Methicillin-resistant Staphylococcal periprosthetic joint infections can be effectively controlled by systemic and local daptomycin.

BACKGROUND: Methicillin-resistant Staphylococcus remains a serious problem in the treatment of periprosthetic joint infection (PJI). Higher failure rates were reported when vancomycin was used in 2-stage exchange arthroplasty. Therefore a better therapeutic drug is needed to treat PJI caused by methicillin-resistant organisms. The purpose of the study was to evaluate the safety and efficacy of daptomycin when administered in bone cement combined with systemic use for methicillin-resistant Staphylococci PJI. METHODS: We conducted a retrospective study from January 2010 to December 2012. Twenty-two patients (10 knees and 12 hips) with PJI caused by methicillin-resistant Staphylococcus species underwent 2-stage revision arthroplasty. In the first stage, 10% daptomycin (weight daptomycin per weight bone cement) was incorporated into polymethylmethacrylate bone cement, and systemic daptomycin (6 mg/kg) was administered postoperatively for 14 days. In the second stage, 2.5% w/w daptomycin was used in the bone cement. The minimum follow-up was 2 years or until recurrence of infection. RESULTS: The infecting organisms included methicillin-resistant Staphylococcus aureus in 10 patients, methicillin-resistant Staphylococcus epidermidis in 8 patients and methicillin-resistant coagulase-negative Staphylococci in 4 patients. The mean follow-up duration was 33.7 months (range, 24-51 months). The treatment success rate was 100%. Only one patient developed asymptomatic transient elevation of the creatine phosphokinase level. No patient experienced any adverse effects related to daptomycin such as myositis, rhabdomyolysis, peripheral neuropathy, derangement of liver function, or eosinophilic pneumonia. CONCLUSIONS: In this series, no serious adverse events occurred. Our protocol, using daptomycin-impregnated cement combined with short duration of systemic daptomycin, appears to be an effective and safe treatment for methicillin-resistant Staphylococcus PJI.

Treatment of critically sized femoral defects with recombinant BMP-2 delivered by a modified mPEG-PLGA biodegradable thermosensitive hydrogel.

BACKGROUND: Reconstruction of a segmental fracture with massive bone loss is still a challenge for orthopaedic surgeons. The aim of our study was to develop a suitable biodegradable thermosensitive hydrogel system as a carrier for bone morphogenetic protein (BMP)-2 delivery in the treatment of critical-sized femoral defects. METHODS: A block copolymer composed of monomethoxypoly(ethylene glycol) (mPEG), poly(lactic-co-glycolic acid) (PLGA) and 2, 2'-Bis (2-oxazolin) (Box) was synthesized by ring opening polymerization. The synthesized block copolymer was characterized by (1)H-NMR spectroscopy and gel permeation chromatography (GPC). Different biophysical and biochemical properties of the synthesized copolymer, including temperature-induced structure changes, degradation rate, pH changes during hydrolytic degradation, cell toxicity, and the release profile of BMP-2, were also evaluated and/or were compared with those of a well-characterized mPEG-PLGA copolymer. In animal testing, rabbits (n = 36) that received critically sized (10 mm) femoral defects were divided into 6 groups. These experimental groups included an untreated group, autograft, and groups treated with the synthesized copolymer carrying different concentrations of BMP-2 (0, 5, 10, and 20 µg/ml). Bone repair was evaluated using X-ray radiography, histological staining, micro-computed tomography (µCT), biomarker examination and biomechanical testing in a 12-week treatment period. RESULTS: A new thermosensitive mPEG-PLGA/Box/mPEG-PLGA block copolymer, or named as BOX copolymer, was successfully prepared. Compared to the reported mPEG-PLGA in vitro, the prepared BOX copolymer at the same weight percent concentrations exhibited wider temperature ranges of gelation, slower degradation rates, higher the pH values, as well as less cytotoxicity. Furthermore, the BMP-2 release from BOX hydrogel exhibited a near-linear release profile in vitro. In animal experiments, treatment of critical-sized bony defects with 25 wt% BOX hydrogel carrying BMP-2 effectively promoted fracture healing during the 12-week trial period and higher concentrations of BMP-2 treatment correlated with better bone quality. Most importantly, clinical outcome and bone healing in the BOX-hydrogel group with 20 µg/ml BMP-2 were nearly equivalent to those in the autograft group in a 12-week treatment course. CONCLUSION: These data support that the use of BOX hydrogel (25 wt%) as a drug delivery system is a promising method in the treatment of large bone defects.

Exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice.

Microplastics (MPs) pollution has become a serious environmental issue worldwide, but its potential effects on health remain unknown. The administration of polystyrene MPs (PS-MPs) to mice for eight weeks impaired learning and memory behavior. PS-MPs were detected in the brain especially in the hippocampus of these mice. Concurrently, the hippocampus had decreased levels of immediate-early genes, aberrantly enhanced synaptic glutamate AMPA receptors, and elevated neuroinflammation, all of which are critical for synaptic plasticity and memory. Interestingly, ablation of the vagus nerve, a modulator of the gut-brain axis, improved the memory function of PS-MPs mice. These results indicate that exposure to PS-MPs in mice alters the expression of neuronal activity-dependent genes and synaptic proteins, and increases neuroinflammation in the hippocampus, subsequently causing behavioral changes through the vagus nerve-dependent pathway. Our findings shed light on the adverse impacts of PS-MPs on the brain and hippocampal learning and memory.

Improved antibiotic impregnated cement prosthesis for treating deep hip infection: a novel design using hip compression screw.

A 2-stage revision arthroplasty has been suggested as the optimal treatment for deep infections in the hip joint. Improvement of the surgical technique to increase the interim function is subject to investigation. From 2004 to 2007, we collected a cohort of 15 consecutive patients who were treated by a novel design augmented with a modified hip compression screw. No fracture of the cement spacer occurred. We believe the modified hip compression screw is a good alternative for the functional endoskeleton of an antibiotic loaded cement prosthesis in the treatment of deep hip infection.

Temporal Change of Interleukin-6, C-Reactive Protein, and Skin Temperature after Total Knee Arthroplasty Using Triclosan-Coated Sutures.

The risk of surgical site infections (SSIs) after total knee arthroplasty (TKA) can never be eliminated. Antimicrobial sutures containing triclosan have been used to decrease SSIs, but whether triclosan-coated sutures are effective with TKA is unclear. Between 2011 and 2012, 102 patients randomly assigned to a triclosan or a control group were prospectively assessed. The incidence of SSI within 3 months of surgery, length of hospital stay, pain scale, functional scores, wound condition, and serum inflammatory markers during hospitalization and within 3 months postoperatively were compared. At the final follow-up, there were 2 patients with superficial infections (3.9%) in the control group but none in the triclosan group. Lower serum IL-6 was detected in the triclosan group at 4 weeks and 3 months. The local skin temperature of the knees-recorded at 3 months using infrared thermography-was lower in the triclosan group than in the control group. More precise analytical measurements are needed to investigate local and systemic complications, especially in the early subclinical stage. This prospective, randomized, open-label clinical trial is in the public registry: ClinicalTrials.gov (NCT02533492).

Dysregulated expression of antioxidant enzymes in polyethylene particle-induced periprosthetic inflammation and osteolysis.

Small wear particles (0.1-10 µm) in total joint replacement are generally considered as the major causative agent leading to periprosthetic inflammation and osteolysis. However, little is known about the roles of larger wear particles (10-100 µm) in periprosthetic inflammation and osteolysis. Additionally, although ample studies demonstrated that increased oxidative stress is critically involved in particle-induced inflammation and osteolysis, detailed changes in antioxidant enzymes expression in the disease development remain largely unclear. Herein, we used a rat knee prosthesis model to assess effects of polyethylene (PE) particles (20-60 µm) on the levels of oxidative stress markers such as malondialdehyde (MDA) and total antioxidant capacity (TAC) in blood plasma, and on the expression profiles of antioxidant enzymes in knee joint tissues. In combination with a forced-exercise intervention for all surgical rats, we found that the rat groups treated with both artificial joint and PE particles exhibited higher MDA levels and lower TAC levels, together with lower levels of physical activity and higher levels of inflammatory markers, than the sham group and the groups receiving artificial joint or PE particles alone at weeks 20-24 post-operatively. Dose-response relationships between the exposure to PE particles and the induction of oxidative stress and inflammation were also observed in the artificial joint/PE groups. Under such conditions, we unexpectedly found that most of antioxidant enzymes displayed pronounced up-regulation, with concomitant induction of inflammatory and osteoclast-inducing factors (including IL-1ß, NF-κB and RANKL), in the artificial joint/PE groups as compared to the sham, artificial joint only, or PE only group. Only a few antioxidant enzymes including SOD2 and GPx2 showed down-regulation. Collectively, our findings demonstrate that implantation of artificial joint along with large PE particles synergistically trigger the induction of oxidative stress; however, down-regulation of many antioxidant enzymes may not necessarily occur during the disease development.

Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1ß) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1ß while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.

Injectable synthetic bone graft substitute combined with core decompression in the treatment of advanced osteonecrosis of the femoral head: A 5-year follow-up.

BACKGROUND: Osteonecrosis of the femoral head can lead to destruction of the hip joint and disabling arthritis in young adults, if left untreated. Among the salvage procedures, core decompression combined with bone graft substitutes is a viable option for joint preservation. The purpose of this study was to review the outcomes of using synthetic bone graft substitute (calcium sulfate and calcium phosphate) for the treatment of late-stage osteonecrosis of the femoral head. METHODS: From November 2008 to May 2009, 19 hips in 18 patients with osteonecrosis of the femoral head [6 hips in Association Research Circulation Osseous (ARCO) stage IIC and 13 hips in stage IIIA] were treated with core decompression combined with PRO-DENSE™ (Injectable Regenerative Graft). The average age of the patients at the time of surgery was 48 years (range 25-67 years). Twelve patients (13 hips) overused alcohol, four patients (4 hips) were idiopathic, one patient (1 hip) used corticosteroids, and one patient (1 hip) was post-traumatic. The clinical failure was defined as conversion to total hip arthroplasty or progression in head collapse. RESULTS: At the conclusion of the study, 3 in the 6 stage IIC hips and 8 in the 13 stage IIIA hips were converted to total hip arthroplasty in an average of 8.5 months (range 4-30 months) postoperatively. Advanced collapse of the femoral head awaiting for total hip arthroplasty was observed in the other six hips. Of the 19 hips, only 2 hips (10.5%) survived without further collapse in the 5-year follow-up. This resulted in 89.5% failure rate with early resorption of the grafting in an average of 5.3 months. CONCLUSIONS: Core decompression combined with an injectable calcium sulfate and calcium phosphate composite graft (PRO-DENSE) were associated high failure rates in the early postoperative period. It is not recommended for the treatment of ARCO stage IIC and IIIA osteonecrosis of the femoral head.

Complications of cement-augmented dynamic hip screws in unstable type intertrochanteric fractures--a case series study.

BACKGROUND: Polymethylmethacrylate (PMMA) cement-augmented dynamic hip screws (DHS) have been used as a solution in unstable intertrochanteric fractures (ITF). Our aim was to investigate the complications in PMMA cement-augmented DHS. METHODS: All patients who had received DHS plate osteosynthesis with or without PMMA cement augmentation from August 2005 to July 2009 in one medical center were retrospectively reviewed. The fractures were classified as unstable (31-A2.2, 31-A2.3 and 31-A3) on the basis of the Arbeitsgemeinschaft für Osteosynthesefragen classification. Inclusion criteria were patients older than 75 years, unstable ITF treated with cement-augmented DHS, and a minimum of 12 months of follow-up. Exclusion criteria were stable ITFs, incomplete chart records and imaging studies, loss to follow-up or death before bone union. RESULTS: Three hundred twenty-one patients received DHS during the study period. Sixty-seven patients were included in the study (25 men and 42 women; mean age, 81.2 years). The mean follow-up time was 40.2 months, and the mean union time was 18.5 weeks (12-40 weeks). No patient had a lag screw cut-out. Six patients had delayed union or nonunion with side plate failures, including side plate breakage in 1 patient, screw breakage in 3, screw pullout in 1, and recurrent side plate breakage and screw breakage in 1. Deep infection occurred in 1 patient, and 1 had osteonecrosis at the femoral head. The procedure-related complication rate was 8.9%. CONCLUSIONS: Cement-augmented DHS have a different failure mode than screw cutout in conventional DHS. Failures tended to be more related to delayed union, nonunion and resultant side plate construct failure.

Treatment of osteomyelitis with teicoplanin-encapsulated biodegradable thermosensitive hydrogel nanoparticles.

Osteomyelitis characterized by an inflammatory response often leads to bone loss and the spread of bacterial infection to surrounding soft tissues. To overcome the side effects induced by the systemic antibiotic treatment for osteomyelitis, recent investigations have explored the use of antibiotic-loaded undegradable or biodegradable delivery implants at the infected bone. Here, we show a novel biodegradable thermosensitive implant composed of poly(ethylene glycol) monomethyl ether (mPEG) and poly(lactic-co-glycolic acid) (PLGA) copolymer as a sol-gel drug delivery system for treating bone infection. The physical properties of a series of mPEG-PLGA nanocomposites, including the critical micelle concentration (CMC), particle size, polyindex (PI), sol-gel transition, viscosity and degradation rate, have been characterized in vitro. This sol-to-gel drug delivery system could provide several advantages in treating osteomyelitis, including easy preparation, 100% encapsulated rate, near-linear sustained release of drugs, injectable design and in situ gelling at the target tissue. Similar to the undegradable teicoplanin-impregnated polymethylmethacylate (PMMA) bone cements, we showed that implantation of the mPEG-PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The use of the mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for other infected diseases.