Creation of a Custom-Length, Humeral Antibiotic Cement Spacer for Use in Treatment of Shoulder Periprosthetic Joint Infection.

Periprosthetic joint infection of the shoulder is a challenging clinical situation to manage owing to the fastidious organisms often present and delayed clinical presentation. While several treatment options have been described, the mainstay of treatment remains a staged revision with the use of a humeral antibiotic cement spacer. Such spacers are commercially available or can be made by hand. When an extended humeral osteotomy is required to remove a well-fixed long stem humeral component, it may be advantageous to place an antibiotic spacer with a stem length approximately as long as the hardware being removed. This technique demonstrates creation of a custom length, humeral antibiotic cement spacer for use in treatment of shoulder periprosthetic joint infection.

The Impact of Author Financial Conflicts on Robotic-Assisted Joint Arthroplasty Research.

BACKGROUND: Recent studies have suggested clinical superiority with robotic-assisted arthroplasty compared to traditional techniques. However, concerns exist regarding the author's financial conflicts of interest (COI), which may influence research outcomes. This study aimed to determine whether COI relating to robotic-assisted arthroplasty influences the results of published outcomes following total hip (THA), total knee (TKA), and unicompartmental knee arthroplasty (UKA). METHODS: We performed a systematic review to identify all studies evaluating the use of robotics in THA, TKA, and UKA. An author's financial COI was identified if they reported a relevant disclosure through the American Academy of Orthopedic Surgeons or within the study article. We then queried the Open Payments website to record all payments made from a robotic company in the year prior to publication. Each study was categorized as either favoring robotics (n = 42), neutral (n = 10), or favoring traditional techniques (n = 2). We then compared the number of conflicted authors, journal impact factor, level of evidence, and mean annual industry payment to each author. RESULTS: Of the 54 studies meeting inclusion criteria, 49 (91%) had an author financial COI. Conflicted studies were more likely to report favorable results of robotics than nonconflicted studies. When compared to studies favoring conventional techniques, those demonstrating favorable robotics outcomes had a higher number of conflicted authors and a higher mean industry payment per author. There was no difference in the level of evidence or journal impact factor. DISCUSSION: Nearly all studies comparing robotic THA, TKA, and UKA to conventional techniques involve financially conflicted authors. Further studies without COI may provide unbiased results.

Mechanical, elution, and antibacterial properties of simplex bone cement loaded with vancomycin.

Prosthetic joint infection (PJI) is one of the most devastating failures in total joint replacement (TJR). Infections are becoming difficult to treat due to the emergence of multi-drug resistant bacteria. These bacteria produce biofilm on the implant surface, rendering many antibiotics ineffective by compromising drug diffusion and penetration into the infected area. With the introduction of new antibiotics there is a need to create benchmark data from the traditional antibiotic loaded bone cements. Vancomycin, one of the commonly used antibiotics, shows activity against Methicillin-resistant Staphylococcus aureus (MRSA) and S.epidermidis. In our study, vancomycin added to bone cement was evaluated for elution properties, antimicrobial properties, and mechanical properties of the bone cement. Vancomycin at five different loading masses (0.125, 0.25, 0.5, 1.0 and 2.0 g) was added to 40 g of Simplex™ P cement. Addition of vancomycin affected the mechanical properties and antimicrobial activity with significant differences from controls. Flexural and compression mechanical properties were compromised with added vancomycin. The flexural strength of samples with added vancomycin of 0.5 g and greater were not greater than ISO 5833 minimum requirements. 2.0 g of vancomycin added to bone cement was able to eliminate completely the four bacterial strains tested. 2.0 g of vancomycin also showed the highest mass elution from the cement over a 60-day period. Given the reduced flexural strength in samples with 0.5 g and greater of added vancomycin and the inability of vancomycin in amounts less than 2.0 g to eliminate bacteria, this study did not find an ideal amount of vancomycin added to Simplex™ P that meets both strength and antibacterial requirements.

Unrecognized Osteoporosis Is Common in Patients With a Well-Functioning Total Knee Arthroplasty.

BACKGROUND: Peri-prosthetic fractures after total knee arthroplasty (TKA) are associated with poorer outcomes and high costs. We hypothesize that osteoporosis is under-recognized in the TKA population. The purpose of this study is to report osteoporosis prevalence in a healthy cohort of patients with well-functioning TKA and to compare prevalence between males and females. METHODS: This study is a cross-sectional study of 30 adults (15 males/15 females) aged 59-80 years without known bone health issues who volunteered to undergo routine dual-energy X-ray absorptiometry 2-5 years (average 3.2 ± 0.8) after primary unilateral TKA. These data plus clinical risk factors were used to estimate fracture risk via the Fracture Risk Assessment Tool and skeletal status (normal, osteopenic, osteoporotic) was determined based on the World Health Organization definition. The National Osteoporosis Foundation criteria for treatment were applied to all patients. RESULTS: Six of 30 (20%) patients had T-score ≤ -2.5. Eighteen of 30 (60%) patients had T-score between -1 and -2.5 and 6 (20%) patients had T-score ≥ -1. Five patients with normal or osteopenic bone mineral density (BMD) had occult vertebral fractures. Eleven of 30 (36.7%) patients met National Osteoporosis Foundation criteria for pharmacologic treatment. CONCLUSION: The prevalence of occult osteoporosis meeting treatment guidelines after TKA is substantial in this sample (36.7%). BMD and osteoporosis prevalence are similar between men and women. This underappreciated prevalence of osteoporosis may contribute to peri-prosthetic fracture risk. Arthroplasty surgeons and bone health specialists must be aware of post-operative changes in bone density. These data support the further study of post-operative osteoporosis and consideration of routine BMD screening after TKA. LEVEL OF EVIDENCE: III.

Osteoporosis Is Common and Undertreated Prior to Total Joint Arthroplasty.

BACKGROUND: Osteoporosis is common in total joint arthroplasty (TJA) patients and likely contributes to the increasing incidence of periprosthetic fracture. Despite this, the prevalence of osteoporosis in patients undergoing elective TJA is inadequately studied. We hypothesize that preoperative osteoporosis is underrecognized and undertreated in the TJA population. The purpose of this study is to report preoperative osteoporosis screening rates and prevalence prior to TJA and rates of pharmacologic osteoporosis treatment in the TJA population. METHODS: This is a retrospective case series of 200 consecutive adults (106F, 94M) aged 48-92 years who underwent elective TJA (100 total hip, 100 total knee) at a single tertiary-care center. Charts were retrospectively reviewed to determine preoperative osteoporosis risk factors, prior dual-energy X-ray absorptiometry (DXA) testing, and prior osteoporosis pharmacotherapy. Fracture risk was estimated using the Fracture Risk Assessment Tool and the National Osteoporosis Foundation criteria for screening and treatment were applied to all patients. RESULTS: One hundred nineteen of 200 patients (59.5%) met criteria for DXA testing. Of these 119, 21 (17.6%) had DXA testing in the 2 years prior to surgery, and 33% had osteoporosis by T-score. Forty-nine patients (24.5%) met National Osteoporosis Foundation criteria for pharmacologic osteoporosis treatment, and 11 of these 49 received a prescription for pharmacotherapy within 6 months before or after surgery. CONCLUSION: One quarter of TJA patients meet criteria to receive osteoporosis medications, but only 5% receive therapy preoperatively or postoperatively. This lack of preoperative osteoporosis screening and treatment may contribute to periprosthetic fracture risk.

Bone Morphogenetic Protein-6 Attenuates Type 1 Diabetes Mellitus-Associated Bone Loss.

Patients with type 1 diabetes mellitus (T1DM) often suffer from osteopenia or osteoporosis. Although most agree that T1DM-induced hyperglycemia is a risk factor for progressive bone loss, the mechanisms for the link between T1DM and bone loss still remain elusive. In this study, we found that bone marrow-derived mesenchymal stem cells (BMSCs) isolated from T1DM donors were less inducible for osteogenesis than those from non-T1DM donors and further identified a mechanism involving bone morphogenetic protein-6 (BMP6) that was produced significantly less in BMSCs derived from T1DM donors than that in control cells. With addition of exogenous BMP6 in culture, osteogenesis of BMSCs from T1DM donors was restored whereas the treatment of BMP6 seemed not to affect non-T1DM control cells. We also demonstrated that bone mineral density (BMD) was reduced in streptozotocin-induced diabetic mice compared with that in control animals, and intraperitoneal injection of BMP6 mitigated bone loss and increased BMD in diabetic mice. Our results suggest that bone formation in T1DM patients is impaired by reduction of endogenous BMP6, and supplementation of BMP6 enhances osteogenesis of BMSCs to restore BMD in a mouse model of T1DM, which provides insight into the development of clinical treatments for T1DM-assocaited bone loss. Stem Cells Translational Medicine 2019;8:522-534.

Endothelin-1 differentially directs lineage specification of adipose- and bone marrow-derived mesenchymal stem cells.

Blood vessels composed of endothelial cells (ECs) contact with mesenchymal stem cells (MSCs) in different tissues, suggesting possible interaction between these 2 types of cells. We hypothesized that endothelin-1 (ET1), a secreted paracrine factor of ECs, can differentially direct the lineages of adipose-derived stem cells (ASCs) and bone marrow-derived MSCs (BMSCs). Predifferentiated ASCs and BMSCs were treated with ET1 for 2 cell passages and then induced for multilineage differentiation. Our results showed that adipogenesis of ET1-pretreated ASCs and osteogenesis of ET1-pretreated BMSCs were increased compared to those of control cells. The effect of ET1 on enhancing adipogenesis of ASCs and osteogenesis of BMSCs was attenuated by blocking endothelin receptor type A (ETAR) and/or endothelin receptor type B (ETBR). Western blot analysis indicated that regulation by ET1 was mediated through activation of the protein kinase B and ERK1/2 signaling pathways. We analyzed subpopulations of ASCs and BMSCs with or without ETAR and/or ETBR, and we found that ETAR+/ETBR- and ETAR-/ETBR+ subpopulations of ASCs and those of BMSCs pretreated with ET1 were prone to turning into adipocytes and osteoblasts, respectively, after differentiation induction. Our findings provide insight into the differential regulation of MSC specification by ET1, which may help develop viable approaches for tissue regeneration.-Lee, M.-S., Wang, J., Yuan, H., Jiao, H., Tsai, T.-L., Squire, M. W., Li, W.-J. Endothelin-1 differentially directs lineage specification of adipose- and bone marrow-derived mesenchymal stem cells.

Vancomycin elution, activity and impact on mechanical properties when added to orthopedic bone cement.

Infection incidence for total hip and knee arthroplasty (THA and TKA, respectively) is between 0.2% and 5% and results in approximately 100,000 device failures per year in the United States. Treatment requires prolonged systemic antibiotic therapy with additional surgical revisions. As a prophylactic measure against infection, antibiotics can be incorporated into bone cement during THA and TKA to provide drug administration at the implant site. Antibiotics in bone cement are only effective if they can elute out of the cement at a concentration that is active against common organisms. There is evidence that added antibiotics may affect the cement's mechanical properties, especially at higher dosages. The purposes of this investigation were to (i) determine the mechanical properties of a commercially available bone cement with the addition of vancomycin, (ii) determine the release characteristics of vancomycin added to bone cement, and (iii) evaluate eluted vancomycin efficacy at eliminating some of the most common causative orthopedic implant pathogens. Palacos bone cement was impregnated with incrementally larger clinically relevant weight percentages of vancomycin. Vancomycin is a treatment standard for invasive gram-positive infections, and Palacos cement is one of the most commonly used bone cements. After 21 days of curing in PBS, added masses of vancomycin greater than 0.5 g per 40.0 g cement packet decreased the cement's compressive yield strength to below ISO standard. The addition of vancomycin reduced the bone cement's mechanical properties in compression more than in bending. Vancomycin eluted from Palacos with a steady rise in eluted volume up to 8 days, after which non-therapeutic elution concentrations were observed up to a 60-day end point. The eluted concentration from samples with greater than 0.25 g vancomycin per Palacos packet was sufficient to eliminate a 103 colony forming unit per mL (CFU/mL) initial inoculum of S. aureus, including methicillin-resistant S. aureus (MRSA). However, none of the tested dosages were able to fully clear a 103 CFU/mL initial inoculum of a known high biofilm producing strain of S. epidermidis. When used for infection prophylaxis at the time of THA and TKA, the findings of this study do not support the addition of more than 0.5 g vancomycin to a 40 g packet of Palacos cement due to a reduction in compression yield strength below ISO standards. Vancomycin doses up to 0.5 g were shown to elute from the bone cement matrix and are effective at treating bacterial infections of 103 CFU/mL in bacterial strains of S. aureus, but may have limited effect against high-biofilm producing strains including S. epidermidis.

Osteochondral Graft Size Is Significantly Associated With Increased Force and Decreased Chondrocyte Viability.

BACKGROUND: Insertion force has been shown to significantly reduce chondrocyte viability during osteochondral allograft transplantation. How graft size influences the required insertion force and chondrocyte viability has yet to be determined. Hypothesis/Purpose: The purpose was to characterize how graft size influences insertion force requirements and chondrocyte viability during osteochondral transplantation. The hypothesis was that larger grafts would require greater force and reduce chondrocyte viability. STUDY DESIGN: Controlled laboratory study. METHODS: Four graft sizes-15 × 5 mm, 15 × 10 mm, 25 × 5 mm, and 25 × 10 mm (diameter × depth)-were harvested from 13 thawed fresh-frozen human cadaveric distal femurs. Average, maximum, and cumulative force and number of impacts were recorded for 44 grafts by a surgical mallet embedded with a calibrated force sensor. In a separate experiment, fresh osteochondral tissues were subjected to mechanical loading. To capture a range of clinically important forces, categories were selected to correspond to impaction force data. Chondrocyte viability was assessed with confocal laser microscopy and live/dead staining. RESULTS: Total force for all grafts averaged 4576 N. Median number of impacts for all grafts was 20 (range, 7-116). The mean number of impacts for 5-mm-deep grafts was 14.2 (95% CI, 10.8-18.6), as compared with 26.3 (95% CI, 19.9-34.4) for 10-mm-deep grafts ( P < .001). The mean cumulative force for 5-mm-deep grafts was 2128 N (95% CI, 1467-3087), as opposed to 4689 N (95% CI, 3232-6803) for 10-mm-deep grafts ( P = .001). For every 1 mm in graft depth, an average of 13.1% (95% CI, 6.2%-20.3%) more impacts are required when controlling for diameter and density ( P < .001). For every 1 mm in graft depth, the force required increases on average by 17.1% (95% CI, 7.7%-27.4%) when controlling for diameter and density ( P = .001). There was a significant reduction in chondrocyte viability for the forces required for graft thickness values >10 mm. Only forces associated with graft thickness <10 mm had chondrocyte viabilities consistently >70%. CONCLUSION: Insertion force increases significantly with increasing graft depth. Controlling for diameter and bone density, a 1-mm increase in graft depth is associated with 13.1% more impacts and 17.1% more force. Chondrocyte viability was significantly reduced to <70% at average forces associated with grafts thicker than 10 mm. CLINICAL RELEVANCE: Based on the current data, graft depth is an important consideration for surgeons when sizing osteochondral allograft transplant for chondral lesions of the knee.

Endothelial cells direct human mesenchymal stem cells for osteo- and chondro-lineage differentiation through endothelin-1 and AKT signaling.

INTRODUCTION: Human mesenchymal stem cells (hMSCs) reside in a perivascular niche of the body, suggesting that they interact closely with vascular endothelial cells (ECs) through cell-cell interaction or paracrine signaling to maintain cell functions. Endothelin-1 (ET1) is a paracrine factor mainly secreted by ECs. We thus hypothesize that ECs can regulate cellular activities of hMSCs and direct their stem cell fate. METHODS: We investigated whether co-cultured human aortic endothelial cells (HAECs) were able to regulate expression of potency- and lineage-related markers in bone marrow-derived hMSCs. We further explored the regulatory effects of ET1 on cell proliferation, expression of surface antigens and pluripotency-related markers, and multilineage differentiation in hMSCs. Activation of the AKT signaling pathway in hMSCs was also analyzed to identify its mechanistic role in the ET1-induced regulation. RESULTS: Co-cultured HAECs enhanced expression of mesenchymal lineage-related markers in hMSCs. Treatment of ET receptor antagonist downregulated the increased expression of CBFA1 in hMSCs cultured with HAEC-conditioned medium. hMSCs treated with ET1 showed cell proliferation and expression of surface antigens, CD73, CD90, and CD105, comparable with those without ET1 treatment. ET1-treated hMSCs also expressed upregulated mRNA transcript levels of OCT3/4, NANOG, CBFA1 and SOX9. When induced for lineage-specific differentiation, hMSCs pre-treated with ET1 showed enhanced osteogenesis and chondrogenesis. However, adipogenic differentiation of hMSCs was not affected by ET1 pretreatment. We further showed that the ET1-induced regulation was mediated by activation of AKT signaling. CONCLUSION: Our results demonstrate that ET1 secreted by HAECs can direct bone marrow-derived hMSCs for osteo- and chondro-lineage differentiation through activation of the AKT signaling pathway, suggesting that ET1 plays a crucial role in regulation of hMSC activity. Our findings may help understand how hMSCs interact with ECs in a perivascular niche.

The influence of low concentrations of a water soluble poragen on the material properties, antibiotic release, and biofilm inhibition of an acrylic bone cement.

Soluble particulate fillers can be incorporated into antibiotic-loaded acrylic bone cement in an effort to enhance antibiotic elution. Xylitol is a material that shows potential for use as a filler due to its high solubility and potential to inhibit biofilm formation. The objective of this work, therefore, was to investigate the usage of low concentrations of xylitol in a gentamicin-loaded cement. Five different cements were prepared with various xylitol loadings (0, 1, 2.5, 5 or 10 g) per cement unit, and the resulting impact on the mechanical properties, cumulative antibiotic release, biofilm inhibition, and thermal characteristics were quantified. Xylitol significantly increased cement porosity and a sustained increase in gentamicin elution was observed in all samples containing xylitol with a maximum cumulative release of 41.3%. Xylitol had no significant inhibitory effect on biofilm formation. All measured mechanical properties tended to decrease with increasing xylitol concentration; however, these effects were not always significant. Polymerization characteristics were consistent among all groups with no significant differences found. The results from this study indicate that xylitol-modified bone cement may not be appropriate for implant fixation but could be used in instances where sustained, increased antibiotic elution is warranted, such as in cement spacers or beads.

Characterization and evaluation of mesenchymal stem cells derived from human embryonic stem cells and bone marrow.

Embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) have been studied for years as primary cell sources for regenerative biology and medicine. MSCs have been derived from cell and tissue sources, such as bone marrow (BM), and more recently from ESCs. This study investigated MSCs derived from BM, H1- and H9-ESC lines in terms of morphology, surface marker and growth factor receptor expression, proliferative capability, modulation of immune cell growth and multipotency, in order to evaluate ESC-MSCs as a cell source for potential regenerative applications. The results showed that ESC-MSCs exhibited spindle-shaped morphology similar to BM-MSCs but of various sizes, and flow cytometric immunophenotyping revealed expression of characteristic MSC surface markers on all tested cell lines except H9-derived MSCs. Differences in growth factor receptor expression were also shown between cell lines. In addition, ESC-MSCs showed greater capabilities for cell proliferation, and suppression of leukocyte growth compared to BM-MSCs. Using standard protocols, induction of ESC-MSC differentiation along the adipogenic, osteogenic, or chondrogenic lineages was less effective compared to that of BM-MSCs. By adding bone morphogenetic protein 7 (BMP7) into transforming growth factor beta 1 (TGFß1)-supplemented induction medium, chondrogenesis of ESC-MSCs was significantly enhanced. Our findings suggest that ESC-MSCs and BM-MSCs show differences in their surface marker profiles and the capacities of proliferation, immunomodulation, and most importantly multi-lineage differentiation. Using modified chondrogenic medium with BMP7 and TGFß1, H1-MSCs can be effectively induced as BM-MSCs for chondrogenesis.

Technologically enhanced total knee replacement: is the juice worth the squeeze?

OBJECTIVE: The purpose of this article is to outline the limb alignment goals for knee replacement, current surgical technologies, and evidence-based medicine principles regarding technologically advanced total knee arthroplasty (TKA). Radiologists need an understanding of the pros and cons of technologically advanced TKA. CONCLUSION: At this time, the appropriate role for TKA has not been determined.

Preoperative "NPO" as an opportunity for diabetes screening.

BACKGROUND: Novel preventive care opportunities, such as in hospitalized patients, may merit further investigation in an Accountable Care Organization (ACO) model. As 40% of patients with diabetes are undiagnosed, diabetes screening is an urgent public health need. Screening fasting preoperative patients may present an effective means to identify patients who might otherwise remain undiagnosed. OBJECTIVE: To pilot an inpatient preventive care strategy for diabetes screening that would ascertain prevalence of unrecognized inpatient diabetes (DM) and impaired fasting glucose (IFG), determine reproducibility of preoperative fasting blood glucose (FBG), and establish feasibility of inpatient preventive screening. DESIGN: Prospective observational study. SETTING: Large Midwestern academic medical center. PATIENTS: Two hundred seventy-five elective orthopedic patients with a preoperative visit between December 1, 2007 and November 30, 2008. Most patients (96.6%) had seen their primary care provider (PCP) within 12 months, and 100% were insured. MEASUREMENTS: Medical history was recorded, and hemoglobin A(1C) (Hgb A(1C) ) and FBG were drawn immediately prior to surgery. Patients with preoperative FBG ≥100 mg/dL had FBG drawn 6-8 weeks postoperatively. RESULTS: Twenty-four percent (67/275) of patients had previously unrecognized DM or IFG by virtue of 2 abnormal values. Sixty-four percent of patients with FBG ≥100 mg/dL preoperatively remained elevated at ambulatory follow-up. No patients with new DM or IFG had point-of-care glucose checks ordered or had dysglycemia mentioned on discharge summary. CONCLUSIONS: Inpatient undiagnosed DM and IFG is common, even in insured, elective surgery patients with recent primary care visits. Preoperative FBG can be used to screen, but results need to be conveyed to PCPs.

Preoperative diagnosis of periprosthetic joint infection: role of aspiration.

OBJECTIVE: The purpose of this article is to illustrate how total knee arthroplasty (TKA) and total hip arthroplasty (THA) aspiration by the radiologist can assist the health care team in determining the presence or absence of periprosthetic joint infection. CONCLUSION: The increasing incidence of periprosthetic TKA and THA infection, as well as the changing role of aspiration for diagnosing periprosthetic joint infection, will likely increase demand for this important procedure in the future.