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Journal of Orthopaedic Research

Wiley Online Library : Journal of Orthopaedic Research

Published: 2017-09-01T00:00:00-05:00


Animal models for studying the etiology and treatment of low back pain


Chronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain. This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of low back pain can be divided into the following five categories: discogenic low back pain, radicular back pain, facet joint osteoarthritis back pain, muscle-induced low back pain, and spontaneous occurring low back pain models. These models are important not only for enhancing our knowledge of how low back pain is generated, but also for the development of novel therapeutic regimens to treat low back pain in patients. This article is protected by copyright. All rights reserved

Plasticizer Di(2-ethylhexyl)phthalate Interferes with Osteoblastogenesis and Adipogenesis in a Mouse Model


Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2 -ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose -dependently decreased by DEHP and MEHP (10 -100 μM) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin, Wnt1, and β -catenin were significantly decreased in DEHP - and MEHP -treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARγ mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated β -catenin/β -catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARγ inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP -treated mice, osteoblastogenesis and Runx2, Wnt1, and β -catenin expression were decreased, but adipogenesis and PPARγ expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/β -catenin -regulated and thus triggering bone loss. PPARγ signaling may play an important role in MEHP - and DEHP -induced suppression of osteogenesis. This article is protected by copyright. All rights reserved

Evaluating instrument responsiveness in joint function: The HOOS JR, the KOOS JR, and the PROMIS PF CAT


Responsiveness is the ability to detect change over time and is an important aspect of measures used to detect treatment effects. The purpose of this study was to assess the responsiveness of the HOOS JR, the KOOS JR, and the PROMIS Physical Function (PF) computerized adaptive test (CAT) in a joint reconstruction practice. 983 patients were evaluated for joint conditions between 2014 and 2017 in an orthopaedic clinic and completed the three instruments at baseline and three and/or six-month follow-up visits. Average age was 61.03 years (SD = 12.33, Range = 18–90 years) and the majority of the patients were White (n=875, 89.0%). Three-month responsiveness was calculated two ways, as between 80 to 100 days and as 90 days and beyond. Six-month responsiveness was calculated as 170–190 days and as 180 days and beyond. All changes from baseline scores were significant at the 3-month, >3-month, and >6-month follow-up (p<0.05). All three measures showed large effect sizes, ranging from 0.80–1.20 at each time-point. The standardized response mean was large for each measure and at each time-point (Range = 1.06–1.53). This study demonstrated the responsiveness of the HOOS JR, KOOS JR, and the PROMIS PF in adult reconstruction patients. The PROMIS PF was consistently the most responsive instrument in this analysis. Clinical Significance: The HOOS JR, KOOS JR and PROMIS PF are useful clinical instruments for assessing treatment change and may be selected as relevant to the specific needs and conditions of the adult joint reconstruction patient population. This article is protected by copyright.All rights reserved

Biomarkers for equine joint injury and osteoarthritis


We report the results of a symposium aimed at identifying validated biomarkers that can be used to complement clinical observations for diagnosis and prognosis of joint injury leading to equine osteoarthritis (OA). Biomarkers might also predict pre-fracture change that could lead to catastrophic bone failure in equine athletes. The workshop was attended by leading scientists in the fields of equine and human musculoskeletal biomarkers to enable cross-disciplinary exchange and improve knowledge in both. Detailed proceedings with strategic planning was written, added to, edited and referenced to develop this manuscript. The most recent information from work in equine and human osteoarthritic biomarkers was accumulated, including the use of personalized healthcare to stratify OA phenotypes, transcriptome analysis of anterior cruciate ligament (ACL) and meniscal injuries in the human knee. The spectrum of "wet" biomarker assays that are antibody based that have achieved usefulness in both humans and horses, imaging biomarkers and the role they can play in equine and human OA was discussed. Prediction of musculoskeletal injury in the horse remains a challenge, and the potential usefulness of spectroscopy, metabolomics, proteomics, and development of biobanks to classify biomarkers in different stages of equine and human OA were reviewed. The participants concluded that new information and studies in equine musculoskeletal biomarkers have potential translational value for humans and vice versa. OA is equally important in humans and horses, and the welfare issues associated with catastrophic musculoskeletal injury in horses add further emphasis to the need for good validated biomarkers in the horse. This article is protected by copyright. All rights reserved

Elevated Solute Transport at Sites of Diffuse Matrix Damage in Cortical Bone: Implications on Bone Repair


Diffuse matrix damage in rat cortical bone has been observed to self-repair efficiently in two weeks without activating bone remodeling, and unlike the case with linear cracks, the local osteocytes at the sites of diffuse damage remain healthy. However, the reason(s) for such high efficiency of matrix repair remains unclear. We hypothesized that transport of minerals and other compounds essential for damage repair is enhanced at the damaged sites and further increased by the application of tensile loading. To test our hypothesis, diffuse damage was introduced in notched bovine wafers under cyclic tensile loading and unloading. Using the Fluorescence Recovery After Photobleaching (FRAP) approach, we measured the transport of a small fluorescent tracer (sodium fluorescein, 376 Da) in damaged vs. undamaged regions and under varying tensile load magnitudes (0.2 N, 10 N, 20 N, and 30 N), which corresponded to nominal strains of 12.5, 625, 1250, and 1875 microstrains, respectively. We found a 37% increase in transport of fluorescein in damaged regions relative to undamaged regions and a further ∼18% increase in transport under 20N and 30N tension compared to the non-loaded condition, possibly due to the opening of the cracking surfaces. The elevated transport of minerals and other adhesive proteins may, at least partially, account for the highly effective repair of diffuse damage observed in vivo. Clinical Significance: Diffuse damage adversely affects bone's fracture resistance and this study provided quantitative data on elevated transport, which may be involved in repairing diffuse damage in vivo. This article is protected by copyright. All rights reserved

Ischemic Femoral Head Osteonecrosis in a Piglet Model Causes Three Dimensional Decrease in Acetabular Coverage


Legg-Calve-Perthes disease (LCPD) is a childhood form of ischemic osteonecrosis marked by development of severe femoral head deformity and premature osteoarthritis. The pathogenesis of femoral head deformity has been studied extensively using a piglet model of ischemic osteonecrosis, however accompanying acetabular changes have not been investigated. The purpose of this study was to determine if acetabular changes accompany femoral head deformity in a well-established piglet model of LCPD and to define the acetabular changes using 3 dimensional computed tomography (3-D CT) and modeling. Twenty-four piglets were surgically induced with ischemic osteonecrosis on the right side. The contralateral hip was used as control. At 8 weeks postoperative, pelvi were retrieved and imaged with CT. Custom software was used to measure acetabular morphologic parameters on 3-D CT images. Moderate to severe femoral head deformities were present in all animals. Acetabula with accompanying femoral head deformity had a significant decrease in acetabular version and tilt (p < 0.001) and in coverage angle in the superior, posterior, and inferior quadrants (p < 0.05). These findings indicate that the development of femoral head deformity following ischemic osteonecrosis produces specific and predictable changes to the shape of the acetabulum. Clinical Relevance: Acetabular changes described in patients with LCPD were observed in the piglet model. This model may serve as a valuable tool to elucidate the relationship between femoral head and acetabular deformities. This article is protected by copyright. All rights reserved

Labral calcification in end-stage osteoarthritis of the hip correlates with pain and clinical function


The acetabular labrum of the hip (ALH) is recognized as a clinically important structure, but knowledge about the pathophysiology of this fibrocartilage is scarce. In this prospective study we determined the prevalence of ALH calcification in patients with end-stage osteoarthritis (OA) and analyzed the relationship of cartilage calcification (CC) with hip pain and clinical function. Cohort of 80 patients (70.2±7.6years) with primary OA scheduled for total hip replacement. Harris Hip Score (HHS) was recorded preoperatively. Total ALH and femoral head (FH) were sampled intraoperatively. CC of the ALH and FH was analyzed by high-resolution digital contact radiography. Histologicaldegeneration of the ALH (Krenn-Score) and FH (OARSI-Score) was determined. Multivariate linear regression model and partial correlation analyses were performed. The prevalence of cartilage calcification both in the ALH and FH was 100%, while the amount of CC in the ALHwas 1.55 times higher than in the FH (p<0.001). There was a significant inverse regression between the amount of calcification of boththe ALH and the FH and preoperative HHS (βALH=−2.1,p=0.04),(βFH=−2.9,p=0.005), but pain wasinfluenced only by ALH calcification (βALH=−2.7,p=0.008). Age-adjusted, there was a significant correlation between cartilage calcification and histological degeneration (ALH:rs=0.53,p<0.001/FH:rs=0.30,p=0.007). Fibrocartilage and articular cartilage calcification are inseparable pathological findings in end-stage osteoarthritis of the hip. Fibrocartilage calcification is associated with poor and painful hip function. Clinical Significance ALH fibrocartilage appears to be particularly prone to calcification, which may explain higher pain levels in individuals with a high degree of ALH calcification independent of age and histological degeneration. This article is protected by copyright. All rights reserved

CXCL10 is Upregulated in Synovium and Cartilage following Articular Fracture


The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) vs. three days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p=0.09) and S-GAG (p=0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. This article is protected by copyright. All rights reserved

Development and initial validation of a novel smoothed-particle hydrodynamics-based simulation model of trabecular bone penetration by metallic implants


A novel computational model of implant migration in trabecular bone was developed using smoothed-particle hydrodynamics (SPH), and an initial validation was performed via correlation with experimental data. Six fresh-frozen human cadaveric specimens measuring 10 × 10 × 20 mm were extracted from the proximal femurs of female donors (mean age of 82 years, range 75–90, BV/TV ratios between 17.88–30.49%). These specimens were then penetrated under axial loading to a depth of 10 mm with 5 mm diameter cylindrical indenters bearing either flat or sharp/conical tip designs similar to blunt and self-tapping cancellous screws, assigned in a random manner. SPH models were constructed based on microCT scans (17.33 µm) of the cadaveric specimens. Two initial specimens were used for calibration of material model parameters. The remaining four specimens were then simulated in silico using identical material model parameters. Peak forces varied between 92.0–365.0 N in the experiments, and 115.5–352.2 N in the SPH simulations. The concordance correlation coefficient between experimental and simulated pairs was 0.888, with a 95% CI of 0.8832–0.8926, a Pearson ρ (precision) value of 0.9396, and a bias correction factor Cb (accuracy) value of 0.945. Patterns of bone compaction were qualitatively similar; both experimental and simulated flat-tipped indenters produced dense regions of compacted material adjacent to the advancing face of the indenter, while sharp-tipped indenters deposited compacted material along their peripheries. Simulations based on SPH can produce accurate predictions of trabecular bone penetration that are useful for characterizing implant performance under high-strain loading conditions. This article is protected by copyright. All rights reserved

The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development


The primary cilium is a solitary, antenna-like sensory organelle with many important roles in cartilage and bone development, maintenance, and function. The primary cilium's potential role as a signaling nexus in the growth plate makes it an attractive therapeutic target for diseases and disorders associated with bone development and maintenance. Many signaling pathways that are mediated by the cilium – such as Hh, Wnt, Ihh/PTHrP, TGFβ, BMP, FGF, and Notch – are also known to influence endochondral ossification, primarily by directing growth plate formation and chondrocyte behavior. Although a few studies have demonstrated that these signaling pathways can be directly tied to the primary cilium, many pathways have yet to be evaluated in context of the cilium. This review serves to bridge this knowledge gap in the literature, as well as discuss the cilium's importance in the growth plate's ability to sense and respond to chemical and mechanical stimuli. Furthermore, we explore the importance of using the appropriate mechanism to study the cilium in vivo and suggest IFT88 deletion is the best available technique. This article is protected by copyright. All rights reserved

Neutral Glenoid Alignment In Reverse Shoulder Arthroplasty Does Not Guarantee Decreased Risk Of Impingement


Reverse Shoulder Arthroplasty (RSA) has gained popularity over the recent years, but impingement concerns are still present. Surgeons aim to correct pre-operative glenoid deformities to reduce impingement but it can be challenging without assistance like patient specific guides. However, it is unclear how accurate glenoid correction affects the impingement. The main objective of this study was to determine whether accurate glenoid correction to neutral version and tilt can reduce the risk of impingement. Two types of virtual surgeries were performed on 22 pre-operative arthritic shoulders: i)'Interactive', the glenoid baseplate could be placed with accuracy, and ii)'Blind', surgeons placed the RSA baseplate while they could only visualize the glenoid. The virtual models were then used in an RSA biomechanical model which recorded impingement for i)Four Range of Motion (ROM) tasks, ii)Ten Activities of Daily Living (ADL). The 'Blind' method resulted in more variable glenoid placement (version and tilt) than the 'Interactive' method (p=0.001). However, both methods showed similar ROM and impingement occurrence in ADLs. The results suggest it is challenging for surgeons to accurately correct version and tilt on arthritic glenoids when only referencing off of the face of the glenoid. However, the variable glenosphere placement observed in the 'Blind' method did not result in worse impingement compared to the accurate 'Interactive' method. This was because both methods had similar inferior baseplate positioning which is more important than correcting version or tilt. Implantation accuracy remains important in RSA, but pre-operative planning should not just target at correcting version and tilt. This article is protected by copyright. All rights reserved

Collagen XI mutation lowers susceptibility to load-induced cartilage damage in mice


Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5N) and high (9.0N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. This article is protected by copyright. All rights reserved

Effect of biomechanical stress on endogenous antioxidant networks in bovine articular cartilage


Mechanosensitve pathways in chondrocytes are essential for maintaining articular cartilage homeostasis. Traumatic loading increases cartilage oxidation and causes cell death and osteoarthritis. However, sub-lethal doses of the pro-oxidant molecule tert-Butyl hydroperoxide (tBHP) protects against loading-induced chondrocyte death. We hypothesized that compressive cyclic loading at moderate strains (<20%) causes sub-lethal cartilage oxidation that induces an adaptive increase in the endogenous antioxidant defense network. We tested this hypothesis by subjecting healthy bovine articular cartilage explants to in vitro static or cyclic (1 Hz) compressive loading at 50kPa (15% strain, “physiologic”) versus 300kPa (40% strain, “hyper-physiologic”) for 12 hours per day for 2 days. We also treated unloaded explants with 100µM tBHP for 12 hours per day for 2 days to differentiate between biomechanical and chemical pro-oxidant stimulation. All loading conditions induced glutathione oxidation relative to unloaded controls, but only the 50kPa cyclic loading condition increased total glutathione content (2-fold). This increase was associated with a greater expression of glutamate-cysteine ligase, the rate-limiting step in glutathione synthesis, compared to 300kPa cyclic loading. 50kPa cyclic loading also increased the expression of superoxide dismutase-1 and peroxiredoxin-3. Like 50kPa loading, tBHP treatment also increased total glutathione content. However, tBHP treatment and 50kPa cyclic loading differed in their effect on the expression of genes regulating antioxidant defense and cartilage matrix synthesis and degradation. These findings suggest that glutathione metabolism is a mechanosensitive antioxidant defense pathway in chondrocytes and that intermittent pro-oxidant treatment alone is insufficient to account for all changes in mediators of cartilage homeostasis associated with cyclic loading. This article is protected by copyright. All rights reserved

Possibility of quantitative T2-mapping MRI of cartilage near metal in high tibial osteotomy: A human cadaver study


T2-mapping is a widely used quantitative MRI technique in osteoarthritis research. An important challenge for its application in the context of high tibial osteotomy (HTO) is the presence of metallic fixation devices. In this study, we evaluated the possibility of performing T2-mapping after a HTO, by assessing the extent of magnetic susceptibility artifacts and the influence on T2 relaxation times caused by two commonly used fixation devices. T2-mapping with a 3D fast spin-echo sequence at 3 Tesla was performed on 11 human cadaveric knee joints before and after implantation of a titanium plate and screws (n = 5) or cobalt chrome staples(n = 6). Mean T2 relaxation times were calculated in 6 cartilage regions, located in the distal and posterior cartilage of femoral condyles and the cartilage of tibial plateaus, both medially and laterally. T2 relaxation times before and after the implantation were compared with paired t-tests and Wilcoxon rank tests. Due to the extent of the magnetic susceptibility artifact, it was not possible to segment the knee cartilage and thus calculate T2 relaxation times in the lateral weight-bearing femoral and tibial cartilage regions only in the cobalt chrome group. In all cartilage regions of the titanium implanted knees and those unaffected by artifacts due to cobalt chrome implants, T2 relaxation times did not significantly differ between the two scans. Our results suggest that accurate T2-mapping after a HTO procedure is possible in all areas after implantation of a titanium fixation device and in most areas after implantation of a cobalt chrome fixation device. This article is protected by copyright. All rights reserved

Evaluation of loading parameters for murine axial tibial loading: Stimulating cortical bone formation while reducing loading duration


Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4 Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p < 0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. −1000 μϵ and a transition from lamellar-woven bone near −2000 μϵ. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1200 to 300 to 60 did not diminish the bone formation response (p > 0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p < 0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to −1800 μϵ peak strain, at 4 Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month old C57Bl/6 female mice. Our results provide a basis for reduction of loading duration (daily cycles and study length) without loss of anabolic effect as measured by dynamic histomorphometry. This article is protected by copyright. All rights reserved

Targeting intracellular Staphylococcus aureus to lower recurrence of orthopaedic infection


Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m-chlorophenyl hydrazone, CCCP) and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10x MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. This article is protected by copyright. All rights reserved

Achieving Interfragmentary Compression Without Special Drilling Technique or Screw Design


Traditional fracture fixation teaching suggests that fully threaded screws do not provide interfragmentary compression unless placed through a glide hole. Based on this assumption, pelvic surgeons typically use fully threaded screws in the treatment of comminuted transforaminal sacral fractures to limit iatrogenic neuroforaminal stenosis. Clinical experience with fully threaded screws suggests that interfragmentary compression actually does occur. We hypothesized that the use of a fully threaded screw does not produce any interfragmentary compression and that there is no difference in insertional torque between partially threaded and fully threaded screws. To test this hypothesis, fully and partially threaded 7.0 millimeter (mm) cannulated screws were placed across two synthetic bone blocks fabricated to simulate normal and osteoporotic bone. We compared two groups of normal and osteoporotic blocks for compression achieved and maximal insertional torque generated with fully threaded and partially threaded screw insertion. A micro computed tomography (CT) scan of the composite blocks was obtained to investigate for structural changes created during screw insertion. For both groups, compression was achieved with fully threaded screws and the maximal insertional torque was higher using fully threaded screws. Micro CT analysis demonstrated local bone damage with structural disruption in the near segment of the fully threaded screw path in comparison to the partially threaded. Clinical Significance: This study demonstrates that compression is generated using fully threaded screws without using a predrilled glide hole. The insertional torque required to generate compression with fully threaded screws is increased but is clinically applicable. This article is protected by copyright. All rights reserved

The seating mechanics of head-neck modular tapers in vitro: Load-displacement measurements, moisture, and rate effects


The mechanically-assisted crevice corrosion performance of head-neck modular tapers is a significant concern in orthopedic biomaterials. Fretting crevice corrosion processes in modular tapers are thought to be influenced by a wide array of factors including seating mechanics of the junction, hence there is a need for in vitro test methods that can assess their performance. This study presented a test method to directly measure the load-displacement seating mechanics of modular tapers and used this method to compare the seating mechanics for different tapers, moisture, seating loads and seating rates. Seating mechanics were explored whereby the instantaneous load-displacement behavior of the head seating onto the neck is captured and used to define the mechanics of seating. Two distinct taper design/material combinations were assembled wet or dry using axially applied loads (500, 1000, 2000 and 4000 N) at two loading rates of 100 and 104 N/s (n = 5 for each condition) using a servohydraulic test frame. The results showed that pull-off strength scaled with seating load and ranged between 43-68% of seating load depending on sample and wetness. Tapers seated wet had higher pull-off strengths (2200 N +/− 300 N) than those seated dry (1800 N +/− 200 N, P < 0.05). Seating mechanics (load-displacement plots) varied due to sample type and due to wetness with differences in seating energy, seating stiffness and seating displacement. These results show the detailed mechanics of seating during assembly and provide significant insight into the complex interplay of factors associated with even “ideal” seating (axial, quasistatic) loading. This article is protected by copyright. All rights reserved

Sclerostin antibody enhances bone formation in a rat model of distraction osteogenesis


Neutralizing monoclonal sclerostin antibodies are effective in promoting bone formation at a systemic level and in orthopedic scenarios including closed fracture repair. In this study we examined the effects of sclerostin antibody (Scl-Ab) treatment on regenerate volume, density and strength in a rat model of distraction osteogenesis. Surgical osteotomy was performed on 179 Sprague Dawley rats. After 1 week, rats underwent distraction for 2 weeks, followed by 6 weeks for consolidation. Two treatment groups received biweekly subcutaneous Scl-AbIII (a rodent form of Scl-Ab; 25 mg/kg), either from the start of distraction onwards or restricted to the consolidation phase. These groups were compared to controls receiving saline. Measurement modalities included longitudinal DXA, ex vivo QCT and microCT, tissue histology, and biomechanical 4-point bending tests. Bone volume was increased in both Scl-Ab treatments regimens by the end of consolidation (+26-38%, p < 0.05), as assessed by microCT. This was associated with increased mineral apposition. Importantly, Scl-Ab led to increased strength in united bones, and this reached statistical significance in animals receiving Scl-Ab during consolidation only (+177%, p < 0.01, maximum load to failure). These data demonstrate that Scl-Ab treatment increases bone formation, leading to regenerates with higher bone volume and improved strength. Our data also suggest that the optimal effects of Scl-Ab treatment are achieved in the latter stages of distraction osteogenesis. These findings support further investigation into the potential clinical application of sclerostin antibody to augment bone distraction, such as limb lengthening, particularly in the prevention of refracture. This article is protected by copyright. All rights reserved

Antibiotic elution from acrylic bone cement loaded with high doses of tobramycin and vancomycin


Two-stage revision treatment of prosthetic joint infection (PJI) frequently employs the use of a temporary bone cement spacer loaded with multiple antibiotic types. Tobramycin and vancomycin are commonly used antibiotics in cement spacers, however, there is no consensus on the relative concentrations and combinations that should be used. Therefore, the purpose of this study was to investigate the influence of dual antibiotic loading on the total antibiotic elution and compressive mechanical properties of acrylic bone cement. Varying concentrations of tobramycin (0–3 g) and vancomycin (0–3 g) were added either alone or in combination to acrylic cement (Palacos R), resulting in 12 experimental groups. Samples were submerged in 37°C saline for 28 d and sampled at specific time points. The collected eluent was analyzed to determine the cumulative antibiotic release. In addition, the cement's compressive mechanical properties and porosity were characterized. Interestingly, the cement with the highest concentration of antibiotics did not possess the best elution properties. Cement samples containing both 3 g of tobramycin and 2 g vancomycin demonstrated the highest cumulative antibiotic release after 28 d, which was coupled with a significant decrease in the mechanical properties and an increased porosity. The collected data also suggests that tobramycin elutes more effectively than vancomycin from cement. In conclusion, this study demonstrates that high antibiotic loading in cement does not necessarily lead to enhanced antibiotic elution. Clinically this information may be used to optimize cement spacer antibiotic loading so that both duration and amount of antibiotics eluted are optimized. This article is protected by copyright. All rights reserved

Patient-specific in silico models can quantify primary implant stability in elderly human bone


Secure implant fixation is challenging in osteoporotic bone. Due to the high variability in inter- and intra-patient bone quality, ex vivo mechanical testing of implants in bone is very material- and time-consuming. Alternatively, in silico models could substantially reduce costs and speed up the design of novel implants if they had the capability to capture the intricate bone microstructure. Therefore, the aim of this study was to validate a micro-finite element model of a multi-screw fracture fixation system. Eight human cadaveric humerii were scanned using micro-CT and mechanically tested to quantify bone stiffness. Osteotomy and fracture fixation were performed, followed by mechanical testing to quantify displacements at twelve different locations on the instrumented bone. For each experimental case, a micro-finite element model was created. From the micro-finite element analyses of the intact model, the patient-specific bone tissue modulus was determined such that the simulated apparent stiffness matched the measured stiffness of the intact bone. Similarly, the tissue modulus of a small damage region around each screw was determined for the instrumented bone. For validation, all in silico models were rerun using averaged material properties, resulting in an average coefficient of determination of 0.89 ± 0.04 with a slope of 0.93 ± 0.19 and a mean absolute error of 43 ± 10 µm when correlating in silico marker displacements with the ex vivo test. In conclusion, we validated a patient-specific computer model of an entire organ bone-implant system at the tissue-level at high resolution with excellent overall accuracy. This article is protected by copyright. All rights reserved

Mechanically stimulated biomarkers signal cartilage changes over 5 years consistent with disease progression in medial knee osteoarthritis patients


Using serum biomarkers to assess osteoarthritis (OA) disease state and risks of progression remain challenging. This study tested the hypothesis that changes to serum biomarkers in response to a mechanical stimulus in patients with medial knee OA signal cartilage thickness changes five years later. Specifically, serum concentrations of a collagen degradation marker (C1,2C) and a chondroitin sulfate synthesis marker (CS846) were measured 0.5 and 5.5 hours after a 30-minute walk in 16 patients. Regional cartilage thickness changes measured from magnetic resonance images obtained at study entry and at 5-year follow-up were tested for correlations with baseline biomarker changes after mechanical stimulus, and for differences between groups stratified based on whether biomarker levels increased or decreased. Results showed that an increase in the degradation biomarker C1,2C correlated with cartilage thinning of the lateral tibia (R=-0.63, P=0.009), whereas an increase in the synthesis marker CS846 correlated with cartilage thickening of the lateral femur (R=0.76, P=0.001). Changes in C1,2C and CS846 were correlated (R2=0.28, P=0.037). Subjects with increased C1,2C had greater (P=0.05) medial tibial cartilage thinning than those with decreased C1,2C. In conclusion, the mechanical stimulus appeared to metabolically link the biomarker responses where biomarker increases signaled more active OA disease states. The findings of medial cartilage thinning for patients with increases in the degradation marker and correlation of cartilage thickening in the less involved lateral femur with increases in the synthetic marker were consistent with progression of medial compartment OA. Thus, the mechanical stimulus facilitated assessing OA disease states using serum biomarkers. This article is protected by copyright. All rights reserved

Accumulation of advanced-glycation end products (AGEs) accelerates arthrogenic joint contracture in immobilized rat knee


Joint mobility decreases in the elderly and in diabetics, this process is thought to be caused by accumulation of advanced-glycation end products (AGEs). Here, we aimed to elucidate the role of AGEs in joint contracture formation in rat knees. Rats were injected with ribose or saline into the knees twice weekly for eight weeks. Pentosidine (AGE) levels were measured in the knee-joint tissues. After serial injections, rats were subjected to unilateral knee-joint immobilization in a flexion position for various periods. At day 21, the passive knee ranges of motions (ROMs) were measured. Knee joint histopathology were assessed, and the expression of fibrotic genes in the posterior joint capsules was examined using real-time PCR. Ribose injection induced a 7.0-fold increase in pentosidine levels relative to saline injection. Joint immobilization resulted in equal myogenic ROM restriction in both groups. Arthrogenic ROM restriction was greater with ribose injection in the immobilized joints (P < 0.05), but was not affected in nonimmobilized joints. Type-I (COL1A1) and type-III (COL3A1) collagen gene expression increased significantly in immobilized joints relative to nonimmobilized joints in the ribose group, but was not affected in the saline group. Ribose injection increased COL1A1 expression slightly and COL3A1 expression significantly in immobilized joints. Histologically, inflammatory changes appeared at day 3 of immobilization and peaked at day 7. These responses trended to be more severe and prolonged in the ribose group than in the saline group. Our data provide evidence for a causal relationship between AGEs and joint contracture formation following immobilization. This article is protected by copyright. All rights reserved

High early post-operative complication rate after elective aseptic orthopedic implant removal of upper and lower limb


The necessity of orthopedic implant removal is under intense discussion and even if it is performed as an elective procedure, the risk of complications is present. Aim of the study was to identify parameters responsible for an increased risk of early post-operative complications after elective aseptic orthopedic implant removal. We reviewed 1545 cases of aseptic and elective orthopedic implant removal between 2009 and 2011. The patient's demographic data, time and duration of operation, patient's comorbidities and presence of complications in the first four weeks after implant removal were evaluated. Patients with signs of infection at the time of the surgical procedure were excluded from this study. 579 women and 966 men who underwent elective aseptic orthopedic implant removal were identified. Mean age at implant removal was 42 years and mean duration of the surgical procedure was 37 minutes. In this cohort, 70 patients (4.5%) underwent elective aseptic implant removal after 6pm. 52 patients (3.37%) operated on during daytime suffered from complications postoperatively and 5 patients (0.3%) who were operated on during the night experienced complications. The parameters age, sex, BMI and surgeon showed no statistically significant differences for the risk of postoperative complications. Patients′ comorbidities such as diabetes seem to have influence but were not statistically significant either. Patients with revision surgery since their first operation, nocturnal surgery and longer duration of the procedure showed a statistically significant higher risk for complications, especially in the lower leg. This article is protected by copyright. All rights reserved

Hyperosmolarity Induces Notochordal Cell Differentiation with Aquaporin3 Upregulation and Reduced N-cadherin Expression


The nucleus pulposus (NP) of intervertebral discs (IVD) undergoes dramatic changes with aging including loss of its gelatinous structure and large, vacuolated notochordal cells (NCs) in favor of a matrix-rich structure populated by small NP cells (sNPCs). NP maturation also involves a loading-pattern shift from pressurization to matrix deformations, and these events are thought to predispose to degeneration. Little is known of the triggering events and cellular alterations involved with NP maturation, which remains a fundamental open spinal mechanobiology question. A mouse IVD organ culture model was used to test the hypotheses that hyperosmotic overloading will induce NP maturation with transition of NCs to sNPCs while also increasing matrix accumulation and altering osmoregulatory and mechanotransductive proteins. Results indicated that static hyperosmolarity, as might occur during growth, caused maturation of NCs to sNPCs and involved a cellular differentiation process since known NC markers (cytokeratin-8, -19 and sonic hedgehog) persisted without increased cell apoptosis. Osmosensitive channels Aquaporin 3 (Aqp3) and transient receptor potential vanilloid-4 (TRPV4) expression were both modified with altered osmolarity, but increased Aqp3 with hyperosmolarity was associated with NC to sNPC differentiation. NC to sNPC differentiation was accompanied by a shift in cellular mechanotransduction proteins with decreased N-cadherin adhesions and increased Connexin 43 connexons. We conclude that hyperosmotic overloading can promote NC differentiation into sNPCs. This study identified osmolarity as a triggering mechanism for notochordal cell differentiation with associated shifts in osmoregulatory and mechanotransductive proteins that are likely to play important roles in intervertebral disc aging. This article is protected by copyright. All rights reserved

Dynamic imaging demonstrates that pulsed electromagnetic fields (PEMF) suppress IL-6 transcription in bovine nucleus pulposus cells


Inflammatory cytokines play a dominant role in the pathogenesis of disc degeneration. Pulsed electromagnetic fields (PEMF) are noninvasive biophysical stimulus that has been used extensively in the orthopaedic field for many years. However, the specific cellular responses and mechanisms involved are still unclear. The objective of this study was to assess the time-dependent PEMF effects on pro-inflammatory factor IL-6 expression in disc nucleus pulposus cells using a novel green fluorescence protein (GFP) reporter system. An MS2-tagged GFP reporter system driven by IL-6 promoter was constructed to visualize PEMF treatment effect on IL-6 transcription in single living cells. IL-6-MS2 reporter-labeled cells were treated with IL-1α to mimic the in situ inflammatory environment of degenerative disc while simultaneously exposed to PEMF continuously for 4 hours. Time-lapse imaging was recorded using a confocal microscope to track dynamic IL-6 transcription activity that was demonstrated by GFP. Finally, real time RT-PCR was performed to confirm the imaging data. Live cell imaging demonstrated that pro-inflammatory factor IL-1α significantly promoted IL-6 transcription over time as compared with DMEM basal medium condition. Imaging and PCR data demonstrated that the inductive effect of IL-1α on IL-6 expression could be significantly inhibited by PEMF treatment in a time-dependent manner (early as 2 hours of stimulus initiation). Our data suggest that PEMF may have a role in the clinical management of patients with chronic low back pain. Furthermore, this study shows that the MS2-tagged GFP reporter system is a useful tool for visualizing the dynamic events of mechanobiology in musculoskeletal research. This article is protected by copyright. All rights reserved

Relationship of cytokine levels and clinical effect on platelet-rich plasma-treated lateral epicondylitis


Lateral epicondylitis (LE) is difficult to manage and can result in significant patient morbidity. Currently, the clinical use of platelet-rich plasma (PRP) for painful tendons has received attention, but its efficacy remains controversial. This study aimed to investigate the clinical effects of PRP and its biological components. 156 patients with LE were randomly divided into group 1, treated with a single injection of 2-mL autologous PRP, and group 2, treated with a control received only physical therapy without injection. Both groups used a tennis elbow strap and performed stretching and strengthening exercises during 24 weeks' follow-up. Pain and functional improvements were assessed using the visual analog scale (VAS), Modified Mayo Clinic Performance Index for the elbow, and magnetic resonance imaging (MRI). White blood cell count, platelet count, and levels of platelet-derived growth factor-AB (PDGF-AB), PDGF-BB, transforming growth factor-β (TGF-β), vascular endothelial growth factor, epithelial growth factor, and interleukin-1 β in PRP were measured and investigated for statistical correlation with the clinical score. At 24 weeks, all pain and functional variables, including VAS score, Mayo Clinic performance scores, and MRI grade, improved significantly in group 1 (P < 0.05). PDGF-AB, PDGF-BB, and TGF-β levels were more significantly increased in PRP than in whole blood. TGF-β level significantly correlated with Mayo Clinic performance score and MRI grade improvement. Thus, TGF-β level in PRP is considered to play a pivotal role in tendon healing. These results may contribute to identifying the best protocol for PRP application in tendinopathies. This article is protected by copyright. All rights reserved

Optimizing a micro-computed tomography-based surrogate measurement of bone-implant contact


Histology and backscatter scanning electron microscopy (bSEM) are the current gold standard methods for quantifying bone-implant contact (BIC), but are inherently destructive. Microcomputed tomography (µCT) is a non-destructive alternative, but attempts to validate µCT-based assessment of BIC in animal models have produced conflicting results. We previously showed in a rat model using a 1.5 mm diameter titanium implant that the extent of the metal-induced artefact precluded accurate measurement of bone sufficiently close to the interface to assess BIC. Recently introduced commercial laboratory µCT scanners have smaller voxels and improved imaging capabilities, possibly overcoming this limitation. The goals of the present study were to establish an approach for optimizing µCT imaging parameters and to validate µCT-based assessment of BIC. In an empirical parametric study using a 1.5 mm diameter titanium implant, we determined 90kVp, 88µA, 1.5µm isotropic voxel size, 1600 projections/180°, and 750 msec integration time to be optimal. Using specimens from an in vivo rat experiment, we found significant correlations between bSEM and µCT for BIC with the manufacturer's automated analysis routine (r = 0.716, p = 0.003) or a line-intercept method (r = 0.797, p = 0.010). Thus, this newer generation scanner's improved imaging capability reduced the extent of the metal-induced artefact zone enough to permit assessment of BIC. This article is protected by copyright. All rights reserved

Trends in hip replacements between 1999 and 2012 in Sweden


National Registers document changes in the circumstance, practice and outcome of surgery with the passage of time. In the context of total hip replacement (THR), registers can help elucidate the relevant factors that affect the clinical outcome. We evaluated the evolution of factors related to patient, surgical procedure, socio-economy and various outcome parameters after merging databases of the Swedish Hip Arthroplasty Register, Statistics Sweden and the National Board of Health and Welfare. Data on 193,253 THRs (164,113 patients) operated between 1999 and 2012 were merged. We studied the evolution of surgical volume, patient demographics, socio-economic factors, surgical factors, length-of-stay, mortality rate, adverse events, re-operation and revision rates and Patient Reported Outcome Measures (PROMs). Throughout this time period the majority of patients were operated on with a diagnosis of primary osteoarthritis. Comorbidity indices increased each year observed. The share of all-cemented implants has dropped from 92% to 68%. More than 88% of the bearings were metal-on-polyethylene. Length-of-stay decreased by 50%. There was a reduction in 30- and 90-day mortality. Re-operation and revision rates at 2 years are decreasing. The postoperative PROMs improved despite the observation of worse preoperative pain scores getting over time. The demographics of patients receiving a THR, their comorbidities and their primary diagnosis are changing. Notwithstanding these changes, outcomes like mortality, re-operations, revisions and PROMs have improved. The practice of hip arthroplasty has evolved, even in a country such as Sweden that is considered to be conservative with regard taking on new surgical practices. This article is protected by copyright. All rights reserved

Metabolic dysregulation accelerates injury-induced joint degeneration, driven by local inflammation; an in vivo rat study


Evidence is growing for the existence of an obesity-related phenotype of osteoarthritis in which low-grade inflammation and a disturbed metabolic profile play a role. The contribution of an obesity induced metabolic dysbalance to the progression of the features of osteoarthritis upon mechanically induced cartilage damage was studied in a rat in vivo model. Forty Wistar rats were randomly allocated 1:1 to a standard diet or a high-fat diet. After 12 weeks, in 14 out of 20 rats in each group, cartilage was mechanically damaged in the right knee joint. The remaining 6 animals in each group served as controls. After a subsequent 12 weeks, serum was collected for metabolic state, subchondral bone changes assessed by µCT imaging, osteoarthritis severity determined by histology, and macrophage presence assessed by CD68 staining. The high-fat diet increased statistically all relevant metabolic parameters, resulting in a dysmetabolic state and subsequent synovial inflammation, whereas cartilage degeneration was hardly influenced. The high-fat condition in combination with mechanical cartilage damage resulted in a clear statistically significant progression of the osteoarthritic features, with increased synovitis and multiple large osteophytes. Both the synovium and osteophytes contained numerous CD68 positive cells. It is concluded that a metabolic dysbalance due to a high-fat diet increases joint inflammation without cartilage degeneration. The dysmetabolic state clearly accelerates progression of osteoarthritis upon surgically induced cartilage damage supported by inflammatory responses as demonstrated by histology and increased CD68 expressing cells localized on the synovial membrane and osteophytes. This article is protected by copyright. All rights reserved

Correlation between RUST Assessments of Fracture Healing to Structural and Biomechanical Properties


Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: a control and a phosphate restricted diet group. Micro-computed tomography (μCT) and torsion testing were carried out at post-operative days (POD) 14, 21, 35, and 42 (n=10-16) per group time-point. Anteroposterior and lateral radiographic views were constructed from the μCT scans and scored by five raters. The raters also indicated if the fracture were healed. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density (BMD) (r = 0.85 and 0.80, p<0.001) and bone volume fraction (BV/TV) (r = 0.86 and 0.80, p<0.001). Both RUST scores positively correlated with callus strength (r = 0.35 and 0.26, p<0.012) and rigidity (r = 0.50 and 0.39, p<0.001). Radiographically healed calluses had a mRUST ≥13 and a RUST ≥ 10 and had excellent relationship to structural and biomechanical metrics. Effect of delayed healing due to phosphate dietary restrictions was found at later time points with all mechanical properties (p<0.011), however no differences found in the RUST scores (p>0.318). Clinical relevance of this study is both RUST scores showed high correlation to physical properties of healing and generally distinguished healed vs. non-healed fractures. This article is protected by copyright. All rights reserved.

Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia


There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two-month-old female Sprague-Dawley rats were ovariectomized and underwent bilateral L4-5 posterolateral intertransverse fusion after ten months. The OVX rats received vehicle (control) treatment, or ZA (100µg/kg, once), or TPTD (60µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at six weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual-energy X-ray absorptiometry (DXA), radiography, micro-computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS) and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. This article is protected by copyright. All rights reserved

Letter to the Editor RE: R.K.Whittaker et al., The variation in taper surface roughness for a single design effects the wear rate in total hip arthroplasty


I read this article with great interest given the subject material and the fact that is supported the interesting finding from David Langton's (1) work. However, I am very concerned about the accuracy of the measurements presented. The study uses roughness measurements to characterise the taper surfaces and cites the appropriate standards for the measurement, but the authors have failed to adhere to the standards and as such the values presented as R values may be subject to measurement errors rendering them inaccurate, which could be affecting the study's findings.This article is protected by copyright. All rights reserved

Muscle Stem Cell Activation in a Mouse Model of Rotator Cuff Injury


Rotator cuff (RC) tears are frequently complicated by muscle atrophy. Muscle stem cells (MuSCs) repair damaged myofibers following injury, but their role in the prevention or pathogenesis of atrophy following RC tears remains undefined. We hypothesized that the RC MuSC population would be affected by supraspinatus (SS) and infraspinatus (IS) tendon transection (TT) compared to uninjured muscle in a mouse model of RC tear. C57BL6/J mice underwent unilateral SS and IS TT and contralateral sham surgery. At 3, 8, or 14 weeks after injury, mice were euthanized and SS and IS were harvested for FACS sorting of CD31-/CD45-/Sca1-/ITGa7 + /VCAM+ MuSCs or histological analysis. Ki-67+ MuSCs from injured muscle increased 3.4 fold at 3 weeks (p = 0.03) and 8.1 fold at 8 weeks (p = 0.04) following TT injury, but returned to baseline by 14 weeks (p = 0.91). Myod1 remained upregulated 3.3 fold at 3 weeks (p = 0.03) and 2.0 fold at 14 weeks (p = 0.0003), respectively. Myofiber cross-sectional area was decreased at both 3 and 14 weeks after injury, but the number of MuSCs per fiber remained relatively constant at 3 (p = 0.3) and 14 (p = 0.6) weeks after TT. In this study, we characterized the longitudinal effect of RC tendon injury on the MuSC population in supraspinatus and infraspinatus muscles. MuSCs are transiently activated, and are not depleted, in spite of persistent muscle atrophy. This article is protected by copyright. All rights reserved

Vein Wrapping Facilitates Basic Fibroblast Growth Factor-induced Heme Oxygenase-1 Expression following Chronic Nerve Constriction Injury


The clinical efficacy of autologous vein wrapping for recurrent compressive neuropathy has been demonstrated; however, the underlying mechanisms of this technique remain unclear. Rats were divided into chronic constriction injury (CCI) and CCI + vein wrapping (CCI + VW) groups. Mechanical allodynia was evaluated using von Frey filaments. To identify the neuroprotective factors released from veins, basic fibroblast growth factor (bFGF) mRNA expression in veins was compared to that in the sciatic nerve. The response of heme oxygenase-1 (HO-1) expression to vein wrapping was evaluated by RT-PCR and enzyme-linked immunosorbent assays. The effects of exogenous bFGF on HO-1 expression were evaluated using a sciatic nerve cell culture. Vein wrapping significantly increased the withdraw threshold levels compared to the untreated CCI group. bFGF mRNA expression in veins was higher than that in untreated sciatic nerves. HO-1 mRNA expression was induced at higher levels in sciatic nerve cells in the presence of exogenous bFGF compared to untreated control cells. HO-1 mRNA and protein expression in the sciatic nerve were also higher in the CCI + VW group compared with the CCI group. Our results suggest that vein-derived bFGF contributes to the therapeutic benefit of vein wrapping through the induction of HO-1 in the sciatic nerve. Vein wrapping is a useful technique for reducing neuropathic pain. Further understanding of the neurotrophic factors released from veins may help to optimize current procedures for treating recurrent compressive neuropathy and traumatic peripheral nerve injury, and lead to the development of new therapeutic methods using recombinant neurotrophic factors. This article is protected by copyright. All rights reserved

Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein-2 and zoledronic acid


Tibial pseudarthrosis associated with Neurofibromatosis type 1 (NF1) is an orthopedic condition with consistently poor clinical outcomes. Using a murine model that features localized double inactivation of the Nf1 gene in an experimental tibial fracture, we tested the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and/or the bisphosphonate zoledronic acid (ZA). Tibiae were harvested at 3 weeks for analysis, at which time there was negligible healing in un-treated control fractures (7% union). In contrast, rhBMP-2 and rhBMP-2/ZA groups showed significantly greater union (87% and 93%, p < 0.01 for both). Treatment with rhBMP-2 led to a 12-fold increase in callus bone volume and this was further increased in the rhBMP-2/ZA group. Mechanical testing of the healed rhBMP-2 and rhBMP-2/ZA fractures showed that the latter group had significantly higher mechanical strength and was restored to that of the un-fractured contralateral leg. Co-treatment with rhBMP-2/ZA also reduced fibrous tissue infiltration at the fracture site compared to rhBMP alone (P = 0.068). These data support the future clinical investigation of this combination of anabolic and anti-resorptive agents for the treatment of NF1 pseudarthrosis. This article is protected by copyright. All rights reserved

Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation


Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5 month-old (young adult) and 25 month-old (geriatric) mice healing utilizing high-throughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days post fracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and cross-sectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both un-fractured and 20 DPF aged mice showed increased expression of immune associated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrix-associated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time post-fracture first and age second. Clinical Significance: Greater understanding of age-dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. This article is protected by copyright. All rights reserved

Primary stability of a cementless acetabular cup in a cohort of patient-specific finite element models


The primary stability achieved during total hip arthroplasty determines the long-term success of cementless acetabular cups. Pre-clinical finite element testing of cups typically use a model of a single patient and assume the results can be extrapolated to the general population. This study explored the variability in predicted primary stability of a Pinnacle® cementless acetabular cup in 103 patient-specific finite element models of the hemipelvis and examined the association between patient-related factors and the observed variability. Cups were inserted by displacement-control into the FE models and then a loading configuration simulating a complete level gait cycle was applied. The cohort showed a range of polar gap of 284–1112 μm and 95th percentile composite peak micromotion (CPM) of 18–624 μm. Regression analysis was not conclusive on the relationship between patient-related factors and primary stability. No relationship was found between polar gap and micromotion. However, when the patient-related factors were categorised into quartile groups, trends suggested higher polar gaps occurred in subjects with small and shallow acetabular geometries and cup motion during gait was affected most by low elastic modulus and high bodyweight. The variation in primary stability in the cohort for an acetabular cup with a proven clinical track record may provide benchmark data when evaluating new cup designs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Key developments that impacted the field of mechanobiology and mechanotransduction


Advances in mechanobiology have evolved through insights from multiple disciplines including structural engineering, biomechanics, vascular biology, and orthopaedics. In this paper, we reviewed the impact of key reports related to the study of applied loads on tissues and cells and the resulting signal transduction pathways. We addressed how technology has helped advance the burgeoning field of mechanobiology (over 33,600 publications from 1970 to 2016). We analyzed the impact of critical ideas and then determined how these concepts influenced the mechanobiology field by looking at the citation frequency of these reports as well as tracking how the overall number of citations within the field changed over time. These data allowed us to understand how a key publication, idea, or technology guided or enabled the field. Initial observations of how forces acted on bone and soft tissues stimulated the development of computational solutions defining how forces affect tissue modeling and remodeling. Enabling technologies, such as cell and tissue stretching, compression, and shear stress devices, allowed more researchers to explore how deformation and fluid flow affect cells. Observation of the cell as a tensegrity structure and advanced methods to study genetic regulation in cells further advanced knowledge of specific mechanisms of mechanotransduction. The future of the field will involve developing gene and drug therapies to simulate or augment beneficial load regimens in patients and in mechanically conditioning organs for implantation. Here, we addressed a history of the field, but we limited our discussions to advances in musculoskeletal mechanobiology, primarily in bone, tendon, and ligament tissues. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Impact insertion of osteochondral grafts: Interference fit and central graft reduction affect biomechanics and cartilage damage


An osteochondral graft (OCG) is an effective treatment for articular cartilage and osteochondral defects. Impact of an OCG during insertion into the osteochondral recipient site (OCR) can cause chondrocyte death and matrix damage. The aim of the present study was to analyze the effects of graft-host interference fit and a modified OCG geometry on OCG insertion biomechanics and cartilage damage. The effects of interference fit (radius of OCG - radius of OCR), loose (0.00 mm), moderate (0.05 mm), tight (0.10 mm), and of a tight fit with OCG geometry modification (central region of decreased radius), were analyzed for OCG cylinders and OCR blocks from adult bovine knee joints with an instrumented drop tower apparatus. An increasingly tight (OCG - OCR) interference fit led to increased taps for insertion, peak axial force, graft cartilage axial compression, cumulative and total energy delivery to cartilage, lower time of peak axial force, lesser graft advancement during each tap, higher total crack length in the cartilage surface, and lower chondrocyte viability. The modified OCG, with reduction of diameter in the central area, altered the biomechanical insertion variables and biological consequences to be similar to those of the moderate interference fit scenario. Micro-computed tomography confirmed structural interference between the OCR bone and both the proximal and distal bone segments of the OCGs, with the central regions being slightly separated for the modified OCGs. These results clarify OCG insertion biomechanics and mechanobiology, and introduce a simple modification of OCGs that facilitates insertion with reduced energy while maintaining a structural interference fit. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Varus knee osteoarthritis: Elevated synovial CD15 counts correlate with inferior biomechanical properties of lateral-compartment cartilage


The study analyzed the influence of synovitis on the histological and biomechanical properties of lateral-compartment cartilage. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included. Osteochondral samples from the distal lateral femur underwent biomechanical and histologic analysis. Synovial tissue was sampled for histological (chronic synovitis score) and immunohistochemical evaluation of the degree of synovitis. CD15 (neutrophils), Ki-67 (dividing cells), and CD68 (macrophages) were tested in all synovial samples. While the histological synovitis score did not correlate with the degree of cartilage degeneration (histological OARSI grades), both CD15 (rs = 0.297, p = 0.006) and Ki-67 (rs = 0.249, p = 0.023) correlated with histological OARSI grades. There was a weak negative correlation of CD15 with biomechanical properties of cartilage of the distal lateral femur (aggregate modulus (Ha): rs = −0.125; p = 0.257; dynamic modulus (DM): rs = −0.216; p = 0.048). No correlations were observed for Ki-67 and CD68. In addition, biomechanical properties were inferior in knees with a CD15 of >8/high power field compared to knees with a CD15 of ≤8/high power field (Ha: p = 0.031, d = 0.46; DM: p = 0.005, d = 0.68). The study demonstrates an association of increased inflammatory activity with advanced cartilage degeneration. Lateral-compartment cartilage in knees with elevated synovial CD15 counts has a reduced ability to withstand compressive loads. CD15 might serve as an indicator for inferior biomechanical cartilage properties. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Rotator cuff healing using demineralized cancellous bone matrix sponge interposition compared to standard repair in a preclinical canine model


This Level II study assessed clinically relevant outcomes for repair of large, retracted infraspinatus tendons (ISTs) using a demineralized bone matrix (DBM) sponge (FlexiGraft) hydrated in platelet-rich plasma (PRP) versus direct repair in a validated canine model. Adult research dogs (n = 10) were used. The IST was transected in each shoulder (n = 20) and randomized to direct repair or repair with DBM-PRP interposition at 4 weeks posttransection. At 12 weeks postrepair, dogs were sacrificed, and the repair evaluated by magnetic resonance imaging (MRI), histology, and biomechanical testing. MRI and histology scores were significantly (p < 0.05) better in the DBM-PRP shoulders. Biomechanical testing revealed significantly improved strength of the DBM-PRP repairs at 5 and 10 mm of displacement, as well as for ultimate failure load. In this canine model of retracted IST repair, DBM-PRP sponge hydrated in PRP was considered safe and effective. In addition, use of DBM-PRP was associated with improved MRI and histologic appearance, and improved strength compared to direct repair. Clinical significance: Based on reported failure rates for repair of large, retracted rotator cuff tears, improving tendon-to-bone healing is critical. Use of DBM combined with PRP shows potential for addressing this critical clinical need. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res In this canine model of retracted infraspinatus tendons repair, demineralized bone matrix sponge hydrated in platelet-rich plasma (DBM-PRP) was considered safe and effective. In addition, use of DBM-PRP was associated with improved MRI and histologic appearance, and improved strength compared to direct repair. Based on reported failure rates for repair of large, retracted rotator cuff tears, improving tendon-to-bone healing is critical. Use of DBM combined with PRP shows potential for addressing this critical clinical need.

Increased vascularization promotes functional recovery in the transected spinal cord rats by implanted vascular endothelial growth factor-targeting collagen scaffold


Spinal cord injury (SCI) is global health concern. The effective strategies for SCI are relevant to the improvement on nerve regeneration microenvironment. Vascular endothelial growth factor (VEGF) is an important cytokine for inducing angiogenesis and accelerating nerve system function recovery from injury. We proposed that VEGF could improve nerve regeneration in SCI. However, an uncontrolled delivery system target to injury site not only decreases the therapeutic efficacy but also increases the risk of tumor information. We implanted collagen scaffold (CS) targeted with a constructed protein, collagen-binding VEGF (CBD-VEGF), to bridge transected spine cord gap in a rat transected SCI model. Functional and histological examinations were conducted to assess the repair capacity of the delivery system CS/CBD-VEGF. The results indicated that the implantation of CS/CBD-VEGF into the model rats improved the survival rate and exerted beneficial effect on functional recovery. The controlled intervention improved the microenvironment, guided axon growth, and promoted neovascularization at the injury site. Therefore, the delivery system with stable binding of VEGF potentially provides a better therapeutic option for SCI. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res We implanted collagen scaffold (CS) targeted with a constructed protein, collagen-binding VEGF (CBD-VEGF), to bridge transected spine cord gap in a rat transected SCI model. The implantation of CS/CBD-VEGF into the model rats exerted beneficial effect on functional recovery. The controlled intervention improved the microenvironment, guided axon growth, and promoted neovascularization at the injury site. Therefore, the delivery system with stable binding of VEGF potentially provides a better therapeutic option for SCI.

In situ force in the anterior cruciate ligament, the lateral collateral ligament, and the anterolateral capsule complex during a simulated pivot shift test


The role of the anterolateral capsule complex in knee rotatory stability remains controversial. Therefore, the objective of this study was to determine the in situ forces in the anterior cruciate ligament (ACL), the anterolateral capsule, the lateral collateral ligament (LCL), and the forces transmitted between each region of the anterolateral capsule in response to a simulated pivot shift test. A robotic testing system applied a simulated pivot shift test continuously from full extension to 90° of flexion to intact cadaveric knees (n = 7). To determine the magnitude of the in situ forces, kinematics of the intact knee were replayed in position control mode after the following procedures were performed: (i) ACL transection; (ii) capsule separation; (iii) anterolateral capsule transection; and (iii) LCL transection. A repeated measures ANOVA was performed to compare in situ forces between each knee state (*p < 0.05). The in situ force in the ACL was significantly greater than the forces transmitted between each region of the anterolateral capsule at 5° and 15° of flexion but significantly lower at 60°, 75°, and 90° of flexion. This study demonstrated that the ACL is the primary rotatory stabilizer at low flexion angles during a simulated pivot shift test in the intact knee, but the anterolateral capsule plays an important secondary role at flexion angles greater than 60°. Furthermore, the contribution of the “anterolateral ligament” to rotatory knee stability in this study was negligible during a simulated pivot shift test. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Chemokine receptor-7 (CCR7) deficiency leads to delayed development of joint damage and functional deficits in a murine model of osteoarthritis


Elevated chemokine receptor Ccr7 is observed in knee osteoarthritis (OA) and associated with severity of symptoms. In this study, we confirmed that CCR7 protein expression is elevated in synovial tissue from OA patients by immunohistochemical staining. We then investigated whether Ccr7 deficiency impacted structural and functional joint degeneration utilizing a murine model of OA. OA-like disease was induced in male C57BL/6 and Ccr7-deficient (Ccr7−/−) mice by destabilization of the medial meniscus (DMM). Functional deficits were measured by computer integrated monitoring of spontaneous activity every 4 weeks after DMM surgery up 16 weeks. Joint degeneration was evaluated at 6 and 19 weeks post-surgery by histopathology, and subchondral bone changes analyzed by microCT. Results showed reduction in locomotor activities in DMM-operated C57BL/6 mice by 8 weeks, while activity decreases in Ccr7−/− mice were delayed until 16 weeks. Histopathologic evaluation showed minimal protection from early cartilage degeneration (p = 0.06) and osteophytosis (p = 0.04) in Ccr7−/− mice 6 weeks post-DMM compared to C57BL/6 controls, but not at 19 weeks. However, subchondral bone mineral density (p = 0.03) and histologic sclerosis (p = 0.02) increased in response to surgery in C57BL/6 mice at 6 weeks, while Ccr7−/− mice were protected from these changes. Our results are the first to demonstrate a role for Ccr7 in early development of functional deficits and subchondral bone changes in the DMM model. Understanding the mechanism of Ccr7 receptor signaling in the initiation of joint pathology and disability will inform the development of innovative therapies to slow symptomatic OA development after injury. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Advantages of RNA-seq compared to RNA microarrays for transcriptome profiling of anterior cruciate ligament tears


Microarrays and RNA-seq are at the forefront of high throughput transcriptome analyses. Since these methodologies are based on different principles, there are concerns about the concordance of data between the two techniques. The concordance of RNA-seq and microarrays for genome-wide analysis of differential gene expression has not been rigorously assessed in clinically derived ligament tissues. To demonstrate the concordance between RNA-seq and microarrays and to assess potential benefits of RNA-seq over microarrays, we assessed differences in transcript expression in anterior cruciate ligament (ACL) tissues based on time-from-injury. ACL remnants were collected from patients with an ACL tear at the time of ACL reconstruction. RNA prepared from torn ACL remnants was subjected to Agilent microarrays (N = 24) and RNA-seq (N = 8). The correlation of biological replicates in RNA-seq and microarrays data was similar (0.98 vs. 0.97), demonstrating that each platform has high internal reproducibility. Correlations between the RNA-seq data and the individual microarrays were low, but correlations between the RNA-seq values and the geometric mean of the microarrays values were moderate. The cross-platform concordance for differentially expressed transcripts or enriched pathways was linearly correlated (r = 0.64). RNA-Seq was superior in detecting low abundance transcripts and differentiating biologically critical isoforms. Additional independent validation of transcript expression was undertaken using microfluidic PCR for selected genes. PCR data showed 100% concordance (in expression pattern) with RNA-seq and microarrays data. These findings demonstrate that RNA-seq has advantages over microarrays for transcriptome profiling of ligament tissues when available and affordable. Furthermore, these findings are likely transferable to other musculoskeletal tissues where tissue collection is challenging and cells are in low abundance. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Transcriptome profiling of anterior cruciate ligament tears as a function of time-from-injury comparing microarrays to RNA-seq showed that the cross-platform concordance for differentially expressed transcripts or enriched pathways was linearly correlated (r = 0.64). RNA-seq was superior in detecting low abundance transcripts and differentiating biologically critical isoforms. Thus, RNA-seq is an extremely promising tool for the assessment of mRNA expression and identification of differentially expressed transcripts, comparable, and to some extent superior, to existing microarrays platforms in the analysis of ligamentous tissues.

Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep


Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found the activity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained unchanged. At 2 weeks after tendon release, muscle volume decreased by 17 cm from an initial 185 cm3, the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm3, contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decrease of muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clinically, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. © 2017 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res

Risk factors can classify individuals who develop accelerated knee osteoarthritis: Data from the osteoarthritis initiative


We assessed which combinations of risk factors can classify adults who develop accelerated knee osteoarthritis (KOA) or not and which factors are most important. We conducted a case-control study using data from baseline and the first four annual visits of the Osteoarthritis Initiative. Participants had no radiographic KOA at baseline (Kellgren-Lawrence [KL]<2). We classified three groups (matched on sex): (i) accelerated KOA: >1 knee developed advance-stage KOA (KL = 3 or 4) within 48 months; (ii) typical KOA: >1 knee increased in radiographic scoring (excluding those with accelerated KOA); and (iii) No KOA: no change in KL grade by 48 months. We selected eight predictors: Serum concentrations for C-reactive protein, glycated serum protein (GSP), and glucose; age; sex; body mass index; coronal tibial slope, and femorotibial alignment. We performed a classification and regression tree (CART) analysis to determine rules for classifying individuals as accelerated KOA or not (no KOA and typical KOA). The most important baseline variables for classifying individuals with incident accelerated KOA (in order of importance) were age, glucose concentrations, BMI, and static alignment. Individuals <63.5 years were likely not to develop accelerated KOA, except when overweight. Individuals >63.5 years were more likely to develop accelerated KOA except when their glucose levels were >81.98 mg/dl and they did not have varus malalignment. The unexplained variance of the CART = 69%. These analyses highlight the complex interactions among four risk factors that may classify individuals who will develop accelerated KOA but more research is needed to uncover novel risk factors. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Customized, degradable, functionally graded scaffold for potential treatment of early stage osteonecrosis of the femoral head


Osteonecrosis of the femoral head (ONFH) is a debilitating disease that results in progressive collapse of the femoral head and subsequent degenerative arthritis. Few treatments provide both sufficient mechanical support and biological cues for regeneration of bone and vascularity when the femoral head is still round and therefore salvageable. We designed and 3D printed a functionally graded scaffold (FGS) made of polycaprolactone (PCL) and β-tricalcium phosphate (β-TCP) with spatially controlled porosity, degradation, and mechanical strength properties to reconstruct necrotic bone tissue in the femoral head. The FGS was designed to have low porosity segments (15% in proximal and distal segments) and a high porosity segment (60% in middle segment) according to the desired mechanical and osteoconductive properties at each specific site after implantation into the femoral head. The FGS was inserted into a bone tunnel drilled in rabbit femoral neck and head, and at 8 weeks after implantation, the tissue formation as well as scaffold degradation was analyzed. Micro-CT analysis demonstrated that the FGS-filled group had a significantly higher bone ingrowth ratio compared to the empty-tunnel group, and the difference was higher at the distal low porosity segments. The in vivo degradation rate of the scaffold was higher in the proximal and distal segments than in the middle segment. Histological analysis of both non-decalcified and calcified samples clearly indicated new bone ingrowth and bone marrow-containing bone formation across the FGS. A 3D printed PCL-β-TCP FGS appears to be a promising customized resorbable load-bearing implant for treatment of early stage ONFH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Rotator cuff repair with a novel mesh suture: An ex vivo assessment of mechanical properties


Surgical repair is a common treatment for rotator cuff tear; however, the retear rate is high. A high degree of suture repair strength is important to ensure rotator cuff integrity for healing. The purpose of this study was to compare the mechanical performance of rotator cuffs repaired with a mesh suture versus traditional polydioxanone suture II and FiberWire sutures in a canine in vitro model. Seventy-two canine shoulders were harvested. An infraspinatus tendon tear was created in each shoulder. Two suture techniques—simple interrupted sutures and two-row suture bridge—were used to reconnect the infraspinatus tendon to the greater tuberosity, using three different suture types: Mesh suture, polydioxanone suture II, or FiberWire. Shoulders were loaded to failure under displacement control at a rate of 20 mm/min. Failure load was compared between suture types and techniques. Ultimate failure load was significantly higher in the specimens repaired with mesh suture than with polydioxanone suture II or FiberWire, regardless of suture technique. There was no significant difference in stiffness among the six groups, with the exception that FiberWire repairs were stiffer than polydioxanone suture II repairs with the simple interrupted technique. All specimens failed by suture pull-out from the tendon. Based on our biomechanical findings, rotator cuff repair with the mesh suture might provide superior initial strength against failure compared with the traditional polydioxanone suture II or FiberWire sutures. Use of the mesh suture may provide increased initial fixation strength and decrease gap formation, which could result in improved healing and lower re-tear rates following rotator cuff repair. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Based on our biomechanical findings, rotator cuff repair with a novel mesh suture might provide superior initial strength against failure compared with the traditional polydioxanone suture II or FiberWire sutures. Use of the mesh suture may provide increased initial fixation strength and decrease gap formation, which could result in improved healing and lower re-tear rates following rotator cuff repair.

Femoral fracture type can be predicted from femoral structure: A finite element study validated by digital volume correlation experiments


Proximal femoral fractures can be categorized into two main types: Neck and intertrochanteric fractures accounting for 53% and 43% of all proximal femoral fractures, respectively. The possibility to predict the type of fracture a specific patient is predisposed to would allow drug and exercise therapies, hip protector design, and prophylactic surgery to be better targeted for this patient rendering fracture preventing strategies more effective. This study hypothesized that the type of fracture is closely related to the patient-specific femoral structure and predictable by finite element (FE) methods. Fourteen femora were DXA scanned, CT scanned, and mechanically tested to fracture. FE-predicted fracture patterns were compared to experimentally observed fracture patterns. Measurements of strain patterns to explain neck and intertrochanteric fracture patterns were performed using a digital volume correlation (DVC) technique and compared to FE-predicted strains and experimentally observed fracture patterns. Although loaded identically, the femora exhibited different fracture types (six neck and eight intertrochanteric fractures). CT-based FE models matched the experimental observations well (86%) demonstrating that the fracture type can be predicted. DVC-measured and FE-predicted strains showed obvious consistency. Neither DXA-based BMD nor any morphologic characteristics such as neck diameter, femoral neck length, or neck shaft angle were associated with fracture type. In conclusion, patient-specific femoral structure correlates with fracture type and FE analyses were able to predict these fracture types. Also, the demonstration of FE and DVC as metrics of the strains in bones may be of substantial clinical value, informing treatment strategies and device selection and design. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res To explain hip-fracture patterns, strains were measured on fourteen cadaveric femora using a digital volume correlation (DVC) technique and compared to strains predicted by computed tomography based finite element (FE-) models. Despite being loaded identically, the femora exhibited different fracture types (six neck and eight intertrochanteric fractures). FE results matched the experimental observations well (86%), compared to DXA-based BMD, and morphological characteristics, demonstrating that patient-specific femoral structure correlates with the fracture type and FE analyses could predict such fractures.

A novel mr-based method for detection of cartilage delamination in femoroacetabular impingement patients


In this study, quantitative magnetic resonance based measurements were used to evaluate T1ρ and T2 mapping and heterogeneity in femoroacetabular impingement (FAI) patients with acetabular cartilage delamination and to determine the ability of these quantitative MR-based measurements in detecting delamination. Unilateral hip joint MR-scans of 36 FAI patients with arthroscopically-confirmed acetabular cartilage delamination and 36 age, gender, and BMI matched controls were obtained. T1ρ and T2 mapping and heterogeneity of the hip joint articular cartilage were assessed in both groups using voxel-based relaxometry (VBR). Quantitative MR-based measurements were compared using statistical parametric mapping (SPM). Receiver operating characteristic (ROC) analysis was used to assess the ability of these quantitative measurements in detecting delamination by calculating the area under the curve (AUC). Pearson partial correlations (r) were used to assess for associations between T1ρ and T2 radial heterogeneity with the alpha angle in FAI patients. T1ρ and T2 global acetabular values were significantly higher in FAI patients with a focal increase within the posterior acetabular cartilage. FAI patients exhibited increased anterior superior acetabular T1ρ and T2 heterogeneity and both of these measures demonstrated a strong ability to detect acetabular cartilage delamination (T1ρ AUC: 0.96, p < 0.001; T2 AUC: 0.93, p < 0.001). FAI patients with a larger alpha angle exhibited increased anterior superior acetabular T1ρ (r = 0.48, p = 0.02) and T2 (r = 0.42, p = 0.03) heterogeneity. T1ρ and T2 heterogeneity within the anterior superior acetabular cartilage was shown to be a sensitive measure in detecting delamination and may prove beneficial to clinicians in determining optimal interventions for FAI patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Identification of good candidates for valgus bracing as a treatment for medial knee osteoarthritis


Valgus unloader braces are a conservative treatment option for medial compartment knee osteoarthritis that aim to unload the damaged medial compartment through application of an external abduction moment. Patient response to bracing is highly variable, however. While some experience improvements in pain, function, and joint loading, others receive little to no benefit. The objective of this work was to analyze clinical measures and biomechanical characteristics of unbraced walking to identify variables that are associated with the mechanical effectiveness of valgus unloader bracing. Seventeen patients with medial knee osteoarthritis walked overground with and without a valgus unloader brace. A musculoskeletal model was used to estimate the contact forces in the medial compartment of the tibiofemoral joint and brace effectiveness was defined as the decrease in peak medial contact force between unbraced and braced conditions. Stepwise linear regression was used to identify clinical and biomechanical measures that predicted brace effectiveness. The final regression model explained 77% of the variance in brace effectiveness using two variables. Bracing was more effective for those with greater peak external hip adduction moments and for those with higher Kellgren–Lawrence grades, indicating more severe radiographic osteoarthritis. The hip adduction moment was the best predictor of brace effectiveness and was well correlated with several other measures indicating that it may be functioning as a “biomarker” for good bracing candidates. Clinical Significance: The ability to predict good candidates for valgus bracing may improve issues of patient compliance and could enable the ability to train patients to respond better to bracing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Ultrasound elastography for carpal tunnel pressure measurement: A cadaveric validation study


Carpal tunnel pressure is a key factor in the etiology of carpal tunnel syndrome. Numerous approaches have been conducted to measure carpal tunnel pressure. However, most techniques are invasive and take time and effort. We have developed an innovative approach to noninvasively assess the tunnel pressure by using the ultrasound surface wave elastography (USWE) technique. In a previous study it was shown that the shear wave speed in a tendon increased linearly with increasing tunnel pressure enclosed the tendon in a simple tendon model. This study aimed to examine the relationship between the carpal tunnel pressure and the shear wave speeds inside and outside the carpal tunnel in a human cadaveric model. The result showed that the shear wave speed inside the carpal tunnel increased linearly with created carpal tunnel pressure, while the shear wave speed outside the carpal tunnel remained constant. These findings suggest that noninvasive measurement of carpal tunnel pressure is possible by measuring the shear wave speed in the tendon. After fully establishing this technology and being applicable in clinic, it would be useful in the diagnosis of carpal tunnel syndrome. For that reason, further validation with this technique in both healthy controls and patients with carpal tunnel syndrome is required. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res For the purpose of deducing the carpal tunnel pressure noninvasively, this study was conducted to evaluate the relationship between the carpal tunnel pressure and the shear wave speeds propagating the tendon inside and outside the carpal tunnel in a human cadaveric model by using the ultrasound surface wave elastography technique. The result showed that the shear wave speed inside the carpal tunnel increased linearly with created carpal tunnel pressure, while the shear wave speed outside the carpal tunnel remained constant.

Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation


The difference in the adult height of mammals, and hence in endochondral bone formation, is not yet fully understood and may serve to identify targets for bone and cartilage regeneration. In line with this hypothesis, the intra-species disparity between the adult height of Great Danes and Miniature Poodles was investigated at a transcriptional level. Microarray analysis of the growth plate of five Great Danes and five Miniature Poodles revealed 2,981 unique genes that were differentially expressed, including many genes with an unknown role in skeletal development. A signaling pathway impact analysis indicated activation of the cell cycle, extracellular matrix receptor interaction and the tight junction pathway, and inhibition of pathways associated with inflammation and the complement cascade. In additional validation steps, the gene expression profile of the separate growth plate zones for both dog breeds were determined. Given that the BMP signaling is known for its crucial role in skeletal development and fracture healing, and BMP-2 is used in orthopaedic and spine procedures for bone augmentation, further investigations concentrated on the BMP pathway.The canonical BMP-2 and BMP-6 signaling pathway was activated in the Great Danes compared to Miniature Poodles. In conclusion, investigating the differential expression of genes involved in endochondral bone formation in small and large breed dogs, could be a game changing strategy to provide new insights in growth plate development and identify new targets for bone and cartilage regeneration. © 2017 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res In Great Danes and Miniature Poodles, with distinct intra-species height differences, 2,981 genes were differentially expressed. Canonical BMP-2/-6 signaling, crucial in skeletal development and fracture healing, was activated in Great Danes versus Miniature Poodles. Furthermore, many genes were identified with an unknown role in skeletal development. Gene expression profiles involved in endochondral bone formation in small and large breed dogs can be a game changing strategy providing insight in growth plate development and new targets for bone and cartilage regeneration.

An investigation of shock wave therapy and low-intensity pulsed ultrasound on fracture healing under reduced loading conditions in an ovine model


The use of shock wave therapy (SWT) and low-intensity pulsed ultrasound (LIPUS) as countermeasures to the inhibited fracture healing experienced during mechanical unloading was investigated by administering treatment to the fracture sites of mature, female, Rambouillet Columbian ewes exposed to partial mechanical unloading or full gravitational loading. The amount of fracture healing experienced by the treatment groups was compared to controls in which identical surgical and testing protocols were administered except for SWT or LIPUS treatment. All groups were euthanized after a 28-day healing period. In vivo mechanical measurements demonstrated no significant alteration in fixation plate strains between treatments within either partial unloading group. Similarly, DXA BMD and 4-point bending stiffness were not significantly altered following either treatment. μCT analyses demonstrated lower callus bone volume for treated animals (SWT and LIPUS, p < 0.01) in the full gravity group but not between reduced loading groups. Callus osteoblast numbers as well as mineralized surface and bone formation rate were significantly elevated to the level of the full gravity groups in the reduced loading groups following both SWT and LIPUS. Although no increase in 4-week mechanical strength was observed, it is possible that an increase in the overall rate of fracture healing (i.e., callus strength) may be experienced at longer time points under partial loading conditions given the increase in osteoblast numbers and bone formation parameters following SWT and LIPUS. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Mechanical stimulation of mesenchymal stem cells: Implications for cartilage tissue engineering


Articular cartilage is a load-bearing tissue playing a crucial mechanical role in diarthrodial joints, facilitating joint articulation, and minimizing wear. The significance of biomechanical stimuli in the development of cartilage and maintenance of chondrocyte phenotype in adult tissues has been well documented. Furthermore, dysregulated loading is associated with cartilage pathology highlighting the importance of mechanical cues in cartilage homeostasis. The repair of damaged articular cartilage resulting from trauma or degenerative joint disease poses a major challenge due to a low intrinsic capacity of cartilage for self-renewal, attributable to its avascular nature. Bone marrow-derived mesenchymal stem cells (MSCs) are considered a promising cell type for cartilage replacement strategies due to their chondrogenic differentiation potential. Chondrogenesis of MSCs is influenced not only by biological factors but also by the environment itself, and various efforts to date have focused on harnessing biomechanics to enhance chondrogenic differentiation of MSCs. Furthermore, recapitulating mechanical cues associated with cartilage development and homeostasis in vivo, may facilitate the development of a cellular phenotype resembling native articular cartilage. The goal of this review is to summarize current literature examining the effect of mechanical cues on cartilage homeostasis, disease, and MSC chondrogenesis. The role of biological factors produced by MSCs in response to mechanical loading will also be examined. An in-depth understanding of the impact of mechanical stimulation on the chondrogenic differentiation of MSCs in terms of endogenous bioactive factor production and signaling pathways involved, may identify therapeutic targets and facilitate the development of more robust strategies for cartilage replacement using MSCs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Mechanical loading disrupts osteocyte plasma membranes which initiates mechanosensation events in bone


Osteocytes sense loading in bone, but their mechanosensation mechanisms remain poorly understood. Plasma membrane disruptions (PMD) develop with loading under physiological conditions in many cell types (e.g., myocytes, endothelial cells). These PMD foster molecular flux across cell membranes that promotes tissue adaptation, but this mechanosensation mechanism had not been explored in osteocytes. Our goal was to investigate whether PMD occur and initiate consequent mechanotransduction in osteocytes during physiological loading. We found that osteocytes experience PMD during in vitro (fluid flow) and in vivo (treadmill exercise) mechanical loading, in proportion to the level of stress experienced. In fluid flow studies, osteocyte PMD preferentially formed with rapid as compared to gradual application of loading. In treadmill studies, osteocyte PMD increased with loading in weight bearing locations (tibia), but this trend was not seen in non-weight bearing locations (skull). PMD initiated osteocyte mechanotransduction including calcium signaling and expression of c-fos, and repair rates of these PMD could be enhanced or inhibited pharmacologically to alter downstream mechanotransduction and osteocyte survival. PMD may represent a novel mechanosensation pathway in bone and a target for modifying skeletal adaptation signaling in osteocytes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Bilateral quadriceps and hamstrings muscle volume asymmetries in healthy individuals


Determining the magnitude of quadriceps and hamstring muscle volume asymmetries in healthy individuals is a critical first step toward interpreting asymmetries as compensatory or abnormal in pathological populations. The purpose of this study was to determine the magnitude of whole and individual muscle volume asymmetries, quantified as right–left volume differences, for the quadriceps and hamstring muscles in a young and healthy population. Twenty-one healthy individuals participated: Eleven females age = 22.6 ± 2.9 years and 10 males age = 23.2 ± 3.4 years. Whole muscle group and individual muscle volume asymmetries were quantified within the context of absolute measurement error using a 95% Limits of Agreement approach. Mean muscle asymmetries ranged from −3.0 to 6.0% for all individual and whole muscle groups. Whole muscle group 95% limits of agreements represented ±11.4% and ±8.8% volume asymmetries for the hamstrings and quadriceps, respectively. Individual muscle asymmetry 95% limits of agreements ranged from ∼ ± 11–13% for the vastii muscles while the biceps femoris short-head (±33.5%), long-head (±20.9%), and the rectus femoris (±21.4%) displayed the highest relative individual asymmetries. Individual muscle asymmetries exceeded absolute measurement error in 70% of all cases, with 26% of all cases exceeding 10% asymmetry. Although whole muscle group asymmetries appear to be near the 10% assumed clinical threshold of normality, the greater magnitude of individual muscle asymmetries highlights the subject- and muscle-specific variability in volume asymmetry. Future research is warranted to determine if volume asymmetry thresholds exist that discriminate between healthy and pathological populations. Statement of Clinical Significance: Muscle volume asymmetries displayed in healthy individuals provide a reference for interpreting asymmetries in pathological populations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration


Rotator cuff (RC) muscles undergo several detrimental changes following mechanical unloading resulting from RC tendon tear. In this review, we highlight the pathological causes and consequences of mechanical alterations at the whole muscle, muscle fiber, and muscle resident cell level as they relate to RC disease progression. In brief, the altered mechanical loads associated with RC tear lead to architectural, structural, and compositional changes at the whole-muscle and muscle fiber level. At the cellular level, these changes equate to direct disruption of mechanobiological signaling, which is exacerbated by mechanically regulated biophysical and biochemical changes to the cellular and extra-cellular environment (also known as the stem cell “niche”). Together, these data have important implications for both pre-clinical models and clinical practice. In pre-clinical models, it is important to recapitulate both the atrophic and degenerative muscle loss found in humans using clinically relevant modes of injury. Clinically, understanding the mechanics and underlying biology of the muscle will impact both surgical decision-making and rehabilitation protocols, as interventions that may be good for atrophic muscle will have a detrimental effect on degenerating muscle, and vice versa. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Collagen organization regulates stretch-initiated pain-related neuronal signals in vitro: Implications for structure–function relationships in innervated ligaments


Injury to the spinal facet capsule, an innervated ligament with heterogeneous collagen organization, produces pain. Although mechanical facet joint trauma activates embedded afferents, it is unclear if, and how, the varied extracellular microstructure of its ligament affects sensory transduction for pain from mechanical inputs. To investigate the effects of macroscopic deformations on afferents in collagen matrices with different organizations, an in vitro neuron-collagen construct (NCC) model was used. NCCs with either randomly organized or parallel aligned collagen fibers were used to mimic the varied microstructure in the facet capsular ligament. Embryonic rat dorsal root ganglia (DRG) were encapsulated in the NCCs; axonal outgrowth was uniform and in all directions in random NCCs, but parallel in aligned NCCs. NCCs underwent uniaxial stretch (0.25 ± 0.06 strain) corresponding to sub-failure facet capsule strains that induce pain. Macroscopic NCC mechanics were measured and axonal expression of phosphorylated extracellular signal-regulated kinase (pERK) and the neurotransmitter substance P (SP) was assayed at 1 day to assess neuronal activation and nociception. Stretch significantly upregulated pERK expression in both random and aligned gels (p [...]

Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections


There has been a dramatic increase in the emergence of antibiotic-resistant bacterial strains, which has made antibiotic choices for infection control increasingly limited and more expensive. In the U.S. alone, antibiotic-resistant bacteria cause at least 2 million infections and 23,000 deaths a year resulting in a $55–70 billion per year economic impact. Antibiotics are critical to the success of surgical procedures including orthopedic prosthetic surgeries, and antibiotic resistance is occurring in nearly all bacteria that infect people, including the most common bacteria that cause orthopedic infections, such as Staphylococcus aureus (S. aureus). Most clinical cases of orthopedic surgeries have shown that patients infected with antibiotic-resistant bacteria, such as methicillin-resistant S. aureus (MRSA), are associated with increased morbidity and mortality. This paper reviews the severity of antibiotic resistance at the global scale, the consequences of antibiotic resistance, and the pathways bacteria used to develop antibiotic resistance. It highlights the opportunities and challenges in limiting antibiotic resistance through approaches like the development of novel, non-drug approaches to reduce bacteria functions related to orthopedic implant-associated infections. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Most of the known urgent, serious, and concerning antibiotic resistant microorganisms have been increasingly reported in orthopedic implant-associated infections. Different antibiotic-resistant profiles have been identified between older and younger patients, and between patients with and without orthopedic implants. Overall, orthopedic infections caused by antibiotic-resistant microorganisms have a less than optimal clinical outcome compared to those caused by antibiotic susceptible microorganisms. Various opportunities and challenges have emerged in limiting antibiotic resistance.

Study of the interactions between proximal femur 3d bone shape, cartilage health, and biomechanics in patients with hip Osteoarthritis


In this study quantitative MRI and gait analysis were used to investigate the relationships between proximal femur 3D bone shape, cartilage morphology, cartilage biochemical composition, and joint biomechanics in subject with hip Osteoarthritis (OA). Eighty subjects underwent unilateral hip MR-imaging: T1ρ and T2 relaxation times were extracted through voxel based relaxometry and bone shape was assessed with 3D MRI-based statistical shape modeling. In addition, 3D gait analysis was performed in seventy-six of the studied subjects. Associations between shape, cartilage lesion presence, severity, and cartilage T1ρ and T2 were analyzed with linear regression and statistical parametric mapping. An ad hoc analysis was performed to investigate biomechanics and shape associations. Our results showed that subjects with a higher neck shaft angle in the coronal plane (higher mode 1, coxa valga), thicker femoral neck and a less spherical femoral head (higher mode 5, pistol grip) exhibited more severe acetabular and femoral cartilage abnormalities, showing different interactions with demographics factors. Subjects with coxa valga also demonstrated a prolongation of T1ρ and T2. Subjects with pistol grip deformity exhibited reduced hip internal rotation angles and subjects with coxa valga exhibited higher peak hip adduction moment and moment impulse. The results of this study establish a clear relationship between 3D proximal femur shape variations and markers of hip joint degeneration—morphological, compositional, well as insight on the possible interactions with demographics and biomechanics, suggesting that 3D MRI-based bone shape maybe a promising biomarker of early hip joint degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res This study investigates relationships between proximal femur 3D bone shape, cartilage morphology, cartilage biochemical composition, and joint biomechanics in subject with hip Osteoarthritis (OA). Subjects with coxal valga and pistol grip deformities exhibited more severe acetabular and femoral cartilage abnormalities. Subjects with coxa valga also demonstrated a prolongation ofT1ρ and T2 relaxation times. Subjects with pistol grip deformity exhibited reduced hip internal rotation angles and subjects with coxa valga exhibited higher peak hip adduction moment and moment impulse.

Gait training for chronic ankle instability improves neuromechanics during walking


A novel gait-training device has been shown to improve gait patterns while patients with chronic ankle instability (CAI) are using the device and our current objective was to analyze the effect of structured gait training with the device on plantar pressure and surface electromyography (sEMG) following repeated gait training sessions. Sixteen CAI patients participated. Plantar pressure and sEMG were collected simultaneously during walking pre- and post-gait training. Plantar pressure (pressure time integral, peak pressure, time to peak pressure, contact area, contact time, and center of pressure trajectory) of the entire foot and nine specific regions of the foot were recorded concurrently with sEMG root mean square amplitudes from the anterior tibialis, peroneus longus, medial gastrocnemius, and gluteus medius. Five gait training sessions were performed with each session lasting approximately 15 min. Pre- and post-gait training self-reported function, plantar pressure, and sEMG were compared using paired t-tests with a priori level of significance of p ≤ 0.05. Gait training improved self-reported function (FAAM-Sport scale: Pre = 75.1 ± 7.1%, Post = 85.7 ± 12.2%, p < 0.001) and caused a medial shift in the COP from 10% of stance through toe-off (p < 0.05 for all analyses). The medial shift in COP was driven by concurrent increases in peroneus longus muscle activity from 21% to 60% and 81% to 90% of stance (p < 0.05 for all analyses). There was a corresponding reduction in gluteus medius muscle activity during 71–100% of stance (p < 0.05 for all analyses). Overall, gait training with a device that targets the peroneus longus and gluteus medius throughout the gait cycle improved gait patterns in CAI patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Polymorphisms of miR-146a, miR-149, miR-196a2, and miR-499 are associated with osteoporotic vertebral compression fractures in Korean postmenopausal women


Genetic factors have been shown to be a small but significant predictor for osteoporosis and osteoporotic fracture risk. We performed a case–control association study to determine the association between miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms and osteoporotic vertebral compression fracture (OVCF) susceptibility. In total, 286 unrelated postmenopausal Korean women (57 with OVCFs, 55 with non-OVCFs, and 174 healthy controls) were recruited. All subjects underwent dual energy X-ray absorptiometry to determine BMD at the lumbar spine and femoral neck. We focused on four single nucleotide polymorphisms (SNPs) of pre-miRNA sequences including miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444). Genotype frequencies of these four SNPs were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. The TT genotype of miR-149aT>C was less frequent in subjects with OVCFs, suggesting a protective effect against OVCF risk (Odds ratio [OR], 0.435; 95% confidence interval [CI], 0.22–0.85, p = 0.014), whereas the miR-146aCG/ miR-196a2TC combined genotype was more frequent in OVCF patients (OR, 5.163; 95%CI, 1.057–25.21, p = 0.043), suggesting an increase in OVCF risk. Additionally, combinations of miR-146a, -149, -196a2, and -449 showed a significant association with increased prevalence of OVCFs in postmenopausal women. In particular, the miR-146aG/-149T/-196a2C/-449G allele combination was significantly associated with an increased risk of OVCF (OR, 35.01; 95% CI, 1.919–638.6, p = 0.001). Our findings suggest that the TT genotype of miR-149aT>C may contribute to decreased susceptibility to OVCF in Korean postmenopausal women. Conversely, the miR-146aCG/ miR-196a2TC combined genotype and the miR-146aG/-149T/-196a2C/-449G allele combination may contribute to increased susceptibility to OVCF. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Immediate and short-term effects of real-time knee adduction moment feedback on the peak and cumulative knee load during walking


The peak external knee adduction moment (pKAM), KAM impulse, and peak knee flexion moment (pKFM) during gait are important loading variables in medial tibiofemoral osteoarthritis. We evaluated the effects of gait modification, using real-time pKAM visual feedback, on pKAM, KAM impulse, and pKFM; and whether participants could maintain the KAM-reducing gait after feedback removal. Eleven healthy individuals performed a series of walking trials on a split-belt instrumented treadmill under four conditions of Baseline, Feedback, No Feedback Early, and No Feedback Late. Guided by real-time feedback of pKAM, they modified their gait patterns to lower pKAM by 20%. Three-dimensional joint kinematics/kinetics during each walking condition were recorded by a 12-camera motion capture system and the instrumented treadmill. Change in each knee loading parameter from baseline across conditions was assessed using one-way repeated-measures analysis-of-variances. In the feedback limb, successful 20% reductions from baseline in pKAM and KAM impulse were achieved across all three conditions. There was a trend for concomitant pKFM increases, partially attenuating the beneficial effects of pKAM reduction. A carry-over effect of KAM reduction in the non-feedback limb was noted. The altered gait patterns were participant-specific and multi-modal; each participant reported a combination of two to three gait modification strategies used for pKAM reduction. Toe-in and medial foot contact were the most reported strategies. The findings support the real-time pKAM visual feedback as a tool for individualized gait modification to reduce knee load. Future studies to evaluate its effectiveness in persons with or at risk for medial knee osteoarthritis is warranted. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Guided by real-time visual feedback of the peak external knee adduction moment (KAM) of the right limb during instrumented-treadmill walking, participants learned to modify their gait patterns and reduced the peak KAM and stance-phase KAM impulse (cumulative load) by 20%. A carry-over effect of KAM reduction in the left limb was noted. The altered gait patterns were participant-specific and multi-modal. The findings support the real-time peak KAM visual feedback[...]

Relevance of bioreactors and whole tissue cultures for the translation of new therapies to humans


The purpose of this review is to provide a brief overview of bioreactor-based culture systems as alternatives to conventional two- and three-dimensional counterparts. The role, challenges, and future aspirations of bioreactors in the musculoskeletal field (e.g., cartilage, intervertebral disc, tendon, and bone) are discussed. Bioreactors, by recapitulating physiological processes, can be used effectively as part of the initial in vitro screening, reducing that way the number of animal required for preclinical assessment, complying with the 3R principles and, in most cases, allowing working with human tissues. The clinical significance of bioreactors is that, by providing more physiologically relevant conditions to customarily used two- and three-dimensional cultures, they hold the potential to provide a testing platform that is more predictable of a whole tissue response, thereby facilitating the screening of treatments before the initiation of clinical trials. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Transcriptional profiling of articular cartilage in a porcine model of early post-traumatic osteoarthritis


To identify the molecular pathophysiology present in early post-traumatic osteoarthritis (PTOA), the transcriptional profile of articular cartilage and its response to surgical PTOA induction were determined. Thirty six Yucatan minipigs underwent anterior cruciate ligament (ACL) transection and were randomly assigned in equal numbers to no further treatment, reconstruction or ligament repair. Cartilage was harvested at 1 and 4 weeks post-operatively and histology and RNA-sequencing were performed and compared to controls. Microscopic cartilage scores significantly worsened at 1 (p = 0.028) and 4 weeks (p = 0.001) post-surgery relative to controls, but did not differ between untreated, reconstruction or repair groups. Gene expression after ACL reconstruction and ACL transection were similar, with only 0.03% (including SERPINB7 and CR2) and 0.2% of transcripts (including INHBA) differentially expressed at 1 and 4 weeks respectively. COL2A1, COMP, SPARC, CHAD, and EF1ALPHA were the most highly expressed non ribosomal, non mitochondrial genes in the controls and remained abundant after surgery. A total of 1,275 genes were differentially expressed between 1 and 4 weeks post-surgery. With the treatment groups pooled, 682 genes were differentially expressed at both time-points, with the most significant changes observed in MMP1, COCH, POSTN, CYTL1, and PTGFR. This study confirmed the development of a microscopic PTOA stage after ACL surgery in the porcine model. Upregulation of multiple proteases (including MMP1 and ADAMTS4) were found; however, the level of expression remained orders of magnitude below that of extracellular matrix protein-coding genes (including COL2A1 and ACAN). In summary, genes with established roles in PTOA as well as novel targets for specific intervention were identified. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Regulation of RANKL-induced osteoclastogenesis by RING finger protein RNF114


Normal bone remodeling is a continuous process orchestrated by bone-resorbing osteoclasts and bone-forming osteoblasts, which an imbalance in bone remodeling results in metabolic bone diseases. RANKL, a member of the TNF cytokine family, functions as a key stimulator for osteoclast differentiation and maturation. Here, we report that RNF114, previously identified as a psoriasis susceptibility gene, plays a regulatory role in the RANKL/RANK/TRAF6 signaling pathway that mediates osteoclastogenesis. Our results demonstrated that RNF114 expression was significantly down-regulated in mouse osteoclast precursor cells undergoing RANKL-induced osteoclast differentiation. RNF114 knockout did not affect development or viability of the subpopulation of bone marrow macrophages capable of differentiating into osteoclasts in culture. However, in the presence of RANKL, RNF114 knockout bone marrow macrophages exhibited enhanced cell proliferation and augmented osteoclast differentiation, as shown by an increased expression of mature osteoclast markers, increased osteoclastic TRAP activity and bone resorption. Conversely, ectopic expression of RNF114 inhibited CTSK expression, TRAP activity, and bone resorption in RANKL-treated pre-osteoclasts. RNF114 also suppressed RANKL-activated NFATc1 expression and NFAT-regulated promoter activity. RNF114 suppressed TRAF6-, but not TAK1/TAB2-mediated NF-κB activation downstream of RANKL/RANK. In particular, TRAF6 protein levels were down-regulated by RNF114, possibly via K48-mediated proteasome-dependent degradation. These data suggested that RNF114's inhibitory effect on RANKL-stimulated osteoclastogenesis was mediated by blocking RANK/TRAF6/NF-κB signal transduction. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Quantification of interfacial motions following primary and revision total knee arthroplasty: A verification study versus experimental data


Motion at the bone–implant interface, following primary or revision knee arthroplasty, can be detrimental to the long-term survival of the implant. This study employs experimentally verified computational models of the distal femur to characterize the relative motion at the bone–implant interface for three different implant types; a posterior stabilizing implant (PS), a total stabilizing implant (TS) with short stem (12 mm × 50 mm), and a total stabilizing implant (TS) with long offset stem (19 mm × 150 mm with a 4 mm lateral offset). Relative motion was investigated for both cemented and uncemented interface conditions. Monitoring relative motion about a single reference point, though useful for discerning global differences between implant types, was found to not be representative of the true pattern and distribution of motions which occur at the interface. The contribution of elastic deformation to apparent reference point motion varied based on implant type, with the PS and TSSS implanted femurs experiencing larger deformations (43 and 39 μm, respectively) than the TSLS implanted femur (22 μm). Furthermore, the pattern of applied loading was observed to greatly influence location and magnitude of peak motions, as well as the surface area under increased motion. Interestingly, the influence was not uniform across all implant types, with motions at the interface of long stemmed prosthesis found to be less susceptible to changes in pattern of loading. These findings have important implications for the optimization and testing of orthopedic implants in vitro and in silico. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Mitochondrial dysfunction is an acute response of articular chondrocytes to mechanical injury


Mitochondrial (MT) dysfunction is known to occur in chondrocytes isolated from end-stage osteoarthritis (OA) patients, but the role of MT dysfunction in the initiation and early pathogenesis of post-traumatic OA (PTOA) remains unclear. The objective of this study was to investigate chondrocyte MT function immediately following mechanical injury in cartilage, and to determine if the response to injury differed between a weight bearing region (medial femoral condyle; MFC) and a non-weight bearing region (distal patellofemoral groove; PFG) of the same joint. Cartilage was harvested from the MFC and PFG of 10 neonatal bovids, and subjected to injurious compression at varying magnitudes (5-17 MPa, 5-34 GPa/s) using a rapid single-impact model. Chondrocyte MT respiratory function, MT membrane polarity, chondrocyte viability, and cell membrane damage were assessed in situ. Cartilage impact resulted in MT depolarization and impaired MT respiratory function within 2 h of injury. Cartilage from a non-weight bearing region of the joint (PFG) was more sensitive to impact-induced MT dysfunction and chondrocyte death than cartilage from a weight-bearing surface (MFC). Our findings suggest that MT dysfunction is an acute response of chondrocytes to cartilage injury, and that MT may play a key mechanobiological role in the initiation and early pathogenesis of PTOA. Clinical significance: Direct therapeutic targeting of MT function in the early post-injury time frame may provide a strategy to block perpetuation of tissue damage and prevent the development of PTOA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Alterations in structural macromolecules and chondrocyte deformations in lapine retropatellar cartilage 9 weeks after anterior cruciate ligament transection


The structural integrity and mechanical environment of the articular cartilage matrix directly affect chondrocyte deformations. Rabbit models of early osteoarthritis at 9 weeks following anterior cruciate ligament transection (ACLT) have been shown to alter the deformation behavior of superficial zone chondrocytes in mechanically loaded articular cartilage. However, it is not fully understood whether these changes in cell mechanics are caused by changes in structural macromolecules in the extracellular matrix. Therefore, the purpose of this study was to characterize the proteoglycan content, collagen content, and collagen orientation at 9 weeks post ACLT using microscopic techniques, and relate these changes to the altered cell mechanics observed upon mechanical loading of cartilage. At 9 weeks following ACLT, collagen orientation was significantly (p < 0.05) altered and proteoglycan content was significantly (p < 0.05) reduced in the superficial zone cartilage matrix. These structural changes either in the extracellular or pericellular matrix (ECM and PCM) were also correlated significantly (p < 0.05) with chondrocyte width and height changes, thereby suggesting that chondrocyte deformation response to mechanical compression in early OA changes primarily because of alterations in matrix structure. However, compared to the normal group, proteoglycan content in the PCM from the ACLT group decreased less than that in the surrounding ECM. Therefore, PCM could play a key role to protect excessive chondrocyte deformations in the ACLT group. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX-XX, 2017. The PG content in the superficial zone PCM decreased in the ACLT group compared to the normal group samples. However, this PCM PG loss was not as extensive as that in the surrounding ECM, which can be observed from the significantly higher PCM to ECM PG content ratio in the ACLT group compared to the normal or C-L group samples (Figure shown as normalized PCM to ECM PG content).

Augmentation of fracture healing by hydroxyapatite/collagen paste and bone morphogenetic protein-2 evaluated using a rat femur osteotomy model


In fracture treatment, biological bone union generally depends on the bone's natural fracture healing capacity, even in surgically treated cases. Hydroxyapatite/collagen composite (HAp/Col) has high osteoconductivity and stimulates osteogenic progenitors. Furthermore, it has the potent capacity to adsorb bone morphogenetic proteins (BMPs). In this study, we prepared an injectable HAp/Col paste and evaluated its augmentation of bone union. Furthermore, the effect of HAp/Col paste combined with BMP-2 was also evaluated. We used a rat femur osteotomy model with a defect size of 1 mm. Male Wistar rats were assigned to one of the following four groups; a control group without any implant, a HAp/Col implant group, a group that received an absorbable collagen sponge (ACS) implant impregnated with BMP-2 (1 μg), and a group that received a HAp/Col implant impregnated with BMP-2 implant. Micro-CT analysis, three-point bending tests, and histological evaluation were performed. Bone union was achieved in two of eight cases in the HAp/Col group, five of eight cases in the ACS + BMP-2 group, and all cases in the HAp/Col + BMP-2 group at 8 weeks post-surgery. The control group did not achieve bone union. In addition, in the HAp/Col + BMP-2 group, the biomechanical strength of the fused femurs was comparable to that of the contralateral intact femur; the ratio of the mechanical load at the breaking point of the osteotomy side relative to that of the contralateral side was 1.00 ± 0.151 (SD). These results indicate that HAp/Col paste with or without BMP-2 augments bone union. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Biomechanical simulations of costo-vertebral and anterior vertebral body tethers for the fusionless treatment of pediatric scoliosis


Compression-based fusionless tethers are an alternative to conventional surgical treatments of pediatric scoliosis. Anterior approaches place an anterior (ANT) tether on the anterolateral convexity of the deformed spine to modify growth. Posterior, or costo-vertebral (CV), approaches have not been assessed for biomechanical and corrective effectiveness. The objective was to biomechanically assess CV and ANT tethers using six patient-specific, finite element models of adolescent scoliotic patients (11.9 ± 0.7 years, Cobb 34° ± 10°). A validated algorithm simulated the growth and Hueter–Volkmann growth modulation over a period of 2 years with the CV and ANT tethers at two initial tensions (100, 200 N). The models without tethering also simulated deformity progression with Cobb angle increasing from 34° to 56°, axial rotation 11° to 13°, and kyphosis 28° to 32° (mean values). With the CV tether, the Cobb angle was reduced to 27° and 20° for tensions of 100 and 200 N, respectively, kyphosis to 21° and 19°, and no change in axial rotation. With the ANT tether, Cobb was reduced to 32° and 9° for 100 and 200 N, respectively, kyphosis unchanged, and axial rotation to 3° and 0°. While the CV tether mildly corrected the coronal curve over a 2-year growth period, it had sagittal lordosing effect, particularly with increasing initial axial rotation (>15°). The ANT tether achieved coronal correction, maintained kyphosis, and reduced the axial rotation, but over-correction was simulated at higher initial tensions. This biomechanical study captured the differences between a CV and ANT tether and indicated the variability arising from the patient-specific characteristics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Compression-based tethers along the costovertebral junction (CV) and anteriorly positioned on the vertebral body (ANT) were simulated using patient-specific finite element models that included growth modulation over a 2-year period. The ANT tether was more efficient than the CV tether to c[...]

Tissue-engineered tendon constructs for rotator cuff repair in sheep


Current rotator cuff repair commonly involves the use of single or double row suture techniques, and despite successful outcomes, failure rates continue to range from 20 to 95%. Failure to regenerate native biomechanical properties at the enthesis is thought to contribute to failure rates. Thus, the need for technologies that improve structural healing of the enthesis after rotator cuff repair is imperative. To address this issue, our lab has previously demonstrated enthesis regeneration using a tissue-engineered graft approach in a sheep anterior cruciate ligament (ACL) repair model. We hypothesized that our tissue-engineered graft designed for ACL repair also will be effective in rotator cuff repair. The goal of this study was to test the efficacy of our Engineered Tissue Graft for Rotator Cuff (ETG-RC) in a rotator cuff tear model in sheep and compare this novel graft technology to the commonly used double row suture repair technique. Following a 6-month recovery, the grafted and contralateral shoulders were removed, imaged using X-ray, and tested biomechanically. Additionally, the infraspinatus muscle, myotendinous junction, enthesis, and humeral head were preserved for histological analysis of muscle, tendon, and enthesis structure. Our results showed that our ETC-RCs reached 31% of the native tendon tangent modulus, which was a modest, non-significant, 11% increase over that of the suture-only repairs. However, the histological analysis showed the regeneration of a native-like enthesis in the ETG-RC-repaired animals. This advanced structural healing may improve over longer times and may diminish recurrence rates of rotator cuff tears and lead to better clinical outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Effects of age and pathology on shear wave speed of the human rotator cuff


Rotator cuff tears are common and often repaired surgically, but post-operative repair tissue healing, and shoulder function can be unpredictable. Tear chronicity is believed to influence clinical outcomes, but conventional clinical approaches for assessing tear chronicity are subjective. Shear wave elastography (SWE) is a promising technique for assessing soft tissue via estimates of shear wave speed (SWS), but this technique has not been used extensively on the rotator cuff. Specifically, the effects of age and pathology on rotator cuff SWS are not well known. The objectives of this study were to assess the association between SWS and age in healthy, asymptomatic subjects, and to compare measures of SWS between patients with a rotator cuff tear and healthy, asymptomatic subjects. SWE images of the supraspinatus muscle and intramuscular tendon were acquired from 19 asymptomatic subjects and 11 patients with a rotator cuff tear. Images were acquired with the supraspinatus under passive and active (i.e., minimal activation) conditions. Mean SWS was positively associated with age in the supraspinatus muscle and tendon under passive and active conditions (p ≤ 0.049). Compared to asymptomatic subjects, patients had a lower mean SWS in their muscle and tendon under active conditions (p ≤ 0.024), but no differences were detected under passive conditions (p ≥ 0.783). These findings identify the influences of age and pathology on SWS in the rotator cuff. These preliminary findings are an important step toward evaluating the clinical utility of SWE for assessing rotator cuff pathology. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Reverse engineering development: Crosstalk opportunities between developmental biology and tissue engineering


The fields of developmental biology and tissue engineering have been revolutionized in recent years by technological advancements, expanded understanding, and biomaterials design, leading to the emerging paradigm of “developmental” or “biomimetic” tissue engineering. While developmental biology and tissue engineering have long overlapping histories, the fields have largely diverged in recent years at the same time that crosstalk opportunities for mutual benefit are more salient than ever. In this perspective article, we will use musculoskeletal development and tissue engineering as a platform on which to discuss these emerging crosstalk opportunities and will present our opinions on the bright future of these overlapping spheres of influence. The multicellular programs that control musculoskeletal development are rapidly becoming clarified, represented by shifting paradigms in our understanding of cellular function, identity, and lineage specification during development. Simultaneously, advancements in bioartificial matrices that replicate the biochemical, microstructural, and mechanical properties of developing tissues present new tools and approaches for recapitulating development in tissue engineering. Here, we introduce concepts and experimental approaches in musculoskeletal developmental biology and biomaterials design and discuss applications in tissue engineering as well as opportunities for tissue engineering approaches to inform our understanding of fundamental biology. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Reduced bone loss in a murine model of postmenopausal osteoporosis lacking complement component 3


The growing field of osteoimmunology seeks to unravel the complex interdependence of the skeletal and immune systems. Notably, we and others have demonstrated that complement signaling influences the differentiation of osteoblasts and osteoclasts, the two primary cell types responsible for maintaining bone homeostasis. However, the net effect of complement on bone homeostasis in vivo was unknown. Our published in vitro mechanistic work led us to hypothesize that absence of complement component 3 (C3), a central protein in the complement activation cascade, protects against bone loss in the ovariectomy-based model of postmenopausal osteoporosis. Indeed, we report here that, when compared to their C57BL/6J (WT) counterparts, ovariectomized C3 deficient mice experienced reduced bone loss at multiple sites and increased stiffness at the femoral neck, the latter potentially improving mechanical function. WT and B6;129S4-C3tm1Crr/J (C3-/-) mice were either ovariectomized or sham-operated at 6 weeks of age and euthanized at 12 weeks. MicroCT on harvested bones revealed that the trabecular bone volume fraction in the metaphyses of both the proximal tibiae and distal femora of ovariectomized C3-/- mice is significantly greater than that of their WT counterparts. Lumbar vertebrae showed significantly greater osteoid content and mineral apposition rates. Mechanical testing demonstrated significantly greater stiffness in the femoral necks of ovariectomized C3-/- mice. These results demonstrate that C3 deficiency reduces bone loss at ovariectomy and may improve mechanical properties. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res MicroCT on bones harvested from C57BL/6J (WT) and B6;129S4 C3tm1Crr/J (C3-/-) mice revealed that the trabecular bone volume fraction in the metaphyses of both the proximal tibiae and distal femora of ovariectomized C3-/- mice is significantly greater than that of their WT counterparts. Their lumbar ver[...]

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury


Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1−/−) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1−/− mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1−/− mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Pirfenidone (PFD)—an anti-inflammatory, anti-fibrotic drug—has shown eff[...]

Histological and reference system for the analysis of mouse intervertebral disc


A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. “Normal NP” exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. “Normal AF” consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Calreticulin inhibits inflammation-induced osteoclastogenesis and bone resorption


Osteoclasts play key roles in bone remodeling and pathologic osteolytic disorders such as inflammation, infection, bone implant loosening, rheumatoid arthritis, metastatic bone cancers, and pathological fractures. Osteoclasts are formed by the fusion of monocytes in response to receptor activators of NF-κB-ligand (RANKL) and macrophage colony stimulating factor 1 (M-CSF). Calreticulin (CRT), a commonly known intracellular protein as a calcium-binding chaperone, has an unexpectedly robust anti-osteoclastogenic effect when its recombinant form is applied to osteoclast precursors in vitro or at the site of bone inflammation externally in vivo. Externally applied Calreticulin was internalized inside the cells. It inhibited key pro-osteoclastogenic transcription factors such as c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-in osteoclast precursor cells that were treated with RANKL in vitro. Recombinant human Calreticulin (rhCRT) inhibited lipopolysaccharide (LPS)-induced inflammatory osteoclastogenesis in the mouse calvarial bone in vivo. Cathepsin K molecular imaging verified decreased Cathepsin K activity when rhCalreticulin was applied at the site of LPS application in vivo. Recombinant forms of intracellular proteins or their derivatives may act as novel extracellular therapeutic agents. We anticipate our findings to be a starting point in unraveling hidden extracellular functions of other intracellular proteins in different cell types of many organs for new therapeutic opportunities. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Intraoperative biomechanics of lumbar pedicle screw loosening following successful arthrodesis


Pedicle screw loosening has been implicated in recurrent back pain after lumbar spinal fusion, but the degree of loosening has not been systematically quantified in patients. Instrumentation removal is an option for patients with successful arthrodesis, but remains controversial. Here, we quantified pedicle screw loosening by measuring screw insertion and/or removal torque at high statistical power (beta = 0.02) in N = 108 patients who experienced pain recurrence despite successful fusion after posterior instrumented lumbar fusion with anterior lumbar interbody fusion (L2–S1). Between implantation and removal, pedicle screw torque was reduced by 58%, indicating significant loosening over time. Loosening was greater in screws with evoked EMG threshold under 11 mA, indicative of screw misplacement. A theoretical stress analysis revealed increased local stresses at the screw interface in pedicles with decreased difference in pedicle thickness and screw diameter. Loosening was greatest in vertebrae at the extremities of the fused segments, but was significantly lower in segments with one level of fusion than in those with two or more. Clinical significance: These data indicate that pedicle screws can loosen significantly in patients with recurrent back pain and warrant further research into methods to reduce the incidence of screw loosening and to understand the risks and potential benefits of instrumentation removal. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res We found that pedicle screw torque was reduced by 58% between insertion and removal in patients with recurrent pain following successful lumbar fusion. Loosening was greatest in vertebrae at the extremities of the fused segments, but was significantly lower in segments with one level of fusion. A theoretical local stress analysis revealed i[...]

Age-related spontaneous lumbar intervertebral disc degeneration in a mouse model


The pathogenesis of intervertebral disc degeneration is unclear, but it is a major cause of several spinal diseases. Animal models have historically provided an appropriate benchmark for understanding the human spine. However, there is little information about when intervertebral disc degeneration begins in the mouse or regarding the relationship between magnetic resonance imaging and histological findings. The aim for this study was to obtain information about age-related spontaneous intervertebral disc degeneration in the mouse lumbar spine using magnetic resonance imaging and a histological score regarding when the intervertebral disc degeneration started and how rapidly it progressed, as well as how our histological score detected the degeneration. The magnetic resonance imaging index yielded a moderate correlation with our Age-related model score. The Pfirrmann grade and magnetic resonance imaging index had moderate correlations with age. However, our Age-related model score had a high correlation with age. Intervertebral disc level was not a significant variable for the severity of disc degeneration. Both Pfirrmann grade and the Age-related model score were higher in the ≥14-month-old group than in the 6-month-old group. The present results indicated that mild but significant intervertebral disc degeneration occurred in 14-month-old mice, and the degree of degeneration progressed slowly, reaching a moderate to severe condition for 22-month-old mice. At least a 14-month follow-up is mandatory for evaluating spontaneous age-related mouse intervertebral disc degeneration. The histological classification score can precisely detect the gradual progression of age-related spontaneous intervertebral disc degeneration in the mouse lumbar spine, and is appropriate for evaluating it. © 2017 Orthopaedic Research Society. Pub[...]

Optimization of puncture injury to rat caudal disc for mimicking early degeneration of intervertebral disc


The caudal discs of rats have been proposed as a puncture model in which intervertebral disc (IVD) degeneration can be induced and novel therapies can be tested. For biological repair, treatments for ongoing IVD degeneration are ideally administered during the earlier stages. The purpose of this study was to elucidate the optimal puncture needle size for creating a model that mimicked the earlier stages of IVD degeneration. According to the disc height index, histologic score, and MRI grading, a puncture needle sized 21G or larger induced rapid degenerative processes in rat caudal discs during the initial 2–4 weeks. The degenerative changes were severe and continued deteriorating after 4 weeks. Conversely, puncture injury induced by needles sized 25G or smaller also produced degenerative changes in rat caudal discs during initial 2–4 weeks; however, the changes were less severe. Furthermore, the degenerative process became stabilized and showed no further deterioration or spontaneous recovery after 4 weeks. In the discs punctured by 25G needles, the expression of collagen I was increased at 2–4 weeks with a gradually fibrotic transformation thereafter. The expressions of collagen II and SOX9 were enhanced initially but returned to pre-injury levels at 4–8 weeks. The above-mentioned findings were more compatible with earlier degeneration in discs punctured by needles sized 25G or smaller than by needles sized 21G or larger, and the appropriate timing for intradiscal administration of proposed therapeutic agents would be 4 weeks or longer after puncture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res According to disc height index, histologic score, and MRI grading, a puncture needle sized 21G or larger induced rapid and severe degenerative process[...]

Bench-to-bedside: Bridge-enhanced anterior cruciate ligament repair


Anterior cruciate ligament (ACL) injuries are one of the most well-known orthopaedic injuries and are treated with one of the most common orthopaedic procedures performed in the United States. This surgical procedure, ACL reconstruction, is successful at restoring the gross stability of the knee. However, the outcomes of ACL reconstruction can be limited by short and long-term complications, including muscle weakness, graft rupture, and premature osteoarthritis. Thus, new methods of treating this injury are being explored. This review details the pathway of how a tissue engineering strategy can be used to improve the healing of the ACL in preclinical studies and then translated to patients in an FDA-approved clinical study. This review paper will outline the clinical importance of ACL injuries, history of primary repair, the pathology behind failure of the ACL to heal, pre-clinical studies, the FDA approval process for a high risk medical device, and the preliminary results from a first-in-human study. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Characteristics of regional bone quality in cervical vertebrae considering BMD: Determining a safe trajectory for cervical pedicle screw fixation


This study aimed to report the mechanical strength and characteristics of the lateral mass and pedicle considering BMD for the safe insertion of pedicle screws in the subaxial cervical level. We evaluated BMD and Hounsfield unit (HU) values of cortical bones at the lateral mass and pedicle of C3-7 from CT images in 99 patients. Patients were divided into three groups (Group A, T-score ≥ −1; Group B, −2.5 [...]

Novel porcine experimental model of severe progressive thoracic scoliosis with compensatory curves induced by interpedicular bent rigid temporary tethering


Using flexible tethering techniques, porcine models of experimental scoliosis have shown scoliotic curves with vertebral wedging but very limited axial rotation. The aim of this experimental work was to induce a severe progressive scoliosis in a growing porcine model for research purposes. A unilateral spinal bent rigid tether was anchored to two ipsilateral pedicle screws in eight pigs. The spinal tether was removed after 8 weeks. Ten weeks later, the animals were sacrificed. Conventional radiographs and 3D CT-scans were taken to evaluate changes in the alignment of the thoracic spine. After the first 8 weeks of rigid tethering, all animals developed scoliotic curves (mean Cobb angle: 24.3°). Once the interpedicular tether was removed, the scoliotic curves progressed in all animals during 10 weeks reaching a mean Cobb angle of 49.9°. The sagittal alignment of the thoracic spine showed loss of physiologic kyphosis (Mean: −18.3°). Axial rotation ranged from 10° to 49° (Mean 25.7°). Release of the spinal tether results in progression of the deformity with the development of proximal and distal compensatory curves. In conclusion, temporary interpedicular tethering at the thoracic spine induces severe scoliotic curves in pigs, with significant wedging and rotation of the vertebral bodies, and true compensatory curves. Clinical Relevance: The tether release model will be used to evaluate corrective non-fusion technologies in future investigations. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res A new experimental model of severe progressive scoliosis was developed in growing pigs by unilateral spinal bent rigid tethering anchored to two ipsilateral pedicle screws. After 8[...]

Pedicle screw augmentation with bone cement enforced Vicryl mesh


Achieving sufficient mechanical purchase of pedicle screws in osteoporotic or previously instrumented bone is technically and biologically challenging. Techniques using different kinds of pedicle screws or methods of cement augmentation have been used to address this challenge, but are associated with difficult revisions and complications. The purpose of this biomechanical trial was to investigate the use of biocompatible textile materials in combination with bone cement to augment pullout strength of pedicle screws while reducing the risk of cement extrusion. Pedicle screws (6/40 mm) were either augmented with standard bone-cement (Palacos LV + G) in one group (BC, n = 13) or with bone-cement enforced by Vicryl mesh in another group (BCVM, n = 13) in osteoporosis-like saw bone blocks. Pullout testing was subsequently performed. In a second experimental phase, similar experiments were performed using human cadaveric lumbar vertebrae (n = 10). In osteoporosis-like saw bone blocks, a mean screw pullout force of 350 N (±125) was significantly higher with the Bone cement (BC) compared to bone-cement enforced by Vicryl mesh (BCVM) technique with 240 N (±64) (p = 0.030). In human cadaveric lumbar vertebrae the mean screw pullout force was 784 ± 366 N with BC and not statistically different to BCVM with 757 ± 303 N (p = 0.836). Importantly, cement extrusion was only observed in the BC group (40%) and never with the BCVM technique. In vitro textile reinforcement of bone cement for pedicle screw augmentation successfully reduced cement extrusion compared to conventionally delivered bone cement. The mechanical strength of textile delivered cement constr[...]

Estimating apparent maximum muscle stress of trunk extensor muscles in older adults using subject-specific musculoskeletal models


Maximum muscle stress (MMS) is a critical parameter in musculoskeletal modeling, defining the maximum force that a muscle of given size can produce. However, a wide range of MMS values have been reported in literature, and few studies have estimated MMS in trunk muscles. Due to widespread use of musculoskeletal models in studies of the spine and trunk, there is a need to determine reasonable magnitude and range of trunk MMS. We measured trunk extension strength in 49 participants over 65 years of age, surveyed participants about low back pain, and acquired quantitative computed tomography (QCT) scans of their lumbar spines. Trunk muscle morphology was assessed from QCT scans and used to create a subject-specific musculoskeletal model for each participant. Model-predicted extension strength was computed using a trunk muscle MMS of 100 N/cm2. The MMS of each subject-specific model was then adjusted until the measured strength matched the model-predicted strength (±20 N). We found that measured trunk extension strength was significantly higher in men. With the initial constant MMS value, the musculoskeletal model generally over-predicted trunk extension strength. By adjusting MMS on a subject-specific basis, we found apparent MMS values ranging from 40 to 130 N/cm2, with an average of 75.5 N/cm2 for both men and women. Subjects with low back pain had lower apparent MMS than subjects with no back pain. This work incorporates a unique approach to estimate subject-specific trunk MMS values via musculoskeletal modeling and provides a useful insight into MMS variation. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Development of overuse tendinopathy: A new descriptive model for the initiation of tendon damage during cyclic loading


Tendinopathic tissue has long been characterized by changes to collagen microstructure. However, initial tendon damage from excessive mechanical loading—a hallmark of tendinopathy development—could occur at the nanoscale level of collagen fibrils. Indeed, it is on this scale that tenocytes interact directly with tendon matrix, and excessive collagen fibril damage not visible at the microscale could trigger a degenerative cascade. In this study, we explored whether initiation of tendon damage during cyclic loading occurs via a longitudinal compression-induced buckling mechanism of collagen fibrils leading to nanoscale kinkband development. Two groups of tendons were cyclically loaded to equivalent peak stresses. In each loading cycle, tendons in one group were unloaded to the zero displacement mark, while those in the other group were unloaded to a nominal level of tension, minimizing the potential for fibril buckling. Tendons that were unloaded to the zero displacement mark ruptured significantly sooner during cyclic loading (1,446 ± 737 vs. 4,069 ± 1,129 cycles), indicating that significant fatigue damage is accrued in the low stress, toe region of the load-deformation response. Ultrastructural analysis using scanning electron microscopy of tendons stopped after 1,000 cycles showed that maintaining a nominal tension slowed the accumulation of kinkbands, supporting a longitudinal compression-induced buckling mechanism as the basis for kinkband development. Based on our results, we present a new descriptive model for the initiation of tendon damage during cyclic loading. The so-called Compression of Unrecovered Elongation[...]

Structure-function relationships at the human spinal disc-vertebra interface


Damage at the intervertebral disc-vertebra interface associates with back pain and disc herniation. However, the structural and biomechanical properties of the disc-vertebra interface remain underexplored. We sought to measure mechanical properties and failure mechanisms, quantify architectural features, and assess structure-function relationships at this vulnerable location. Vertebra-disc-vertebra specimens from human cadaver thoracic spines were scanned with micro-computed tomography (μCT), surface speckle-coated, and loaded to failure in uniaxial tension. Digital image correlation (DIC) was used to calculate local surface strains. Failure surfaces were scanned using scanning electron microscopy (SEM), and adjacent sagittal slices were analyzed with histology and SEM. Seventy-one percent of specimens failed initially at the cartilage endplate-bone interface of the inner annulus region. Histology and SEM both indicated a lack of structural integration between the cartilage endplate (CEP) and bone. The interface failure strength was increased in samples with higher trabecular bone volume fraction in the vertebral endplates. Furthermore, failure strength decreased with degeneration, and in discs with thicker CEPs. Our findings indicate that poor structural connectivity between the CEP and vertebra may explain the structural weakness at this region, and provide insight into structural features that may contribute to risk for disc-vertebra interface injury. The disc-vertebra interface is the site of failure in the majority of herniation injuries. Here we show new structure-function relationships at this interf[...]

Near infrared spectroscopy for measuring changes in bone hemoglobin content after exercise in individuals with spinal cord injury


Bone blood perfusion has an essential role in maintaining a healthy bone. However, current methods for measuring bone blood perfusion are expensive and highly invasive. This study presents a custom built near-infrared spectroscopy (NIRS) instrument to measure changes in bone blood perfusion. We demonstrated the efficacy of this device by monitoring oxygenated and deoxygenated hemoglobin changes in the human tibia during and after exercise in able-bodied and in individuals with spinal cord injury (SCI), a population with known impaired peripheral blood perfusion. Nine able-bodied individuals and six volunteers with SCI performed a 10 min rowing exercise (functional electrical stimulation rowing for those with SCI). With exercise, during rowing, able-bodied showed an increase in deoxygenated hemoglobin in the tibia. Post rowing, able-bodied showed an increase in total blood content, characterized by an increase in total hemoglobin content due primarily to an increase in deoxygenated hemoglobin. During rowing and post-rowing, those with SCI showed no change in total blood content in the tibia. The current study demonstrates that NIRS can non-invasively detect changes in hemoglobin concentration in the tibia. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Estrogen-dependent efficacy of limb ischemic preconditioning in female rats


Our aim was to examine the effects of ischemic preconditioning (IPC) on the local periosteal and systemic inflammatory consequences of hindlimb ischemia-reperfusion (IR) in Sprague–Dawley rats with chronic estrogen deficiency (13 weeks after ovariectomy, OVX) in the presence and absence of chronic 17beta-estradiol supplementation (E2, 20 µg kg−1, 5 days/week for 5 weeks); sham-operated (non-OVX) animals served as controls. As assessed by intravital fluorescence microscopy, rolling and the firm adhesion of polymorphonuclear neutrophil leukocytes (PMNs) gave similar results in the Sham + IR and OVX + IR groups in the tibial periosteal microcirculation during the 3-h reperfusion period after a 60-min tourniquet ischemia. Postischemic increases in periosteal PMN adhesion and PMN-derived adhesion molecule CD11b expressions, however, were significantly reduced by IPC (two cycles of 10′/10′) in Sham animals, but not in OVX animals; neither plasma free radical levels (as measured by chemiluminescence), nor TNF-alpha release was affected by IPC. E2 supplementation in OVX animals restored the IPC-related microcirculatory integrity and PMN-derived CD11b levels, and TNF-alpha and free radical levels were reduced by IPC only with E2. An enhanced estrogen receptor beta expression could also be demonstrated after E2 in the periosteum. Overall, the beneficial periosteal microcirculatory effects of limb IPC are lost in chronic estrogen deficiency, but they can be restored by E2 supplementation. This suggests that the presence of endogenous estrogen i[...]

Viable bacteria persist on antibiotic spacers following two-stage revision for periprosthetic joint infection


Treatment in periprosthetic joint infection (PJI) remains challenging. The failure rate of two-stage revision and irrigation and debridement with component retention in PJI suggests that biofilm cells have a high tolerance to antibiotic chemotherapy. Previous work has demonstrated that biofilm cells have high antibiotic tolerance in vitro, but there is little clinical evidence to support these observations. The aim of this study was to determine if retrieved antibiotic spacers from two-stage revision total knee arthroplasty for PJI have evidence of remaining viable bacteria. Antibiotic poly (methyl methacrylate) (PMMA) spacers from two-stage revision total knee arthroplasty for PJI were prospectively collected and analyzed for bacterial 16s rRNA using polymerase chain reaction (PCR), reverse transcription (RT)-PCR, quantitative RT-PCR (qRT-PCR), and single genome analysis (SGA). PCR and RT-PCR identified bacterial species on 53.8% (7/13) of these samples. When initial culture negative cases are excluded, 68% (6/9) samples were identified with bacterial species. A more rigorous qRT-PCR analysis showed a strong positive signal for bacterial contamination in 30.7% (4/13) of cases. These patients did not show any clinical evidence of PJI recurrence after 15 months of follow-up. Because the half-life of bacterial rRNA is approximately a few days, the identification of bacteria rRNA on antibiotic PMMA spacers suggests that viable bacteria were present after conclusion of antibiotic therapy. This study provides evidence for the high t[...]

Arthrotomy-based preclinical models of particle-induced osteolysis: A systematic review


We completed a systematic literature review of in vivo animal models that use arthrotomy-based methods to study particle-induced peri-implant osteolysis. The purpose of the review was to characterize the models developed to date, to determine the questions addressed, to assess scientific rigor and transparency, and to identify gaps in knowledge. We probed three literature databases (Medline, Embase, and Scopus) and found 77 manuscripts that fit the search parameters. In the most recent 10 years, researchers mainly used rat and mouse models, whereas in the previous 20 years, large animal, canine, and rabbit models were more common. The studies have demonstrated several pathophysiology pathways, including macrophage migration, particle phagocytosis, increased local production of cytokines and lysosomal enzymes, elevated bone resorption, and suppressed bone formation. The effect of variation in particle characteristics and concentration received limited attention with somewhat mixed findings. Particle contamination by endotoxin was shown to exacerbate peri-implant osteolysis. The possibility of early diagnosis was demonstrated through imaging and biomarker approaches. Several studies showed that both local and systemic delivery of bisphosphonates inhibits the development of particle-induced osteolysis. Other methods of inhibiting osteolysis include the use of anabolic agents and altering the implant design. Few studies examined non-surgical rescue of loosened implants, with conflicting results with alend[...]

Strontium(II) and mechanical loading additively augment bone formation in calcium phosphate scaffolds


Calcium phosphate cements (CPCs) are widely used for bone-defect treatment. Current developments comprise the fabrication of porous scaffolds by three-dimensional plotting and doting using biologically active substances, such as strontium. Strontium is known to increase osteoblast activity and simultaneously to decrease osteoclast resorption. This study investigated the short- and long-term in vivo performances of strontium(II)-doted CPC (SrCPC) scaffolds compared to non-doted CPC scaffolds after implantation in unloaded or load-bearing trabecular bone defects in sheep. After 6 weeks, both CPC and SrCPC scaffolds exhibited good biocompatibility and osseointegration. Fluorochrome labeling revealed that both scaffolds were penetrated by newly formed bone already after 4 weeks. Neither strontium doting nor mechanical loading significantly influenced early bone formation. In contrast, after 6 months, bone formation was significantly enhanced in SrCPC compared to CPC scaffolds. Energy dispersive X-ray analysis demonstrated the release of strontium from the SrCPC into the bone. Strontium addition did not significantly influence material resorption or osteoclast formation. Mechanical loading significantly stimulated bone formation in both CPC and SrCPC scaffolds after 6 months without impairing scaffold integrity. The most bone was found in SrCPC scaffolds under load-bearing conditions. Concluding, these results demonstrate that strontium doting and mechanical loading additively s[...]

Quantification of regional variations in glenoid trabecular bone architecture and mineralization using clinical computed tomography images


The purpose of this study was to demonstrate feasibility of a clinical CT imaging and analysis technique to quantify regional variations in trabecular bone architecture and mineralization of glenoid bones. Specifically, our objective was to determine to what extent clinical CT imaging of intact upper extremities can describe variations of trabecular bone architectures at anatomic and peri-implant regions by comparing trabecular bone architectures as measured by high-resolution, micro CT imaging of same excised glenoid bones. Bone volume fraction (BVF), trabecular bone thickness (TbTh), number of trabecular bone (TbN), spacing (TbS), pattern factor (TbPf), bone surface area (BSA), and skeletal connectivity (Conn.), in addition to bone mineral content (BMC) and bone mineral density (BMD), were quantified from both clinical and micro CT images using whole bone, anatomic, and peri-implant bone masks. Strong correlations of BVF, TbTh, TbSp, BMC, and BMD were found between clinical CT and micro CT imaging methods. The variations in BVF, TbTh, TbSp, TbN, BMC, and BMD at anatomical and peri-implant regions were larger than those at whole bone regions. In this study, we have demonstrated that this clinical CT imaging methodology can be used to quantify variations of a patient's glenoid bone at anatomic and peri-implant levels. Statement of Clinical Significance. An in vivo quantitative assessment of glenoid trabecular bone architecture in the anatomic and [...]

Issue Information - Cover


Inhibition of fracture healing in the presence of contamination by Staphylococcus aureus: Effects of growth state and immune response


Extremity injuries comprise a significant portion of trauma, affecting quality of life, financial burden, and return to duty. Bacterial contamination is commonly associated with failure to heal, despite antibiotic treatment, suggesting that additional therapies must be developed to combat these complications. Treatment failure is likely due to the presence of resistant microbial communities known as biofilms. Biofilm bacteria are able to elicit a direct inhibition of healing through a multitude of known factors. However, they likely also inhibit healing through alteration of the inflammatory response. As inflammation is a critical step in fracture healing, how the presence of biofilm bacteria shifts this response to one that is suboptimal for healing is an important consideration that is currently understudied. The profile of inflammatory factors in response to biofilm bacteria is unique and distinct from those induced during normal healing or by planktonic bacteria alone. This review will examine the presence of inflammatory factors during normal healing and those induced by contaminating bacteria, and will discuss how these differences may ultimately lead to nonunion. Specifically, this review will focus on the Th1/Th2/Th17 type inflammatory responses and how shifts in the balance of these responses during infection can lead to both ineffective clearance and disruption of fracture healing. [...]

Building better bone: The weaving of biologic and engineering strategies for managing bone loss


Segmental bone loss remains a challenging clinical problem for orthopaedic trauma surgeons. In addition to the missing bone itself, the local tissues (soft tissue, vascular) are often highly traumatized as well, resulting in a less than ideal environment for bone regeneration. As a result, attempts at limb salvage become a highly expensive endeavor, often requiring multiple operations and necessitating the use of every available strategy (autograft, allograft, bone graft substitution, Masquelet, bone transport, etc.) to achieve bony union. A cost-sensitive, functionally appropriate, and volumetrically adequate engineered substitute would be practice-changing for orthopaedic trauma surgeons and these patients with difficult clinical problems. In tissue engineering and bone regeneration fields, numerous research efforts continue to make progress toward new therapeutic interventions for segmental bone loss, including novel biomaterial development as well as cell-based strategies. Despite an ever-evolving literature base of these new therapeutic and engineered options, there remains a disconnect with the clinical practice, with very few translating into clinical use. A symposium entitled “Building better bone: The weaving of biologic and engineering strategies for managing bone loss,” was presented at the 2016 Orthopaedic Research Society Conference to further explor[...]