Overwrapping Bivalved Casts: Does the Material Matter?

BACKGROUND: Circumferential integrity of bivalved casts (cut twice longitudinally) can be restored by overwrapping with different materials. This study compared the mechanical properties of solid casts and bivalved casts overwrapped with semirigid fiberglass (SF), elastic bandages (EB), and rigid fiberglass (RF) using an overwrapped-bivalved cast-bone fracture (OBCBF) model. METHODS: This study used an MTS Bionix Servohydraulic system to test properties of OBCBF models in 4 conditions: intact Control made of RF (not bivalved or overwrapped), a Rigid overwrapped model made of a Control bivalved and overwrapped with RF, a Semirigid overwrapped model made of a Control bivalved and overwrapped with SF, and an Elastic model made of a Control bivalved and overwrapped with EB. Constructs were tested in 4-point bending. Force-displacement curves (FDC) were generated to calculate load-at-critical-failure (LCF, angulation > 10 degrees = 6.6 mm vertical deformation) and stiffness. RESULTS: Five controls and 30 OBCBF models with 3 overwrapped cast types were tested, with each overwrapped cast type tested with 2 orientations of the initial cast bivalve axis, yielding 7 conditions (Control, Rigid 0 degrees, Rigid 90 degrees, Semirigid 0 degrees, Semirigid 90 degrees, Elastic 0 degrees, Elastic 90 degrees). Mean LCF was: Rigid 90 degrees > Rigid 0 degrees > Control > Semirigid 0 degrees > Semirigid 90 degrees > Elastic 90 degrees > Elastic 0 degrees (P<0.0001). Mean stiffness was: Rigid 0 degrees > Rigid 90 degrees > Control > Semirigid 90 degrees > Semirigid 0 degrees > Elastic 0 degrees > Elastic 90 degrees (P<0.0001). Multiple comparisons indicated no significant difference between LCF and stiffness for Semirigid 0 degrees/90 degrees casts compared with Controls. CONCLUSIONS: Mechanical properties of overwrapped bivalved casts change depending on the materials used to overwrap, with higher LCF and stiffness when overwrapping with RF > SF > EB; however, mean comparisons indicate that rigid bivalved casts overwrapped with SF did not have significantly different mean stiffness and LCF from controls and other cast models. CLINICAL RELEVANCE: This study compares the bending properties of a bivalved cast-construct overwrapped with different materials, providing basic science evidence for orthopaedic surgeons who have several choices of materials to overwrap bivalved casts.

Severity Of Radiographic Osteoarthritis: Association with Improved Patient Reported Outcomes Following Knee Arthroplasty.

INTRODUCTION: The Kellgren and Lawrence (KL) classification for knee osteoarthritis estimates disease severity. Its utility in predicting patient-reported outcomes (PROs) after primary total knee arthroplasty (pTKA) has been suggested. We hypothesized that patients who had higher preoperative KL grades would demonstrate greater improvements in PROs after pTKA. METHODS: This was a retrospective review of patients who underwent pTKA between 2016 and 2021. Two observers graded preoperative radiographs (KL1/2, KL3, and KL4). Knee Injury and Osteoarthritis Outcome Score (KOOS) for activities of daily living (KOOS-ADL) and pain (KOOS-Pain) were collected at preoperative and 12-month postoperative visits. Changes in KOOS-ADL (ΔADL) and changes in KOOS-Pain (ΔPain) scores were compared from the preoperative to 12-month postoperative mark across different groups, with the minimal clinically important difference (MCID) for both ΔADL (MCID-ADL) and ΔPain (MCID-Pain) also being calculated. A P-value of < 0.05 was considered statistically significant. RESULTS: A total of 1651 patients were included in the study. The KL3 and KL4 groups exhibited significantly higher ΔADL scores and ΔPain scores compared with the KL1/2 group (P < 0.01). Patients who had KL3 and KL4 were 1.42 (P = 0.03) and 1.88 (P < 0.01) times, respectively, more likely to achieve MCID-ADL compared with those who had KL1/2. Furthermore, patients who had a KL4 were 1.92 times (P < 0.01) more likely to reach MCID-Pain compared with those who had KL1/2. CONCLUSIONS: This study determined that patients who had higher preoperative KL grades experienced markedly greater improvements in KOOS-ADL and KOOS-Pain scores than those who had lower KL grades. These findings offer surgeons an objective tool when counseling patients on expected outcomes after pTKA.

Non-inferiority and Safety of Increased Povidone-Iodine (Betadine) Concentration for Irrigation Following Primary Total Joint Arthroplasty (TJA).

Introduction Diluted Betadine (Purdue Pharma, Stamford, Conn) irrigation following primary total joint arthroplasty (pTJA) may reduce the risk of periprosthetic joint infection (PJI). A recent in vitro study found a minimal inhibitory concentration (MIC) of 0.63% Povidone-iodine (Betadine) for several bacterial isolates. This study reports outcomes of patients undergoing TJA using 0.54% Betadine irrigation compared to a historical cohort using 0.3% Betadine irrigation. Methods A retrospective chart review of patients who underwent pTJA from September 2017 to December 2020. 0.3% Betadine was used in a historical cohort and 0.54% Betadine in the experimental group. Patient demographics, intra-operative data, all-cause revision, and infection data were collected for the three-month post-operative period. Outcome frequencies between groups were compared using Fisher-Exact tests. Results Six hundred sixty-one patients underwent pTJA: 308 total knee arthroplasty (TKA), and 353 total hip arthroplasty (THA). 0.3% Betadine group had seven (3.1%) revisions: five (2.2%) underwent a revision for non-infectious reasons, and two (0.9%) for PJI. 0.54% Betadine group had 11 (2.5%) revisions: nine (2.1%) underwent revision for non-infectious reasons, two (0.4%) for PJI. No significant difference was found for rates of all-cause revision or infection between groups. No adverse intra-operative events occurred with the higher Betadine concentration. Conclusion This study demonstrated no difference in rates of all-cause revision or PJI when using 0.3% Betadine versus 0.54% Betadine for irrigation following pTJA. No adverse intraoperative events occurred with 0.54% Betadine irrigation. Given recent in vitro data supporting increased Betadine MIC, our results showed safety and non-inferiority with respect to three-month post-operative complication rates. Further investigation through a large powered randomized controlled study is needed to determine the optimal Betadine irrigation concentration for PJI prevention is required.

Risk Factors for Increased Hospital Costs for Primary Total Hip Arthroplasty.

BACKGROUND: Patient medical complexity increases the cost of primary total hip arthroplasty (THA). The goal of this study was to quantify the impact of specific medical comorbidities on the real hospital cost of primary THA. METHODS: This study consisted of a retrospective analysis of 1,222 patient encounters for Current Procedural Terminology code 27130 (primary THA) between January 2017 and March 2020 at a high-volume urban academic medical center. Patient demographics, comorbidities, and admission data were collected, and univariate and multivariate gamma regression analyses were performed to identify associations with increased costs incurred during THA admission. RESULTS: The median total cost for THA was $30,580. Univariate analysis showed increased cost for body mass index (BMI) > 35 versus BMI < 35 ($31,739 versus 30,071; P < .05), American Society of Anesthesiologists (ASA) score 3 to 4 versus ASA 1 to 2 ($32,268 versus 30,045; P < .05), prevalence of diabetes ($31,523 versus 30,379; P < .05), congestive heart failure ($34,814 versus 30,584; P < .05), peripheral vascular disease (PVD) ($35,369 versus 30,573; P < .05), chronic pulmonary disease (CPD) ($34,625 versus 30,405; P < .05), renal disease ($31,973 versus 30,352; P < .05), and increased length of stay (r = 0.424; P < .05). Multivariate gamma regression showed that BMI > 35 (relative risk [RR] = 1.05), ASA 3 to 4 (RR = 1.07), PVD (RR = 1.29), CPD (RR = 1.13), and renal disease (RR = 1.09) were independently associated with increased THA hospital cost (P < .01). Increased costs seen in BMI > 35 versus BMI < 35 patients were largely due to hospital room and board ($6,345 versus 5,766; P = .01) and operating room costs ($5,744 versus 5,185; P < .05). CONCLUSIONS: A BMI > 35, PVD, CPD, renal disease, and ASA 3 to 4 are associated with higher inpatient hospital costs for THA. LEVEL OF EVIDENCE: Level III; Retrospective cohort study.

Social Media Use and Its Impact on Physician Review Website Ratings in Hip and Knee Arthroplasty.

BACKGROUND: The growth in social media (SM) use and consumer-driven health care has led more patients to rate surgeons on physician review websites (PRWs). This study assessed surgeon's professional SM presence and its relationship to PRW ratings. METHODS: This was a cross-sectional study of the American Association of Hip and Knee Surgeons members as of June 15, 2021. The presence of SM (Facebook, Twitter, Instagram, YouTube, LinkedIn, ResearchGate, and personal professional website) and PRW (Google [G], Healthgrades [HG], and Vitals [V]) ratings were collected. Statistical analyses compared PRW ratings among surgeons who did and did not have Any SM, defined as having at least one of the following SM accounts: Facebook; Twitter; Instagram; or YouTube. RESULTS: Of the 2,455 surgeons, 550 (22%) had Any SM. Compared to surgeons who did not have Any SM, surgeons who had Any SM had significantly higher G, HG, and V overall scores (G:4.1 versus 3.7; HG:4.3 versus 4.1; V:4.0 versus 3.8; P < .01), number of ratings (G:36.9 versus 26.5; HG:56.8 versus 38.3; V:45.6 versus 30.9; P < .01), and number of comments (G:24.4 versus 16.4; HG:35.2 versus 22.0; V:21.5 versus 12.3; P < .01). Surgeons who had Any SM were 1.8 (1.4 to 2.3; P < .01), 1.5 (1.2 to 1.9; P < .01), and 1.5 (1.2 to 1.9; P < .01) times more likely to have a G, HG, and V score of ≥4.0, respectively, than surgeons who did not have Any SM. CONCLUSIONS: Surgeons who had Any SM demonstrated a significant association with higher PRW overall scores, number of ratings, and number of comments, suggesting that SM presence may increase surgeon PRW ratings.

Increased 90-Day Mortality and Morbidity Among Patients Recovering From Elective Primary Arthroplasty During the COVID-19 Pandemic in New York City.

All elective procedures were stopped in March 2020 because of the coronavirus disease 2019 (COVID-19) pandemic. We report the 90-day mortality and complications of patients who underwent primary arthroplasty before the stopping of elective procedures at a single academic medical center. A retrospective cohort study was conducted including patients who underwent elective primary arthroplasty between December 2019 and mid-March 2020. Their 90-day postoperative mortality and medical complications were statistically compared with those of a historical cohort from the same operative period in 2019. The 2020 and 2019 cohorts included 372 and 410 patients, respectively. Except for the prevalence of diabetes, there was no significant difference between the two cohorts regarding baseline characteristics or preoperative health. The 2020 cohort had statistically significant higher rates of pneumonia (2.7% vs 0.7%; P=.03), readmission (9.1% vs 5.4%; P=.04), pulmonary embolism (1.6% vs 0.2%; P=.04), and 90-day mortality (1.1% vs 0%; P=.04). The 2020 cohort also had a trend for increased rates of deep venous thrombosis (1.1% vs 0.7%; P=.7) and cardiac complications (1.9% vs 0.5%; P=.07) and no change in emergency department visits (14.0% vs 11.7%; P=.3). There were 7 confirmed cases of COVID-19 in the 2020 cohort and 1 death. This study demonstrates that patients who underwent primary arthroplasty procedures at our institution close to the time of the first wave of the COVID-19 pandemic experienced a statistically significant increase in mortality, pneumonia, pulmonary embolism, and readmission compared with a historical cohort. As elective procedures have resumed during the ongoing pandemic, providers and patients should be aware of these increased risks. [Orthopedics. 202x;4x(x):xx-xx.].

Skin Reactions Following Primary Total Knee Arthroplasty With an Adhesive Superficial Closure System: A Case Series.

BACKGROUND: We investigated a skin adhesive closure device consisting of a self-adhesive polyester mesh placed over the surgical incision, followed by a liquid adhesive that is spread over the mesh and surrounding the skin. It is intended to reduce wound closure times, scarring, and skin complications associated with traditional closure with sutures or staples. The aim of this study was to report on skin reactions in patients who underwent primary total knee arthroplasty (TKA) using the skin adhesive closure system. METHODS: A retrospective review of patients who underwent TKA using adhesive closure between 2016 to 2021 at a single institute was performed. A total of 1,719 cases were analyzed. Patient demographics were collected. The primary outcome was any postoperative skin reaction. Skin reactions were classified as allergic dermatitis, cellulitis, or other. Treatment(s), duration of symptoms, and surgical infections were also collected. RESULTS: A total of 5.0% (86) of patients were found to have any type of skin reaction following their TKA. Of these 86, 39 (2.3%) had symptoms of allergic dermatitis (AD), 23 (1.3%) had symptoms of cellulitis, and 24 (1.4%) had other symptoms. A total of 27 (69%) allergic dermatitis patients were treated with a topical corticosteroid cream only; their symptoms resolved within an average of 25 days. There was only 1 case of superficial infection (<0.001%). No prosthetic joint infections were observed. CONCLUSION: Despite skin reactions appearing in 5.0% of cases, the rate of infection was low. A patient-specific preoperative workup and effective treatment strategies can minimize complications associated with adhesive closure system and increase patient satisfaction following TKA.

Validation of 2 Novel and Complementary Training Platforms for Small Joint Arthroscopy.

PURPOSE: We developed 2 complementary low-fidelity models to be used to create the tool skills needed to perform small joint arthroscopy. The purpose of the study was to establish the face and construct validity of the 2 models. METHODS: The "foundation model" was constructed from lemon and radish sections, and the "advanced model" was constructed from a chicken knee. Using both models, novice, intermediate, and experienced participants were asked to perform specific tasks and were timed and scored on their performance. The experienced surgeons were given a 16-item survey to rate how closely each model emulated reality to determine face validity. RESULTS: For the foundation model, the mean total time for the completion of tasks was 1,138 seconds for novices, 1,059 seconds for intermediates, and 631 seconds for experienced, with significant differences between the groups for time to complete 2 of the tasks. With a maximum possible score of 50 points for the correct performance of all tasks, the mean total performance score was 23 for novices, 31.8 for intermediates, and 42.2 for experienced operators. For the advanced model, the mean total time for completion was 266 seconds for novices, 147 seconds for intermediates, and 72 seconds for experienced participants. With a maximum possible score of 31 points for the correct performance of all tasks, the mean total performance score was 1.9 for novices, 15.0 for intermediates, and 24.3 for experienced participants. The average scores for the face validity surveys using a 5-point Likert scale were 4.2 and 4.5 of 5 possible points for the foundation and advanced models, respectively. CONCLUSIONS: Experienced operators completed the tasks more quickly and had higher performance scores than the operators in other groups. This correlation between experience and performance suggests that both models have construct validity. The face validity scores were on the upper end of the scale, suggesting that both models emulate reality for experienced operators. CLINICAL RELEVANCE: These novel models provide low-cost, available and valid simulations conducive to high-repetition training.

Black and Hispanic Patients Do Not Stay Longer After Primary Total Knee Arthroplasty: Results From an Urban Center Serving a Predominantly Minority Cohort.

INTRODUCTION: Previous reports identified minority race/ethnicity to be an independent risk factor for prolonged length of stay (LOS); however, these cohorts consisted of predominantly White patients. This study sought to evaluate minority status as an independent risk factor for prolonged LOS after primary total knee arthroplasty (TKA) in a predominantly Hispanic and Black cohort. METHODS: This was a retrospective study using an institutional database of patients who underwent primary TKA between the years 2016 and 2019. Demographic and socioeconomic data, smoking, body mass index (BMI), medical comorbidities, discharge disposition, and 30-day readmission rates were collected. Patients were first categorized into racial/ethnic groups (Hispanic, Black, or White). An univariate analysis was performed comparing patient characteristics between racial/ethnic groups using the Wilcoxon rank sum, chi-squared, and Fisher exact tests. We then categorized patients into two groups-normal LOS (discharged on postoperative day 1 to 2) and prolonged LOS (discharged after postoperative day 2). An univariate analysis was again performed comparing patient characteristics between LOS groups using Wilcoxon rank sum, chi-squared, and Fisher exact tests. After identifying risk factors markedly associated with LOS, a multivariate logistic regression analysis was performed to identify independent risk factors for prolonged LOS. RESULTS: A total of 3,093 patients were included-47.9% Hispanic and 38.3% Black. Mean LOS was 2.9 ± 1.6 days. An univariate analysis found race/ethnicity, age, low socioeconomic status (SES), discharge disposition, insurance type, weekday of surgery, BMI >40, smoking, increased American Society of Anesthesiologists (ASA)/Charlson Comorbidity Index (CCI) and several medical comorbidities to be associated with prolonged LOS (P < 0.05). A multivariate logistic regression analysis found Black and Hispanic patients were less likely to have prolonged LOS after adjusting for associated risk factors. White race/ethnicity, nonhome discharge, low SES, weekday of surgery, smoking, BMI >40, and increased ASA and CCI were identified as independent risk factors for prolonged LOS (P < 0.05). The overall 30-day readmission rate was 3.6%, with no notable difference between racial/ethnic and LOS groups (P = 0.98 and P = 0.78). CONCLUSION: In contrast to previous reports, our study found that after adjusting for associated risk factors, minority patients do not have prolonged LOS after primary TKA in an urban, socioeconomically disadvantaged, predominantly minority patient cohort. White race/ethnicity, nonhome discharge, low SES, weekday of surgery, smoking, BMI >40, increased CCI, and ASA were all found to be independent risk factors for prolonged LOS. These findings highlight the need to further investigate the role of race/ethnicity on LOS after primary TKA using large-scale, randomized controlled trials with equally represented patient cohorts.

Estrogen depletion on In vivo osteocyte calcium signaling responses to mechanical loading.

Microstructural adaptation of bone in response to mechanical stimuli is diminished with estrogen deprivation. Here we tested in vivo whether ovariectomy (OVX) alters the acute response of osteocytes, the principal mechanosensory cells of bone, to mechanical loading in mice. We also used super resolution microscopy (Structured Illumination microscopy or SIM) in conjunction with immunohistochemistry to assess changes in the number and organization of "osteocyte mechanosomes" - complexes of Panx1 channels, P2X7 receptors and CaV3 voltage-gated Ca2+ channels clustered around αvß3 integrin foci on osteocyte processes. Third metatarsals bones of mice expressing an osteocyte-targeted genetically encoded Ca2+ indicator (DMP1-GCaMP3) were cyclically loaded in vivo to strains from 250 to 3000 µÎµ and osteocyte intracellular Ca2+ signaling responses were assessed in mid-diaphyses using multiphoton microscopy. The number of Ca2+ signaling osteocytes in control mice increase monotonically with applied strain magnitude for the physiological range of strains. The relationship between the number of Ca2+ signaling osteocytes and loading was unchanged at 2 days post-OVX. However, it was altered markedly at 28 days post-OVX. At loads up to 1000 µÎµ, there was a dramatic reduction in number of responding (i.e. Ca2+ signaling) osteocytes; however, at higher strains the numbers of Ca2+ signaling osteocytes were similar to control mice. OVX significantly altered the abundance, make-up and organization of osteocyte mechanosome complexes on dendritic processes. Numbers of αvß3 foci also staining with either Panx 1, P2X7R or CaV3 declined by nearly half after OVX, pointing to a loss of osteocyte mechanosomes on the dendritic processes with estrogen depletion. At the same time, the areas of the remaining foci that stained for αvß3 and channel proteins increased significantly, a redistribution of mechanosome components suggesting a potential compensatory response. These results demonstrate that the deleterious effects of estrogen depletion on skeletal mechanical adaptation appear at the level of mechanosensation; osteocytes lose the ability to sense small (physiological) mechanical stimuli. This decline may result at least partly from changes in the structure and organization of osteocyte mechanosomes, which contribute to the distinctive sensitivity of osteocytes (particularly their dendritic processes) to mechanical stimulation.

Role of pannexin 1 channels in load-induced skeletal response.

The pannexin 1 (Panx1) channel is a mechanosensitive channel that interacts with P2X7 receptors (P2X7R) to form a functional complex that has been shown in vitro to play an essential role in osteocyte mechanosignaling. While the participation of P2X7R in skeletal responses to mechanical loading has been demonstrated, the role of Panx1 and its interplay with P2X7R still remain to be determined. In this study, we use a global Panx1-/- mouse model and in vivo mechanical loading to demonstrate that Panx1 channels play an essential role in load-induced skeletal responses. We found that absence of Panx1 not only disrupts the P2X7R-Panx1 signaling complex, but also alters load-induced regulation of P2X7R expression. Moreover, lack of Panx1 completely abolished load-induced periosteal bone formation. Load-induced regulation of ß-catenin and sclerostin expression was dysregulated in Panx1-/- , compared to wild-type, bone. This finding suggests that Panx1 deficiency disrupts Wnt/ß-catenin signaling by lowering ß-catenin while favoring inhibition of bone formation by increasing load-induced sclerostin expression. This study demonstrates the existence of a Panx1-dependent mechanosensitive mechanism that not only modulates ATP signaling but also coordinates Wnt/ß-catenin signaling that is essential for proper skeletal response to mechanical loading.

Osteocyte calcium signals encode strain magnitude and loading frequency in vivo.

Osteocytes are considered to be the major mechanosensory cells of bone, but how osteocytes in vivo process, perceive, and respond to mechanical loading remains poorly understood. Intracellular calcium (Ca2+) signaling resulting from mechanical stimulation has been widely studied in osteocytes in vitro and in bone explants, but has yet to be examined in vivo. This is achieved herein by using a three-point bending device which is capable of delivering well-defined mechanical loads to metatarsal bones of living mice while simultaneously monitoring the intracellular Ca2+ responses of individual osteocytes by using a genetically encoded fluorescent Ca2+ indicator. Osteocyte responses are imaged by using multiphoton fluorescence microscopy. We investigated the in vivo responses of osteocytes to strains ranging from 250 to 3,000 [Formula: see text] and frequencies from 0.5 to 2 Hz, which are characteristic of physiological conditions reported for bone. At all loading frequencies examined, the number of responding osteocytes increased strongly with applied strain magnitude. However, Ca2+ intensity within responding osteocytes did not change significantly with physiological loading magnitudes. Our studies offer a glimpse into how these critical bone cells respond to mechanical load in vivo, as well as provide a technique to determine how the cells encode magnitude and frequency of loading.

Lactation-Induced Changes in the Volume of Osteocyte Lacunar-Canalicular Space Alter Mechanical Properties in Cortical Bone Tissue.

Osteocytes can remove and remodel small amounts of their surrounding bone matrix through osteocytic osteolysis, which results in increased volume occupied by lacunar and canalicular space (LCS). It is well established that cortical bone stiffness and strength are strongly and inversely correlated with vascular porosity, but whether changes in LCS volume caused by osteocytic osteolysis are large enough to affect bone mechanical properties is not known. In the current studies we tested the hypotheses that (1) lactation and postlactation recovery in mice alter the elastic modulus of bone tissue, and (2) such local changes in mechanical properties are related predominantly to alterations in lacunar and canalicular volume rather than bone matrix composition. Mechanical testing was performed using microindentation to measure modulus in regions containing solely osteocytes and no vascular porosity. Lactation caused a significant (∼13%) reduction in bone tissue-level elastic modulus (p < 0.001). After 1 week postweaning (recovery), bone modulus levels returned to control levels and did not change further after 4 weeks of recovery. LCS porosity tracked inversely with changes in cortical bone modulus. Lacunar and canalicular void space increased 7% and 15% with lactation, respectively (p < 0.05), then returned to control levels at 1 week after weaning. Neither bone mineralization (assessed by high-resolution backscattered scanning electron microscopy) nor mineral/matrix ratio or crystallinity (assessed by Raman microspectroscopy) changed with lactation. Thus, changes in bone mechanical properties induced by lactation and recovery appear to depend predominantly on changes in osteocyte LCS dimensions. Moreover, this study demonstrates that tissue-level cortical bone mechanical properties are rapidly and reversibly modulated by osteocytes in response to physiological challenge. These data point to a hitherto unappreciated role for osteocytes in modulating and maintaining local bone mechanical properties. © 2016 American Society for Bone and Mineral Research.

A new perspective on mechanisms governing skeletal complications in type 1 diabetes.

This review focuses on bone mechanobiology in type 1 diabetes (T1D), an area of research on diabetes-associated skeletal complications that is still in its infancy. We first provide a brief overview of the deleterious effects of diabetes on the skeleton and of the knowledge gained from studies with rodent models of T1D. Second, we discuss two specific hallmarks of T1D, low insulin and high glucose, and address the extent to which they affect skeletal health. Third, we highlight the mechanosensitive nature of bone tissue and the importance of mechanical loading for bone health. We also summarize recent advances in bone mechanobiology that implicate osteocytes as the mechanosensors and major regulatory cells in the bone. Finally, we discuss recent evidence indicating that the diabetic bone is "deaf" to mechanical loading and that osteocytes are central players in mechanisms that lead to bone loss in T1D.

P2X7R-Panx1 Complex Impairs Bone Mechanosignaling under High Glucose Levels Associated with Type-1 Diabetes.

Type 1 diabetes (T1D) causes a range of skeletal problems, including reduced bone density and increased risk for bone fractures. However, mechanisms underlying skeletal complications in diabetes are still not well understood. We hypothesize that high glucose levels in T1D alters expression and function of purinergic receptors (P2Rs) and pannexin 1 (Panx1) channels, and thereby impairs ATP signaling that is essential for proper bone response to mechanical loading and maintenance of skeletal integrity. We first established a key role for P2X7 receptor-Panx1 in osteocyte mechanosignaling by showing that these proteins are co-expressed to provide a major pathway for flow-induced ATP release. To simulate in vitro the glucose levels to which bone cells are exposed in healthy vs. diabetic bones, we cultured osteoblast and osteocyte cell lines for 10 days in medium containing 5.5 or 25 mM glucose. High glucose effects on expression and function of P2Rs and Panx1 channels were determined by Western Blot analysis, quantification of Ca2+ responses to P2R agonists and oscillatory fluid shear stress (± 10 dyne/cm(2)), and measurement of flow-induced ATP release. Diabetic C57BL/6J-Ins2Akita mice were used to evaluate in vivo effects of high glucose on P2R and Panx1. Western blotting indicated altered P2X7R, P2Y2R and P2Y4R expression in high glucose exposed bone cells, and in diabetic bone tissue. Moreover, high glucose blunted normal P2R- and flow-induced Ca2+ signaling and ATP release from osteocytes. These findings indicate that T1D impairs load-induced ATP signaling in osteocytes and affects osteoblast function, which are essential for maintaining bone health.

Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes.

Osteocyte apoptosis is required to induce intracortical bone remodeling after microdamage in animal models, but how apoptotic osteocytes signal neighboring "bystander" cells to initiate the remodeling process is unknown. Apoptosis has been shown to open pannexin-1 (Panx1) channels to release adenosine diphosphate (ATP) as a "find-me" signal for phagocytic cells. To address whether apoptotic osteocytes use this signaling mechanism, we adapted the rat ulnar fatigue-loading model to reproducibly introduce microdamage into mouse cortical bone and measured subsequent changes in osteocyte apoptosis, receptor activator of NF-κB ligand (RANKL) expression and osteoclastic bone resorption in wild-type (WT; C57Bl/6) mice and in mice genetically deficient in Panx1 (Panx1KO). Mouse ulnar loading produced linear microcracks comparable in number and location to the rat model. WT mice showed increased osteocyte apoptosis and RANKL expression at microdamage sites at 3 days after loading and increased intracortical remodeling and endocortical tunneling at day 14. With fatigue, Panx1KO mice exhibited levels of microdamage and osteocyte apoptosis identical to WT mice. However, they did not upregulate RANKL in bystander osteocytes or initiate resorption. Panx1 interacts with P2X7 R in ATP release; thus, we examined P2X7 R-deficient mice and WT mice treated with P2X7 R antagonist Brilliant Blue G (BBG) to test the possible role of ATP as a find-me signal. P2X7 RKO mice failed to upregulate RANKL in osteocytes or induce resorption despite normally elevated osteocyte apoptosis after fatigue loading. Similarly, treatment of fatigued C57Bl/6 mice with BBG mimicked behavior of both Panx1KO and P2X7 RKO mice; BBG had no effect on osteocyte apoptosis in fatigued bone but completely prevented increases in bystander osteocyte RANKL expression and attenuated activation of resorption by more than 50%. These results indicate that activation of Panx1 and P2X7 R are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes and implicate ATP as an essential signal mediating this process.

Bone microdamage, remodeling and bone fragility: how much damage is too much damage?

Microdamage resulting from fatigue or 'wear and tear' loading contributes to bone fragility; however, the full extent of its influence is not completely understood. Linear microcracks (∼50-100 µm) and diffuse damage (clusters of sublamellar-sized cracks) are the two major bone microdamage types, each with different mechanical and biological consequences. Healthy bone, due to its numerous microstructural interfaces and its ability to affect matrix level repair, deals effectively with microdamage. From a material standpoint, healthy bone behaves much like engineering composites like carbon-fiber reinforced plastics. Both materials allow matrix damage to form during fatigue loading and use microstructural interfaces to dissipate energy and limit microcrack propagation to slow fracture. The terms fracture toughness and 'toughening mechanism', respectively, describe mechanical behavior and microstructural features that prevent crack growth and make it harder to fracture a material. Critically, toughness is independent of strength. In bone, primary toughening features include mineral and collagen interfaces, lamellae and tissue heterogeneity among osteons. The damage tolerance of bone and other composites can be overcome with sustained loading and/or matrix changes such that the microstructure no longer limits microcrack propagation. With reduced remodeling due to aging, disease or remodeling suppression, microdamage accumulation can occur along with loss of tissue heterogeneity. Both contribute additively to reduced fracture toughness. Thus, the answer to the key question for bone fragility of how much microdamage is too much is extremely complex. It ultimately depends on the interplay between matrix damage content, internal repair and effectiveness of matrix-toughening mechanisms.

Structural and mechanical repair of diffuse damage in cortical bone in vivo.

Physiological wear and tear causes bone microdamage at several hierarchical levels, and these have different biological consequences. Bone remodeling is widely held to be the mechanism by which bone microdamage is repaired. However, recent studies showed that unlike typical linear microcracks, small crack damage, the clusters of submicron-sized matrix cracks also known as diffuse damage (Dif.Dx), does not activate remodeling. Thus, the fate of diffuse damage in vivo is not known. To examine this, we induced selectively Dif.Dx in rat ulnae in vivo by using end-load ulnar bending creep model. Changes in damage content were assessed by histomorphometry and mechanical testing immediately after loading (ie, acute loaded) or at 14 days after damage induction (ie, survival ulnae). Dif.Dx area was markedly reduced over the 14-day survival period after loading (p < 0.02). We did not observe any intracortical resorption, and there was no increase in cortical bone area in survival ulnae. The reduction in whole bone stiffness in acute loaded ulnae was restored to baseline levels in survival ulnae (p > 0.6). Microindentation studies showed that Dif.Dx caused a highly localized reduction in elastic modulus in diffuse damage regions of the ulnar cortex. Moduli in these previously damaged bone areas were restored to control values by 14 days after loading. Our current findings indicate that small crack damage in bone can be repaired without bone remodeling, and they suggest that alternative repair mechanisms exist in bone to deal with submicron-sized matrix cracks. Those mechanisms are currently unknown and further investigations are needed to elucidate the mechanisms by which this direct repair occurs.

In muscle lengthening surgery multiple aponeurotomy does not improve intended acute effects and may counter-indicate: an assessment by finite element modelling.

The goal was to assess the effects of multiple aponeurotomy on mechanics of muscle with extramuscular myofascial connections. Using finite element modelling, effects of combinations of the intervention carried out at a proximal (P), an intermediate (I) and a distal (D) location were studied: (1) Case P, (2) Case P-I, (3) Case P-D and (4) Case P-I-D. Compared to Case P, the effects of multiple interventions on muscle geometry and sarcomere lengths were sizable for the distal population of muscle fibres: e.g. at high muscle length (1) summed gap lengths between the cut ends of aponeurosis increased by 16, 25 and 27% for Cases P-I, P-D and P-I-D, respectively, (2) characteristic substantial sarcomere shortening became more pronounced (mean shortening was 26, 29, 30 and 31% for Cases P, P-I, P-D and P-I-D, respectively) and (3) fibre stresses decreased (mean stress equalled 0.49, 0.39, 0.38 and 0.33 for Cases P, P-I, P-D and P-I-D, respectively). In contrast, no appreciable effects were shown for the proximal population. The overall change in sarcomere length heterogeneity was limited. Consequently, the effects of multiple aponeurotomy on muscle length-force characteristics were marginal: (1) a limited reduction in active muscle force (maximal 'muscle weakening effect' remained between 5 and 11%) and (2) an even less pronounced change in slack to optimum length range of force exertion (maximal 'muscle lengthening effect' distally was 0.2% for Case P-I-D) were shown. The intended effects of the intervention were dominated by the one intervention carried out closer to the tendon suggesting that aponeurotomies done additionally to that may counter-indicated.