Addressing bone defects is a complex medical challenge that involves dealing with various skeletal conditions, including fractures, osteoporosis (OP), bone tumours, and bone infection defects. Despite the availability of multiple conventional treatments for these skeletal conditions, numerous limitations and unresolved issues persist. As a solution, advancements in biomedical materials have recently resulted in novel therapeutic concepts. As an emerging biomaterial for bone defect treatment, graphene oxide (GO) in particular has gained substantial attention from researchers due to its potential applications and prospects. In other words, GO scaffolds have demonstrated remarkable potential for bone defect treatment. Furthermore, GO-loaded biomaterials can promote osteoblast adhesion, proliferation, and differentiation while stimulating bone matrix deposition and formation. Given their favourable biocompatibility and osteoinductive capabilities, these materials offer a novel therapeutic avenue for bone tissue regeneration and repair. This comprehensive review systematically outlines GO scaffolds’ diverse roles and potential applications in bone defect treatment.

Cite this article: Bone Joint Res 2024;13(12):725–740.

Aims. Calcaneal osteomyelitis remains a difficult condition to treat with high rates of recurrence and below-knee amputation, particularly in the presence of severe soft-tissue destruction. This study assesses the outcomes of single-stage orthoplastic surgical treatment of calcaneal osteomyelitis with large soft-tissue defects. Methods. A retrospective review was performed of all patients who underwent combined single-stage orthoplastic treatment of calcaneal osteomyelitis (01/2008 to 12/2022). Primary outcome measures were osteomyelitis recurrence and below-knee amputation (BKA). Secondary outcome measures included flap failure, operating time, complications, and length of stay. Results. A total of 30 patients (14 female, 16 male; mean age 53.7 years (95% CI 48.0 to 59.5)) underwent combined orthoplastic surgical treatment for BACH “complex” calcaneal osteomyelitis with a median follow-up of 31 months (IQR 11.75 to 49.25). Of these, 19 received a local flap and 11 received a free flap. The most common causes were fracture-related infection (n = 12; 40%) and ulceration (n = 10; 33%); 21 patients (70%) had already undergone at least one operation elsewhere. Osteomyelitis was eradicated in 23 patients (77%). There were seven patients who developed recurrent osteomyelitis (23%), all in the local flap group. One patient required a BKA. Univariate analysis revealed that local flap reconstruction (OR 13.5 (95% CI 0.7 to 269.7); p = 0.029) and peripheral vascular disease (OR 16.5 (95% CI 1.35 to 203.1); p = 0.008) were associated with increased risk of recurrence. Free flap reconstruction took significantly longer intraoperatively than local flaps (mean 481 minutes (408 to 554) vs mean 168 minutes (119 to 216); p < 0.001), but without significant differences in length of stay or frequency of outpatient appointments. Conclusion. In our study involving 30 patients, single-stage orthoplastic management was associated with 77% (n = 23) eradication of infection and only one amputation in this complex and comorbid patient group. Risk factors for failure were peripheral vascular disease and local flap reconstruction. While good outcomes can be achieved, this treatment requires high levels of inpatient and outpatient care. Cite this article: Bone Joint J 2024;106-B(12):1443–1450

Aim. To report outcomes of soft tissue reconstruction using free tissue transfer for the treatment of tibial osteomyelitis as part of a single-stage, ortho-plastic procedure. Method. Patients who underwent ortho-plastic reconstructive surgery to excise tibial osteomyelitis in combination with free tissue transfer in one stage were included. Patients underwent surgery between 2015 and 2024 in a single specialist centre within the UK. Baseline patient information, demographics, and infection information was recorded. Adverse outcomes were defined as (i) flap salvage required, (ii) flap failure and (iii) recurrence of infection. Patient reported quality of life was measured using the EuroQol EQ-5D-5L index score. Pre-operative QoL was compared to QoL at 1 year with a control group of 53 similar patients who underwent surgical treatment for tibial osteomyelitis without a free flap (local flap or primary closure). Results. Ninety-three patients were eligible for inclusion, with a mean age of 52 years (range 18–90). 77/93 (82.8%) had a free muscle flap with the remainder (17.2%) receiving a fasciocutaneous flap. The donor tissue was defined as 57 gracilis, 6 latissimus dorsi, 14 hemi-latissimus dorsi, and 16 anterolateral thigh. The recipient area of the tibia was distal 1/3 in 52 cases, middle 1/3 in 27 cases and proximal 1/3 in 12 cases. The average flap ischaemic time was 70 minutes (range 28 to 125). Seven patients (7.5%) required urgent flap salvage at a median time of 1.0 day (range 0.5 – 4.0). Of these, 4 (4.3%) went on to have total flap failure, of which 2 patients underwent below knee amputation subsequently. Flap failure was due to either arterial (n=2) or venous (n=2) anastomotic thrombus. There were 3 (3.2%) episodes of confirmed infection recurrence within the first year after the index procedure. EQ-index scores at 1-year post-operatively were significantly improved when compared to pre-operative scores (p=0.008). At 1-year post-operatively, EQ-index scores in patients who underwent free flap was similar compared to local flaps (p=0.410) and in those who underwent primary closure for tibial osteomyelitis (p=0.070). Conclusions. Microsurgical single stage surgery can achieve high flap survival rate (95.7%). Free flaps fail early due to anastomotic thrombus with no late failures seen. Free tissue transfer does not appear to give inferior QoL compared to matched patients with local flaps or direct closure in tibial osteomyelitis

Aims

This study aimed to investigate the clinical characteristics and outcomes associated with culture-negative limb osteomyelitis patients.

Background. Calcaneal osteomyelitis remains a difficult condition to treat with high rates of recurrence and below knee amputation; particularly in cases of severe soft tissue destruction. Aim. Assess the outcomes of combined ortho-plastics treatment of complex calcaneal osteomyelitis. Method. A retrospective review was performed of all patients who underwent combined single stage ortho-plastics treatment of calcaneal osteomyelitis (2008–2022). Primary outcome measures were osteomyelitis recurrence and BKA. Secondary outcome measures included flap failure, operative time, complications, length of stay. Results. 33 patients (16 female, 17 male, mean age = 54.4 years) underwent combined ortho-plastics surgical treatment for BACH “complex” calcaneal osteomyelitis with a median follow-up of 31 months (s.d. 24.3). 20 received a local flap, 13 received a free flap. Fracture-related infection (39%) and diabetic ulceration (33%) were the commonest causes. 54% of patients had already undergone at least one operation elsewhere. There were seven cases of recurrent osteomyelitis (21%); all in the local flap group. One patient required a BKA (3%). Recurrence was associated with increased mortality risk (OR 18.8 (95% CI 1.5–227.8), p=0.004) and reduced likelihood of walking independently (OR 0.14 (95% CI 0.02–0.86), p=0.042). Local flap reconstruction (OR 15 (95% CI 0.8–289.6), p=0.027) and peripheral vascular disease (OR 39.7 (95% CI 1.7–905.6), p=0.006) were associated with increased recurrence risk. Free flap reconstruction took significantly longer intra-operatively than local flaps (443 vs 174 minutes, p<0.001), but without significant differences in length of stay or frequency of out-patient appointments. Conclusions. Single stage ortho-plastic management was associated with 79% eradication of infection and 3% amputation in this complex and co-morbid patient group. Risk factors for failure were peripheral vascular disease and local flap reconstruction. Whilst good outcomes can be achieved, this treatment requires high levels of in-patient and out-patient care

Aim. This study assessed quality of life (QoL) in patients having external fixation for treatment of osteomyelitis and fracture-related infection (OM/FRI). Method. Patients who had surgery for OM/FRI and who completed the EuroQoL EQ-5D-5L or EQ-5D- 3L questionnaires, were identified between 2010 and 2020. Patients were followed-up for 2 years after surgery. QoL was compared between patients who had either an Ilizarov frame or a monolateral external fixator with those who did not receive external fixation. Results. 165 patients were included. Of these, 37 (22.4%) underwent application of external fixation which included 23 circular frames and 14 monolateral external fixators. Patients in the frame group had more BACH ‘Complex’ infections (34/37; 91.9%), compared to non-frame patients (57/81; 70.3%). Pre-operatively, the mean EQ-index score for patients planned to receive a frame (0.278 SD 0.427) was worse compared to other treatments (0.453 SD 0.338, p=0.083). At 6 weeks after surgery, the EQ-index score remained significantly lower in frame patients compared to non-frame patients (frame: 0.379 SD 0.363; no frame: 0.608 SD 0.326, p=0.016). By 6 months, 26/37 patients had undergone frame removal. The patients who had frames in situ at 6 months had lower EQ-index scores when compared to patients who had their frames removed (frame in situ: 0.187 SD 0.213; frame removed 0.674 SD 0.206, p=0.076). At one year, 36/37 (97.3%) patients had their frame removed. QoL had greatly improved, to levels similar to non-frame patients (no frame: 0.652 SD 0.357; frame removed: 0.657 SD 0.247, p=0.949). Conclusions. Frame treatment leads to significant improvement in Quality of Life in patients suffering from osteomyelitis, with similar results in EQ5D scores after 1 year compared to patients who did not need an external fixator. These effects cannot be felt until after the frame has been removed with impaired QoL during frame treatment, especially in those patients with frames in situ for more than 6 months. This underlines the need for close and professional patient support during frame treatment for bone infection

Aim. Calcaneal osteomyelitis remains a difficult condition to treat with high rates of recurrence and below knee amputation; particularly in cases of severe soft tissue destruction. This study assesses the outcomes of combined ortho-plastics treatment of complex calcaneal osteomyelitis. Method. A retrospective review was performed of all patients who underwent combined single stage ortho-plastics treatment of calcaneal osteomyelitis (2008- 2022). Primary outcome measures were osteomyelitis recurrence and BKA. Secondary outcome measures included flap failure, operative time, complications, length of stay. Results. 33 patients (16 female, 17 male, mean age = 54.4 years) underwent combined ortho-plastics surgical treatment for BACH “complex” calcaneal osteomyelitis with a median follow-up of 31 months (s.d. 24.3). 20 received a local flap, 13 received a free flap. Fracture-related infection (39%) and diabetic ulceration (33%) were the commonest causes. 54% of patients had already undergone at least one operation elsewhere. There were seven cases of recurrent osteomyelitis (21%); all in the local flap group. One patient required a BKA (3%). Recurrence was associated with increased mortality risk (OR 18.8 (95% CI 1.5–227.8), p=0.004) and reduced likelihood of walking independently (OR 0.14 (95% CI 0.02–0.86), p=0.042). Local flap reconstruction (OR 15 (95% CI 0.8–289.6), p=0.027) and peripheral vascular disease (OR 39.7 (95% CI 1.7–905.6), p=0.006) were associated with increased recurrence risk. Free flap reconstruction took significantly longer intra-operatively than local flaps (443 vs 174 minutes, p<0.001), but without significant differences in length of stay or frequency of out-patient appointments. Conclusions. Single stage ortho-plastic management was associated with 79% eradication of infection and 3% amputation in this complex and co-morbid patient group. Risk factors for failure were peripheral vascular disease and local flap reconstruction. Whilst good outcomes can be achieved, this treatment requires high levels of in-patient and out-patient care

Aim. The use of bone substitutes such as calcium sulfate (CaSO4) and hydroxyapatite with local antibiotics are crucial in the treatment of osteomyelitis. They allow the treatment of the dead space and locally provide large concentrations of antibiotics. However, it is unknown whether use of local vancomycin may elute and influence on vancomycin plasma levels. The aim of this study is to assess whether the addition of vancomycin to CaSO4 with hydroxyapatite may increase vancomycin plasma concentrations in in patients with osteomyelitis and therefore alter dosage adjustments. Method. The present study investigates the vancomycin plasma concentrations at 72–94 h post-surgery after the application of local vancomycin within CaSO4 (660mg vancomycin/10cc) and hydroxyapatite bone substitute in patients treated with empiric intravenous vancomycin and surgically treated for osteomyelitis. Vancomycin plasma concentrations were analyzed in twelve patients with osteomyelitis surgically treated with local release of vancomycin by CaSO4 and hydroxyapatite and undergoing therapeutic drug monitoring (TDM) of their vancomycin plasma concentrations as it is routinely done in our hospital. From 2019 to 2022, demographic data, microbiology, type of osteomyelitis, amount of local vancomycin applied, alteration of renal function, and vancomycin levels were retrospectively analyzed. Results. Twelve patients were included: 9(75%) were men. Median (range) demographic and clinical data: age: 51(26–67) years; body mass index: 27.7(18–46.4) kg/m2;baseline serum creatinine: 0.85 (0.7–1.24)mg/dl and 5(41.7%) with and glomerular filtration rate < 90ml/min(CPD-EPI, ml/min). Most frequently isolated microorganisms were Staphylococci (58%). Seven (54%) patients were classified as Cierny-Mader Osteomyelitis type III, 3(23%) as type IV and 2(23%) as type I. Treatment data: initial dose of vancomycin: 1g/8h in 9(75.0%) and 1g/12h in 3(25%) patients, total daily dose/body weight: 35.3(15.9–46.2) mg/kg. Pharmacokinetic data:days of iv vancomycin treatment until first TDM measurement: 3(3–4) days; minimum and maximum vancomycin plasma concentrations: 9.4(3–17.3) mg/L and 19.6(11.3–33.4) mg/L, respectively; patients with therapeutic concentrations: 6(50%); infratherapeutic: 4(33.3%) and supratherapeutic/potentially toxic: 2(16.7%). These 2 patients were young, had a baseline conserved renal function and were receiving the higher dose of 1g/8h. Conclusions. Vancomycin incorporated into the bone substitute appears not to increase blood concentrations of the glycopeptide in patients with osteomyelitis treated surgically and with intravenous vancomycin. However, 2 of the 12 patients presented supratherapeutic and potentially nephrotoxic vancomycin concentrations in the first TDM measurement, even though they were young and without renal impairment and needed and unexpected dose reduction. These results suggest the need to confirm the safety of local vancomycin in further larger clinical studies

Aim. Patient quality of life (QoL) in untreated bone infection was compared to other chronic conditions and stratified by disease severity. Method. Patients referred for treatment of osteomyelitis (including fracture related infection) were identified prospectively between 2019 and 2023. Patients with confirmed infection completed the EuroQol EQ-5D-5L questionnaire. Clinicians blinded to EQ-index score, grouped patients according to JS-BACH Classification into ‘Uncomplicated’, ‘Complex’ or ‘Limited treatment options’. A systematic review of the literature was performed of other conditions that have been stratified using EQ-index score. Results. 257 patients were referred, and 219 had suspected osteomyelitis. 196 patients had long bone infection and reported an average EQ-index score of 0.455 (SD 0.343). 23 patients with pelvic osteomyelitis had an average EQ-index score of 0.098 (SD 0.308). Compared to other chronic conditions, patients with long-bone osteomyelitis had worse QoL when compared to different types of malignancy (including bladder, oropharyngeal, colorectal, thyroid and myeloma), cardiorespiratory disease (including asthma, COPD and ischaemic heart disease), psychiatric conditions (including depression, pain and anxiety), endocrine disorders (including diabetes mellitus), neurological conditions (including Parkinson's disease, chronic pain and radiculopathy) and musculoskeletal conditions (including osteogenesis imperfecta, fibrous dysplasia and x-linked hypophosphataemic rickets). QoL in long-bone infection was similar to conditions such as Prada-Willi syndrome, Crohn's disease and juvenile idiopathic arthritis. Patients who had a history of stroke or multiple sclerosis reported worse QoL scores compared to long-bone infection. Patients who had pelvic osteomyelitis gave significantly lower QoL scores when compared to all other conditions that were available for comparison in the literature. In long bone infection, 41 cases (21.0%) were classified as ‘Uncomplicated’, 136 (69.4%) as ‘Complex’ and 19 (9.7%) as ‘Limited treatment options available’. Within classification stratification, patients with ‘Uncomplicated’ long bone infections reported a mean EQ-index score of 0.618 (SD 0.227) which was significantly higher compared to ‘Complex’ (EQ-index: 0.410 SD 0.359, p=0.004) and ‘Limited treatment options available’ (EQ-index: 0.400 SD 0.346, p=0.007). Conclusions. Bone and joint infections have a significant impact on patient quality of life. It is much worse when compared to other common chronic conditions, including malignancy, cardiovascular and neurological diseases. This has not been previously reported but may focus attention on the need for more investment in this patient group

Fracture related infection, in particular chronic osteomyelitis, requires complex management plans. Meta analyses and systematic reviews have not found a gold standard of treatment for this disease. In 2017 an alternative treatment protocol was undertaken in our institution; whereby staged surgery with the use of cheaply manufactured tailored antibiotic cement rods was used in the treatment of chronic osteomyelitis, secondary to traumatic long bone fractures. Short term outcomes for this protocol demonstrated a 75.7% microbiological resolution to a negative culture and a good clinical outcome of 84.2% overall was demonstrated in terms of sinus resolution, skin changes, pain and function. Our aim now was to assess the long term outcomes of this treatment strategy. A cross-sectional study of patients who had previously undergone the set treatment protocol was performed. Patient satisfaction, effects on activities of daily living, return to work and clinical improvement at 5 years following the intervention were assessed using a patient questionnaire and the validated AAOS lower limb score. The average AAOS lower limb score was 88 which was en par to other similar studies. 80% of patients had returned to some form of work. Ongoing mild pain was a persistent problem for 50% of the patients however 98% of the patients were overall satisfied with the treatment satisfaction at 5 years. Only 1 patient required further treatment. 8 patients could not be located for follow up. Chronic osteomyelitis remains a complex disease to treat. This treatment protocol demonstrates favourable microbiological, serological and clinical short term outcomes and favourable patient satisfaction and functional long term outcomes at 5 years. Our study highlights antibiotic targeted cement rods as a feasible treatment option in managing chronic osteomyelitis

Aims. This study was designed to characterize the recurrence incidence and risk factors of antibiotic-loaded cement spacer (ALCS) for definitive bone defect treatment in limb osteomyelitis. Methods. We included adult patients with limb osteomyelitis who received debridement and ALCS insertion into the bone defect as definitive management between 2013 and 2020 in our clinical centre. The follow-up time was at least two years. Data on patients’ demographics, clinical characteristics, and infection recurrence were retrospectively collected and analyzed. Results. In total, 314 patients with a mean age of 52.1 years (SD 12.1) were enrolled. After a mean of 50 months’ (24 to 96) follow-up, 53 (16.9%) patients had infection recurrence including 32 tibiae, ten femora, ten calcanea, and one humerus. Of all patients with recurrence, 30 (9.6%) occurred within one year and 39 (12.4%) within two years. Among them, 41 patients needed reoperation, five received antibiotics treatment only, and seven ultimately required amputations. Following multivariable analysis, we found that patients infected with Gram-negative bacilli were more likely to have a recurrence (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.20 to 6.94; p = 0.046) compared to Staphylococcus aureus; segmental bone defects (OR 5.25, 95% CI 1.80 to 15.26; p = 0.002) and smoking (OR 3.00, 95% CI 1.39 to 6.50; p = 0.005) were also independent risk factors for recurrence after treatment. Conclusion. Permanent ALCS might be an alternative strategy for definitive bone defect management in selected osteomyelitis cases. However, the overall high recurrence found suggests that it should be cautiously treated. Additionally, segmental defects, Gram-negative infections, and smoking were associated with an increased risk of infection recurrence. Cite this article: Bone Joint Res 2023;12(8):467–475

Aims

Musculoskeletal infection is a devastating complication in both trauma and elective orthopaedic surgeries that can result in significant morbidity. Aim of this study was to assess the effectiveness and complications of local antibiotic impregnated dissolvable synthetic calcium sulphate beads (Stimulan Rapid Cure) in the hands of different surgeons from multiple centres in surgically managed bone and joint infections.

Aims. Dead-space management, following dead bone resection, is an important element of successful chronic osteomyelitis treatment. This study compared two different biodegradable antibiotic carriers used for dead-space management, and reviewed clinical and radiological outcomes. All cases underwent single-stage surgery and had a minimum one-year follow-up. Methods. A total of 179 patients received preformed calcium sulphate pellets containing 4% tobramycin (Group OT), and 180 patients had an injectable calcium sulphate/nanocrystalline hydroxyapatite ceramic containing gentamicin (Group CG). Outcome measures were infection recurrence, wound leakage, and subsequent fracture involving the treated segment. Bone-void filling was assessed radiologically at a minimum of six months post-surgery. Results. The median follow-up was 4.6 years (interquartile range (IQR) 3.2 to 5.4; range 1.3 to 10.5) in Group OT compared to 4.9 years (IQR 2.1 to 6.0; range 1.0 to 8.3) in Group CG. The groups had similar defect sizes following excision (both mean 10.9 cm. 3. (1 to 30)). Infection recurrence was higher in Group OT (20/179 (11.2%) vs 8/180 (4.4%), p = 0.019) than Group CG, as was early wound leakage (33/179 (18.4%) vs 18/180 (10.0%), p = 0.024) and subsequent fracture (11/179 (6.1%) vs 1.7% (3/180), p = 0.032). Group OT cases had an odds ratio 2.9-times higher of developing any one of these complications, compared to Group CG (95% confidence interval 1.74 to 4.81, p < 0.001). The mean bone-void healing in Group CG was better than in Group OT, in those with ≥ six-month radiological follow-up (73.9% vs 40.0%, p < 0.001). Conclusion. Local antibiotic carrier choice affects outcome in chronic osteomyelitis surgery. A biphasic injectable carrier with a slower dissolution time was associated with better radiological and clinical outcomes compared to a preformed calcium sulphate pellet carrier. Cite this article: Bone Joint Res 2023;12(7):412–422

Aims

The aim of this study was to determine the consensus best practice approach for the investigation and management of children (aged 0 to 15 years) in the UK with musculoskeletal infection (including septic arthritis, osteomyelitis, pyomyositis, tenosynovitis, fasciitis, and discitis). This consensus can then be used to ensure consistent, safe care for children in UK hospitals and those elsewhere with similar healthcare systems.

Treatment of tibial osteomyelitis can be challenging and lengthy, with numerous complications possible during rehabilitation. We report on the usage of the Taylor Spatial Frame (TSF) for a large cohort of patients, and analyse factors that affect outcomes. Between 2015-2020, 51 patients were treated with TSF for osteomyelitis at a major trauma centre. Demographic, infection and treatment factors of: age, smoking status, diabetes, and BMI, acute (<6 weeks post injury) or chronic (>6 weeks) osteomyelitis, bacteria isolated, time to debridement, therapy/surgery number of TSF, time TSF was in, antibiotic treatment period, time to partial weight bear (PWB) and full weight bear (FWB) prescriptions, were collected. Outcomes of complications and time to union were obtained. Radiological union was achieved at mean 11.0 months. Mean follow up was 24.1 months. Six and three patients were further treated with fusion and amputation respectively. Mean treatment time with TSF was 12.1 months. 78% had some complications, with pin site infection, malunion, and non-union being most prevalent. Univariate factor analysis, multicollinearity diagnostics, then multivariate model construction were performed. Staphylococcus Epidermidis in bone debridement microbiology was significantly negatively associated with pin site infection (OR 0.093, 95% CI 0.011-0.828) and malunion (OR 0.698, 95% CI 0.573-0.849), and enterococcus with non-union (OR 0.775, 95% CI 0.656-0.916), during the treatment period. Time to union was significantly positively associated with time from admission to debridement (p=0.035), time TSF was in (p=0.021), presence of complications (p=0.045), bone loss complication(p=0.037), time to FWB prescription(p=0.001). We have analysed the effectiveness of TSF in the treatment of tibial osteomyelitis, and elucidated important injury, treatment and rehabilitation factors that affect outcome. The negative bacterial-complication cross associations could be due to successful eradication as culture specific antibiotics were used postoperatively. Earlier patient full weight bearing could enhance callous formation leading to faster union

Infections represent a devastating complication in orthopedic and traumatological surgery, with high rates of morbidity and mortality. An early intervention is essential, and it includes a radical surgical approach supported by targeted intravenous antimicrobial therapy. The availability of parenteral antibiotics at the site of infection is usually poor, so it is crucial to maximize local antibiotic concentration using local carriers. Our work aims to describe the uses of one of these systems, Stimulan®, for the management and prevention of infections at our Institution. Analysing the reported uses of Stimulan®, we identified two major groups: bone substitute and carrier material for local antibiotic therapy. The first group includes its application as a filler of dead spaces within bone or soft tissues resulting from traumatic events or previous surgery. The second group comprehends the use of Stimulan® for the treatment of osteomyelitis, post-traumatic septic events, periprosthetic joint infections, arthroplasty revision surgery, prevention in open fractures, surgery of the diabetic foot, oncological surgery and for all those patients susceptible to a high risk of infection. We used Stimulan® in several complex clinical situations: in PJIs, in DAPRI procedure and both during the first and the second stage of a 2-stage revision surgery; furthermore, we started to exploit this antibiotic carrier also in prophylaxis of surgical site infections, as it happens in open fractures, and when a surgical site remediation is required, like in osteomyelitis following ORIF. Stimulan® is an extremely versatile and polyhedric material, available in the form of beads or paste, and can be mixed to a very broad range of antibiotics to better adapt to different bacteria and their antibiograms, and to surgeon's needs. These properties make it a very useful adjuvant for the management of complex cases of infection, and for their prevention, as well

Aim. Several local antibiotic-eluting drug delivery systems have been developed to treat bacterial bone infections. However, available systems have significant shortcomings, including suboptimal drug-release profiles with a burst followed by subtherapeutic release, which may lead to treatment failure and selection for drug resistance. Here, we present a novel injectable, biocompatible, in situ-forming depot, termed CarboCells, which can be fine-tuned for the desired antibiotic-release profile. The CarboCell technology has flexible injection properties that allow surgeons to accurately place antibiotic-eluting depots within and surrounding infectious sites in soft tissue and bones. The CarboCell technology is furthermore compatible with clinical image-guided injection technologies. These studies aimed to determine the therapeutic potential of CarboCell formulations for treatment of implant-associated osteomyelitis by mono- and dual antimicrobial therapy. Methods. The solubility and stability of several antibiotics were determined in various CarboCell formulations, and in vitro drug release was characterized. Lead candidates for antimicrobial therapy were selected using a modified semi-solid biofilm model with 4-day-matured Staphylococcus aureus biofilm (osteomyelitis-isolate, strain S54F9). Efficacy was investigated in a rat implant-associated osteomyelitis model established in the femoral bone by intraosseous implantation of a stainless-steel pin with 4-day-old in vitro-matured S. aureus biofilm. CarboCells were injected subcutaneously at the femur, and antimicrobial efficacy was evaluated 7 days post-implantation. Lead formulations were subsequently tested in a well-established translational implant-associated tibial S. aureus osteomyelitis pig model. Infection was established for 7 days before revision surgery consisting of debridement, washing, implantation of a new stainless-steel pin, and injection of antibiotic-releasing CarboCells into the debrided cavity and in the surrounding bone- and soft-tissue. Seven days post-revision, pigs were euthanized, and samples were collected for microbial and histopathological evaluation. Results. Lead antimicrobial agents were soluble in high concentrations and were stable in CarboCell formulations. Three combinations completely eradicated bacteria in the in vitro semi-solid biofilm model. In the rat osteomyelitis model, CarboCell formulations of the lead combinations also eradicated bacteria in bone and implant in several rats and significantly reduced infection in all treated rats. In the pig model, CarboCell antimicrobial monotherapy demonstrated promising therapeutic efficacy, including complete eradication of infection in bone and implants in several pigs and significantly reduced bacterial burden in others. Conclusions. Using the CarboCell technology for antimicrobial delivery exert substantial loco-regional efficacy. The attractive sustained high-dose antibiotic release profile combined with the flexible injection technology allows surgeons to accurately place effective drug-eluting depots in key areas not accessible to competing technologies

Aim. Osteomyelitis is a difficult-to-treat disease with high chronification rates. The surgical amputation of the afflicted limb sometimes remains as the patients’ last resort. Several studies suggest an increase in mitochondrial fission as a possible contributor to the accumulation of intracellular reactive oxygen species and thereby to cell death of infectious bone cells. The aim of this study is to analyze the ultrastructural impact of bacterial infection and its accompanying microenvironmental tissue hypoxia on osteocytic and osteoblastic mitochondria. Method. 19 Human bone tissue samples from patients with osteomyelitis were visualized via light microscopy and transmission electron microscopy. Osteoblasts, osteocytes and their respective mitochondria were histomorphometrically analyzed. The results were compared to the control group of 5 non-infectious human bone tissue samples. Results. The results depicted swollen hydropic mitochondria including depleted cristae and a decrease in matrix density in the infectious samples as a common finding in both cell types. Furthermore, perinuclear clustering of mitochondria could also be observed regularly. Additionally, increases in relative mitochondrial area and number could be found as a sign for increased mitochondrial fission. Conclusions. The results show that mitochondrial morphology is altered during osteomyelitis in a comparable way to mitochondria from hypoxic tissues. This suggests that manipulation of mitochondrial dynamics in a way of inhibiting mitochondrial fission may improve bone cell survival and exploit bone cells regenerative potential to aid in the treatment of osteomyelitis

Aims

Excision of chronic osteomyelitic bone creates a dead space which must be managed to avoid early recurrence of infection. Systemic antibiotics cannot penetrate this space in high concentrations, so local treatment has become an attractive adjunct to surgery. The aim of this study was to present the mid- to long-term results of local treatment with gentamicin in a bioabsorbable ceramic carrier.