Comparison of bone microstructures via high-resolution peripheral quantitative computed tomography in patients with different stages of chronic kidney disease before and after starting hemodialysis.

Chronic kidney disease (CKD) negatively affects bone strength; however, the osteoporotic conditions in patients with CKD are not fully understood. Moreover, the changes in bone microstructure between pre-dialysis and dialysis are unknown. High-resolution peripheral quantitative computed tomography (HR-pQCT) reveals the three-dimensional microstructures of the bone. We aimed to evaluate bone microstructures in patients with different stages of CKD. This study included 119 healthy men and 40 men admitted to Nagasaki University Hospital for inpatient education or the initiation of hemodialysis. The distal radius and tibia were scanned with HR-pQCT. Patient clinical characteristics and bone microstructures were evaluated within 3 months of initiation of hemodialysis (in patients with CKD stage 5 D), patients with CKD stage 4-5, and healthy volunteers. Cortical bone parameters were lower in the CKD group than in healthy controls. Tibial cortical and trabecular bone parameters (cortical thickness, cortical area, trabecular volumetric bone mineral density, trabecular-bone volume fraction, and trabecular thickness) differed between patients with CKD stage 5 D and those with CKD stage 4-5 (p < 0.01). These differences were also observed between patients with CKD stage 5 and those with CKD stage 5 D (p < 0.017), but not between patients with CKD stage 4 and those with CKD stage 5, suggesting that the bone microstructure rapidly changed at the start of hemodialysis. Patients with CKD stage 5 D exhibited tibial microstructural impairment compared with those with CKD stage 4-5. HR-pQCT is useful for elucidation of the pathology of bone microstructures in patients with renal failure.

Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing.

Developmental osteogenesis, physiological bone remodelling and fracture healing require removal of matrix and cellular debris. Osteoclasts generated by the fusion of circulating monocytes degrade bone, whereas the identity of the cells responsible for cartilage resorption is a long-standing and controversial question. Here we show that matrix degradation and chondrocyte phagocytosis are mediated by fatty acid binding protein 5-expressing cells representing septoclasts, which have a mesenchymal origin and are not derived from haematopoietic cells. The Notch ligand Delta-like 4, provided by endothelial cells, is necessary for septoclast specification and developmental bone growth. Consistent with the termination of growth, septoclasts disappear in adult and ageing bone, but re-emerge in association with growing vessels during fracture healing. We propose that cartilage degradation is mediated by rare, specialized cells distinct from osteoclasts. Our findings have implications for fracture healing, which is frequently impaired in aging humans.

Exquisite air sac histological traces in a hyperpneumatized nanoid sauropod dinosaur from South America.

This study reports the occurrence of pneumosteum (osteohistological structure related to an avian-like air sac system) in a nanoid (5.7-m-long) saltasaurid titanosaur from Upper Cretaceous Brazil. We corroborate the hypothesis of the presence of an air sac system in titanosaurians based upon vertebral features identified through external observation and computed tomography. This is the fifth non-avian dinosaur taxon in which histological traces of air sacs have been found. We provided a detailed description of pneumatic structures from external osteology and CT scan data as a parameter for comparison with other taxa. The camellate pattern found in the vertebral centrum (ce) of this taxon and other titanosaurs shows distinct architectures. This might indicate whether cervical or lung diverticula pneumatized different elements. A cotylar internal plate of bone tissue sustains radial camellae (rad) in a condition similar to Alamosaurus and Saltasaurus. Moreover, circumferential chambers (cc) near the cotyle might be an example of convergence between diplodocoids and titanosaurs. Finally, we also register for the first time pneumatic foramina (fo) and fossae connecting camellate structures inside the neural canal in Titanosauria and the second published case in non-avian dinosaurs. The extreme pneumaticity observed in this nanoid titanosaur contrasts with previous assumptions that this feature correlates with the evolution of gigantic sizes in sauropodomorphs. This study reinforces that even small-bodied sauropod clades could present a hyperpneumatized postcranial skeleton, a character inherited from their large-bodied ancestors.

Efficacy for Whitlockite for Augmenting Spinal Fusion.

Whitlockite (WH) is the second most abundant inorganic component of human bone, accounting for approximately 25% of bone tissue. This study investigated the role of WH in bone remodeling and formation in a mouse spinal fusion model. Specifically, morphology and composition analysis, tests of porosity and surface area, thermogravimetric analysis, an ion-release test, and a cell viability test were conducted to analyze the properties of bone substitutes. The MagOss group received WH, Group A received 100% beta-tricalcium phosphate (ß-TCP), Group B received 100% hydroxyapatite (HAp), Group C received 30% HAp/70% ß-TCP, and Group D received 60% HAp/40% ß-TCP (n = 10 each). All mice were sacrificed 6 weeks after implantation, and micro-CT, hematoxylin and eosin (HE) staining, and Masson trichome (MT) staining and immunohistochemistry were performed. The MagOss group showed more homogeneous and smaller grains, and nanopores (<500 nm) were found in only the MagOss group. On micro-CT, the MagOss group showed larger fusion mass and better graft incorporation into the decorticate mouse spine than other groups. In the in vivo experiment with HE staining, the MagOss group showed the highest new bone area (mean: decortication group, 9.50%; A, 15.08%; B, 15.70%; C, 14.76%; D, 14.70%; MagOss, 22.69%; p < 0.0001). In MT staining, the MagOss group demonstrated the highest new bone area (mean: decortication group, 15.62%; A, 21.41%; B, 22.86%; C, 23.07%; D, 22.47%; MagOss, 26.29%; p < 0.0001). In an immunohistochemical analysis for osteocalcin, osteopontin, and CD31, the MagOss group showed a higher positive area than other groups. WH showed comparable bone conductivity to HAp and ß-TCP and increased new bone formation. WH is likely to be used as an improved bone substitute with better bone conductivity than HAp and ß-TCP.

Who was buried with Nestor's Cup? Macroscopic and microscopic analyses of the cremated remains from Tomb 168 (second half of the 8th century BCE, Pithekoussai, Ischia Island, Italy).

Cremation 168 from the second half of the 8th century BCE (Pithekoussai's necropolis, Ischia Island, Italy), better known as the Tomb of Nestor's Cup, is widely considered as one of the most intriguing discoveries in the Mediterranean Pre-Classic archaeology. A drinking cup, from which the Tomb's name derives, bears one of the earliest surviving examples of written Greek, representing the oldest Homeric poetry ever recovered. According to previous osteological analyses, the Cup is associated with the cremated remains of a juvenile, aged approximately 10-14 years at death. Since then, a vast body of literature has attempted to explain the unique association between the exceptionality of the grave good complex, the symposiac and erotic evocation of the Nestor's Cup inscription with the young age of the individual buried with it. This paper reconsiders previous assessments of the remains by combining gross morphology with qualitative histology and histomorphometric analyses of the burnt bone fragments. This work reveals the commingled nature of the bone assemblage, identifying for the first time, more than one human individual mixed with faunal remains. These outcomes dramatically change previous reconstructions of the cremation deposit, rewriting the answer to the question: who was buried with Nestor's Cup?.

Regional specialization and fate specification of bone stromal cells in skeletal development.

Bone stroma contributes to the regulation of osteogenesis and hematopoiesis but also to fracture healing and disease processes. Mesenchymal stromal cells from bone (BMSCs) represent a heterogenous mixture of different subpopulations with distinct molecular and functional properties. The lineage relationship between BMSC subsets and their regulation by intrinsic and extrinsic factors are not well understood. Here, we show with mouse genetics, ex vivo cell differentiation assays, and transcriptional profiling that BMSCs from metaphysis (mpMSCs) and diaphysis (dpMSCs) are fundamentally distinct. Fate-tracking experiments and single-cell RNA sequencing indicate that bone-forming osteoblast lineage cells and dpMSCs, including leptin receptor-positive (LepR+) reticular cells in bone marrow, emerge from mpMSCs in the postnatal metaphysis. Finally, we show that BMSC fate is controlled by platelet-derived growth factor receptor ß (PDGFRß) signaling and the transcription factor Jun-B. The sum of our findings improves our understanding of BMSC development, lineage relationships, and differentiation.

Genetically Modified Ferritin Nanoparticles with Bone-Targeting Peptides for Bone Imaging.

Bone homeostasis plays a major role in supporting and protecting various organs as well as a body structure by maintaining the balance of activities of the osteoblasts and osteoclasts. Unbalanced differentiation and functions of these cells result in various skeletal diseases, such as osteoporosis, osteopetrosis, and Paget's disease. Although various synthetic nanomaterials have been developed for bone imaging and therapy through the chemical conjugation, they are associated with serious drawbacks, including heterogeneity and random orientation, in turn resulting in low efficiency. Here, we report the synthesis of bone-targeting ferritin nanoparticles for bone imaging. Ferritin, which is a globular protein composed of 24 subunits, was employed as a carrier molecule. Bone-targeting peptides that have been reported to specifically bind to osteoblast and hydroxyapatite were genetically fused to the N-terminus of the heavy subunit of human ferritin in such a way that the peptides faced outwards. Ferritin nanoparticles with fused bone-targeting peptides were also conjugated with fluorescent dyes to assess their binding ability using osteoblast imaging and a hydroxyapatite binding assay; the results showed their specific binding with osteoblasts and hydroxyapatite. Using in vivo analysis, a specific fluorescent signal from the lower limb was observed, demonstrating a highly selective affinity of the modified nanoparticles for the bone tissue. These promising results indicate a specific binding ability of the nanoscale targeting system to the bone tissue, which might potentially be used for bone disease therapy in future clinical applications.

Global and Spatial Compartmental Interrelationships of Bone Density, Microstructure, Geometry and Biomechanics in the Distal Radius in a Colles' Fracture Study Using HR-pQCT.

Background: Bone parameters derived from HR-pQCT have been investigated on a parameter-by-parameter basis for different clinical conditions. However, little is known regarding the interrelationships of bone parameters and the spatial distribution of these interrelationships. In this work: 1) we investigate compartmental interrelationships of bone parameters; 2) assess the spatial distribution of interrelationships of bone parameters; and 3) compare interrelationships of bone parameters between postmenopausal women with and without a recent Colles' fracture. Methods: Images from the unaffected radius in fracture cases (n=84), and from the non-dominant radius of controls (n=98) were obtained using HR-pQCT. Trabecular voxel-based maps of local bone volume fraction (L.Tb.BV/TV), homogenized volumetric bone mineral density (H.Tb.BMD), homogenized µFEA-derived strain energy density (H.Tb.SED), and homogenized inter-trabecular distances (H.Tb.1/N) were generated; as well as surface-based maps of apparent cortical bone thickness (Surf.app.Ct.Th), porosity-weighted cortical bone thickness (Surf.Ct.SIT), mean cortical BMD (Surf.Ct.BMD), and mean cortical SED (Surf.Ct.SED). Anatomical correspondences across the parametric maps in the study were established via spatial normalization to a common template. Mean values of the parametric maps before spatial normalization were used to assess compartmental Spearman's rank partial correlations of bone parameters (e.g., between H.Tb.BMD and L.Tb.BV/TV or between Surf.Ct.BMD and Surf.app.Ct.Th). Spearman's rank partial correlations were also assessed for each voxel and vertex of the spatially normalized parametric maps, thus generating maps of Spearman's rank partial correlation coefficients. Correlations were performed independently within each group, and compared between groups using the Fisher's Z transformation. Results: All within-group global trabecular and cortical Spearman's rank partial correlations were significant; and the correlations of H.Tb.BMD-L.Tb.BV/TV, H.Tb.BMD-H.Tb.1/N, L.Tb.BV/TV-H.Tb.1/N, Surf.Ct.BMD-Surf.Ct.SED and Surf.Ct.SIT-Surf.Ct.SED were significantly different between controls and fracture cases. The spatial analyses revealed significant heterogeneous voxel- and surface-based correlation coefficient maps across the distal radius for both groups; and the correlation maps of H.Tb.BMD-L.Tb.BV/TV, H.Tb.BMD-H.Tb.1/N, L.Tb.BV/TV-H.Tb.1/N, H.Tb.1/N-H.Tb.SED and Surf.app.Ct.Th - Surf.Ct.SIT yielded small clusters of significant correlation differences between groups. Discussion: The heterogeneous spatial distribution of interrelationships of bone parameters assessing density, microstructure, geometry and biomechanics, along with their global and local differences between controls and fracture cases, may help us further understand different bone mechanisms of bone fracture.

Impaired Bone Microarchitecture in Premenopausal Women With Acromegaly: The Possible Role of Wnt Signaling.

CONTEXT: Acromegaly can impair bone integrity, increasing the risk of vertebral fractures (VFs). OBJECTIVE: To evaluate the impact of isolated GH/IGF-I hypersecretion on bone turnover markers, Wnt inhibitors, bone mineral density (BMD), microarchitecture, bone strength and vertebral fractures in female patients with acromegaly (Acro), compared with healthy control group (HC). DESIGN, SETTING, AND PATIENTS: Cross-sectional study including 83 premenopausal women without any pituitary deficiency:18 acromegaly in remission (AcroR), 12 in group with active acromegaly (AcroA), and 53 HC. Serum procollagen type 1 N-terminal propeptide, ß-carboxy-terminal crosslinked telopeptide of type 1 collagen, osteocalcin, sclerostin, and DKK1 were measured in blood samples. dual-energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography (HR-pQCT) and vertebral fractures evaluation were also assessed simultaneously. MAIN OUTCOME AND RESULTS: AcroA showed significantly lower sclerostin and higher DKK1 compared with HC. On HR-pQCT of tibia and radius, Acro showed impairment of trabecular (area and trabecular number), increased cortical porosity, and increased cortical area and cortical thickness compared with HC. The only significant correlation found with HR-pQCT parameters was a positive correlation between cortical porosity and serum DKK1 (R = 0.45, P = 0.044). Mild VFs were present in approximately 30% of patients. CONCLUSIONS: Eugonadal women with acromegaly without any pituitary deficiency showed increased cortical BMD, impairment of trabecular bone microstructure, and increased VF. Sclerostin was not correlated with any HR-pQCT parameters; however, DKK1 was correlated with cortical porosity in tibia (P = 0.027). Additional studies are needed to clarify the role of Wnt inhibitors on bone microarchitecture impairment in acromegaly.

Fracture Risk Assessment: An Update.

➤: Our ability to accurately identify high fracture risk in individuals has improved as the volume of clinical data has expanded and fracture risk assessment tools have been developed. ➤: Given its accessibility, affordability, and low radiation exposure, dual x-ray absorptiometry (DXA) remains the standard for osteoporosis screening and monitoring response to treatment. ➤: The trabecular bone score (TBS) is a DXA software add-on that uses lumbar spine DXA imaging to produce an output that correlates with bone microarchitecture. It has been identified as an independent fracture risk factor and may prove useful in further stratifying fracture risk among those with a bone mineral density (BMD) in the osteopenic range (-1.0 to -2.4 standard deviations), in those with low-energy fractures but normal or only mildly low BMD, or in those with conditions known to impair bone microarchitecture. ➤: Fracture risk assessment tools, including the Fracture Risk Assessment Tool (FRAX), Garvan fracture risk calculator, and QFracture, evaluate the impact of multiple clinical factors on fracture risk, even in the absence of BMD data. Each produces an absolute fracture risk output over a defined interval of time. When used appropriately, these enhance our ability to identify high-risk patients and allow us to differentiate fracture risk among patients who present with similar BMDs. ➤: For challenging clinical cases, a combined approach is likely to improve accuracy in the identification of high-risk patients who would benefit from the available osteoporosis therapies.

A prospective case-control pilot study to evaluate bone microarchitecture in children and teenagers on long-term parenteral nutrition using HR-pQCT.

Long-term parenteral nutrition (PN) may induce bone complications. Tridimensional bone imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) allow the assessment of both compartmental volumetric densities and microarchitecture. Our aim was to evaluate these parameters in children and teenagers receiving long-term PN. This cross-sectional, case-control study included children older than 9 years undergoing PN for at least 2 years. They were age-, gender- and puberty-matched with healthy controls (1:2). Evaluation included biological assessment of bone metabolism (serum calcium, phosphate, and albumin; urinary calcium and creatinine; 25-OH vitamin D, osteocalcin and PTH), dual X-ray absorptiometry (DXA) and HR-pQCT at the ultradistal tibia and radius. Results are presented as median [range]. Eleven patients (3 girls) with a median age of 16 [9-19] years were included. Bone parameters assessed by HR-pQCT at the ultradistal radius and tibia were similar in patients and controls. Parathyroid hormone (PTH) levels were higher (14 [7-115] vs 16 [12-27]) and osteocalcin levels were lower (44 [15-65] vs 65 [38-142]) in patients than in controls, although within the normal range. Conclusions: there were no differences for compartmental bone densities and microarchitecture in patients undergoing chronic PN. Further longitudinal studies are required to confirm these quite reassuring preliminary results.

Liquid-phase ASEM imaging of cellular and structural details in cartilage and bone formed during endochondral ossification: Keap1-deficient osteomalacia.

Chondrogenesis and angiogenesis drive endochondral ossification. Using the atmospheric scanning electron microscopy (ASEM) without decalcification and dehydration, we directly imaged angiogenesis-driven ossification at different developmental stages shortly after aldehyde fixation, using aqueous radical scavenger glucose solution to preserve water-rich structures. An embryonic day 15.5 mouse femur was fixed and stained with phosphotungstic acid (PTA), and blood vessel penetration into the hypertrophic chondrocyte zone was visualised. We observed a novel envelope between the perichondrium and proliferating chondrocytes, which was lined with spindle-shaped cells that could be borderline chondrocytes. At postnatal day (P)1, trabecular and cortical bone mineralisation was imaged without staining. Additional PTA staining visualised surrounding soft tissues; filamentous connections between osteoblast-like cells and osteocytes in cortical bone were interpreted as the osteocytic lacunar-canalicular system. By P10, resorption pits had formed on the tibial trabecular bone surface. The applicability of ASEM for pathological analysis was addressed using knockout mice of Keap1, an oxidative-stress sensor. In Keap1-/- femurs, we observed impaired calcification and angiogenesis of epiphyseal cartilage, suggesting impaired bone development. Overall, the quick ASEM method we developed revealed mineralisation and new structures in wet bone tissue at EM resolution and can be used to study mineralisation-associated phenomena of any hydrated tissue.

In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength and Low Bone Turnover.

INTRODUCTION: Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture, and strength in the obese population remains unknown. METHODS: Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay, body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry, whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography. Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D. RESULTS: Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49 ±â€…3.0 and 6.03 ±â€…2.47 vs 4.24 ±â€…2.72 ng/mL, respectively, P = 0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28 ±â€…0.10 and 0.29 ±â€…0.13 vs 0.21 ±â€…0.15 ng/mL, respectively, P = 0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (P = 0.003) and CTx (P = 0.005), greater trabecular separation at the tibia and radius (P = 0.03 and P = 0.04, respectively), and lower tibial failure load and stiffness (both P = 0.04), relative to obese men without T2D. CONCLUSION: In men, the combination of obesity and T2D is associated with reduced bone turnover and poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D, suggesting worse bone disease.

Netrin-1 regulates ERK1/2 signaling pathway and autophagy activation in wear particle-induced osteoclastogenesis.

BACKGROUND: Artificial joint replacement surgery is often accompanied by osteolysis induced aseptic loosening around the prosthesis. Wear particles from joint replacement are thought to be one of the main factors leading to local inflammation and osteolysis at the prosthesis site. The aim of this study was to investigate the molecular mechanism of osteoclast formation and dissolution induced by wear particles and the potential roles of Netrin-1, the ERK1/2 pathway and autophagy activation in this process. METHODS: The messenger RNA levels in cells and tissues were detected with real-time quantitative PCR. The western blotting was used to detect the expression of proteins. A CCK-8 kit was used to detect the viability of RAW 264.7 cells. Moreover, an air pouch model of bone resorption was established. Immunohistochemistry was used to detect the expression of TRAP and Netrin-1 in rat bone tissue. Cell culture supernatants were collected in the rat air pouch model of bone resorption, and the levels of RANKL and OPG were detected with enzyme-linked immunosorbent assay. The protein levels of TRAP and Netrin-1 in bone tissue were examined by immunohistochemistry. RESULTS: Titanium wear particles induced osteoclast formation and autophagy activation. Moreover, blocking autophagy suppressed the osteoclastogenesis after exposure to wear particles in vitro. The activation of the ERK1/2 pathway and the overexpression of Netrin-1 were both found to play important roles in osteoclastogenesis mediated by autophagy. Moreover, 3-MA effectively decreased the secretion of proinflammatory cytokines mediated by wear particles. CONCLUSION: Blockade of autophagy inhibits the osteoclastogenesis and inflammation induced by wear particles, thus potentially providing novel treatment strategies for abnormal osteoclastogenesis and aseptic prosthesis loosening induced by wear particles.

Investigation of Mechanical, Material, and Compositional Determinants of Human Trabecular Bone Quality in Type 2 Diabetes.

CONTEXT: Increased bone fragility and reduced energy absorption to fracture associated with type 2 diabetes (T2D) cannot be explained by bone mineral density alone. This study, for the first time, reports on alterations in bone tissue's material properties obtained from individuals with diabetes and known fragility fracture status. OBJECTIVE: To investigate the role of T2D in altering biomechanical, microstructural, and compositional properties of bone in individuals with fragility fracture. METHODS: Femoral head bone tissue specimens were collected from patients who underwent replacement surgery for fragility hip fracture. Trabecular bone quality parameters were compared in samples of 2 groups, nondiabetic (n = 40) and diabetic (n = 30), with a mean duration of disease 7.5 ± 2.8 years. RESULTS: No significant difference was observed in aBMD between the groups. Bone volume fraction (BV/TV) was lower in the diabetic group due to fewer and thinner trabeculae. The apparent-level toughness and postyield energy were lower in those with diabetes. Tissue-level (nanoindentation) modulus and hardness were lower in this group. Compositional differences in the diabetic group included lower mineral:matrix, wider mineral crystals, and bone collagen modifications-higher total fluorescent advanced glycation end-products (fAGEs), higher nonenzymatic cross-link ratio (NE-xLR), and altered secondary structure (amide bands). There was a strong inverse correlation between NE-xLR and postyield strain, fAGEs and postyield energy, and fAGEs and toughness. CONCLUSION: The current study is novel in examining bone tissue in T2D following first hip fragility fracture. Our findings provide evidence of hyperglycemia's detrimental effects on trabecular bone quality at multiple scales leading to lower energy absorption and toughness indicative of increased propensity to bone fragility.

Time-lapsed imaging of nanocomposite scaffolds reveals increased bone formation in dynamic compression bioreactors.

Progress in bone scaffold development relies on cost-intensive and hardly scalable animal studies. In contrast to in vivo, in vitro studies are often conducted in the absence of dynamic compression. Here, we present an in vitro dynamic compression bioreactor approach to monitor bone formation in scaffolds under cyclic loading. A biopolymer was processed into mechanically competent bone scaffolds that incorporate a high-volume content of ultrasonically treated hydroxyapatite or a mixture with barium titanate nanoparticles. After seeding with human bone marrow stromal cells, time-lapsed imaging of scaffolds in bioreactors revealed increased bone formation in hydroxyapatite scaffolds under cyclic loading. This stimulatory effect was even more pronounced in scaffolds containing a mixture of barium titanate and hydroxyapatite and corroborated by immunohistological staining. Therefore, by combining mechanical loading and time-lapsed imaging, this in vitro bioreactor strategy may potentially accelerate development of engineered bone scaffolds and reduce the use of animals for experimentation.

Enhanced BMP-2-Mediated Bone Repair Using an Anisotropic Silk Fibroin Scaffold Coated with Bone-like Apatite.

The repair of large bone defects remains challenging and often requires graft material due to limited availability of autologous bone. In clinical settings, collagen sponges loaded with excessive amounts of bone morphogenetic protein 2 (rhBMP-2) are occasionally used for the treatment of bone non-unions, increasing the risk of adverse events. Therefore, strategies to reduce rhBMP-2 dosage are desirable. Silk scaffolds show great promise due to their favorable biocompatibility and their utility for various biofabrication methods. For this study, we generated silk scaffolds with axially aligned pores, which were subsequently treated with 10× simulated body fluid (SBF) to generate an apatitic calcium phosphate coating. Using a rat femoral critical sized defect model (CSD) we evaluated if the resulting scaffold allows the reduction of BMP-2 dosage to promote efficient bone repair by providing appropriate guidance cues. Highly porous, anisotropic silk scaffolds were produced, demonstrating good cytocompatibility in vitro and treatment with 10× SBF resulted in efficient surface coating. In vivo, the coated silk scaffolds loaded with a low dose of rhBMP-2 demonstrated significantly improved bone regeneration when compared to the unmineralized scaffold. Overall, our findings show that this simple and cost-efficient technique yields scaffolds that enhance rhBMP-2 mediated bone healing.

Synthesis of N,N'-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide that ameliorate osteoarthritis symptoms and improve bone marrow matrix structure and cartilage alterations induced by monoiodoacetate in the rat model: "Suggested potent anti-inflammatory agent against COVID-19".

To assess the chondroprotective effect and influence of N,N'-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide (dpdo) that was synthesized through the reaction of phenazone with sebacoyl chloride and screened for its biological activity especially as anti-arthritic and anti-inflammatory agent in a monoiodoacetate (MA)-induced experimental osteoarthritis (OA) model. Thirty male albino rats weighing "190-200 g" were divided randomly into three groups (10 each): control, MA-induced OA, and MA-induced OA + dpdo. In MA-induced OA rat, the tumor necrosis factor alpha, interleukin 6, C-reactive protein, rheumatoid factors, reactive oxygen species, as well as all the mitochondrial markers such as mitochondria membrane potential, swelling mitochondria, cytochrome c oxidase (complex IV), and serum oxidative/antioxidant status (malondialdehyde level and activities of myeloperoxidase and xanthine oxidase) are elevated. Also, the activity of succinate dehydrogenase (complex II), levels of ATP, the level of glutathione (GSH), and thiol were markedly diminished in the MA-induced OA group compared to the normal control rats. These findings showed that mitochondrial function is associated with OA pathophysiological alterations and high gene expressions of (IL-6, TNF-a, and IL-1b) and suggests a promising use of dpdo as potential ameliorative agents in the animal model of OA and could act as anti-inflammatory agent in case of severe infection with COVID-19. It is clearly appeared in improving the bone cortex and bone marrow in the treated group with the novel compound in histological and transmission electron microscopic sections which is a very important issue today in fighting severe infections that have significant effects on the blood indices and declining of blood corpuscles like COVID-19, in addition to declining the genotoxicity and inflammation induced by MA in male rats. The novel synthesized compound was highly effective in improving all the above mentioned parameters.

Laser fabrication of structural bone: surface morphology and biomineralization assessment.

The current work explores the surface morphology of the laser-ablated bone using Yb-fiber coupled Nd:YAG laser (λ = 1064 nm) in continuous wave mode. As the laser-ablated region contains physiochemically modified carbonized and nonstructural region, it becomes unknown material for the body. Thus, biomineralization on such a laser-ablated region was assessed by in vitro immersion test in noncellular simulated body fluid. The presence of hydroxyapatite was detected in the precipitated mineral product using scanning electron microscopy equipped with energy dispersive spectroscopy, and X-ray diffraction analysis. The effect of varying laser parameters on distribution of surface morphology features was identified and its corresponding effect on biomineralization was studied.

The Effects of Ivacaftor on Bone Density and Microarchitecture in Children and Adults with Cystic Fibrosis.

CONTEXT: Cystic fibrosis (CF) transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown. OBJECTIVE: To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF. DESIGN: Prospective observational multiple cohort study. SETTING: Outpatient clinical research center within a tertiary academic medical center. PATIENTS OR OTHER PARTICIPANTS: Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within 3 months (Ivacaftor cohort), 26 subjects with CF were not treated with ivacaftor (CF Control cohort), and 26 healthy volunteers. INTERVENTIONS: All treatments, including Ivacaftor, were managed by the subjects' pulmonologists. MAIN OUTCOME MEASURES: Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years. RESULTS: Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children. CONCLUSIONS: Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.