Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis.

Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.

Stemless Humeral Implants in Total Shoulder Arthroplasty.

Through an iteration of various advancements, both short stem and stemless options for humeral fixation have been proposed and have shown clinical promise. The proposed benefits of a stemless humeral implant include greater bone preservation, less stress shielding, less risk of a diaphyseal stress riser, decreased surgical time, and less intraoperative blood loss. Potential downsides include the dependence on proximal bone quality for fixation, increased cost, the dependence on the strength of subscapularis fixation, and pending FDA approval for multiple implants. The purpose of this article is to review the evidence behind stemless implants including the biomechanical advantages and disadvantages, surgical technique, and clinical outcomes.

Radiographic restoration of native anatomy: a comparison between stemmed and stemless shoulder arthroplasty.

BACKGROUND: Shoulder arthroplasty is a reliable procedure for patients with degenerative glenohumeral disease, and reproduction of native shoulder anatomy leads to superior outcomes. The aim of this study was to compare the ability of stemmed and stemless implants to radiographically restore native glenohumeral anatomy. METHODS: Shoulder arthroplasties were performed in 79 patients, with 58 receiving a stemless implant and 21 receiving a stemmed implant. Preoperative and postoperative radiographs were assessed for humeral head height, humeral head centering, humeral head medial offset, humeral head diameter, humeral neck angle, and lateral humeral offset by 2 independent viewers. Measurements were scored and summed to identify the anatomic reconstruction index (ARI). Radiographic measurements were compared using the Student t test, and significance was set at P < .05 for all statistical analyses. Interobserver agreement of radiographic analyses was assessed using the intraclass correlation coefficient, finding excellent reliability (intraclass correlation coefficient, 0.92). RESULTS: Five of six radiographic measurements along with the calculated ARI demonstrated no differences between stemmed and stemless shoulder implants (humeral head diameter, P = .651; humeral head height, P = .813; humeral head medial offset, P = .592; lateral humeral offset, P = .311; humeral head centering, P = .414; and ARI, P = .862). Stemless implants showed improved restoration of the native humeral neck angle (0° for stemless vs. -3° for stemmed, P = .017). CONCLUSION: Radiographic restoration of anatomy is similar for stemmed and stemless shoulder arthroplasty implants.

One and two-year clinical outcomes for a polyethylene glenoid with a fluted peg: one thousand two hundred seventy individual patients from eleven centers.

PURPOSE: Clinical shoulder science lacks a benchmark against which the early clinical value of new glenoid components can be compared; such a benchmark may be derived from a multicenter study of patients receiving an established, internationally used design of glenoid component. METHODS: We obtained data from 11 centers on 1270 patients having total shoulder arthroplasty using an all-polyethylene component with a fluted central peg. We analyzed individual patient outcomes at 1 and 2 years after surgery. We compared the improvement for each patient to the minimal clinically important difference (MCID) and calculated each patient's improvement as a percent of maximal possible improvement (MPI). RESULTS: The preoperative scores improved from SST 3 ± 2, ASES 37 ± 15, Constant score 36 ± 16, and Penn score 30 ± 19 to SST 10 ± 2, ASES 90 ± 12, Constant 76 ± 13, and Penn 80 ± 24 (p < 0.001 for each). A high percentage of patients improved by more than the MCID (SST 96%, ASES 98%, Constant 94%, Penn 93%) and obtained improvement of at least 30% of the MPI (SST 95%, ASES 98%, Constant 91%, Penn 87%). The clinical outcomes realized with this glenoid design were not worse for the 41% of shoulders with preoperative type B glenoids or for the 30% of shoulders with more than 15 degrees of glenoid retroversion. CONCLUSIONS: Individual patients from 11 international practices having total shoulder arthroplasty using a basic glenoid component design obtained highly significant clinical outcomes, providing a benchmark against which the early outcomes of new designs can be compared to determine whether they provide increased clinical value.

Bone-targeting liposome formulation of Salvianic acid A accelerates the healing of delayed fracture Union in Mice.

Delayed fracture union is a significant clinical challenge in orthopedic practice. There are few non-surgical therapeutic options for this pathology. To address this challenge, we have developed a bone-targeting liposome (BTL) formulation of salvianic acid A (SAA), a potent bone anabolic agent, for improved treatment of delayed fracture union. Using pyrophosphorylated cholesterol as the targeting ligand, the liposome formulation (SAA-BTL) has demonstrated strong affinity to hydroxyapatite in vitro, and to bones in vivo. Locally administered SAA-BTL was found to significantly improve fracture callus formation and micro-architecture with accelerated mineralization rate in callus when compared to the dose equivalent SAA, non-targeting SAA liposome (SAA-NTL) or no treatment on a prednisone-induced delayed fracture union mouse model. Biomechanical analyses further validated the potent therapeutic efficacy of SAA-BTL. These results support SAA-BTL formulation, as a promising therapeutic candidate, to be further developed into an effective and safe clinical treatment for delayed bone fracture union.

Changing Body Movement Patterns in 9-Year-Old Baseball Pitchers: A Pilot Study.

BACKGROUND: Arm injuries in throwing athletes continue to increase. Injuries may be due to multiple variables, including inefficient body movement patterns, especially in young baseball throwers. It is unclear whether these patterns can be efficiently altered in this population. PURPOSE/HYPOTHESIS: To investigate the effect of a novel 21-day throwing program on body movement patterns in youth baseball players using common practical tools. Our hypothesis was that this program would change body movement patterns over a relatively short period. STUDY DESIGN: Descriptive laboratory study. METHODS: Ten 9-year-old baseball athletes were asked to participate in a 21-consecutive day throwing program focused on decreasing inefficiencies. All participants underwent video evaluation from 2 vantage points as well as radar evaluation before and after the programs. Throwing arm humerothoracic and antecubital angles as well as pelvic angles in the frontal view were measured at the time of front (directional) leg heel/toe down (late cocking) for each of 3 pitches. Glove-side humerothoracic angles and back leg minimum popliteal angles were measured from behind for each of 3 additional pitches. Velocity was measured using a radar gun. All angular measurements were performed by a physical therapist blinded to the purposes of the program and study as well as to video chronology. RESULTS: Throwing arm antecubital angle (P = .01) and humerothoracic angle (P = .03) as well as back leg minimum popliteal angle (P = .03) all decreased, with mean decreases of 35°, 10°, and 8°, respectively. Velocity increased with decreased back leg popliteal angles (P = .019); mean velocity increased 2.6 mph (P = .016). CONCLUSION: Young baseball throwers can quickly retrain their bodies to accomplish different movement patterns. CLINICAL RELEVANCE: This novel throwing program may have implications for injury prevention and treatment as we identify better baseball-throwing movement patterns.

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model.

N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers were previously found to represent a versatile delivery platform for the early detection and intervention of orthopedic implant loosening. In this article, we evaluated the impact of different structural parameters of the HPMA copolymeric system (e.g., molecular weight (MW), drug content) to its pharmacokinetics and biodistribution (PK/BD) profile. Using 125I, Alexa Fluor 488, and IRDye 800 CW-labeled HPMA copolymer-dexamethasone (P-Dex) conjugates with different MW and dexamethasone (Dex) contents, we found the MW to be the predominant impact factor on the PK/BD profiles of P-Dex, with Dex content as a secondary impact factor. In gamma counter-based PK/BD studies, increased MW of P-Dex reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (AUC and MRT). In the semiquantitative live animal optical imaging evaluation, the distribution of P-Dex to the peri-implant inflammatory lesion increased when MW was increased. This result was further confirmed by FACS analyses of cells isolated from peri-implant regions after systemic administration of Alexa Fluor 488-labeled P-Dex. Since the in vitro cell culture study suggested that the internalization of P-Dex by macrophages is generally independent of P-Dex's MW and Dex content, the impact of the MW and Dex content on its PK/BD profile was most likely exerted at physiological and pathophysiological levels rather than at the cellular level. In both gamma counter-based PK/BD analyses and semiquantitative optical imaging analyses, P-Dex with 6 wt % Dex content showed fast clearance. Dynamic light scattering analyses unexpectedly revealed significant molecular aggregation of P-Dex at this Dex content level. The underlining mechanisms of the aggregation and fast in vivo clearance of the P-Dex warrant further investigation.

The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model.

PURPOSE: To evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracture mouse model. METHODS: The amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracture mouse model was established using a three-points bending device. The mice with established closed femoral fractures were treated with SIM/SIM-mPEG micelles, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation. RESULTS: Near Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEG micelles to the bone lesion of the mice with closed femoral fractures. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated ipsilateral tibia bone loss. CONCLUSION: SIM/SIM-mPEG micelles were found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union.

Intramedullary nailing of the proximal humerus: evolution, technique, and results.

Proximal humerus fractures are the third most common fracture in the elderly. Although most fractures can be treated conservatively with acceptable outcomes, certain fracture patterns are at high risk for progression to humeral malunions, nonunions, stiffness, and post-traumatic arthrosis. The goal of antegrade humeral nailing of proximal humerus fractures is to provide stability to a reduced fracture that allows early motion to optimize patient outcomes. Certain technical pearls are pivotal in managing these difficult fractures with nails; these include rotator cuff management, respect of the soft tissues, anatomic tuberosity position, blood supply maintenance, knowledge of the deforming forces on the proximal humerus, fracture reduction, and rehabilitation strategies. Modern proximal humeral nail designs and techniques assist the surgeon in adhering to these principles and have demonstrated promising outcomes. Humeral nail designs have undergone significant innovation during the past 40 years and now can provide stable fixation in the humeral shaft distally as well as improved stability in the head and tuberosity fragments, which were the common site of fixation failure with earlier generation implants. Compared with other fixation strategies, such as locking plate fixation, no compelling evidence exists to suggest one technique over another. The purpose of this review is to describe the history, results, new designs, and techniques that make modern intramedullary nailing of proximal humerus fractures a viable treatment option.

The association of incomplete glenoid component seating and periprosthetic glenoid radiolucencies after total shoulder arthroplasty.

BACKGROUND: Radiolucent lines surrounding prosthetic glenoid components are commonly seen after unconstrained total shoulder arthroplasty and can be a harbinger of subsequent glenoid component failure. Whether less than 100% glenoid seating is associated with the development of radiolucent lines around glenoid prostheses is unknown. This study investigated the association between incomplete glenoid component seating and periprosthetic glenoid radiolucencies. METHODS: Thirty-six unconstrained total shoulder arthroplasties were performed in 29 patients for primary glenohumeral osteoarthritis with a minimum 2-year follow-up. All were implanted with a partially cemented all-polyethylene glenoid prosthesis. Patients were evaluated with standardized plain films preoperatively and postoperatively and with thin-cut computed tomography (CT) scans at the latest follow-up. The Lazarus and Yian classifications were used to assess radiolucency and seating on radiographs and CT scans. Ratings were calculated for intraobserver and interobserver reliability and given κ, the Kendall coefficient, and interclass correlation coefficient values. RESULTS: At a mean of 43 months (range 24-26 months) after surgery, neither Lazarus plain film radiolucency scores (P = .78) nor Yian CT radiolucency scores (P = .68) were associated with Lazarus plain film seating scores. Neither Lazarus plain film radiolucency scores (P = .25) nor Yian CT radiolucency scores (P = .91) were associated with modified Lazarus CT scan seating scores. CT allowed for better intraobserver and interobserver reliability in all categories. CONCLUSION: Radiolucencies around a partially cemented glenoid component were not associated with the degree of component seating. Complete seating of the glenoid component is not necessary to achieve radiographic implant stability at a mean follow-up of 43 months.

Quantification of B2 glenoid morphology in total shoulder arthroplasty.

BACKGROUND: B2 glenoid morphology is challenging to address with shoulder reconstruction. Deformity often renders current techniques inadequate, necessitating compromises that limit long-term implant durability. The purpose of this study was to perform in vivo measurements of glenoid deformity to better appreciate the orientation of the B2 biconcavity demarcation and erosion that surgeons face intraoperatively. MATERIALS AND METHODS: A consecutive 106 total shoulder arthroplasty cases for primary glenohumeral osteoarthritis were studied. We classified glenoids by direct visualization and noted lines of biconcavity demarcation and erosion in B2s. We then calculated the "angle of erosion" as that between the back side of the unsupported, smooth-backed glenoid sizer disk and the neoglenoid. We obtained depth measurements throughout the reaming process and monitored subchondral bone. RESULTS: We classified 43 of 106 glenoids (41%) as B2. A biconcavity demarcation line between the paleoglenoid and the neoglenoid was present, on average, from the 1-o'clock to the 7-o'clock position for a left shoulder. Mean depth of erosion was 4.4 mm, occurring at 114° on a Cartesian coordinate system for a left shoulder. The mean angle of erosion was 18° (range, 8°-43°). Despite reaming, 20 of 43 B2 glenoids (47%) had incompletely supported components at final seating. CONCLUSIONS: Arthritic B2 glenoids are common, and their maximal erosion is usually posteroinferior. Use of standard glenoid components to reconstruct them may require significant subchondral bone removal to achieve complete bone support. Alternatively, as a compromise, maintenance of subchondral bone in these cases requires implanting components with incomplete bony support.

Simvastatin prodrug micelles target fracture and improve healing.

Simvastatin (SIM), a widely used anti-lipidemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug's hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles' therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing.

Early diagnosis of orthopedic implant failure using macromolecular imaging agents.

PURPOSE: To develop and evaluate diagnostic tools for early detection of wear particle-induced orthopaedic implant loosening. METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer was tagged with a near infrared dye and used to detect the inflammation induced by polymethylmethacrylate (PMMA) particles in a murine peri-implant osteolysis model. It was established by inserting an implant into the distal femur and challenging with routine PMMA particles infusion. The osteolysis was evaluated by micro-CT and histological analysis at different time points. RESULTS: Significant peri-implant osteolysis was found 3-month post PMMA particle challenge by micro-CT and histological analysis. At 1-month post challenge, when there was no significant peri-implant bone loss, the HPMA copolymer-near infrared dye conjugate was found to specifically target the femur with PMMA particles deposition, but not the contralateral control femur with phosphate buffered saline (PBS) infusion. CONCLUSION: The results from this study demonstrate the feasibility of utilizing the macromolecular diagnostic agent to detect particle-induced peri-implant inflammation prior to the development of detectable osteolysis. Recognition of this early pathological event would provide the window of opportunity for prevention of peri-implant osteolysis and subsequent orthopaedic implant failure.

Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects.

Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis.

Rheumatoid arthritis patients are not at increased risk for 30-day cardiovascular events, infections, or mortality after total joint arthroplasty.

INTRODUCTION: Serious infection, cardiovascular disease, and mortality are increased in rheumatoid arthritis (RA). Whether RA affects the risk for these complications after total joint arthroplasty (TJA) is unknown, we hypothesize that it does. We compared the occurrence of 30-day postoperative complications and mortality in a large cohort of RA and osteoarthritis (OA) patients undergoing hip or knee TJA. METHODS: Analyses included 7-year data from the Veterans Affairs Surgical Quality Improvement Program. The 30-day complications were compared by diagnosis by using logistic regression, and long-term mortality was examined by using Cox proportional hazards regression. All analyses were adjusted for age, sex, and clustering by surgical site. Additional covariates included sociodemographics, comorbidities, health behaviors, and operative risk factors. RESULTS: The 34,524 patients (839 RA, 33,685 OA) underwent knee (65.9%) or hip TJA. Patients were 95.7% men with a mean (SD) age of 64.4 (10.7) years and had 3,764 deaths over a mean follow-up of 3.7 (2.3) years. Compared with OA patients, those with RA were significantly more likely to require a return to the operating room (odds ratio (OR), 1.45 (95% CI, 1.08 to 1.94), but had similar rates of 30-day postoperative infection, OR 1.02 (0.72 to 1.47), cardiovascular events, OR 0.69 (0.37 to 1.28), and mortality, OR 0.94 (0.38 to 2.33). RA was associated with a significantly higher long-term mortality; hazard ratio (HR), 1.22 (1.00 to 1.49). CONCLUSION: In this study of US veterans, RA patients were not at an increased risk for short-term mortality or other major complications after TJA, although they returned to the operating room more often and had increased long-term mortality.

Titanium implant with nanostructured zirconia surface promotes maturation of peri-implant bone in osseointegration.

The goal of the experiment outlined in this article is to improve upon noncemented methods of arthroplasty for clinical application in elderly patients. This was done by determining whether titanium implants with a novel nanostructured zirconia surface, which was created by ion beam-assisted deposition, would prevent impaired osseointegration of intramedullary implants in 1-year-old rats receiving a protein-deficient diet. Specifically, we asked whether the implant with the nanostructured zirconia surface would increase expression of markers of bone maturation within the remodeling of peri-implant woven bone. The control implants, which were made of commercially pure titanium, had a polished surface ex vivo but are known to acquire a microstructured titania surface in vivo. Ten 1-year-old rats received experimental implant (group A) and 10 had control (group B) implants. Ten 3-month-old rats received normal protein diet and the control implant (group C). Animals were euthanized 8 weeks after implantation, and transverse sections of femur-implant samples were used for histology, micro-computed tomography and immunohistochemical evaluations. In group B, the expression of α2ß1 and α5ß1 integrins, which are known to mediate osteoblast adhesion, glycosaminoglycans, heparan sulfate and chondroitin sulfate, was less than half of that in group C. Important to this study, the zirconia surface used in group A prevented these deficiencies. Therefore, these results indicate that nanostructured zirconia surface created on clinical implants by ion beam-assisted deposition may prevent impaired osseointegration in elderly patients by promoting quicker maturation of peri-implant woven bone.

Short, locked humeral nailing via Neviaser portal: an anatomic study.

OBJECTIVE: Supraspinatus tendon trauma may contribute to residual shoulder pain after nail fixation for proximal humeral fractures. Some have proposed a more medial starting point for humeral nail insertion to avoid cuff tendon footprint damage. We hypothesized that percutaneous nail insertion via Neviaser portal would not only be possible, but would avoid tendon trauma, while sacrificing articular cartilage. MATERIALS AND METHODS: Under c-arm guidance and in percutaneous fashion, we nailed 16 consecutive complete (head and neck, etc, intact) specimen right proximal humeri with locked short humeral nails (Aequalis) via Neviaser portal. Each shoulder was dissected to study the damage to the rotator cuff and long head of the biceps tendons as well as to the articular surfaces. We measured the humeral-thoracic abduction arc before the damaged articular surface contacted the superior glenoid. There were 5 male specimens and 11 female specimens with a mean age of 83 years at the time of death. RESULTS: We successfully inserted 15 of 16 humeral nails through this percutaneous approach. No supraspinatus tendon or long head of the biceps tendon was damaged. All nails passed entirely through supraspinatus muscle belly. Thirteen of 15 starting points were entirely on articular surface. Mean arc of abduction before superior glenoid contact was 76 degrees (range, 50 degrees-130 degrees). Mean distance from the edge of the articular surface to the most lateral part of the nail insertion was 11 mm (0-25 mm). CONCLUSIONS: Short, locked humeral nail insertion is possible in percutaneous fashion via Neviaser portal without tendon injury. However, successful insertion comes at the cost of articular cartilage damage.

Impact of total shoulder arthroplasty on generic and shoulder-specific health-related quality-of-life measures: a systematic literature review and meta-analysis.

BACKGROUND: Total shoulder arthroplasty is increasingly used in the treatment of arthritis. However, the effect of total shoulder arthroplasty on health-related quality of life has not been fully established. The goal of this systematic review and meta-analysis was to characterize the change in generic and shoulder-specific health-related quality-of-life measures resulting from total shoulder arthroplasty. METHODS: We identified published studies reporting preoperative and postoperative health-related quality-of-life outcomes for patients receiving total shoulder arthroplasty. Health-related quality-of-life measures were identified, and meta-analysis was used to calculate standardized mean differences (SMDs, reflective of the effect size) and 95% confidence intervals for each scale. RESULTS: Twenty studies (1576 total shoulder replacements) met the inclusion criteria. Outcome measures were analyzed after an average postoperative follow-up duration of 3.7 ± 2.2 years. The Short Form-36 demonstrated significant improvement in physical component summary scores (SMD = 0.7, p < 0.001) but not in mental component summary scores (SMD = 0.2, p = 0.37). Significant improvements were observed in the visual analog scale score for pain (SMD = -2.5, p < 0.001) and scores on three shoulder-specific measures: the Constant score (SMD = 2.7, p < 0.001), American Shoulder and Elbow Surgeons score (SMD = 2.9, p < 0.001), and Simple Shoulder Test (SMD = 2.3, p < 0.001). CONCLUSIONS: Total shoulder arthroplasty leads to significant improvements in scores for function and pain. Shoulder-specific measures of function consistently showed the greatest degree of improvement, with large effect sizes. Total shoulder arthroplasty also leads to significant improvements in overall physical well-being, with a moderate-to-large effect size.

Prevention of orthopedic device-associated osteomyelitis using oxacillin-containing biomineral-binding liposomes.

PURPOSE: To develop novel biomineral-binding liposomes (BBL) for the prevention of orthopedic implant associated osteomyelitis. METHODS: A biomineral-binding lipid, alendronate-tri(ethyleneglycol)-cholesterol conjugate (ALN-TEG-Chol), was synthesized through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a versatile click reaction). Mixing with other excipients, the new lipid was used to develop BBL. Thermodynamic behavior was studied by differential scanning calorimetry (DSC). In vitro biomineral-binding potential and kinetics were evaluated on hydroxyapatite (HA, a widely used material for orthopedic implant devices) particles. Oxacillin was encapsulated into BBL and used for in vitro evaluation in preventing Staphylococcus aureus biofilm formation. RESULTS: DSC analysis showed that ALN-TEG-Chol could inhibit the phase transition of liposomes by reducing its cooperativity, yielding liposomes with thermodynamic stability similar to liposomes containing regular cholesterol. BBL showed fast and strong binding ability to HA. Oxacillin-loading BBL demonstrated significantly better preventive efficacy against bacteria colonization when challenged with S. aureus isolate, implying its potential in preventing orthopedic implant associated osteomyelitis. CONCLUSIONS: In this proof of concept study, novel BBL has been successfully developed and validated for reducing the frequency of implantable device-related infections.