed to further understand ectopic bone etiology and develop new pragmatic solutions for reducing HO formation and recurrence.

Objective: This study outlines the optimization of a blast system that may be used to simulate combat-relevant trauma for HO and replicate percussion blast experienced in theater.

Methods: We tested the repeatability and reproducibility of an air impact device (AID) at various pressure settings and compared it with a model of blunt force trauma for HO induction. Furthermore, we assessed the ability of the higher-power air delivery system to injure host tissue, displace metal particulate, and disperse bone chips in cadaveric sheep limbs.

Results: Data demonstrated that the air delivery setup generated battlefield-relevant blast forces. When the AID was charged to 40, 80, and 100 psi, the outputs were 229 (SD 13) N, 778 (SD 50) N, and 1085 (SD 114) N, respectively, compared with the blunt force model which proposed only 168 (SD 11) N. For the 100-psi AID setup, the force equaled a 5.8-kg charge weight of trinitrotoluene at a standoff distance of approximately 2.62 m, which would replicate a dismounted improvised explosive device blast in theater. Dispersion data showed that the delivery system would have the ability to cause host tissue trauma and effectively disperse metal particulate and host bone chips in local musculature compared with the standard blunt force model (13 mm vs 2 mm).

Conclusions: Our data showed that a high-pressure AID was repeatable or reproducible, had the ability to function as a simulated battlefield blast that can model military HO scenarios, and will allow for factors including blast trauma to translate toward a large animal model.

In Vitro Testing of a First-In-Class Tri-Alkylnorspermidine-Biaryl Antibiotic in an Anti-Biofilm Silicone Coating

Ashton NN, Allyn G, Porter ST, Haussener TJ, Sebahar PR, Looper RE, Williams DL.
Acta Biomater. 2019 Jul 15;93:25-35. doi: 10.1016/j.actbio.2019.02.010. Epub 2019 Feb 12.
PMID: 30769135

Abstract
Biofilm-related infection is among the worst complication to prosthetic joint replacement procedures; once established on the implant surface, biofilms show strong recalcitrance to clinical antibiotic therapy, frequently requiring costly revision procedures and prolonged systemic antibiotics for their removal. A well-designed active release coating might assist host immunity in clearing bacterial contaminants within the narrow perioperative window and ultimately prevent microbial colonization of the joint prosthesis. A first-in-class compound (CZ-01127) was tested as the active release agent in a silicone (Si) coating using an in vitro dynamic flow model of surgical site contamination and compared with analogous coatings containing clinical gold-standard antibiotics vancomycin and gentamicin; the CZ-01127 coating outperformed both vancomycin and gentamicin coatings and was the only to decrease the methicillin-resistant Staphylococcus aureus (MRSA) inocula below detectable limits for the first 3 days. The antimicrobial activity of CZ-01127, and for comparison vancomycin and gentamicin, were characterized against both planktonic and biofilm MRSA using the minimum inhibitory concentration (MIC) assay, serial passages, and serial dilution tests against established biofilms grown with a CBR 90 CDC biofilm reactor. Despite a similar MIC (1 µg/ml) and behavior in a 25-day serial passage analysis, CZ-01127 displayed much greater bactericidal activity against established biofilms and was the only to decrease biofilm colony forming units (CFUs) below detectable limits at the highest concentration tested (500 µg/ml). Coating release profiles were characterized using ATR-FTIR and displayed burst release kinetics within the decisive period of the perioperative window suggesting the silicon carrier is broadly useful for screening antibiotic compound for local delivery applications. STATEMENT OF SIGNIFICANCE: With an aging population, an increasing number of people are undergoing total joint replacement procedures in which diseased joint tissues are replaced with permanent metallic implants. Some of these procedures are burdened by costly and debilitating infections. A promising approach to prevent infections is the use of an antimicrobial coating on the surface of the implant which releases antibiotics into the surgical site to prevent infection. In this study, we tested a new antibiotic compound formulated in a silicone coating. Data showed that this compound was more effective at killing pathogenic methicillin resistant Staphylococcus aureus (MRSA) bacteria than two clinical gold-standard antibiotics-vancomycin and gentamicin-and could be a promising agent for antimicrobial coating technologies.

In Vivo Analysis of a First-In-Class Tri-Alkyl Norspermidine-Biaryl Antibiotic in an Active Release Coating to Reduce the Risk of Implant-Related Infection

Williams DL, Epperson RT, Ashton NN, Taylor NB, Kawaguchi B, Olsen RE, Haussener TJ, Sebahar PR, Allyn G, Looper RE.
Acta Biomater. 2019 Jul 15;93:36-49. doi: 10.1016/j.actbio.2019.01.055. Epub 2019 Jan 31.
PMID: 30710710

Abstract
Prosthetic joint infection (PJI) is a well-known and persisting problem. Active release coatings have promise to provide early protection to an implant by eradicating small colony biofilm contaminants or planktonic bacteria that can form biofilm. Traditional antibiotics can be limited as active release agents in that they have limited effect against biofilms and develop resistance at sub-lethal concentrations. A unique first-in-class compound (CZ-01127) was assessed as the active release agent in a silicone (Si)-based coating to prevent PJI in a sheep model of joint space infection. Titanium (Ti) plugs contained a porous coated Ti (PCTi) region and polymer-coated region. Plugs were implanted into a femoral condyle of sheep to assess the effect of the Si polymer on cancellous bone ingrowth, the effect of CZ-01127 on bone ingrowth, and the ability of CZ-01127 to prevent PJI. Microbiological results showed that CZ-01127 was able to eradicate bacteria in the local region of the implanted plugs. Data further showed that Si did not adversely affect bone ingrowth. However, bacteria that reached the joint space (synovium) were not fully eradicated. Outcomes suggested that the CZ-01127 coating provided local protection to the implant system in a challenging model, the design of which could be beneficial for testing future antimicrobial therapies for PJI. STATEMENT OF SIGNIFICANCE: Periprosthetic joint infection (PJI) is now commonplace, and constitutes an underlying problem that patients and physicians face. Active release antibiotic coatings have potential to prevent these infections. Traditional antibiotics are limited in their ability to eradicate bacteria that reside in biofilms, and are more susceptible to resistance development. This study addressed these limitations by testing the efficacy of a unique antimicrobial compound in a coating that was tested in a challenging sheep model of PJI. The unique coating was able to eradicate bacteria and prevent infection in the environment adjacent to the implant. Bacteria that escaped into the joint space still caused infection, yet benchmark data can be used to optimize the coating and translate it toward clinical use.

Ability of a Wash Regimen to Remove Biofilm From the Exposed Surface of Materials Used in Osseointegrated Implants

Allyn G, Bloebaum RD, Epperson RT, Nielsen MB, Dodd KA, Williams DL.
J Orthop Res. 2019 Jan;37(1):248-257. doi: 10.1002/jor.24161. Epub 2018 Nov 19.
PMID: 30341934

Abstract
The skin/implant interface of osseointegrated (OI) implants is susceptible to infection, causing excess pain, increased morbidity, and possibly implant removal. Novel distal femoral OI implants with binary nitride coatings have been developed with little physiological modeling to collect microbiological evidence of resistance to bacterial attachment. This in vitro study evaluated a Ti-6Al-4V alloy coated with TiNbN and treated with low plasticity burnishing (LPB) to assess attachment and biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) under physiologically modeling conditions compared to standard Ti-6Al-4V alloy materials with a polished ("Color Buff") or non-polished finish ("Satin Finish"). Washability of the materials were also assessed and compared. It was hypothesized that the TiNbN/LPB treatments would resist bacterial adhesion and biofilm formation to a greater degree than the other two materials, and have a higher degree of bacterial removal following a clinically relevant wash regimen. Material types were exposed to a constant flow of broth containing MRSA and were analyzed using bacterial quantification, surface coverage analysis, and SEM imaging. Quantification data showed no difference in bacterial attachment among the varying material types both with and without the wash regimen. Surface coverage and SEM analysis confirmed results. The wash regimen led to an approximately 3 log10 reduction in bacteria for all material types. Though the results did not support the hypothesis that a TiNbN coating/LPB treatment might resist bacterial attachment/biofilm formation more than other alloys, or have less bacteria after cleaning, results did support the potential importance of a daily wound-hygiene regimen at the skin/implant interface of OI materials. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Revisiting the Anterior Glenoid: An Analysis of the Calcified Cartilage Layer, Capsulolabral Complex, and Glenoid Bone Density

Karns MR, Epperson RT, Baran S, Nielsen MB, Taylor NB, Burks RT.
Arthroscopy. 2018 Aug;34(8):2309-2318. doi: 10.1016/j.arthro.2018.03.017. Epub 2018 Jul 7.
PMID: 30078426

Abstract
Purpose: In this cadaveric study, we aim to define the basic anatomy of the anterior glenoid with attention to the relationships of calcified cartilage, capsulolabral complex, and osseous morphology of the anterior glenoid.

Methods: Seventeen cadaveric glenoid specimens (14 male, 3 female, mean age 53.9 ± 10) were imaged with micro-computed tomography (CT) and embedded in poly-methyl-methacrylate. Specimens were included for final analysis only if the entire glenoid articular cartilage, labrum, capsule, and biceps insertion were pristine and without evidence of injury, degeneration, or damage during the preparation process. Group 1 members (n = 9) were axially sectioned through 3 to 9 o'clock and 4 to 8 o'clock; group 2 members (n = 8) were radially sectioned through 3, 4, 5, and 9 o'clock. A scanning electron microscope (SEM) analysis quantified the percentage of bone within a 5 × 2.5 mm region at the glenoid rim. Micro-CT, SEM, and light microscopy evaluated the capsulolabral complex and calcified fibrocartilage.

Results: A 7 ± 2.1 mm region of calcified fibrocartilage at 4 o'clock was identified from the articular face to the medial glenoid neck supporting the overlying capsulolabral footprint and was >3× thicker at the articular attachment (316 ± 153 μm) versus the glenoid neck (92 ± 66 μm). At 3 to 9 o'clock and 4 to 8 o'clock 79.2% ± 5.4% and 75.2% ± 7.8% of the glenoid osseous width was covered with articular cartilage. The labrum accounted for 13.1% ± 3.4% of the glenoid width at 4 o'clock. SEM analysis demonstrated decreased glenoid bone density at 3, 4, and 5 o'clock (P ≤ .015) and no difference (P = .448) at 9 o'clock versus central subchondral bone.

Conclusions: The capsulolabral footprint contributes significantly to the glenoid face, inserts directly adjacent to the articular cartilage, and extends medially along the glenoid neck. A layer of calcified fibrocartilage lies immediately beneath the capsulolabral footprint and is 3× thicker at the articular insertion compared with the glenoid neck. Lastly, there is a bone density gradient at the anterior-inferior rim versus the central subchondral bone.

Clinical relevance: Arthroscopic Bankart repair has been reported to have a significant failure rate in many settings. It is felt that reproducing anatomy with the repair could help improve outcomes. Based on this study's findings, an arthroscopic Bankart technique that most closely reproduces native anatomy and potentially optimizes soft-tissue healing could be performed. This includes removal of 1 to 2 mm of articular cartilage from the glenoid face with anchor placement at this location to appropriately reposition the capsulolabral complex.

Flash Autoclave Settings May Influence Eradication but Not Presence of Well-Established Biofilms on Orthopaedic Implant Material

Williams DL, Taylor NB, Epperson RT, Rothberg DL.
J Orthop Res. 2018 May;36(5):1543-1550. doi: 10.1002/jor.23764. Epub 2017 Nov 22.
PMID: 28976597

Abstract
Flash autoclaving is one of the most frequently utilized methods of sterilizing devices, implants or other materials. For a number of decades, it has been common practice for surgeons to remove implantable devices, flash autoclave and then reimplant them in a patient. Data have not yet indicated the potential for biofilms to survive or remain on the surface of orthopaedic-relevant materials following flash autoclave. In this study, monomicrobial and polymicrobial biofilms were grown on the surface of clinically relevant titanium materials and exposed to flash autoclave settings that included varying times and temperatures. Data indicated that when the sterilization and control temperatures of an autoclave were the same, biofilms were able to survive flash autoclaving that was performed for a short duration. Higher temperature and increased duration rendered biofilms non-viable, but none of the autoclave settings had the ability to remove or disperse the presence of biofilms from the titanium surfaces. These findings may be beneficial for facilities, clinics, or hospitals to consider if biofilms are suspected to be present on materials or devices, in particular implants that have had associated infection and are considered for re-implantation

Effect of Silver-Loaded PMMA on Streptococcus Mutans in a Drip Flow Reactor

Williams DL, Epperson RT, DeGrauw JP, Nielsen MB, Taylor NB, Jolley RD.
J Biomed Mater Res A. 2017 Sep;105(9):2632-2639. doi: 10.1002/jbm.a.36112. Epub 2017 Jun 27.
PMID: 28512783

Abstract
Orthodontic retention has been proposed as a life-long commitment for patients who desire to maintain straight teeth. However, the presence of foreign material increases risk of bacterial colonization and caries formation, of which Streptococcus mutans is a key contributor. Multiple studies have assessed the ability of silver to be added to base plate material and resist attachment of S. mutans. However, it does not appear that long-term washout in connection with biofilm growth under physiologically relevant conditions has been taken into consideration. In this study, silver was added to base plate material and exposed to short- or long-term washout periods. Materials were then assessed for their ability to resist biofilm formation of S. mutans using a drip flow reactor that modeled the human oral environment. Data indicated that silver was able to resist biofilm formation following short-term washout, but long-term washout periods resulted in a lack of ability to resist biofilm formation. These data will be important for future development of base plate materials to achieve long-term antimicrobial efficacy to reduce risk of caries formation and benefit patients in the long term.

Transcortical or Intracondylar? Which Model Is Accurate for Predicting Biomaterial Attachment in Total Joint Replacement?

Bloebaum RD, Abdo NT, Hofmann AA, Epperson RT, Olsen RE, Chalayon O.
J Biomed Mater Res B Appl Biomater. 2018 Feb;106(2):578-588. doi: 10.1002/jbm.b.33873. Epub 2017 Feb 28.

Abstract
Despite four decades of research on material and porous coatings intended for cementless fixation in total joint replacement (TJR), aseptic mechanical loosening unrelated to particulate disease remains a concern. One main question asked is how translational are the animal models used to screen material and porous coatings intended for TJR fixation? Another question is how specific are the translational models at targeting the cementless TJR components that have the highest loosening rates? The hypothesis tested was that the bone response would be different between the two bone types-cortical and cancellous-used in translational animal modeling. The osteoblastic jumping distance (OJD), percent ingrowth, and appositional bone response were measured to assess the response between cancellous and cortical bone at two different anatomical locations, within the same limb. With 500 µm inset, titanium porous coated implants and negative control dinosaur (coprolite) implants were investigated. The data demonstrated that cortical bone had 7 times OJD than cancellous bone. The bone ingrowth data demonstrated 16 times higher bone ingrowth than the cancellous bone. Light microscopy showed predominately fibrous tissue attachment (98%) in cancellous bone. Screening of materials intended for TJR require a translational model predictive of the clinical condition. The results demonstrated that the transcortical model rendered false-positive data.

Sustained Tobramycin Release From Polyphosphate Double Network Hydrogels

Lane DD, Fessler AK, Goo S, Williams DL, Stewart RJ.
Acta Biomater. 2017 Mar 1;50:484-492. doi: 10.1016/j.actbio.2016.12.030. Epub 2016 Dec 18.
PMID: 27993638

Abstract
Sustained local delivery of antibiotics from a drug reservoir to treat or prevent bacterial infections can avoid many of the drawbacks of systemic administration of antibiotics. Prolonged local release of high concentrations of antibiotics may also be more effective at treating bacteria in established biofilm populations that are resistant to systemic antibiotics. A double network hydrogel comprising an organic polyphosphate pre-polymer network polymerized within a polyacrylamide network de-swelled to about 50% of its initial volume when the polyphosphate network was crosslinked with polycationic tobramycin, an aminoglycoside antibiotic. The antibiotic-loaded hydrogels contained approximately 200mg/ml of tobramycin. The hydrogels continuously released daily amounts of tobramycin above the Pseudomonas aeruginosa minimal bactericidal concentration for greater than 50days, over the pH range 6.0-8.0, and completely eradicated established P. aeruginosa biofilms within 72h in a flow cell bioreactor. The presence of physiological concentrations of Mg2+ and Ca2+ ions doubled the cumulative release over 60days. The polyphosphate hydrogels show promise as materials for sustained localized tobramycin delivery to prevent post-operative P. aeruginosa infections including infections established in biofilms.

Statement of significance: Polyphosphate hydrogels were loaded with high concentrations of tobramycin. The hydrogels provided sustained release of bactericidal concentrations of tobramycin for 50days, and were capable of completely eradicating P. aeruginosa in established biofilms. The hydrogels have potential for localized prevention or treatment of P. aeruginosa infections.

Link Between Clinical Predictors of Heterotopic Ossification and Histological Analysis in Combat-Injured Service Members

Isaacson BM, Potter BK, Bloebaum RD, Epperson RT, Kawaguchi BS, Swanson TM, Pasquina PF.
J Bone Joint Surg Am. 2016 Apr 20;98(8):647-57. doi: 10.2106/JBJS.15.00895.
PMID: 27098323

Abstract
Background: Heterotopic ossification (HO) is a debilitating condition that occurs following traumatic injury and may restrict range of motion and delay rehabilitation. The timing and efficacy of surgical resection have varied widely, and there is a gap in knowledge between clinical predictors of HO recurrence and histological analysis.

Methods: Thirty-three service members seen at Walter Reed National Military Medical Center for symptomatic HO were enrolled in an institutional review board-approved study. Participants took oxytetracycline on four scheduled days prior to HO resection to determine the mineral apposition rate (bone growth rate).

Results: Detailed histological analyses included scanning electron microscopy with backscattered electron imaging and light microscopy. Data indicated that the mineral apposition rate of trauma-induced HO was approximately 1.7 μm/day at the time of operative intervention, which was 1.7 times higher than the rate in non-pathological human bone. The mineral apposition rate and postoperative alkaline phosphatase values were demonstrated to be positively and significantly related (ρ = 0.509, p = 0.026, n = 19). When the analysis was limited to patients with no more than a two-year period from injury to excision (thereby removing outliers who had a longer time period than their counterparts) and traumatic brain injury and nonsteroidal anti-inflammatory drugs (known correlates with HO development) were controlled for in the statistical analysis, the mineral apposition rate and recurrence severity were significantly related (ρ = -0.572, p = 0.041, n = 11).

Conclusions: Data demonstrated a link between benchtop research and bedside care, with the mineral apposition rate elevated in patients with HO and correlated with recurrence severity; however, a larger sample size and more clinical factors are needed to refine this model.

Determining the Mineral Apposition Rate of Heterotopic Ossification in Military Healthcare System Patients after Total Joint Replacement: A Case Series

Isaacson, B. M.; Potter, B. K.; Bloebaum, R. D.; Epperson, R. T.; Kawaguchi, B.; Swanson, T. M.; Pasquina, P. F.
Bone & Tissue Regeneration Insights . 2016, Issue 7, p1-5. 5p.

Abstract
Heterotopic ossification (HO) is frequently reported following total joint replacement (TJR) surgery. Symptomatic HO may limit the range of motion, cause pain, and require surgical excision. Deciding an appropriate time for ectopic bone excision is based on clinical judgment, and a more well-defined link between clinical predictors and histological analysis is needed to minimize recurrence. A case series was performed with military healthcare system patients undergoing TJR, who required removal of periarticular ectopic bone. Patients were prescribed oxytetracycline to assess the mineral apposition rate (MAR; ie, bone growth rate) of HO, and excised specimens were analyzed using scanning electron microscopy and light microscopy. Two males and one female were enrolled in this study, with height of 69.0 ± 7.8 inches, weight of 237.7 ± 28.3 pounds, and age of 61 ± 7 years at the time of HO removal. Ectopic bone occurred in two cases following total knee arthroplasty and one total hip arthroplasty. Data indicated that MAR levels were 1.7 times higher than that reported previously for nonpathological human bone (1.7 ± 0.7 µm/day; range: 1.3–2.6 µm/day), and microscopic imaging confirmed that the osseous tissues were still actively remodeling at the time of surgical intervention. Further characterization is needed to optimize HO excision timing and to better understand this pathological bone disorder.

Does Vitamin E-blended UHMWPE Prevent Biofilm Formation?

Williams DL, Vinciguerra J, Lerdahl JM, Bloebaum RD.
Clin Orthop Relat Res. 2015 Mar;473(3):928-35. doi: 10.1007/s11999-014-3673-z.
PMID: 24832828

Abstract
Background: Biofilm-related periprosthetic infections are catastrophic to patients and clinicians. Data suggest the addition of vitamin E to UHMWPE may have the ability to reduce biofilm formation on the surface of UHMWPE; however, previous studies were performed using stagnant broth solutions that may not have simulated a physiologic environment. In addition, the observed differences in levels of bacterial attachment, though statistically significant, may not be clinically significant.

Questions/purposes: We blended vitamin E with UHMWPE material and tested it for the ability to resist biofilm formation using a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA). Three additional materials were tested for comparison: highly crosslinked UHMWPE, compression-molded UHMWPE, and polyetheretherketone. We also determined whether the surface roughness of these materials facilitated biofilm formation.

Methods: Using a flow cell system, samples of each material type were placed into separate chambers. A 10% solution of brain-heart infusion broth containing 10(5) colony-forming units (CFUs)/mL was flowed through the flow cell over 48 hours. The number of bacteria that adhered to the surface was quantified and biofilm formation was observed qualitatively using scanning electron microscopy. Optical profilometry was used to determine the surface roughness of each material type.

Results: Vitamin E-blended UHMWPE did not reduce biofilm formation of a clinically relevant strain of MRSA compared to materials that did not have vitamin E. More specifically, vitamin E-blended materials had similar amounts of biofilm formation (~ 8 log10 CFUs/cm(2)) compared to materials not containing vitamin E (~ 8.1 log10 CFUs/cm(2)) (p > 0.4). The roughness of vitamin E-blended material surfaces (mean ± SD: 1.85 ± 0.46 µm) compared to that of materials without vitamin E (2.06 ± 1.24 µm) did not appear to influence biofilm formation.

Conclusions: Under physiologically relevant conditions, vitamin E-blended UHMWPE did not have the ability to reduce the formation of biofilms by MRSA.

Clinical relevance: These data indicate that the addition of vitamin E to UHMWPE may not reduce clinically relevant rates of biofilm-related periprosthetic infections of total joint arthroplasty devices.

In Vitro Efficacy of a Novel Active-Release Antimicrobial Coating to Eradicate Biofilms of Pseudomonas Aeruginosa

Williams DL, Lerdahl JM, Haymond BS, Bloebaum RD.
Antimicrob Agents Chemother. 2014;58(4):2400-4. doi: 10.1128/AAC.01798-13. Epub 2014 Jan 6.
PMID: 24395238

Abstract
Implant-related infections are becoming increasingly difficult to treat due to the formation of biofilms on implant surfaces. This study analyzed the in vitro efficacy of a novel antimicrobial coating against biofilms of Pseudomonas aeruginosa, using a flow cell system. Results indicated that P. aeruginosa biofilms were reduced by greater than 8 log10 units in less than 24 h. Data indicated that this active-release coating may be promising for preventing biofilm implant-related infections

The Significance of Calcified Fibrocartilage on the Cortical Endplate of the Translational Sheep Spine Model

Sinclair SK, Bell S, Epperson RT, Bloebaum RD.
Anat Rec (Hoboken). 2013 May;296(5):736-44. doi: 10.1002/ar.22683. Epub 2013 Mar 12.
PMID: 23494918

Abstract
To gain an understanding of the vertebral cortical endplate and factors that may affect the ability to achieve skeletal attachment to intervertebral implants and fusion, this study aimed to characterize the hypermineralized tissue on the cortical endplate of the vertebral body on a commonly used animal model. Skeletally mature sheep were injected with tetracycline prior to euthanasia and the C2-C3, T5-T6, and L2-L3 spinal motion segments were excised and prepared. Vertebral tissues were imaged using backscatter electron (BSE) imaging, histology, and tetracycline labeling was used to assess bone remodeling within different tissue layers. It was determined that the hypermineralized tissue layer was calcified fibrocartilage (CFC). No tetracycline labels were identified in the CFC layer, in contrast to single and double labels that were present in the underlying bone, indicating the CFC present on the cortical endplate was not being actively remodeled. The average thickness of the CFC layer was 146.3 ± 70.53 µm in the cervical region, 98.2 ± 40.29 µm in the thoracic region, and 150.89 ± 69.25 µm in the lumbar region. This difference in thickness may be attributed to the regional biomechanical properties of the spine. Results from this investigation indicate the presence of a nonremodeling tissue on the cortical endplate of the vertebral body in sheep spines, which attaches the intervertebral disc to the vertebrae. This tissue, if not removed, would likely prevent successful bony attachment to an intervertebral device in spinal fusion studies and total disc replacement surgeries.

Model Development for Determining the Efficacy of a Combination Coating for the Prevention of Perioperative Device Related Infections: A Pilot Study

Sinclair KD, Pham TX, Williams DL, Farnsworth RW, Loc-Carrillo CM, Bloebaum RD.
J Biomed Mater Res B Appl Biomater. 2013 Oct;101(7):1143-53. doi: 10.1002/jbm.b.32924. Epub 2013 Apr 6.
PMID: 23564717

Abstract
Antibiotic resistant bacterial infections are a growing problem in patient care. These infections are difficult to treat and severely affect the patient's quality of life. The goal of this translational experiment was to investigate the antimicrobial potential of cationic steroidal antimicrobial-13 (CSA-13) for the prevention of perioperative device-related infections in vivo. It was hypothesized that when incorporated into a polymeric device coating, the release of CSA-13 could prevent perioperative device-related infection without inhibiting skeletal attachment. To test this hypothesis, 12 skeletally mature sheep received a porous coated titanium implant in the right femoral condyle. Group 1 received the titanium implant and an inoculum of 5 × 10(8) CFU of methicillin-resistant Staphylococcus aureus (MRSA). Group 2 received a CSA-13 coated implant and the MRSA inoculum. Group 3 received only the CSA-13 coated implant and Group 4 received only the implant-without the CSA-13 coating or MRSA inoculum. In conclusion, the CSA-13 combination coating demonstrated bactericidal potential without adversely affecting skeletal attachment. The CSA-13 containing groups exhibited no evidence of bacterial infection at the conclusion of the 12 week study and established skeletal attachment consistent with Group 4. In contrast, all of the Group 1 animals became infected and required euthanasia within 6-10 days. The significance of this finding is that this combination coating could be applied to implanted devices to prevent perioperative device-related infections. This method may facilitate significantly reduced incidences of device-related infections as well as a new method to treat and prevent resistant strain bacterial infections.

Characterization of a Novel Active Release Coating to Prevent Biofilm Implant-Related Infections

Williams DL, Sinclair KD, Jeyapalina S, Bloebaum RD.
J Biomed Mater Res B Appl Biomater. 2013 Aug;101(6):1078-89. doi: 10.1002/jbm.b.32918. Epub 2013 Apr 4.
PMID: 23559470

Abstract
Biofilm implant-related infections cost the US healthcare system billions of dollars each year. For several decades, device coatings have been developed that actively release antimicrobial compounds in an attempt to prevent these infections from developing. To date, few coatings have been put into clinical use. These have shown limited to no efficacy in clinical trials. Recent data have shown the in vitro and in vivo efficacy of a novel active release coating that may address the limitations of coatings that are used clinically. In this study, the novel active release coating was characterized to gain an understanding of the effects of combining an antimicrobial additive, cationic steroid antimicrobial-13 (CSA-13), to a medical grade polydimethylsiloxane (PDMS) material. Results indicated that the addition of CSA-13 did influence the physical properties of the PDMS, but not with adverse effects to the desired material properties. Furthermore, there was no indication of chemical reactivity. It was shown that CSA-13 was uniformly dispersed as small particles throughout the PDMS matrix. These particles were able to dissolve and elute out of the PDMS within a 30-day period. The results of this work suggested that the PDMS with CSA-13 was thermally, chemically and physically stable when used as a device coating to treat local infection and/or prevent biofilm implant-related infections from developing.

Development of a Broad Spectrum Polymer-Released Antimicrobial Coating for the Prevention of Resistant Strain Bacterial Infections

Sinclair KD, Pham TX, Farnsworth RW, Williams DL, Loc-Carrillo C, Horne LA, Ingebretsen SH, Bloebaum RD.
J Biomed Mater Res A. 2012 Oct;100(10):2732-8. doi: 10.1002/jbm.a.34209. Epub 2012 May 24.
PMID: 22623404

Abstract
More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.

In Vivo Efficacy of a silicone‒cationic Steroid Antimicrobial Coating to Prevent Implant-Related Infection

Williams DL, Haymond BS, Beck JP, Savage PB, Chaudhary V, Epperson RT, Kawaguchi B, Bloebaum RD.
Biomaterials. 2012 Nov;33(33):8641-56. doi: 10.1016/j.biomaterials.2012.08.003. Epub 2012 Aug 30.
PMID: 22940221

Abstract
Active release antimicrobial coatings for medical devices have been developed to prevent and treat biofilm implant-related infections. To date, only a handful of coatings have been put into clinical use, with limited success. In this study, a novel antimicrobial compound was incorporated into a silicone (polydimethylsiloxane or PDMS) polymer to develop a novel active release coating that addressed several limitations of current device coatings. The efficacy of this coating was optimized using an in vitro flow cells system, then translated to an animal model of a simulated Type IIIB open fracture wherein well-established biofilms were used as initial inocula. Results indicated that the novel coating was able to prevent infection in 100% (9/9) of animals that were treated with biofilms and the novel coating (treatment group). In contrast, 100% (9/9) of animals that were inoculated with biofilms and not treated with the coating (positive control), did develop infection. Nine animals were used as negative controls, i.e., those that were not treated with biofilms, and showed a rate of infection of 11% (1/9). Eight animals were treated with the novel coating only to determine its effect on host tissue. Results indicated that the novel active release coating may have significant promise for future application to prevent biofilm implant-related infections in patients.

Experimental Model of Biofilm Implant-Related Osteomyelitis to Test Combination Biomaterials Using Biofilms as Initial Inocula

Williams DL, Haymond BS, Woodbury KL, Beck JP, Moore DE, Epperson RT, Bloebaum RD.
J Biomed Mater Res A. 2012 Jul;100(7):1888-900. doi: 10.1002/jbm.a.34123. Epub 2012 Apr 10.
PMID: 22492534

Abstract
Currently, the majority of animal models that are used to study biofilm-related infections use planktonic bacterial cells as initial inocula to produce positive signals of infection in biomaterials studies. However, the use of planktonic cells has potentially led to inconsistent results in infection outcomes. In this study, well-established biofilms of methicillin-resistant Staphylococcus aureus were grown and used as initial inocula in an animal model of a Type IIIB open fracture. The goal of the work was to establish, for the first time, a repeatable model of biofilm implant-related osteomyelitis, wherein biofilms were used as initial inocula to test combination biomaterials. Results showed that 100% of animals that were treated with biofilms developed osteomyelitis, whereas 0% of animals not treated with biofilm developed infection. The development of this experimental model may lead to an important shift in biofilm and biomaterials research by showing that when biofilms are used as initial inocula, they may provide additional insights into how biofilm-related infections in the clinic develop and how they can be treated with combination biomaterials to eradicate and/or prevent biofilm formation.

(Preprint) Examination of a first-in-class bis-dialkylnorspermidine-terphenyl antibiotic in topical formulation against mono and polymicrobial biofilm.

bioRxiv 2020.06.04.133934; doi: https://doi.org/10.1101/2020.06.04.133934

Histological Analysis of a Retrieved Porous Tantalum Total Ankle Replacement: A Case Report.

Epperson RT, Barg A, Williams DL, Saltzman CL.

JBJS Case Connect. 2020 Jan-Mar;10(1):e0379. doi: 10.2106/JBJS.CC.19.00379.PMID: 32224645

Assessing the effect of physeal biopsy on angular deformity in a rabbit model.

Stevens P, Epperson RT, Taylor NB, Dickerson M, Williams DL.

J Pediatr Orthop B. 2019 Oct 22. doi: 10.1097/BPB.0000000000000687. PMID: 31651751

Plume height and surface coverage analysis of methicillin-resistant Staphylococcus aureus isolates grown in a CDC biofilm reactor.

Rasmussen RM, Epperson RT, Taylor NB, Williams DL.

Biofouling. 2019 Apr;35(4):463-471. doi: 10.1080/08927014.2019.1612381. Epub 2019 May 30.PMID: 31144524

Growth substrate may influence biofilm susceptibility to antibiotics.

Williams DL, Smith SR, Peterson BR, Allyn G, Cadenas L, Epperson RT, Looper RE.

PLoS One. 2019 Mar 14;14(3):e0206774. doi: 10.1371/journal.pone.0206774. eCollection 2019.PMID: 30870411

System Setup to Deliver Air Impact Forces to a Sheep Limb: Preparation for Model Development of Blast-Related Heterotopic Ossification.

Williams DL, Epperson RT, Taylor NB, Nielsen MB, Kawaguchi BS, Rothberg DL, Pasquina PF, Isaacson BM.

JMIR Res Protoc. 2019 Feb 22;8(2):e12107. doi: 10.2196/12107.PMID: 30794203

In vitro testing of a first-in-class tri-alkylnorspermidine-biaryl antibiotic in an anti-biofilm silicone coating.

Ashton NN, Allyn G, Porter ST, Haussener TJ, Sebahar PR, Looper RE, Williams DL.

Acta Biomater. 2019 Jul 15;93:25-35. doi: 10.1016/j.actbio.2019.02.010. Epub 2019 Feb 12.PMID: 30769135

In vivo analysis of a first-in-class tri-alkyl norspermidine-biaryl antibiotic in an active release coating to reduce the risk of implant-related infection.

Williams DL, Epperson RT, Ashton NN, Taylor NB, Kawaguchi B, Olsen RE, Haussener TJ, Sebahar PR, Allyn G, Looper RE.

Acta Biomater. 2019 Jul 15;93:36-49. doi: 10.1016/j.actbio.2019.01.055. Epub 2019 Jan 31.PMID: 30710710

Ability of a wash regimen to remove biofilm from the exposed surface of materials used in osseointegrated implants.

Allyn G, Bloebaum RD, Epperson RT, Nielsen MB, Dodd KA, Williams DL.

J Orthop Res. 2019 Jan;37(1):248-257. doi: 10.1002/jor.24161. Epub 2018 Nov 19.PMID: 30341934

Revisiting the Anterior Glenoid: An Analysis of the Calcified Cartilage Layer, Capsulolabral Complex, and Glenoid Bone Density.

Karns MR, Epperson RT, Baran S, Nielsen MB, Taylor NB, Burks RT.

Arthroscopy. 2018 Aug;34(8):2309-2318. doi: 10.1016/j.arthro.2018.03.017. Epub 2018 Jul 7.PMID: 30078426

Flash autoclave settings may influence eradication but not presence of well-established biofilms on orthopaedic implant material.

Williams DL, Taylor NB, Epperson RT, Rothberg DL.

J Orthop Res. 2018 May;36(5):1543-1550. doi: 10.1002/jor.23764. Epub 2017 Nov 22.PMID: 28976597

Effect of silver-loaded PMMA on Streptococcus mutans in a drip flow reactor.

Williams DL, Epperson RT, DeGrauw JP, Nielsen MB, Taylor NB, Jolley RD.

J Biomed Mater Res A. 2017 Sep;105(9):2632-2639. doi: 10.1002/jbm.a.36112. Epub 2017 Jun 27.PMID: 28512783

Sustained tobramycin release from polyphosphate double network hydrogels.

Lane DD, Fessler AK, Goo S, Williams DL, Stewart RJ.

Acta Biomater. 2017 Mar 1;50:484-492. doi: 10.1016/j.actbio.2016.12.030. Epub 2016 Dec 18.PMID: 27993638

Transcortical or intracondylar? Which model is accurate for predicting biomaterial attachment in total joint replacement?

Bloebaum RD, Abdo NT, Hofmann AA, Epperson RT, Olsen RE, Chalayon O.

J Biomed Mater Res B Appl Biomater. 2018 Feb;106(2):578-588. doi: 10.1002/jbm.b.33873. Epub 2017 Feb 28.PMID: 28244245

Link Between Clinical Predictors of Heterotopic Ossification and Histological Analysis in Combat-Injured Service Members.

Isaacson BM, Potter BK, Bloebaum RD, Epperson RT, Kawaguchi BS, Swanson TM, Pasquina PF.

J Bone Joint Surg Am. 2016 Apr 20;98(8):647-57. doi: 10.2106/JBJS.15.00895.PMID: 27098323

Determining the Mineral Apposition Rate of Heterotopic Ossification in Military Healthcare System Patients after Total Joint Replacement: A Case Series.

Isaacson, B.M., B.K. Potter, R.D. Bloebaum, R.T. Epperson, B. Kawaguchi, T.M. Swanson, and P.F. Pasquina.

Bone and Tissue Regeneration Insights, (January 2016). doi:10.4137/BTRI.S38041.

Does vitamin E-blended UHMWPE prevent biofilm formation?

Williams DL, Vinciguerra J, Lerdahl JM, Bloebaum RD.

Clin Orthop Relat Res. 2015 Mar;473(3):928-35. doi: 10.1007/s11999-014-3673-z.PMID: 24832828

In vitro efficacy of a novel active-release antimicrobial coating to eradicate biofilms of Pseudomonas aeruginosa.

Williams DL, Lerdahl JM, Haymond BS, Bloebaum RD.

Antimicrob Agents Chemother. 2014;58(4):2400-4. doi: 10.1128/AAC.01798-13. Epub 2014 Jan 6.PMID: 24395238

Model development for determining the efficacy of a combination coating for the prevention of perioperative device related infections: a pilot study.

Sinclair KD, Pham TX, Williams DL, Farnsworth RW, Loc-Carrillo CM, Bloebaum RD.

J Biomed Mater Res B Appl Biomater. 2013 Oct;101(7):1143-53. doi: 10.1002/jbm.b.32924. Epub 2013 Apr 6.PMID: 23564717

The significance of calcified fibrocartilage on the cortical endplate of the translational sheep spine model.

Sinclair SK, Bell S, Epperson RT, Bloebaum RD.

Anat Rec (Hoboken). 2013 May;296(5):736-44. doi: 10.1002/ar.22683. Epub 2013 Mar 12.PMID: 23494918

Characterization of a novel active release coating to prevent biofilm implant-related infections.

Williams DL, Sinclair KD, Jeyapalina S, Bloebaum RD.

J Biomed Mater Res B Appl Biomater. 2013 Aug;101(6):1078-89. doi: 10.1002/jbm.b.32918. Epub 2013 Apr 4.PMID: 23559470

In vivo efficacy of a silicone‒cationic steroid antimicrobial coating to prevent implant-related infection.

Williams DL, Haymond BS, Beck JP, Savage PB, Chaudhary V, Epperson RT, Kawaguchi B, Bloebaum RD.

Biomaterials. 2012 Nov;33(33):8641-56. doi: 10.1016/j.biomaterials.2012.08.003. Epub 2012 Aug 30.PMID: 22940221

Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

Sinclair KD, Pham TX, Farnsworth RW, Williams DL, Loc-Carrillo C, Horne LA, Ingebretsen SH, Bloebaum RD.

J Biomed Mater Res A. 2012 Oct;100(10):2732-8. doi: 10.1002/jbm.a.34209. Epub 2012 May 24.PMID: 22623404

Experimental model of biofilm implant-related osteomyelitis to test combination biomaterials using biofilms as initial inocula.

Williams DL, Haymond BS, Woodbury KL, Beck JP, Moore DE, Epperson RT, Bloebaum RD.

J Biomed Mater Res A. 2012 Jul;100(7):1888-900. doi: 10.1002/jbm.a.34123. Epub 2012 Apr 10.PMID: 22492534

Host bone response to polyetheretherketone versus porous tantalum implants for cervical spinal fusion in a goat model.

Sinclair SK, Konz GJ, Dawson JM, Epperson RT, Bloebaum RD.

Spine (Phila Pa 1976). 2012 May 1;37(10):E571-80. doi: 10.1097/BRS.0b013e318240f981.PMID: 22146277

Efficacy of a porous-structured titanium subdermal barrier for preventing infection in percutaneous osseointegrated prostheses.

Jeyapalina S, Beck JP, Bachus KN, Williams DL, Bloebaum RD.

J Orthop Res. 2012 Aug;30(8):1304-11. doi: 10.1002/jor.22081. Epub 2012 Jan 31.PMID: 22294380

Using biofilms as initial inocula in animal models of biofilm-related infections.

Williams DL, Costerton JW.

J Biomed Mater Res B Appl Biomater. 2012 May;100(4):1163-9. doi: 10.1002/jbm.b.31979. Epub 2011 Nov 28.PMID: 22120924

A modified CDC biofilm reactor to produce mature biofilms on the surface of peek membranes for an in vivo animal model application.

Williams DL, Woodbury KL, Haymond BS, Parker AE, Bloebaum RD.

Curr Microbiol. 2011 Jun;62(6):1657-63. doi: 10.1007/s00284-011-9908-2. Epub 2011 Mar 25.PMID: 21437591

Characterization of bacterial isolates collected from a sheep model of osseointegration.

Williams DL, Bloebaum RD, Beck JP, Petti CA.

Curr Microbiol. 2010 Dec;61(6):574-83. doi: 10.1007/s00284-010-9655-9. Epub 2010 May 11.PMID: 20458482

Observing the biofilm matrix of Staphylococcus epidermidis ATCC 35984 grown using the CDC biofilm reactor.

Williams DL, Bloebaum RD.

Microsc Microanal. 2010 Apr;16(2):143-52. doi: 10.1017/S143192760999136X. Epub 2010 Mar 8.PMID: 20205969

Assessing peri-implant tissue infection prevention in a percutaneous model.

Perry EL, Beck JP, Williams DL, Bloebaum RD.

J Biomed Mater Res B Appl Biomater. 2010 Feb;92(2):397-408. doi: 10.1002/jbm.b.31528.PMID: 19927331

Protein phosphorylation in irradiated human melanoma cells.

Warters RL, Williams DL, Zhuplatov SB, Pond CD, Leachman SA.

Radiat Res. 2007 Nov;168(5):535-44. doi: 10.1667/RR0404.1.PMID: 17973544

Deparaffinizing Soft–Tissue Sections for Elemental Analysis of Wear Particulate

Koller, K.E., Epperson, R.T., & Bloebaum, R.D.

Journal of Histotechnology (2006). 29, 233 - 235.

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