A multimodality approach is needed for management of infected joint replacement prostheses and infected skeletal metalwork. We present our results in six patients managed surgically with standard techniques, with the addition of a local antibiotic delivery system using absorbable Calcium Sulphate beads. A retrospective study was undertaken of 6 patients with established musculoskeletal infection in relation to existing metalwork. Two patients had infection in the hip replacement prosthesis, three had infected prosthetic knee joints and one had infection in a femoral locking plate. All were treated with extensive debridement, revision / retention of implants, parenteral antibiotics and local antibiotics. Patients were followed up in clinic for resolution of inflammatory markers and subsidence of signs of infection. Control of infection was achieved in five patients at average 19 months followup. One patient had persistent infection and has undergone further surgery. In this preliminary study, we found local antibiotic delivery using absorbable calcium sulphate beads to be an effective adjuvant to standard debridement, parenteral antibiotics and revision of implants

Aim

The objective of this systematic review is to evaluate the current evidence for or against this up-and-coming treatment modality.

Aim. The treatment of chronic orthopedic device-related infection (ODRI) often requires multiple surgeries and prolonged antibiotic therapy. In a two-stage exchange procedure, the treatment protocol includes device removal and placement of an antibiotic-loaded bone cement spacer to achieve high local antibiotic concentrations. At the second stage, further surgery is required to remove the spacer and replace it with the definitive device. We have recently developed a thermo-responsive hyaluronan hydrogel (THH) that may be loaded with antibiotics and used as delivery system. Since the material is bio-resorbable, it does not require surgical removal and may therefore be suitable for use as treatment strategy in a single-stage exchange. This aim of this study was to evaluate gentamicin sulphate (Genta)-loaded THH (THH-Genta) for treating a chronic Staphylococcus aureus ODRI in sheep using a single-stage procedure. Methods. Twelve Swiss-alpine sheep received an IM tibia nail and an inoculation of a gentamicin-sensitive clinical strain of Staphylococcus aureus. After letting a chronic infection develop for 8 weeks, a revision procedure was performed: the implant was removed, the IM canal debrided and biopsies were taken for culture. The IM canal was then filled with 25ml THH-Genta (1% Genta) or left empty (control group) prior to the implantation of a sterile nail. An ultrafiltration probe was placed within the IM cavity to collect extracellular fluid and determine local antibiotic levels for 10 days. Both groups received systemic amoxicillin and clavulanic acid for 2 weeks, followed by 2 weeks without treatment for antibiotic washout. At euthanasia, IM nail, bone marrow, bone and tissue samples were harvested for quantitative bacteriology. Results. All sheep were infected at revision surgery as confirmed by cultures of biopsies and sonication of the IM nail. Local Genta concentrations ranged on average from 830µg/ml postoperatively to below 5µg/ml after 8 days. At euthanasia, S. aureus was detected in 5/5 IM nails, 5/5 bone marrow samples, and 8/25 superficial soft tissue samples in the control group (one control sheep was excluded for having a superinfection). In the THH-Genta group, S. aureus was cultured from 0/6 IM nails, 1/6 bone marrow samples, and 1/30 superficial soft tissue samples. Conclusions. The THH showed a Genta release pattern that started with high local concentrations and decreased to low concentrations within 10 days. Local Genta delivery by THH combined with systemic antibiotics significantly reduced infection rates whereas systemic therapy alone was unable to eradicate infection in any animal

Antibiotic-loaded bone cements are used to decrease occurrence of bone infections in cemented arthroplasties and actually being considered as a more cost-effective procedure when compared to cementless implants [1]. However, considering the challenge of treating device-associated infections there is a reduced number of formulations in the market. Response from the industry to medical need is still slow considering the rapid change in the infecting microbial profile and the emergence of multiresistant strains [2]. In this context, the aim of the work is to evaluate the role of lactose (L), as a porogen, on the antibiotic release from bone cement (BC). Levofloxacin (Lev) and minocycline (M) were the selected antibiotics to be individually loaded into BC due to their low cost and potential application in bone infections [3,4].

Two types of matrices were prepared: 1) Loaded with 2.5% of antibiotics (controls) and 2) Loaded with 10% lactose and 2.5% antibiotic. In vitro drug release and microbiological tests against representative strains causative of bone infections were assessed.

Lactose significantly increased the release of both antibiotics. Complete minocycline release after one-week was observed (Fig.1A). Also, lactose increased 3.5-fold the levofloxacin released from BC (Fig.1B).

Furthermore, microbiological studies showed that no interaction was observed between lactose and antibiotic as no decrease in drugs antimicrobial activity was observed (Table 1).

Considering the results, L-BC matrix appears to be a valuable alternative to available formulations. Future work will include testing other antibiotics as well as mixtures of drugs.

Fundação para a Ciência e Tecnologia (Portuguese government) for financial support: EXCL/CTM-NAN/0166/2012 and strategic project PEst-OE/SAU/UI4013/2011.

Aims. The standard of wide tumour-like resection for chronic osteomyelitis (COM) has been challenged recently by adequate debridement. This paper reviews the evolution of surgical debridement for long bone COM, and presents the outcome of adequate debridement in a tertiary bone infection unit. Methods. We analyzed the retrospective record review from 2014 to 2020 of patients with long bone COM. All were managed by multidisciplinary infection team (MDT) protocol. Adequate debridement was employed for all cases, and no case of wide resection was included. Results. A total of 53 patients (54 bones) with median age of 45.5 years (interquartile range 31 to 55) and mean follow-up of 29 months (12 to 59) were included. In all, ten bones were Cierny-Mader type I, 39 were type III, and five were type IV. All patients were treated with single-staged management, except for one (planned two-stage stabilization). Positive microbial cultures grew in 75%. Overall, 46 cases (85%) had resolution of COM after index procedure, and 49 (90.7%) had resolution on last follow-up. Four patients (7%) underwent second surgical procedure and six patients (11%) had complications. Conclusion. We challenge the need for wide tumour-like resection in all cases of COM. Through detailed preoperative evaluation and planning with MDT approach, adequate debridement and local delivery of high concentration of antibiotic appears to provide comparable outcomes versus radical debridement. Cite this article: Bone Jt Open 2023;4(8):643–651

Introduction. The treatment of chronic bone infection often involves excision of dead bone and implantation of biomaterials which elute antibiotics. Gentamicin is a preferred drug for local delivery, but its systemic use carries a well-established risk of nephrotoxicity. We aim to establish the risk of renal injury with local delivery in a ceramic carrier. Materials and Methods. 163 consecutive patients with Cierny-Mader Type 3 or 4 chronic osteomyelitis were treated with a single-stage operation which included filling of the osseous defect with a calcium sulphate-hydroxyapatite carrier containing gentamicin. The mean carrier volume used was 10.9mls, leading to a mean implanted gentamicin dose of 191.3mg (maximum 525mg). Serum creatinine levels were collected pre-operatively and during the first seven days post-operatively. Renal impairment was graded using the Chronic Kidney Disease (CKD) Staging system, and AKI was assessed using the RIFLE criteria. Results. 155 cases had adequate data to allow calculation of pre- and post-operative GFR. 7 patients had pre-existing renal disease. 70 patients (45.2%) had a temporary eGFR drop post-operatively, with the greatest decrease occurring a mean 3.06 days following surgery. Twenty cases had a >10% decline in eGFR, but 12 resolved within 7 days. 7 patients transiently fell into the “Risk” category according to RIFLE criteria, but no patient had a change consistent with “Injury”, “Failure” or “Loss” of renal function and none had clinical signs of new acute renal impairment post-operatively. Conclusions. The implantation of up to 525mg of gentamicin contained within Cerament G, as part of the surgical treatment of osteomyelitis, is safe and carries minimal risk of significant acute kidney injury. A small, transient increase in serum creatinine may be observed in the early post-operative period, and attention should be paid to limit patients exposure to other nephrotoxic agents. The majority of patients will return to their baseline renal function within 7 days following the operation. The presence of pre-existing renal disease is not a contraindication to local gentamicin therapy

Introduction. Wide, tumor-like resection for chronic osteomyelitis (COM), a standard practice previously, has been challenged recently with adequate, local debridement. This paper reviews the evolution of surgical debridement for long bone osteomyelitis, and presents the outcome of adequate debridement in a tertiary bone infection unit. Materials & Methods. Retrospective review of records from 2014 to 2020 of patients with long bone osteomyelitis. All records were searched electronically and imaging reviewed. All patients were managed by Multidisciplinary Infection Team protocol. Results. 53 patients (54 bones) with median age of 45.5 years (IQR 31 to 55) and mean follow-up of 29 months (12 – 59) were identified. According to Cierny-Mader classification, ten bones were type I, 39 were type III, and five were type IV; via the BACH classification of long bone osteomyelitis 21 were uncomplicated, 32 were complex, and one had limited options. All patients were treated with single-staged management with one planned second stage stabilization. Seventy-five percent grew positive microbial cultures. Forty-six (85%) cases had resolution of COM after index procedure and 51 (94%) had resolution at last follow up. Four (7%) patients underwent second surgical procedure and six (11%) patients had complications. Conclusions. We report high COM resolution rate through detailed pre operative evaluation and planning with multidisciplinary team approach. We challenge the need for wide tumor-like resection and the need for regenerative procedures in all cases of COM. Adequate debridement and local delivery of high concentration of antibiotic appears to provide comparable outcomes

Aim. Determine the time concentration profile required to achieve vancomycin-mediated eradication of Staphylococcus aureus biofilm. This is critical for the identification of performance targets for local antibiotic delivery, yet has not been described. Method. Mature S. aureus UAMS-1 biofilms were grown on titanium-aluminum-niobium discs in Mueller Hinton broth (MHB). After 7 days, the discs were incubated in MHB containing vancomycin at 100, 200, 500, 1′000 and 2′000 mg/L. Both static and shaking conditions were tested. Samples were retrieved at intervals for up to 28 days for quantification of residual biofilm by sonication and serial dilution plating. One additional disc was processed per time point for scanning electron microscopy. Results. Progressive and significant reduction of viable bacteria was observed over time at all vancomycin concentrations in both static and shaking conditions. After 28 days under static conditions, the S. aureus biofilm was completely eradicated at 200 mg/L vancomycin and higher concentrations. Biofilm could could however not be eradicated under shaking conditions at any concentration. Logistic regression documents time of exposure at ≥200 mg/L as being the essential determinant of eradication. Conclusions. The clinical relevance of the present study is that it is not impossible to eradicate mature S. aureus biofilm from metal implants by vancomycin alone, fostering efforts to optimize local delivery. The required time concentration profile cannot be achieved yet by systemic administration or any of the local delivery vehicles available. Even longer exposure as 28 days might be required as wound fluid flow might influence unfavourably biofilm resistance to vancomycin

Aim. Chronic osteomyelitis reflects a progressive inflammatory process of destruction and necrosis affecting bone architecture. It presents a challenge to manage, requiring multi-stage multidisciplinary interventions, and the literature reports a wide variety of treatment strategies. This systematic scoping review aims to map and summarise existing literature on treatment of chronic osteomyelitis of the femur and tibia and investigates the full range of treatments reported in order to enhance the reader's understanding of how to manage this complex condition. Method. A comprehensive computer-based search was conducted in PubMed, EMBASE, MEDLINE, Emcare and CINAHL for articles reporting treatment of chronic tibial/femoral osteomyelitis. Two reviewers independently performed a two-stage title/abstract and full-text screening, followed by data collection. Studies were included if they described any treatment strategy including at least one surgical intervention. Key information extracted included causative pathogens, treatment protocol and outcome i.e. both success rate, defined as remission achieved following initial treatment with no recurrence during followup, and recurrence rate. Results. A total of 1230 articles were identified, and 40 articles (2529 patients) ultimately included. Although a wide variety of treatment protocols are reported, all revolve around three key principles: removal of infected tissue, dead space management and antibiotic therapy. Variations are evident when considering use of extensive versus more conservative debridement techniques, and delivery and regime of antibiotic therapy, e.g. whether to use one of, or both systemic and local delivery. The majority (84.5%) of patients presented with stage III or IV disease according to the Cierny-Mader classification and staphylococcus aureus was the most commonly isolated organism. Although there is heterogeneity across studies in reporting outcomes, with only 29 studies reporting success rate as defined in this review, 25 (86.2%) of these reported a success rate of at least 80%. Conclusions. It is difficult to identify the optimal treatment strategy when reporting of outcomes is not standardised across studies, even in the context of similar techniques being used. Success rates across studies may also vary depending on patient demographics, comorbidities, severity, type and number of causative pathogens and follow-up length. It is now essential to identify specific patient and treatment related factors that may affect clinical outcomes. Given the current dominance of case series in the literature, there is a need for randomised controlled trials to yield further information that could aid future efficient management

Aim. Chronic bone infections and infected fractures are often treated with excision of the dead bone and implantation of biomaterials which elute antibiotics. Gentamicin has been a preferred drug for local delivery, but this could induce renal dysfunction due to systemic toxicity. This is a particular concern in patients with pre-existing chronic renal disease treated with new antibiotic carriers which achieve very high peak levels of gentamicin in the first few days after surgery. Method. 163 patients (109 males; average age 51.6 years) with Cierny-Mader Type 3 or 4 chronic osteomyelitis had a single-stage operation with excision of the dead bone, filling of the osseous defect with a calcium sulphate-hydroxyapatite carrier, containing gentamicin and immediate soft tissue closure. 2. No patient was given systemic gentamicin or other renal toxic antibiotics. Mean carrier volume was 10.9mls (range 1–30mls) and mean gentamicin dosing was 190.75mg (maximum 525mg). Seven patients had pre-existing renal disease (4 diabetic nephropathy, 1 nephrotic syndrome, 1 renal transplant and 1 previous acute kidney injury). Serum creatinine levels were collected pre-operatively and during the first seven days post-operatively. Glomerular filtration rate (GFR) was calculated using the CKD-epi creatinine equation. Renal function was defined using the Chronic Kidney Disease (CKD) Staging system. Results. 155 cases had adequate data to allow calculation of pre- and post-operative GFR. Pre-operative CKD staging demonstrated 118 Class I (normal renal function), 30 Class II, 3 Class IIIa, 3 Class IIIb, and 1 Class V disease. Mean pre-operative GFR (99.7ml/min/1.73m. 2. , SD 21.0) was no different to post-operative GFR (103.2ml/min/1.73m. 2. , SD 21.3), p= 0.0861. Four cases had a >10% decline in GFR below normal, with only one case dropping a CKD stage, from I (normal) to II (mildly decreased). Only 1/7 cases with pre-existing renal disease had a GFR drop of >10% (from 11ml/min/1.73m. 2. to 8ml/min/1.73m. 2. ). 70/155 (45.2%) had a temporary GFR drop post-operatively, with the biggest drop occurring a mean 3.06 days following surgery (SD 2.1). No patient had clinical signs of new acute renal impairment post-operatively. Conclusions. Renal function is not significantly affected by local implantation of gentamicin up to 525mg. The presence of pre-existing renal disease is not a contraindication to local gentamicin therapy

Fracture non-union can be as high as 20% in certain clinical scenarios and has a high associated socioeconomic burden. Boron has been shown to regulate the Wnt/β-catenin pathway in other bodily processes. However, this pathway is also critical for bone healing. Here we aim to demonstrate that the local delivery of boric acid can accelerate bone healing, as well as to elucidate how boric acid, via the regulationtheWnt/β-catenin pathway, impacts theosteogenic response of bone-derived osteoclasts and osteoblasts during each phase of bone repair. Bilateral femoral cortical defects were created in 32 skeletally mature C57 mice. On the experimental side, boric acid (8mg/kg concentration) was injected locally at the defect site whereas on the control side, saline was used. Mice were euthanized at 7, 14, and 28 days. MicroCT was used to quantify bone regeneration at the defect. Histological staining for ALP and TRAP was used to quantify osteoblast and osteoclast activity respectively. Immunohistochemical antibodies, β-catenin and CD34 were used to quantify active β-catenin levels and angiogenesis respectively. Sclerostin and GSK3β were also quantified and are both inhibitors of the wnt signaling pathway via degradation and inactivation of β-catenin. The boron group exhibited higher bone volume and trabecular thickness at the defect site by 28 days on microCT. ALP activity was significantly higher in boron group at 7 days whereas boron had no effect on TRAP activity. Additionally, CD34 staining revealed increased angiogenesis at 14 days in boron treated groups. β-catenin activity on immunohistochemistry was significantly higher in the boron group at 7 days, GSK3β was significantly higher in the boron group at 14 days and Sclerostin was significantly higher in the boron group at 28 days. Boron appears to increase osteoblast activity at the earlier phases of healing. The corresponding early increase in β-catenin along with ALP likely supports that boron increases osteoblast activity via the wnt/β-catenin pathway. Increased angiogenesis at 14 days could be a separate mechanism increasing bone formation independent of wnt/β-catenin activation. Neither GSK3β or Sclerostin levels correlated with β-catenin activity therefore boron likely increases β-catenin through a mechanism independent of both GSK3β and Sclerostin. The addition of this inexpensive and widely available ion could potentially become a non-invasive, cost-effective treatment modality to augment fracture healing and decrease non-union rates in high risk patients

Bone metastases are the most common cause of cancer-related pain and often lead to other complications such as pathological fractures and spinal cord compression. Bisphosphonates (BP) are a class of potent anti-resorptive agents commonly prescribed to retard osteoporosis progression. Interestingly, BP may have indirect anti-tumour properties through negative effects on macrophages, osteoclasts, endothelial cells and their ability to suppress matrix metalloproteinase (MMP) activity. Currently, the use of bisphosphonates for cancer therapy is generally restricted to high dose systemic delivery. The purpose of this study was to investigate the effects of direct local delivery of Zoledronate at the metastatic site in a mouse model of breast cancer metastasis to bone. Seven days following intra-tibial inoculation with MDA-MB-231 (N = 1× 105) breast cancer cells in athymic mice, the experimental group (N = 11) was treated by direct infusion of 2µg of Zoledronate into the tibial lesion (three times/week for three weeks) and compared to vehicle-treated mice (N = 5). The formation of bone metastases and growth of the lesions were followed up by weekly bioluminescence imaging. In a subsequent experiment, a comparison of the effects of local versus systemic delivery of Zoledronate on the formation of osteolytic bone metastases was carried in athymic mice (N = 15). Seven days following intra-tibial inoculation with MDA-MB-231 breast cancer cells, the systemic group (N = 5) was treated with Zoledronate (0.025mg/kg) once per week for four weeks and compared to systemic delivery of vehicle (N = 4). Following treatment, the mice were sacrificed, and micro-CT images of the right tibia were obtained. Bone volume to tissue volume ratio (BV/TV%) was determined using µ-CT biomarkers. The first experiment showed a statistically significant increase in mean bone volume/tissue volume ratio% (BV/TV%) in the treated group (7.0±1.54%) as compared to the control group (3.8±0.48%) (P <0.001, 95%CI=1.9–4.3). This corresponded to a net increase of 84.21% in response to Zoledronate treatment. Comparison between the local and systemic effects of Zoledronate also revealed a significant increase in the BV/TV% in the locally treated group (6.69±0.62%) when compared to the cohort administered systemic bisphosphonate treatment (4.03±0.44%) (P<0.001, 95%CI=1.24–3.20), corresponding to a net increase of 66.0%. These preliminary results suggest that high dose sustained release of Zoledronate can lead to a significant inhibition of tumor-induced osteolysis. Moreover, comparison between local and systemic delivery revealed that the effect of local bisphosphonate administration exceeds the benefits of systemic delivery in terms of osteolysis inhibition. Lastly, the noted effects of Zoledronate local delivery triggers the need for further assessment of its anti-tumour activity

Aim. The duration of systemic antibiotic therapy following first-stage surgery is contentious. Our Institution's philosophy is to perform an aggressive debridement, use high concentration targeted antibiotics through cement beads and systemic prophylactic antibiotics alone. In the presence of significant soft tissue infection or microbiological diagnostic uncertainty; systemic antibiotics may be prescribed for 5 days whilst awaiting tissue culture results. The aim of this study was to assess the success of our philosophy in the management of PJI of the hip using our two-stage protocol. Method. A retrospective review of our Institution's prospectively-collected database was performed to identify those patients who were planned to undergo a two-stage hip revision procedure for PJI. All patients had a confirmed diagnosis of PJI as per the major criteria of MSIS 2013, a minimum 5-years follow up and were assessed at the time of review using the MSIS working group outcome-reporting tool (2018). They were then grouped into “successful” or “unsuccessful” (suppressive antibiotics, further revision for infection, death within 1 year). Results. 299 intended two-stage hip revisions in 289 patients (6 repeat ipsilateral two-stage, 4 bilateral two-stage) met our inclusion criteria. 258 (86%) patients proceeded to 2. nd. stage surgery. Median follow up was 10.7 years. 91% success rate was observed for those patients who underwent reimplantation; dropping to 86% when including the patients who did not proceed to second stage surgery. The median duration of post-operative systemic antibiotics following first stage surgery was 5 days (IQR 5–9). No significant difference in outcome was observed in patients who received either; < / = 48 hours (86%; n=70) compared to > 48 hours antibiotics (86%; n=229; p=0.96) or </= 5 days of antibiotics (88%; n=202) compared to > 5 days antibiotics (82%; p=0.38). A significant majority had gram-positive (88%) infection with 30% being polymicrobial. Greater success rates were observed for gram-positive PJI (87%); than for gram-negative PJI (84%) and mixed Gram infection (72%; p=0.098). Conclusion. Aggressive surgical debridement with high concentration, targeted local antibiotic delivery at time of first stage hip surgery, without prolonged systemic antibiotics, provides a high rate of success, responsible antibiotic stewardship and reduced hospital costs

Introduction. Treatment of non-union in open tibial fractures Gustilo-Anderson(GA)-3A/3B fractures remains a challenging problem. Most of these can be dealt using treatment methods that requires excision of the non-union followed by bone grafting, masquelet technique, or acute shortening. Circular fixators with closed distraction or bone transport also remains a useful option. However, sometimes due to patient specific factors these cannot be used. Recently antibiotic loaded bone substitutes have been increasingly used for repairing infected non-unions. They provide local antibiotic delivery, fill dead space, and act as a bone conductive implant, which is resorted at the end of a few months. We aimed to assess the outcome of percutaneous injection of bone substitute while treating non-union of complex open tibial fractures. Materials & Methods. Three cases of clinical and radiological stiff tibial non-union requiring further intervention were identified from our major trauma open fracture database. Two GA-3B cases, treated with a circular frame developed fracture-related-infection(FRI) manifesting as local cellulitis, loosened infected wires/pins with raised blood-markers, and one case of GA-3A treated with an intramedullary nail. At the time of removal of metalwork/frame, informed consent was obtained and Cerament-G. TM. (bone-substitute with gentamicin) was percutaneously injected through a small cortical window using a bone biopsy(Jamshedi needle). All patients were allowed to weight bear as tolerated in a well-fitting air-cast boot and using crutches. They were followed up at 6 weekly intervals with clinical assessment of their symptoms and radiographs. Fracture union was assessed using serial radiographs with healing defined as filling of fracture gap, bridging callus and clinical assessment including return to full painless weight bearing. Results. Follow-up at 6 months showed all fractures had healed with no defect or gaps with evidence of new trabecular bone and significant resorption of Cerament-G. TM. at final follow-up. There was no evidence of residual infection with restoration of normal limb function. Fractures with no internal fixation showed a mild deformity that had developed during the course of the healing, presumed due to mild collapse in the absence of fixation. These were less than 10 degrees in sagittal and coronal planes and were clinically felt to be insignificant by the patients. Conclusions. Cerament-G's unique combination of high dose antibiotics and hydroxy apatite matrix provided by calcium sulphate might help provide an osteoconductive environment to allow these stiff non-unions to heal. The matrix appears to provide a scaffold-like structure that allows new bone in-growth with local release of antibiotics helping reduce deep-seated infections. The final deformation at fracture site underlines the need for fixation- and it is very unlikely that this technique will work in mobile nonunions. Whilst similar fractures may heal without the use of bone substitute injections, the speed of healing in presence of significant fracture gap suggests the use of these bone substitutes did help in our cases. Further studies with a larger cohort, including RCTs, to evaluate the effectiveness of this technique compared to other methods are needed

Despite the increasing availability of bone grafting materials, the regeneration of large bone defects remains a challenge. Especially infection prevention while fostering regeneration is a crucial issue. Therefore, loading of grafting material with antibiotics for direct delivery to the site of need is desired. This study evaluates the concept of local delivery using in vitro and in vivo investigations. We aim at verifying safety and reliability of a perioperative enrichment procedure of demineralized bone matrix (DBM) with gentamicin. DBM (DBMputty, DIZG, Germany) was mixed with antibiotic using a syringe with an integrated mixing propeller (Medmix Systems, Switzerland). Gentamicin, as powder or solution, was mixed with DBM at different concentrations (25 −100 mg/g DBM), release and cytotoxicity was analyzed. For in vivo analysis, sterile drill hole defects (diameter: 6 mm, depth: 15 mm) were created in diaphyseal and metaphyseal bones of sheep (Pobloth et al. 2016). Defects (6 – 8 per group and time point) were filled with DBM or DBM enriched with gentamicin (50 mg/g DBM) or left untreated. After three and nine weeks, defect regeneration was analyzed by µCT and histology. The release experiments revealed a burst release of gentamicin from DBM independent of the used amount, the sampling strategy, or the formulation (powder or solution). Gentamicin was almost completely released after three days in all set-ups. Eluates showed an antimicrobial activity against S. aureus over at least three days. Eluates had no negative effect on viability and alkaline phosphatase activity of osteoblast-like cells (partially published Bormann et al. 2014). µCT and histology of the drill hole defects revealed a reduced bone formation with gentamicin loaded DBM. After nine weeks significantly less mineralized tissue was detectable in metaphyseal defects of the gentamicin group. Histological evaluation revealed new bone formation starting at the edges of the drill holes and growing into the center over time. The amount of DBM decreased over time due to the active removal by osteoclasts while osteoblasts formed new bone. Using this mixing procedure, loading of DBM was fast, reliable and possible during surgical setting. In vitro experiments revealed a burst and almost complete release after three days, antimicrobial activity and good biocompatibility of the eluates. Gentamicin/DBM concentration was in the range of clinically used antibiotic-loaded-cement for prophylaxis and treatment in joint replacement (Jiranek et al. 2006). The delayed healing seen in vivo was unexpected due to the good biocompatibility found in vitro. A reduced healing was also seen in spinal fusion where DBM was mixed with vancomycin (Shields et al. 2017), whereas DBM with gentamicin or DBM/bioactive glass with tobramycin had no negative effect on osteoinductivity or femur defect healing, respectively (Lewis et al. 2010, Shields et al. 2016). In conclusion, loading of DBM with gentamicin showed a proper antibiotic delivery over several days, covering the critical phase shortly after surgery. Due to the faster and complete release of the antibiotic compared to antibiotic loaded cement, the amount of antibiotic should be much lower in the DBM compared to cement

Aim. Allograft bone chips used in complex bone reconstruction procedures are associated with an increased infection risk. The perioperative use of systemic cefazolin is standard to prevent infection, but is less effective in the presence of avascular bone grafts. Bone chips have been described as a carrier for local delivery of antibiotics, but impregnation with cefazolin in a prophylactic setting has not been described. We aimed to obtain a prolonged cefazolin release from bone chips to maximize the prophylactic effect. Method. Three types of bone chips were evaluated: fresh frozen, decellularized frozen and decellularized lyophilized. Bone chips were incubated with 20 mg/ml cefazolin or treated with liquid hydrogel containing either 1 mg/ml fibrin or 1 mg/ml collagen and 20 mg/ml cefazolin. The cefazolin hydrogel was distributed in the porous structure by short vacuum treatment. Bone chips with cefazolin but without hydrogel were incubated for 20 min- 4h under atmospheric pressure or under vacuum. Cefazolin elution of bone chips was carried out in fetal bovine serum and analyzed by Ultra Performance Liquid Chromatography – Diode Array Detection. Results. Without hydrogel, cefazolin release was limited to 4 hours. When vacuum was applied during impregnation, elution of cefazolin exceeding the MIC (minimal inhibitory concentration) from decellularized lyophilized bone chips was obtained for 36 hours. Use of a collagen hydrogel and vacuum treatment resulted in a high concentration at 24 hours, but did not support prolonged release for any of the three types of tested bone chips. In contrast, combination of decellularized frozen bone chips with fibrin hydrogel resulted in an initial release of 533 μg/ml, declining to the MIC at 72 hours, while no longer measurable after 92 hours. Such elution profile is desirable, since high initial levels are important to maximize antibacterial action whereas the complete wash out prevents antibiotic resistance. By increasing the cefazolin concentration during impregnation, elution above the MIC could be obtained for 120 hours. Impregnated bone chips stored at −20° C for 3 months performed similarly to freshly impregnated bone chips. Conclusions. Bone chips processed with the described hydrogel-based impregnation protocol allows tunable delivery of cefazolin for a local prophylactic effect

Introduction. Antibiotic loaded absorbable calcium sulphate beads (ALCSB) are an increasingly popular adjunct in the treatment of musculoskeletal infections including osteomyelitis and peri-prosthetic joint infections (PJI). Limited data exist regarding the clinical indications and biochemical outcomes of ALCSB in PJI cases. Aims. To determine the proportion of organisms that were sensitive to the gentamicin and vancomycin that we add to the ALCSB as a part of our treatment protocol and to determine the prevalence of postoperative hypercalcaemia when used for treatment of hip and knee DAIR (debridement and implant retention) and revision arthroplasty for PJI. Methods. A retrospective review of 160 hip and knee revisions using ALCSB performed between June 2015 and May 2018 at a tertiary unit was performed. 10–40 cc of ALCSB was used for each case containing vancomycin and gentamicin. Data recorded included patient demographics, comorbidities, indication for surgery, operative intervention, microbiological results and serum biochemistry for calcium levels. Results. The cohort consisted of 91 males and 69 females, with a mean age of 69.0 years (21.3 to 93.1) and mean BMI of 34.7(12.6 to 48.1). 56 (35%) had single-stage revision, 45 (28.1%) had first stage revision, 35 (21.9) had DAIR, 19 (11.9%) had second stage revision and 5 (3.1%) other procedures. Organisms included staphylococcus aureus (30.0%), culture-negative (27.5%), staphylococcus epidermidis (18.1%), and pseudomonas aeruginosa (3.1%). 54.3% were sensitive to both vancomycin and gentamicin, 25.0% to vancomycin only and 8.6% to gentamicin only. 11.9% (19/160) of patients had transient post-operative hypercalcaemia (normal range 2.2–2.7mmol/L), peaking at day 6–7 and resolved with hydration by day 10 postoperatively. Preoperatively, 26.9% had albumin <35 g/L and 49.3% had some degree of renal impairment with an eGFR <90 ml/min. Conclusion. The use of ALCSB allows local delivery of vancomycin and gentamicin in lower limb PJI. Organisms were sensitive to this antibiotic combination in 88% cases. Care must be taken to monitor calcium for 10 days post-operatively

There has been an evolution in revision hip arthroplasty towards cementless reconstruction. Whilst cemented arthroplasty works well in the primary setting, the difficulty with achieving cement fixation in femoral revisions has led to a move towards removal of cement, where it was present, and the use of ingrowth components. These have included proximally loading or, more commonly, distally fixed stems. We have been through various iterations of these, notably with extensively porous coated cobalt chrome stems and recently with taper-fluted titanium stems. As a result of this, cemented stems have become much less popular in the revision setting. Allied to concerns about fixation and longevity of cemented fixation revision, there were also worries in relation to bone cement implantation syndrome when large cement loads were pressurised into the femoral canal at the time of stem cementation. This was particularly the case with longer stems. Technical measures are available to reduce that risk but the fear is nevertheless there. In spite of this direction of travel and these concerns, there is, however, still a role for cemented stems in revision hip arthroplasty. This role is indeed expanding. First and foremost, the use of cement allows for local antibiotic delivery using a variety of drugs both instilled in the cement at the time of manufacture or added by the surgeon when the cement is mixed. This has advantages when dealing with periprosthetic infection. Thus, cement can be used both as interval spacers but also for definitive fixation when dealing with periprosthetic hip infection. The reconstitution of bone stock is always attractive, particularly in younger patients or those with stove pipe canals. This is achieved well using impaction grafting with cement and is another extremely good use of cement. In the very elderly or those in whom proximal femoral resection is needed at the time of revision surgery, distal fixation with cement provides a good solution for immediate weight bearing and does not have the high a risk of fracture seen with large cementless stems. Cement is also useful in cases of proximal femoral deformity or where cement has been used in a primary arthroplasty previously. We have learnt that if the cement is well-fixed then the bond of cement-to-cement is excellent and therefore retention of the cement mantle and recementation into that previous mantle is a great advantage. This avoids the risks of cement removal and allows for much easier fixation. Stems have been designed specifically to allow this cement-in-cement technique. It can be used most readily with polished tapered stems - tap out a stem, gain access at the time of revision surgery and reinsert it. It is, however, now increasingly used when any cemented stems are removed provided that the cement mantle is well fixed. The existing mantle is either wide enough to accommodate the cement-in-cement revision or can be expanded using manual instruments or ultrasonic tools. The cement interface is then dried and a new stem cemented in place. Whilst the direction of travel in revision hip arthroplasty has been towards cementless fixation, particularly with tapered distally fixed designs, the reality is that there is still a role for cement for its properties of immediate fixation, reduced fracture risk, local antibiotic delivery, impaction grafting and cement-in-cement revision

Great strides have been made in the early detection and treatment of cancer which is resulting in improved survivability and more Canadians living with cancer. Approximately 80% of primary breast, lung, and prostate cancers metastasize to the spine. Poly-methyl methacrylate (PMMA) bone cement is one of the most commonly used bone substitutes in spine surgery. In clinical practice it can be loaded with various drugs, such as antibiotics or chemotheraputic drugs, as a means of local drug delivery. However, studies have shown that drugs loaded into PMMA cement tend to release in small bursts in the first 48–72 hours, and the remaining drug is trapped without any significant release over time. The objective of this study is to develop a nanoparticle-functionalized PMMA cement for use as a sustained doxorubicin delivery device. We hypothesize that PMMA cement containing mesoporous silica nanoparticles will release more doxorubicin than regular PMMA. High viscosity SmartSet ™ PMMA cement by DePuy Synthes was used in this study. The experimental group consisted of 3 replicates each containing 0.24 g of mesoporous silica nanoparticles, 1.76 g of cement powder, 1ml of liquid cement monomer and 1 mg of doxorubicin. The control group consisted 3 replicates each containing 2.0 g of cement powder, 1ml of liquid cement monomer and 1 mg of doxorubicin. The experimental group contained an average of 8.18 ± 0.008 % (W/W) mesoporous silica nanoparticles. Each replicate was casted into a cylindrical block and incubated in a PBS solution which was changed at predetermined intervals for 45 days. The concentration of eluted doxorubicin in each solution was measured using a florescent plate reader. The mechanical properties of cement were assessed by unconfined compression testing. The effect of the doxorubicin released from cement on prostate and breast tumor cell metabolic activity was assessed using the Alamar Blue test. After 45 days the experimental group released 3.24 ± 0.25 % of the initially loaded doxorubicin which was more than the 2.12 ± 0.005% released by the control group (p 0.03). There was no statistically significant difference in Young's elasticity modulus between groups (p 0.53). Nanoparticle functionalized PMMA suppressed the metabolic activity of prostate cancer by more than 50 percent but did not reach statistical significance. Nanoparticle functionalized PMMA suppressed the metabolic activity of breast cancer cells by 69 % (p < 0.05). Nanoparticle-functionalized PMMA cement can release up to 1.53 times more doxorubicin than the standard PMMA. The use of mesoporous silica nanoparticles to improve drug release from PMMA cement shows promise. In the future, in vivo experiments are required to test the efficacy of released doxorubicin on tumor cell growth

To demonstrate the role of an antibiotic containing bone substitute, native bone active proteins and muscle transforming into bone. Recurrent osteomyelitis was eradicated and filled with a gentamycin eluting bone substitute (Cerament™l G) consisting of sulphate and apatite phases and covered by a muscle flap. C2C12 muscle cells were seeded on the bone substitute in-vitro and their phenotype was studied. Another muscle cell line L6 was seeded with osteoblast conditioned medium containing bone active proteins and specific markers were studied for bone differentiation. A chronic, longstanding, fistulating osteomyelitis was operated with radical eradication and filling of the cavity with gentamycin eluting bone substitute. At one year, the patient had no leg pain and a healed wound. Significant bone was also seen in the overlaying muscle, at one month post-op disappearing after 6-months. Local delivery of gentamycin had a protective effect on bone formation. C2C12 cells seeded on the gentamycin eluting bone substitute depicted no difference in proliferation when compared to plain bone substitute and expressed 4 folds higher Alkaline phosphatase (ALP) compared to controls. C2C12 cells expressed proteins and genes coding for collagen type 1 (Col 1), osteocalcin (OCN), osteopontin (OPN) and bonesialoprotein (BSP). L6 cells cultured with osteoblast conditioned medium remained uninucleated and expressed osteoblastic proteins like Col 1, OCN, OPN and BSP. Bone substitute with gentamycin leads to differentiation of mesenchymal cells into bone in-vitro. Native bone active proteins from an osteoblast culture can induce differentiation of muscle cells in-vitro. Clinical observations with rapid bone formed in the bone substitute and in some cases in the muscle are a consequence of both leakage of bone active proteins and also from osteoprogenitor cells coming from the overlaying muscle interacting with the osteoinductive bone substitute