Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis.

Recent evidence suggests that physical exercise (EX) promotes skeletal development. However, the impact of EX on the progression of bone loss and deterioration of mechanical strength in mice with type 2 diabetic mellitus (T2DM) remains unexplored. In the current study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established with a high-fat diet with two streptozotocin injections (50 mg/kg/body wt) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 min/day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through oxidative stress and suppressed FNDC5/Irisin by binding to its 3'-untranslated region. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine or anti-miRNA-150 transfection in T2DM mice restored FNDC5/Irisin expression and bone formation. Furthermore, EX or recombinant irisin administration prevented T2DM-Induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (si-Nlrp3) or pyroptosis inhibitor (Ac-YVADCMK [AYC]) treatment restores bone mineralization in diabetic mice. Micro-computed tomography scans and mechanical testing revealed that trabecular bone microarchitecture and bone mechanical properties were improved after EX in diabetic mice. Irisin, either induced by skeleton or daily EX or directly administered, prevents bone loss by mitigating inflammasome-associated pyroptosis signaling in diabetic mice. This study demonstrates that EX-induced skeletal irisin ameliorates diabetes-associated glucose intolerance and bone loss and possibly provides a mechanism of its effects on metabolic osteoporosis.

Diabetic Covid-19 severity: Impaired glucose tolerance and pathologic bone loss.

Diabetes mellitus (DM), hypertension, and cardiovascular diseases (CVDs) are the leading chronic comorbidities that enhance the severity and mortality of COVID-19 cases. However, SARS-CoV-2 mediated deregulation of diabetes pathophysiology and comorbidity that links the skeletal bone loss remain unclear. We used both streptozocin-induced type 2 diabetes (T2DM) mouse and hACE2 transgenic mouse to enable SARS-CoV-2-receptor binding domain (RBD) mediated abnormal glucose metabolism and bone loss phenotype in mice. The data demonstrate that SARS-CoV-2-RBD treatment in pre-existing diabetes conditions in hACE2 (T2DM + RBD) mice results in the aggravated osteoblast inflammation and downregulation of Glucose transporter 4 (Glut4) expression via upregulation of miR-294-3p expression. The data also found increased fasting blood glucose and reduced insulin sensitivity in the T2DM + RBD condition compared to the T2DM condition. Femoral trabecular bone mass loss and bone mechanical quality were further reduced in T2DM + RBD mice. Mechanistically, silencing of miR-294 function improved Glut4 expression, glucose metabolism, and bone formation in T2DM + RBD + anti-miR-294 mice. These data uncover the previously undefined role of SARS-CoV-2-RBD treatment mediated complex pathological symptoms of diabetic COVID-19 mice with abnormal bone metabolism via a miRNA-294/Glut4 axis. Therefore, this work would provide a better understanding of the interplay between diabetes and SARS-CoV-2 infection.

Headless Compression Screw Fixation for Proximal Phalanx Fractures: A Biomechanical Study.

Background: Proximal phalanx fractures are common injuries of the hand with multiple treatment options. Intramedullary (IM) screw fixation has become more widely used, and early outcomes are promising. However, biomechanical data regarding this type of fixation are sparse. Methods: Two methods of IM screw fixation of proximal phalanx fractures were tested in cadaver specimens. All specimens were treated with a single antegrade headless compression screw, with half getting the addition of a blocking screw. To test the most common deforming force of flexion-extension, each phalanx was subjected to apex volar 3-point bending using the Materials Testing System test frame. Results: There was no significant difference in the stiffness of 3-point bending with single antegrade screws alone and with a blocking screw (mean, 63.1 vs 52.2 N/mm; P = .27). When comparing smaller with larger specimens, stiffness of the small group was significantly greater than that of the large group when both fixation methods were included (85.3 vs 30.1 N/mm; P < .0002). When comparing stiffness with percent fill of the screw within bone, there was a moderately positive correlation (0.51). Conclusions: Addition of a blocking screw did not increase the stability of the IM screw fixation construct for proximal phalanx fractures. When comparing specimen size, the smaller bones were stiffer under 3-point bending load, regardless of the type of fixation. In addition, those specimens that had a larger longitudinal screw length to bone length ratio were stiffer. These findings provide valuable information as techniques for IM screw fixation of proximal phalanx fractures continue to evolve.

Dual pitch screw design provides equivalent fixation to upsized screw diameter in revision pedicle screw instrumentation: a cadaveric biomechanical study.

BACKGROUND CONTEXT: There are situations that require the replacement of pedicle screws. They are often exchanged when loose or broken or to accommodate a different sized rod or pedicle screw system. Traditionally, pedicle screws are replaced by up-sizing the core diameter until an interference fit is obtained. However, this method carries a risk of pedicle screw breach. PURPOSE: To determine if dual pitch screws, with cancellous pitch in the vertebral body and cortical pitch throughout the pedicle, allows for in-line screw revision without upsizing screw diameter. STUDY DESIGN: Cadaveric biomechanical Study PATIENT SAMPLE: Not applicable OUTCOME MEASURES: Not applicable METHODS: Pedicle screws were tested in the lumbar vertebrae from eleven cadavers. Standard pitch 5.5 mm screws were inserted and loaded using a "break-in" protocol. Screws were removed and replaced with one of four screw types: 5.5 mm Standard Pitch, 5.5 mm Dual Pitch, 6.0 mm Standard Pitch, or 6.0 mm Dual Pitch. Failure testing was done using a stepwise increasing cyclic loading protocol for 100 cycles at each increasing load level. The loading consisted of a combined axial and bending load simulating the load seen by the most inferior screw. RESULTS: Failure was consistent, with the tip of the screw displacing inferiorly into the vertebral body while simultaneously pulling out. Failure strength was lowest in the 5.5mm Standard (135.8±29.4N) followed by 6.0mm Standard (141.8±38.6N), 5.5mm Dual (158.1±53.8N), and 6.0mm Dual (173.6±52.1N, p=.023). There was no difference in the failure strength between the 5.5mm Dual and 6.0mm Standard. Lumbar level (p=.701) and donor spine (p=.062) were not associated with failure strength. CONCLUSIONS: After pedicle screw removal, screws with a larger core diameter or with a dual pitch have similar failure strengths. Dual pitch screws may allow for in-line revision of screws without upsizing screw diameter, minimizing the risk of pedicle breach or fracture. CLINICAL SIGNIFICANCE: Dual pitch screws, with cancellous pitch in the vertebral body and cortical pitch through the pedicle, allows for in-line revision of pedicle screws without upsizing screw diameter; reducing the risk of pedicle breach or fracture when exchanging screws.

Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice.

Rationale: Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied. Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS- heterozygous mouse model. Methods: Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis. Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19. A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1). We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis in vivo. Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice. Results: BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101. In vitro, BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis. Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells. Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling. Treatment of BMMSC-Exo also restored the bone formation and mechanical quality in vivo. Conclusion: These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.

In Vitro Comparison between the Pulvertaft Weave and the Modified Core Suture Pulvertaft Weave.

Background: The Pulvertaft weave was described more than 50 years ago and is still used in tendon transfers. The aim of this study was to evaluate the strength of a modified core suture Pulvertaft weave technique and compare it to the original Pulvertaft weave traditionally used in tendon transfer surgery. Methods: 12 extensor pollicis longus tendons and extensor indices proprius tendons were harvested from fresh frozen cadavers. Six Pulvertaft weaves were performed using FiberWire 4.0 and six core suture tendon weave were performed using FiberLoop 4.0. Biomechanical analysis was performed and stifness, first failure load and ultimate failure load were measured for both set of repairs. Results: The stiffness of the core suture tendon repair (9.5 N/mm) was greater than that of the Pulvertaft repair (2.5 N/mm) The first failure load of the core suture tendon repairs (68.9 N) was greater than the Pulvertaft repairs (19.2 N) and the ultimate failure load of the core suture tendon repairs (101.8 N) was greater than the Pulvertaft repairs (21.9 N). All of these differences were statistically significant. Conclusions: The core suture Pulvertaft weave is a modification to the Pulvertaft weave used in tendon transfers. The results of this cadaveric study suggest it is 5 times stronger than the traditional Pulvertaft repair, potentially allowing it to be used with early active motion protocols after tendon transfers.

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations.

Rationale: Manipulation of the gut microbiome can prevent pathologic bone loss. However, the effects of probiotics on mitochondrial epigenetic remodeling and skeletal homeostasis in the high-fat diet (HFD)-linked obesity remains to be explored. Here, we examined the impact of probiotics supplementation on mitochondrial biogenesis and bone homeostasis through the histone methylation mechanism in HFD fed obese mice. Methods: 16S rRNA gene sequencing was performed to study the microbiota composition in the gut and microbial dysbiosis in obese mouse model. High resolution (microPET/CT) imaging was performed to demonstrate the obese associated colonic inflammation. Obese-associated upregulation of target miRNA in osteoblast was investigated using a microRNA qPCR array. Osteoblastic mitochondrial mass was evaluated using confocal imaging. Overexpression of mitochondrial transcription factor (Tfam) was used to investigate the glycolysis and mitochondrial bioenergetic metabolism using Tfam-transgenic (Tg) mice fed on HFD. The bone formation and mechanical strength was evaluated by microCT analysis and three-point bending analysis. Results: High-resolution imaging (µ-CT) and mechanical testing revealed that probiotics induced a significant increase of trabecular bone volume and bone mechanical strength respectively in obese mice. Probiotics or Indole-3-propionic acid (IPA) treatment directly to obese mice, prevents gut inflammation, and improved osteoblast mineralization. Mechanistically, probiotics treatment increases mitochondrial transcription factor A (Tfam) expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the Tfam promoter. Furthermore, Tfam-transgenic (Tg) mice, fed with HFD, did not experience obesity-linked reduction of glucose uptake, mitochondrial biogenesis and mineralization in osteoblasts. Conclusions: These results suggest that the probiotics mediated changes in the gut microbiome and its derived metabolite, IPA are potentially be a novel agent for regulating bone anabolism via the gut-bone axis.

Bicortical versus unicortical fixation of plated clavicular fractures: A biomechanical study.

PURPOSE: To compare the biomechanical properties of three plate stabilization techniques for midshaft clavicle fractures: anatomical bicortical locking construct, anatomical unicortical locking construct, and reconstruction bicortical locking construct. METHODS: We analyzed superior plating of the clavicle using an anatomical clavicle plate (Acumed) with both bicortical or unicortical screw fixation and a locking reconstruction plate (DePuy-Synthes). Twenty-one fourth generation composite clavicles were used for non-destructive stiffness testing in axial loading, bending, and torsion. Fifteen composite clavicles and 17 foam clavicles were used for cyclic failure testing using a combined loading method that included all three loading modes. RESULTS: No significant differences were found between the three constructs in torsional stiffness nor in vertical bending loading. In axial loading, the anatomical bicortical locking construct was significantly stiffer than either anatomical unicortical locking construct or the reconstruction bicortical locking construct. The unicortical fixation was also significantly stiffer than the reconstruction bicortical locking construct. Regarding failure testing, there was not a significant difference between the bicortical and unicortical anatomical locking constructs; however, both were significantly stronger than bicortical screw fixation in the reconstruction plate. CONCLUSION: Based on the biomechanical performance of these constructs, unicortical locked plate fixation may be a reasonable option in the treatment of displaced midshaft clavicle fracture fixation.

A consideration of factors affecting palliative oral appliance effectiveness for obstructive sleep apnea: a scoping review.

STUDY OBJECTIVES: This scoping review allows physicians, researchers, and others interested in obstructive sleep apnea to consider effectiveness of oral appliances (OAs). The intent is to improve understanding of OA effectiveness by considering morphologic interaction in patients with obstructive sleep apnea. METHODS: Morphologic and biomechanical criteria for positional alterations of the mandible assessed success rates of OA appliances. Searches of databases (Medline, PubMed, The Cochrane Library, EBSCO) using terms: OA treatment effectiveness and positive and/or negative outcome predictors. Craniofacial predictors of OAs and obstructive sleep apnea biomechanical factors of anatomical traits associated with OA effectiveness were included. Databases searched radiographic cephalometric imaging for morphology/phenotypes and apnea-hypopnea index responses. Articles were excluded if title or abstract was not relevant or a case report. If the analysis did not report mean or standard deviation for apnea-hypoxia index, it was excluded. No language, age, or sex restrictions were applied. RESULTS: Analysis of 135 articles included in searched literature indicated alterations in musculature and pharyngeal airway structure through OA use. These alterations were individually unpredictable with wide variability 61.81% ± 12.29 (apnea-hypoxia index mean ± standard deviation). Morphologic variations as predictors were typically weak and idiosyncratic. Biomechanical factors and wide variations in the metrics of appliance application were unclear, identifying gaps in knowledge and practice of OAs. CONCLUSIONS: An integrated basis to identify morphologic and biomechanical elements of phenotypic expressions of sleep-disordered breathing in the design and application of OAs is needed. Current knowledge is heterogeneous and shows high variability. Identification of subgroups of patients with obstructive sleep apnea responding to OAs is needed.

Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism.

Previously, we have shown hyperhomocysteinemia (HHcy) to have a detrimental effect on bone remodeling, which is associated with osteoporosis. During transsulfuration, Hcy is metabolized into hydrogen sulfide (H2S), a gasotransmitter molecule known to regulate bone formation. Therefore, in the present study, we examined whether H2S ameliorates HHcy induced epigenetic and molecular alterations leading to osteoporotic bone loss. To test this mechanism, we employed cystathionine-beta-synthase heterozygote knockout mice, fed with a methionine rich diet (CBS+/- +Met), supplemented with H2S-donor NaHS for 8 weeks. Treatment with NaHS, normalizes plasma H2S, and completely prevents trabecular bone loss in CBS+/- mice. Our data showed that HHcy caused inhibition of HDAC3 activity and subsequent inflammation by imbalancing redox homeostasis. The mechanistic study revealed that inflammatory cytokines (IL-6, TNF-α) are transcriptionally activated by an acetylated lysine residue in histone (H3K27ac) of chromatin by binding to its promoter and subsequently regulating gene expression. A blockade of HDAC3 inhibition in CBS+/- mice by HDAC activator ITSA-1, led to the remodeling of histone landscapes in the genome and thereby attenuated histone acetylation-dependent inflammatory signaling. We also confirmed that RUNX2 was sulfhydrated by administration of NaHS. Collectively, restoration of H2S may provide a novel treatment for CBS-deficiency induced metabolic osteoporosis.

Musculoskeletal Outcomes from Chronic High-Speed, High-Impulse Resistance Exercise.

While bones and muscles adapt to mechanical loading, it appears that very specific types of stimuli must be applied to achieve osteogenesis. Our study assessed musculoskeletal outcomes to 30 training sessions on an Inertial Exercise Trainer (Newnan, GA). Subjects (n=13) performed workouts with their left leg, while their right served as an untreated control. Workouts entailed three 60-s sets each of knee extension, hip extension and calf press exercises, separated by 90-s rests. Before and after the 30 training sessions, subjects underwent strength tests (knee and ankle extensors of both legs), DEXA scans (hip, knee and ankles of both legs), and blood draws. After 30 training sessions 2×2 ANOVAs showed left leg peak torques rose significantly. 2×2 ANCOVAs, with bone scan area as a covariate, showed significant left leg calcaneal bone mineral content (+29%) and density (+33%) increases after 30 training sessions. A significant decline in C-terminal telopeptides of type I collagen, a blood marker of bone resorption, also occurred after 30 training sessions. The Inertial Exercise Trainer's large volume of training session repetitions elicited high peak force, peak acceleration and impulses that likely provided a mechanical loading stimulus that evoked calcaneal accretion.

Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice.

Hydrogen sulfide (H2S) is a novel gasotransmitter produced endogenously in mammalian cells, which works by mediating diverse physiological functions. An imbalance in H2S metabolism is associated with defective bone homeostasis. However, it is unknown whether H2S plays any epigenetic role in bone loss induced by hyperhomocysteinemia (HHcy). We demonstrate that diet-induced HHcy, a mouse model of metabolite induced osteoporosis, alters homocysteine metabolism by decreasing plasma levels of H2S. Treatment with NaHS (H2S donor), normalizes the plasma level of H2S and further alleviates HHcy induced trabecular bone loss and mechanical strength. Mechanistic studies have shown that DNMT1 expression is higher in the HHcy condition. The data show that activated phospho-JNK binds to the DNMT1 promoter and causes epigenetic DNA hyper-methylation of the OPG gene. This leads to activation of RANKL expression and mediates osteoclastogenesis. However, administration of NaHS could prevent HHcy induced bone loss. Therefore, H2S could be used as a novel therapy for HHcy mediated bone loss.

Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification.

Approximately 10% of all bone fractures do not heal, resulting in patient morbidity and healthcare costs. However, no pharmacological treatments are currently available to promote efficient bone healing. Inhibition of Ca2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) reverses age-associated loss of trabecular and cortical bone volume and strength in mice. In the current study, we investigated the role of CaMKK2 in bone fracture healing and show that its pharmacological inhibition using STO-609 accelerates early cellular and molecular events associated with endochondral ossification, resulting in a more rapid and efficient healing of the fracture. Within 7 days postfracture, treatment with STO-609 resulted in enhanced Indian hedgehog signaling, paired-related homeobox (PRX1)-positive mesenchymal stem cell (MSC) recruitment, and chondrocyte differentiation and hypertrophy, along with elevated expression of osterix, vascular endothelial growth factor, and type 1 collagen at the fracture callus. Early deposition of primary bone by osteoblasts resulted in STO-609-treated mice possessing significantly higher callus bone volume by 14 days following fracture. Subsequent rapid maturation of the bone matrix bestowed fractured bones in STO-609-treated animals with significantly higher torsional strength and stiffness by 28 days postinjury, indicating accelerated healing of the fracture. Previous studies indicate that fixed and closed femoral fractures in the mice take 35 days to fully heal without treatment. Therefore, our data suggest that STO-609 potentiates a 20% acceleration of the bone healing process. Moreover, inhibiting CaMKK2 also imparted higher mechanical strength and stiffness at the contralateral cortical bone within 4 weeks of treatment. Taken together, the data presented here underscore the therapeutic potential of targeting CaMKK2 to promote efficacious and rapid healing of bone fractures and as a mechanism to strengthen normal bones. © 2018 American Society for Bone and Mineral Research.

Biomechanics of the Injured Fibula Following Plate Fixation of a Concomitant Tibia Fracture To Fix or Not to Fix?

BACKGROUND: The mechanical role of supplemental fibula fixation in both bone lower leg fractures is not well defined. The benefit of fibula plate fixation in this context is controversial. The purpose of this study was to ascertain the mechanical contributions of the fibula under three conditions (intact, fractured, or plated fibula) following standard tibia locked plating. METHODS: A laboratory fracture model was created with 10 cadaveric legs (5 matched pairs) with no known history of lower extremity trauma or other musculoskeletal conditions. A both bone lower leg fracture was simulated by performing distal osteotomies, 3 to 5 cm above the tibia plafond, leaving a bony defect to simulate an unstable fracture (AOTrauma OTA classification 43-A3). Coronal and sagittal gauge-pins were placed above and below the fracture sites to measure relative displacement across three planes of motion. Axial and torsional loads were applied to the leg under the following conditions: tibia intact and fibula intact (control 1), tibia fracture and fibula intact, tibia fracture and fibula fracture (control 2), and the three conditions of primary interest: tibia plated and fibula intact, tibia plated and fibula fracture (osteotomy), and tibia plated and fibula plated. The load applied for level 1 was 75 N of axial compression and 0.3 Nm of torque, and the load for level 2 was 175 N of axial compression and 1.3 Nm of torque. RESULTS: There were significant differences in motion across the fracture site of the injured leg when the tibia was not plated compared with an intact and plated tibia, p < 0.05. However, when the tibia was plated, there were no significant differences in fracture motion when the fibula was left either intact, osteotomized, or underwent supplemental plate fixation, p > 0.05. This was true regardless of the loads applied. CONCLUSION: The mechanical stability of supplemental fibula fixation in a both bone lower leg fracture model was not significantly improved from standalone distal tibia fixation in this laboratory model. The clinical effects of these findings are yet to be demonstrated.

Assessment of Distal Radioulnar Joint Stability After Reconstruction With the Brachioradialis Wrap.

BACKGROUND: The brachioradialis (BR) wrap technique is an option to restore the stability of the distal radioulnar joint (DRUJ). The technique capitalizes on the BR's advantageous insertion point on the radial styloid and the ability of the BR to be harvested with minimal to no deficit. The tendon can then be wrapped around the radius and ulna, tunneling under the pronator quadratus and extensor compartments and secured back into its insertion to provide stability. In this cadaveric study, we used micro-computed tomography (CT) to assess the stability restored by this procedure. METHODS: Axial CT scans were taken of cadaveric specimens (n = 10) in 3 different positions (neutral, 60° pronation, and 60° supination) to establish the baseline measurements of each DRUJ. Surgical disruption of the dorsal and volar ligaments of each DRUJ then simulated a destabilizing injury and the specimens were scanned again. The specimens then underwent the BR wrap procedure and were scanned once more. Degree of ulnar subluxation with respect to the Sigmoid notch was determined using the modified radioulnar line method. RESULTS: The mean percentages of subluxation in the neutral position for the normal, injured, and reconstructed DRUJ were 22.4±4.9%, 56.2±12.9%, and 29.0±6.5%, respectively. In 60° pronation, these values were 15.4±4.7%, 53.5±15.0%, and 36.5±11.8%, respectively. In 60° supination, these values were 18.6±2.5%, 69.7±20.5%, and 31.9±8.7%, respectively. CONCLUSIONS: Values differed significantly between normal and injured conditions in all positions. No significant difference was noted between normal and reconstructed conditions, suggesting reconstruction improves DRUJ biomechanics and more closely approximates normal stability.

Optimal radial force and size for palliation in gastroesophageal adenocarcinoma: a comparative analysis of current stent technology.

BACKGROUND: The optimal use of esophageal stents for malignant and benign esophageal strictures continues to be plagued with variability in pain tolerance, migration rates, and reflux-related symptoms. The aim of this study was to evaluate the differences in radial force exhibited by a variety of esophageal stents with respect to the patient's esophageal stricture. METHODS: Radial force testing was performed on eight stents manufactured by four different companies using a hydraulic press and a 5000 N force gage. Radial force was measured using three different tests: transverse compression, circumferential compression, and a three-point bending test. Esophageal stricture composition and diameters were measured to assess maximum diameter, length, and proximal esophageal diameter among 15 patients prior to stenting. RESULTS: There was a statistically significant difference in mean radial force for transverse compression tests at the middle (range 4.25-0.66 newtons/millimeter N/mm) and at the flange (range 3.32-0.48 N/mm). There were also statistical differences in mean radial force for circumferential test (ranged from 1.19 to 10.50 N/mm, p < 0.001) and the three-point bending test (range 0.08-0.28 N/mm, p < 0.001). In an evaluation of esophageal stricture diameters and lengths, the smallest median diameter of the stricture was 10 mm (range 5-16 mm) and the median proximal diameter normal esophagus was 25 mm (range 22-33 mm), which is currently outside of the range of stent diameters. CONCLUSIONS: Tested stents demonstrated significant differences in radial force, which provides further clarification of stent pain and intolerance in certain patients, with either benign or malignant disease. Similarly, current stent diameters do not successfully exclude the proximal esophagus, which can lead to obstructive-type symptoms. Awareness of radial force, esophageal stricture composition, and proximal esophageal diameter must be known and understood for optimal stent tolerance.

Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice.

Shorter generation time and the power of genetic manipulation make mice an ideal model system to study bone biology as well as bone diseases. However their small size presents a challenge to perform strength measurements, particularly of the weight-bearing cancellous bone in the murine long bones. We recently developed an improved method to measure the axial compressive strength of the cancellous bone in the distal femur metaphysis in mice. Transverse micro-computed tomography image slices that are 7µm thick were used to locate the position where the epiphysis-metaphysis transition occurs. This enabled the removal of the distal femur epiphysis at the exact transition point exposing the full extent of metaphyseal trabecular bone, allowing more accurate and consistent measurement of its strength. When applied to a murine model system consisting of five month old male wild-type (WT) and Ca(2+)/calmodulin dependent protein kinase kinase 2 (CaMKK2) knockout (KO) Camkk2(-/-) mice that possess recorded differences in trabecular bone volume, data collected using this method showed good correlation between bone volume fraction and strength of trabecular bone. In combination with micro-computed tomography and histology, this method will provide a comprehensive and consistent assessment of the microarchitecture and tissue strength of the cancellous bone in murine mouse models.

Polyaxial Screws in Locked Plating of Tibial Pilon Fractures.

This study examined the axial and torsional stiffness of polyaxial locked plating techniques compared with fixed-angle locked plating techniques in a distal tibia pilon fracture model. The effect of using a polyaxial screw to cross the fracture site was examined to determine its ability to control relative fracture site motion. A laboratory experiment was performed to investigate the biomechanical stiffness of distal tibia fracture models repaired with 3.5-mm anterior polyaxial distal tibial plates and locking screws. Sawbones Fourth Generation Composite Tibia models (Pacific Research Laboratories, Inc, Vashon, Washington) were used to model an Orthopaedic Trauma Association 43-A1.3 distal tibia pilon fracture. The polyaxial plates were inserted with 2 central locking screws at a position perpendicular to the cortical surface of the tibia and tested for load as a function of axial displacement and torque as a function of angular displacement. The 2 screws were withdrawn and inserted at an angle 15° from perpendicular, allowing them to span the fracture and insert into the opposing fracture surface. Each tibia was tested again for axial and torsional stiffness. In medial and posterior loading, no statistically significant difference was found between tibiae plated with the polyaxial plate and the central screws placed in the neutral position compared with the central screws placed at a 15° position. In torsional loading, a statistically significant difference was noted, showing greater stiffness in tibiae plated with the polyaxial plate and the central screws placed at a 15° position compared with tibiae plated with the central screws placed at a 0° (or perpendicular) position. This study showed that variable angle constructs show similar stiffness properties between perpendicular and 15° angle insertions in axial loading. The 15° angle construct shows greater stiffness in torsional loading.

Inhibition of CaMKK2 reverses age-associated decline in bone mass.

Decline in bone formation is a major contributing factor to the loss of bone mass associated with aging. We previously showed that the genetic ablation of the tissue-restricted and multifunctional Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) stimulates trabecular bone mass accrual, mainly by promoting anabolic pathways and inhibiting catabolic pathways of bone remodeling. In this study, we investigated whether inhibition of this kinase using its selective cell-permeable inhibitor STO-609 will stimulate bone formation in 32 week old male WT mice and reverse age-associated of decline in bone volume and strength. Tri-weekly intraperitoneal injections of saline or STO-609 (10 µM) were performed for six weeks followed by metabolic labeling with calcein and alizarin red. New bone formation was assessed by dynamic histomorphometry whereas micro-computed tomography was employed to measure trabecular bone volume, microarchitecture and femoral mid-shaft geometry. Cortical and trabecular bone biomechanical properties were assessed using three-point bending and punch compression methods respectively. Our results reveal that as they progress from 12 to 32 weeks of age, WT mice sustain a significant decline in trabecular bone volume, microarchitecture and strength as well as cortical bone strength. However, treatment of the 32 week old WT mice with STO-609 stimulated apposition of new bone and completely reversed the age-associated decrease in bone volume, quality, as well as trabecular and cortical bone strength. We also observed that regardless of age, male Camkk2(-/-) mice possessed significantly elevated trabecular bone volume, microarchitecture and compressive strength as well as cortical bone strength compared to age-matched WT mice, implying that the chronic loss of this kinase attenuates age-associated decline in bone mass. Further, whereas STO-609 treatment and/or the absence of CaMKK2 significantly enhanced the femoral mid-shaft geometry, the mid-shaft cortical wall thickness and material bending stress remained similar among the cohorts, implying that regardless of treatment, the material properties of the bone remain similar. Thus, our cumulative results provide evidence for the pharmacological inhibition of CaMKK2 as a bone anabolic strategy in combating age-associated osteoporosis.