The potential of sericin, a protein derived from silkworms, is explored in bone graft applications. Sericin's biocompatibility, hydrophilic nature, and cost-effectiveness make it a promising candidate for enhancing traditional graft materials. Its antioxidant, anti-inflammatory, and UV-resistant properties contribute to a healthier bone-healing environment, and its incorporation into 3D-printed grafts could lead to personalized medical solutions. However, despite these promising attributes, there are still gaps in our understanding. The precise mechanism through which sericin influences bone cell growth and healing is not fully understood, and more comprehensive clinical trials are needed to confirm its long-term biocompatibility in humans. Furthermore, the best methods for incorporating sericin into existing graft materials are still under investigation, and potential allergic reactions or immune responses to sericin need further study.

Bone Scan Index (BSI) is an image biomarker for quantification on bone metastasis of cancers. To compute BSI, not only the hotspots (metastasis) but also the bones have to be segmented. Most related researches focus on binary classification on bone scintigraphy: having metastasis or none. Rare studies focus on pixelwise segmentation. In this study we compare three advanced convolutional neural network (CNN) based models to explore the bone segmentation on dataset in house. The best model is Mask R-CNN, which reaches the precision, sensitivity and F1-score: 0.93, 0.87, 0.90 for prostate cancer patients and 0.92, 0.86, 0.88 for breast cancer patients, respectively. The results are the average of 10-fold cross-validation, which reveals the reliability for clinical use on bone segmentation.

Thermoplastic molded regenerated silk was proposed as structural material in tissue engineering applications, mainly for application in bone. The protocol allows to obtain a compact non-porous material with a compression modulus in the order of a Giga Pascal starting from silk fibroin by compressing a silk fibroin lyophilized sponge of powder in mold at temperature higher than the glass transition temperature (Tg). The main purpose of the produced resin was the osteofixation and other structural applications in which the lack of porosity was not an issue. In this work, we introduced the use of citric acid in the thermoplastic molding protocol of SF to obtain a porosity inside the structural material. In addition to the previously developed protocols the addition of citric acid allowed us to obtain a structural material. The CA powder during the compression acted as a template for the pore formation. In addition, the CA was able to effectively crosslink the SF chain improving the mechanical strength. This effect was proved both evaluating the compression modulus and by studying the spectra obtained by Fourier infrared spectroscopy (FTIR). This protocol may be applied in the near future to the production of a structural bone scaffold.

Purpose: to assess any differences on marginal bone loss between bone-level or tissue-level dental implants through a review of literature until September 2019. Materials and methods: MEDLINE, Embase and other database were searched by two independent authors. The search was limited to articles in English. Results: The search provided 1028 records and, after removing the duplicates through titles and abstracts screening, 45 full-text articles were assessed for eligibility. For qualitative analysis 20 articles were included, 17 articles of them for quantitative analysis. A total of 1161 patients (mean age 54,4 years) and 2933 implants were observed, 1427 (Tissue-level) and 1506 (Bone-level). The survival rate and the success rate were more than 90%, except for 2 studies with a success rate of 88% and 86.2%. No studies reported any differences between groups in term of success and survival rates. Three studies showed that BL-implants had statistically less marginal bone loss (P< 0.05). Only one study reported statistically less marginal bone loss in TL-implants (P< 0.05). In the most part of the studies, differences between implant types in marginal bone loss were not statistically significant. Conclusion: Despite to the peri-implant tissue around transmucosal implants has been reported to be inflammation-free because of the absence of bacterial infiltration in the micro-gap between the fixture and abutment, no clinical and radiological differences were highlighted between groups from the included studies after a variable period of follow-up ranged between 1 to 5 years.

The objective of this case report is to introduce a customized CAD/CAM freeze-dried bone allograft (FDBA) block for its use in Guided Bone Regeneration (GBR) procedures for severely deficient maxillary bones. Additionally, a special newly developed remote incision technique is presented to avoid wound dehiscence. The results show an optimal integration behaviour of the FDBA block after six months and the formation of new vital bone. Thus, the results of the present case report confirm the use of the customized CAD/CAM bone block for augmentation of complex defects in the maxillary aesthetic zone as a successful treatment concept.

Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs) were mediated one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with invaded naïve PD-MSCs, invaded PRL-1(+) PD-MSCs showed improved integrin-dependent migration ability through RHO family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplanted PRL-1(+) PD-MSCs through the integrin family. Additionally, an increase in PDGFRA by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSCs transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs by activating IL-6 signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understanding of therapeutic mechanisms based on miRNA-mediated stem cell therapy in liver diseases.

Octacalcium phosphate (OCP) is a precursor of biological apatite crystals that has attracted attention as a possible bone substitute. On the other hand, few studies have examined this material at the experimental level due to the limitations of OCP mass production. Recently, mass production technology of OCP was developed, and the launch of OCP bone substitutes is occurring. In this study, the bone regeneration capacity of OCP products was compared with two of the most clinically used materials: heat-treated bovine bone (BHA) and sintered biphasic calcium phosphate (BCP). Twelve rabbits were used, and defects in each tibia were filled with OCP, BHA, BCP, and left unfilled as control (CON). The tibias were harvested at 4 and 12 weeks, and 15 μm slides were prepared using the diamond grinding method after being embedded in resin. Histological and histomorphometric analyses were performed to evaluate the bone regeneration ability and mechanism. The OCP showed significantly higher resorption and new bone formation in both periods analysed (p<0.05). Overall, OCP bone substitutes can enhance bone regeneration significantly by activating osteoblasts and a rapid phase transition of OCP crystals to biological apatite crystals (mineralisation), as well as providing additional space for new bone formation by rapid resorption.

Listeria monocytogenes is a Gram-positive pathogenic bacterium which can be found in soil or water. Infection with the microorganism can occur after ingestion of contaminated food products. Small and large outbreaks of listeriosis have been described in the past. L. monocytogenes can cause a number of different clinical syndromes, most frequently sepsis, meningitis, and rhombencephalitis, particularly in immunocompromised hosts. L. monocytogenes systemic infections can develop following tissue penetration across the gastrointestinal tract or to hematogenous spread to sterile sites, possibly evolving towards bacteremia. L. monocytogenes only rarely causes bone or joint infections, usually in the context of prosthetic material that can provide a site for bacterial seeding. We describe here the clinical findings of invasive listeriosis, mainly focusing on diagnosis, clinical management and treatment of bone and vertebral infections occurring in the context of invasive listeriosis.

Abstract: A biomaterial is proposed for closing extensive bone defects in the maxillofacial region. The composition of the biomaterial includes high-molecular chitosan, chondroitin sulfate, hyaluronate, heparin, alginate and inorganic nanostructured hydroxyapatite. The purpose of the study is to demonstrate morphological and histological early signs of reconstruction of a bone cavity of critical size. The studies were carried out on 84 white female rats weighing 200-250 g. The study group consisted of 84 subjects in total, 40 in the experimental group and 44 in the control group. In all animals, three-walled bone defects measuring 0.5 x 04 x 05 cm were applied subperiosteally in the region of the angle of the lower jaw and filled in experimental group using lyophilized gel mass of chitosan-alginate-hydroxyapatite (CH-SA-HA). In control animals, the bone cavities were filled with an auto-blood clot after bone trepanation and bleeding. The observation periods are 3.5.7 days, 2.3.4.6.8 and 10 weeks. The control of bone regeneration was carried out using multiple morphological and histological analyses. Results showed that following implantation the chitosan construct actively replaced early-stage defects with the formation of a full-fledged new bone tissue as compared to the control group. Already, by the 7th day morphological analysis showed that formation of spongy bone tissue could be seen. After 2 weeks there was a pronounced increase in bone volume (P<0.01), and at 6 weeks after surgical intervention the closure of the defect was 70-80%, after 8 weeks - 100% without violation of bone morphology with a high degree of mineralization. Thus, the use of modified chitosan after filling eliminates bone defects of a critical size in the maxillofacial region, reveals early signs of bone regeneration, and serves as a promising material in reconstructive dentistry.

Thyroid hormones have a catabolic effect on bone homeostasis. Hence, this study aimed to evaluate serum vitamin D, calcium, and phosphate and bone marker levels and bone mineral density (BMD) among patients with different thyroid diseases. This cross-sectional study included patients with underlying thyroid diseases (n=64, hyperthyroid; n=53 euthyroid; and n=18, hypothyroid) and healthy controls (n=64). BMD was assessed using z-score and left hip and lumbar bone density (g/cm2). Results showed that the mean serum vitamin D Levels of all groups was low (<50 nmol/L). Thyroid patients had higher serum vitamin D levels than healthy controls. All groups had normal serum calcium and phosphate levels. The bone marker levels were significantly high in the hyperthyroid group and low in the hypothyroid group. The z-score for hip and spine did not significantly differ between thyroid patients and control groups. The hip bone density was remarkably low in the hyperthyroid group. In all groups, the serum vitamin D levels were below the cutoff value. However, thyroid patients had a higher serum vitamin D level than healthy controls. The carboxy terminal collagen crosslink and procollagen type I N-terminal propeptide levels were high in hyperthyroid patients and low in hypothyroid patients. Further, hyperthyroid patients had a low hip BMD.

Blood-derived products (BP) like citrate-platelet-rich plasma (CPRP) or hyperacute serum (HAS) are known to contain many growth factors. Combined mitogenic and DNA damaging stimuli might lead to increased senescent cell burden and altered senescence-associated secretory pheno-type (SASP). Therefore, the senescent state was extensively tested by γH2AX staining, p21 Q-PCR and western blot, growth curves and senescence associated ß-galactosidase staining. Two main treatments with BP were performed early (immediately after etoposide) and late (after addition-al 11days). Effects of the BP treatment was evaluated by IL-6 and IL-8 measurement as well as collagen (COL1) and p21 mRNA expression. Additionally, XTT assays, cell size measurements, viability assays, and cell number calculations were performed. HAS treated cells in early treat-ment had the lowest observed IL-6 and IL-8. In contrast, there was a clear inflammatory response for IL-8 on HAS and CPRP treated cells in late treatment. For COL1 expression an upregulation in early treatment could be shown, meanwhile cells in the late treatment group remained unaf-fected. In CPRP treated cells, the COL1 expression decreased. All in all, BP treatment seems to have slightly positive effects regarding skin rejuvenation.

If an algebra of type $A$ contains a subalgebra which is also an algebra of type $B$, then it is a Smarandache $B$-type $A$-algebra provided the subalgebra of type $B$ contains at least two elements. This generalizes the notion of Smarandache group, where the group of order $\geq 2$ is a subsemigroup of a semigroup. In this paper we investigate a number of such pairings and we deduce a number of conclusions as a consequence.

Based on recent contributions regarding the treatment of unsteady hydraulic conditions into the state-of-the-art of scour literature, the theoretically derived probability distribution of bridge scour is introduced. The model is derived assuming a rectangular hydrograph shape with a given duration, and random flood peak following a Gumbel distribution. A model extension for a more complex flood event is also presented, assuming a synthetic exponential hydrograph shape. The mathematical formulation can be extended to any flood-peak probability distribution. The aim of the manuscript is to move forward the current approaches adopted for the bridge design coupling hydrological, hydraulic, and erosional models in a mathematical closed form.

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification, resulting in angiogenin (ANG) dependent tsRNA formation. More specifically, m5U54 hypomodification is followed by ANG overexpression and tRNA cleavage near the anticodon, resulting in accumulation of 5’tRNA-derived stress-induced RNAs (5’tiRNAs), in particular 5’tiRNA-GlyGCC and 5’tiRNA-GluCTC. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tsRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tsRNA formation in mammalian cells. These results establish a link between tRNA demethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

Low dietary intake of calcium, vitamin D, vitamin C and magnesium has been associated with increased risk of osteoporosis. The purpose of the study was to evaluate changes in several bone health indicators and metabolic biomarkers in postmenopausal women, with high osteopenia or osteoporosis, followed by a nutritional intervention program. 115 apparently healthy postmenopausal women (52±8 years old) were randomized into four groups: group I (n=40) received daily 1000 mg vitamin C, 100 mcg vitamin D3, 500 mg calcium(Ca) and 300 mg magnesium (Mg); group II (n=42) received daily 100 mcg vitamin D3, 500 mg Ca and 300 mg Mg; group III (n=18) received daily 5 mg bisphosphonates, 100 mcg vitamin D3, 500 mg Ca and 300 mg Mg; and group IV (n=15) received daily about 364 mg polyphenols via an innovative functional food (50 g olive paste enriched with mountain tea extract) along with 100 mcg vitamin D3, 500 mg Ca and 300 mg Mg. Groups I -III received supplementation for a year whereas group IV for 5 months. Changes in bone health indicators and metabolic biomarkers were assessed at the beginning and at the end of the study. Anthropometric indices and whole-body bone mineral density (BMD) were also evaluated at the beginning and at the end of the intervention period. The results revealed improved elevated levels of 25(OH)D3, in groups II, III and IV (+3,71% and +1.45% and +5.62% respectively). Significant positive changes were recorded, for whole-body BMD, in all four study groups. Significant beneficial changes for total cholesterol were observed in group IV (-2.07%, P&lt;0.05) and positive changes in group I for HDL biomarker (+61.62%, P&lt;0.05). Additional larger-scale clinical trials and intervention studies are considered essential, to fully investigate and elucidate associations between dietary components and biochemical indices of bone health.

Abstract. Introduction: BMD study gives partial information on bone health in patients with TSH suppression therapy due to Differentiated Thyroid Cancer (DTC). TBS, a new parameter of bone microarchitecture is propose for bone quality study. This study analyze their long-term use in patients with DTC. Methods: BMD was measured by DXA and TBS with iNsigth software in 145 postmenopausal DTC patients. Vertebral Fractures (VFs) with a semi-quantitative x-ray method. Results: BMD at the end study was not different from initial. TBS decreased from 1.35±0.1 to 1.27±0.1 (p=0.002). PTH, Osteocalcin, and BAP were increased, suggesting increased bone remodeling. There was an increase in osteoporosis and osteopenia (40.6% and 16.5% to 46.6% and 18.6%); 31% had partially degraded and 15.1% degraded TBS changed to 48,9% and 24,8% at the end study. VFs in 30 patients, was not different in age, BMI, calcium and alcohol ingestion, smoking, radioiodine, or thyroid parameters vs. without VFs. Odds ratio for VFs increased with osteopenia (OR 2.63). Combination of TBS plus TBS did not improve discrimination. Conclusions: TBS was lowered while BMD did not differ. Percentage of osteoporosis and osteopenia and of partially degraded and degraded TBS was higher at the end study. Predominant discordance rate was found in partially degraded microarchitecture, in which the proportion of osteopenia was higher than normal or osteoporotic patients. AUC of TBS plus BMD did not improve discrimination. TBS, radioactive iodine, and sedentary lifestyle were the main differential data for patients with DTC and VFs.

Rosavin, a phenylpropanoid in Rhodiola rosea's rhizome, an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin rings formation, and lowers osteoclastogenesis-related gene expression (cathepsin K, CTR, TRAF6, TRAP, MMP-9). It also impedes NFATc1, c-Fos, NF-κB, and MAPK signaling pathways, and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis, osteoblast differentiation and increases Runx2 and OCN expression. In vivo studies show its effectiveness in enhancing BMD in PMOP mice, re-straining osteoclast maturation, and increasing active osteoblast percentage in bone tissue. It modulates mRNA expressions (increasing EEF2 and decreasing HDAC1, thereby activating os-teoprotective epigenetic mechanisms) and alters various serum markers, including decrease of CTX-1, TRAcp5b, RANKL, M-CSF, TRAP, and increase of ALP and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic MMP-3, IL-6, TNF-α, and en-hances anti-osteoporotic IL-10 and TIMP3 expressions. This paper aims to systematically review rosavin's impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions.

(1) Background : Low dietary intake of calcium, vitamin D, vitamin C and magnesium has been associated with increased risk of osteoposrosis. The purpose was to evaluate changes in biomarkers of bone metabolism, and cardiometabolic health in postmenopausal women, with high risk of osteoporosis, followed by a nutritional intervention program. (2) Method: It was a prospective randomized controlled trial. A sample of 115 apparently healthy postmenopausal women(45 -75 years of age) randomized into four groups: (I) nutritional intervention group(n=40) received daily 1000mg vitamin C, 500mg vitamin D3, 500mg calcium(Ca) and 300mg magnesium (Mg); (II) control group(n=42) received daily 500mg vitamin D3, 500mg Ca and 300mg Mg; (III) nutritional intervention group (n=18) received daily 150mg bisphosphonates, 500mg vitamin D3, 500mg Ca and 300mg Mg; and (IV) nutritional intervention group (n=15) received daily about 364 mg polyphenols via an innovative functional food (50g olive paste enriched with mountain tea extract) along with 500mg vitamin D3, 500mg Ca and 300mg Mg. Groups I -III received supplementation for a year whereas group IV for 5 months. Changes in calciregulatory hormone parathormone (PTH) were evaluated at the beginning of the study as well as at 5 and 12 months intervals. Blood levels of vitamin D, vitamin C, Ca, Mg and the lipid profile were assessed at the beginning and at the end of the study. Anthropometric indices (weight, body fat(Kg), Body Mass Index(BMI) and bone mineral density(BMD) were evaluated at the beginning and at the end of the study. Statistical analysis was performed with IBM-SPSS Statistics-21. The level of statistical significance was set at p<0.05. (3) Results: 25(OH)D3 levels were improved, in groups II, III and IV (+3,71% and +1.45% and +5.62% respectively). PTH levels were increased at the end of the intervention period, for groups I and IV. Significant positive changes recorded, in total BMD, in all four study groups. Significant beneficial changes for total cholesterol was observed in group IV (-2.07%, P<0.05) and positive changes in group I for HDL biomarker (+61.62%, P<0.05) (4) Conclusions:. Additional larger-scale clinical trials and intervention studies are considered essential, in order to fully investigate and elucidate associations between dietary components and biochemical indices of bone metabolism.

Pain in osteoarthritis (OA) results from erosion of joint cartilage, resulting in bone contacting bone without an intervening cushion. The periosteum, including its nociceptive innervation, ends at the border of the cartilage meaning that there is no extrinsic neuronal pathway between the opposing denuded bone surfaces to carry a bone-on-bone pain signal to the brain. The pain signaling pathway must therefore originate in nociceptive sensory endings within the subchondral bone itself. Selective ablation of this intrinsic nerve pathway, using any of a variety of approaches, is expected to permanently eliminate OA pain.

Background: Initial phases of molecular and cellular maladaptive bone response at early CKD remain mostly unknown. Methods: We induced mild CKD in SHRs by either arterial hypertension lasting six months (sham-operated rats, SO6) or in its’ combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, correspondently). Sham operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. We measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact PTH and FGF23, Klotho, dickkopf-1, sclerostin. And assessed bone response by static histomorphometric indices and gene expression profiles. Results: Mild CKD groups had no increase in renal Pi excretion, FGF23 and PTH levels. Serum Pi, dickkopf-1, and sclerostin were higher in Nx6. Decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast number. The decline in eroded perimeter was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. Conclusions: We found an association of mild CKD with histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.

Aim: the purpose of the present prospective, case series study were to report implant survival rate and marginal bone remodeling expected five years after loading using dental implants placed in in the daily practice. Material and Methods: this research was designed as an open-cohort, prospective case series study. Any completely or partially edentulous patients scheduled to receive at least one bone leve were considered eligible for this study. Primary outcomes were: cumulative implant (ISR) and prosthetic (PSR) survival rates, and any complications experienced up the five years follow-up. Secondary outcomes were: marginal bone remodeling, implant insertion torque, implant stability quotient (ISQ), and thickness of gingival biotype. Results: ninety consecutive patients (34 males and 56 females; mean age 53.2±15.4 years; range of 24–81 years), 243 implants were placed and followed for at least five years after loading (mean of 65.4±3.1 months; range of 60–72 months). The mean implant insertion torque was 42.9±4.8 Ncm (range from 15 to 45 Ncm). Overall, 83.5% of the implants (n=203) were placed with an insertion torque between 35 and 45 Ncm. At the one year follow-up, no drop-outs were recorded, but 17 patients (18.9%) with 18 restorations (12.6%) delivered on 34 implants (14%) were lost at the five years examination. At the five-year examination, six implants failed in six patients, resulting in a cumulative ISR of 97.5%. At the five-year follow-up, four prostheses failed (2.8%) resulting in a cumulative PSR of 97.2%. At the five-year examination, five complications were reported by five different patients, resulting in a prosthetic success rate of 96.5%, measured at patient level. Five years after loading, mean MBL was 0.41 ± 0.30 mm (95% CI: 0.26–0.34). Difference from the one year data was 0.04 ± 0.19 mm (95% CI: 0.01–0.07). The mean ISQ value at implant placement was 71.6 ± 5.5 (range of 45–88). Six months later, the mean ISQ was 76.7 ± 4.4 (range of 66–89). The difference was statistically significant (P=0.0001). Statistically significant higher MBL was found for smokers, and patient with thin gingival biotype. Conclusions: High implant survival and success rates could be expected with stable marginal bone remodeling up to five years after loading. Smoking and thin tissue biotype were the most important variabilities associated with higher MBL. Further research are needed to confirm these results.

Tissue engineering and regenerative medicine has gradually evolved as a promising therapeutic strategy to the modern healthcare of the aging and diseased population. In this study, we developed a novel nano-fibrous scaffold and verified its application in the critical bone defect regeneration. The metformin-incorporated nano-gelatin/hydroxyapatite fibers (NGF) was produced by electrospinning, cross-linked, and then characterized by XRD and FTIR. Cytotoxicity, cells adhesion, cell differentiation, and quantitative osteogenic gene and protein expression were analyzed by bone marrow stem cells from rat. Rat forearm critical bone defect model was performed for the in vivo study. The nano-gelatin/hydroxyapatite fibers (NGF) were characterized by their porous structures with proper interconnectivity without significant cytotoxic effects; the adhesion of bone marrow stem cells on the nano-gelatin/hydroxyapatite fibers (NGF) could be enhanced. The osteogenic gene and protein expression were upregulated. Post implantation, the new regenerated bone in bone defect was well demonstrated in the NGF samples. We demonstrated that the metformin-incorporated nano-gelatin-hydroxyapatite fibers greatly improved healing potential on the critical sized bone defect. Although metformin-incorporated nano-gelatin/hydroxyapatite fibers had advantageous effectiveness during bone regeneration, further validation is required before it can be applied to clinical applications.

Pericytes, as perivascular cells, are present in all vascularized organs and tissues, and they actively interact with endothelial cells in capillaries and microvessels. Their involvement includes functions like blood pressure regulation, tissue regeneration, and scarring. Studies have confirmed that pericytes play a crucial role in bone tissue regeneration through direct osteodifferentiation processes, paracrine actions, and vascularization. Recent pre-clinical and clinical experiments have shown that combining perivascular cells with osteogenic factors and tissue-engineered scaffolds can be therapeutically effective in restoring bone defects. This approach holds promise for addressing bone-related medical conditions. In this review, we have emphasized the characteristics of pericytes and their involvement in angiogenesis and osteogenesis. Furthermore, we have explored recent advancements in the use of pericytes in preclinical and clinical investigations, indicating their potential as a therapeutic resource in clinical applications.

Intense alterations of mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and represent an important cause of morbidity and decreased quality of life. These disor-ders have traditionally been defined as renal osteodystrophy and classified based on bone biop-sy, but due to a lack of bone biopsy data and validated radiological methods to evaluate bone morphology in children, it has been difficult to adequately evaluate renal osteodystrophy in pe-diatric CKD. This has led to suboptimal management of bone disorders in children. CKD-mineral and bone disorder (CKD-MBD) is a new term used to describe a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is a triad of biochemical imbalances of cal-cium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calci-fication. This literature review aims to explore the pathogenesis, diagnostic approach, and treat-ment of CKD-MBD in children and the specific consequences of renal osteodystrophy on growing skeleton, with a specific focus on the biological basis of this peculiar condition.

Gilbert Syndrome, is a benign condition characterized by persistent indirect hyperbilirubinemia due to reduced UDP-glucuronyltransferase enzyme activity. Its coexistence with other clinical disorders has important clinical and pharmacological implications. GS is known to coexist with many hemolytic conditions and may lead to diagnostic difficulty and also increased incidence of gallstones. UGT1A1 gene has been shown to be involved in the conjugation of various physiologically important endogenous and exogenous compounds, so individuals with Gilbert mutation (the variant allele UGT1A1*28) have an increased risk of toxicity of various drugs and endogenous compounds like irinotecan, steroid hormones, implicated in various human carcinoma like colorectal and breast carcinoma. Deferiprone (DFP) is an orally available chelator used in the management of iron overload in patients with Transfusion Dependent Thalassemia (TDT). In this study, fifteen out of 275 patients with TDT, had a deferiprone-induced joint deformity. Among these fifteen patients with joint deformity, eleven patients (four patients were homozygous for TA 7 repeats and seven were heterozygous for TA7 repeats) had associated gilbert mutation. Therefore, we hypothesize that patients of TDT who had underlying Gilbert mutation might have decreased enzymatic activity of UGTIA6, which metabolizes the DFP, leading to more prominent adverse effects related to DFP.

Aim: In a human pilot case, we used a root formed temporary prosthetical device (Intra-alveolar Device - IAD), to investigate the effect of mechanical stimulation on hard tissue clinically and radiographically. Background: The extraction of a tooth determines the resorption of the alveolar bone. This determines challenge to place an implant and to integrate the prosthesis in soft tissue. Mechanical stimulation is fundamental for bone tropism but is not understood the effect of mechanical stimulation on post-extraction site. Case presentation: A 24 years old woman was enrolled. The IAD’s were used as expected by protocol. Clinical healing was uneventfully. Vertical radiographical bone resorption measured on CBCT was -0,14mm (5,6%) while horizontal bone resorption was -0,21mm (12,36%). Conclusion: This study demonstrated the feasibility of the proposed model. We need clinical prospectical studies enrolling more patients

Tissue engineering has the potential for repairing large bone defects, which impose a heavy financial burden on the public health. However, difficulties with O₂ delivery to the cells residing in the interior of tissue engineering scaffolds make it challenging to grow artificial tissues of clinically-relevant sizes. This study uses image-based simulation in order to provide insight into how to better optimize the scaffold manufacturing parameters, and the culturing conditions, in order to resolve the O₂ bottleneck. To do this, high resolution 3D X-ray images of two common scaffold types (salt leached foam and non-woven fiber mesh) are fed into a Lattice Boltzmann Method fluid dynamics and reactive Lagrangian Scalar Tracking mass transfer solvers. The obtained findings indicate that the scaffolds should have maximal surface area-to-solid volume ratios, for higher chances of the molecular collisions with the cells. Furthermore, the cell culture media should be flown through the scaffold pores as fast as practically possible (without detaching or killing the cells). Finally, we have provided a parametric sweep that maps how the molecular transport within the scaffolds is affected by variations in rates of O₂ consumption by the cells. Ultimately, the results of this study are expected to benefit the computer-assisted design of tissue engineering scaffolds and culturing experiments.

Large volume bone defect regeneration is complex and demands time to complete. Several regeneration phases with unique characteristics including immune responses follow, overlap, and interdepend on each other and, if successful, lead to the regeneration of the organ bone's form and function. However, during traumatic, infectious, or neoplastic clinical cases, the intrinsic bone regeneration capacity may exceed, and surgical intervention is indicated. Scaffold-guided bone regeneration (SGBR) has recently shown efficacy in preclinical and clinical studies. To investigate different SGBR strategies over periods of up to 3 years we have established a well characterized large segmental tibial bone defect ovine model, for which we have developed and optimized immunohistochemistry (IHC) protocols. We present an overview of the immunohistochemical characterization of different experimental groups in which all ovine segmental defects were treated with a bone grafting technique combined with a three-dimensionally printed medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP) scaffold. The qualitative data set is based on osteoimmunological findings gained from IHC analyses of over &gt;350 sheep surgeries over the past two decades. Our systematic and standardized IHC protocols enabled us to gain further insight into the complex and long-drawn-out bone regeneration processes, which ultimately proved to be a critical element for successful translational research.

To evaluate the relative importance of IGF-I expression in various cell types for endochon-dral ossification, we quantified the trabecular bone at the secondary spongiosa and epiphysis of the distal femur in 8-12-week-old male mice with a global knockout of the Igf-I gene as well as conditional deletion of the Igf-I gene in osteoblasts, chondrocytes, osteo-blasts/chondrocytes, and their corresponding control wild type littermates. The osteoblast-, chondrocyte- and osteoblast/chondrocyte-specific Igf-I conditional knockout mice were generated by crossing Igf-I floxed mice with Cre transgenic mice in which Cre expression is under the control of Col1α2 or Col2α1 promoter. We found that global disruption of Igf-I resulted in 80% and 70% reduction in bone size, which is defined as total volume, at the secondary spongiosa and epiphysis of the distal femur, respectively. Abrogation of Igf-I in Col1α2-producing osteoblasts, but not Col2α1-producing chondrocytes, decreased bone size by 25% at both the secondary spongiosa and epiphysis while deletion of the Igf-I globally or specifically in osteoblasts or chondrocytes reduced trabecular bone mass by 25%. By contrast, global Igf-I knockout but not conditional knockout of Igf-I in osteoblasts and/or chondrocytes reduced trabecular bone mass in the epiphysis. The reduced trabecu-lar bone mass at the secondary spongiosa in osteoblast- and/or chondrocyte-specific Igf-I conditional knockout mice is caused by reduced trabecular number and increased trabec-ular separation. Immunohistochemistry studies revealed that expression levels of chon-drocyte (COL10, MMP13) and osteoblast (BSP) markers were reduced in the secondary spongiosa and the epiphyses in the global Igf-I knockout mice. Our data indicate that local and endocrine IGF-I actions in bone are pleiotropic and dependent on cell type as well as the bone compartment where IGF-I acts.

The purpose of this study was to clarify the attachment types of the tibialis anterior tendon (TAT) in Japanese fixed cadavers and to determine the attachment site area in three dimensions. We examined 100 feet from 50 Japanese cadavers. The TAT was classified according to differences in the number of fiber bundles as: Type I, with one fiber bundle; Type II, with two fiber bundles; and Type III, with three fiber bundles. The attachment site area of the TAT was measured using a three-dimensional scanner. Cases were Type II in 95% and Type III in 5%, with no cases of Type I identified. In Type II, mean attachment site areas were 85.2 ± 18.2 mm2 for the medial cuneiform bone (MCB) and 72.4 ± 19.0 mm2 for the first metatarsal bone (1MB), showing a significantly larger area for MCB than for 1MB. These findings suggest the possibility of ethnic differences in TAT attachment types and suggest that TAT attachments in Japanese individuals are highly likely to be Type II, with rare cases of Type III. Accurate measurement of attachment site areas is possible with appropriate three-dimensional measurements.

The risk of malignant transformation of induced pluripotent stem cells (iPSC)-derived cells in response to DNA damage is a potential concern as the tumor suppressor genes TP53 and CDKN2A are transiently inactivated during reprogramming. Here, we evaluated the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using a variety of functional assays, we show that the capacity of i-HF to enter senescence and repair DSB is not compromised after damage induced by ionizing radiation (IR) or overexpression of H-RASV12. Still, i-HF lines are transcriptionally different from their parental lines, showing enhanced metabolic activity and higher expression of p53-related effector genes. As a result, i-HF lines generally exhibit increased sensitivity to various stresses, have an elevated senescence-associated secretory phenotype (SASP) and cannot be immortalized unless p53 expression is knocked down. In conclusion, while our results suggest that i-HF are not at a greater risk of transformation, their overall hyperactivation of senescence pathways may impede their function as a cell therapy product.

Krill oil (KO) shows promise as a natural marine-derived ingredient for improving skin health. This study investigated its antioxidant, anti-inflammatory, anti-wrinkle, and moisturizing effects on skin cells and UVB-induced skin photoaging in hairless mice. In vitro assays on HDF, HaCaT, and B16/F10 cells, and in vivo experiments on 66 hairless mice, were conducted. Mice received oral KO administration (100, 200, or 400 mg/kg) once a day for 15 weeks and UVB radiation three times a week. In vitro, KO significantly countered UVB-induced oxidative stress, reduced wrinkles, and prevented skin water loss by enhancing collagen and hyaluronic synthesis. In vivo, all KO dosages showed dose-dependent inhibition of oxidative stress-induced inflammatory photoaging-related skin changes. Skin mRNA expressions for hyaluronan synthesis and collagen synthesis genes also increased dose-dependently after KO treatment. Histopathological analysis confirmed that Krill Oil (KO) ameliorated the damage caused by UVB-irradiated skin tissues. These findings suggest that KO may be a valuable intervention to mitigate UVB-induced skin photoaging and address various skin concerns.

Background: Chronic Back Pain due to Facet Joint Syndrome is a common and debilitating con-dition. Advances in regenerative medicine have shown that Autologous Unmodified Adipose Tissue-Derived Regenerative Cells (ADRC) provide several beneficial effects [1,2]. These regen-erative cells can differentiate into various tissues [3] and exhibit a strong anti-inflammatory po-tential. ADRCs can be obtained from a small amount of fatty tissue derived from the patient´s abdominal fat. Methods: We report long-term results of 37 patients (age 31-78 years, mean 62.5) suffering from “Facet Joint Syndrome” The pathology was confirmed by clinical, radiological examinations and fluoroscopically guided test injections. Then liposuction was performed. 50-100 cc of fat were harvested. To recover stem cells from adipose tissue, we use the CE-certified Transpose RT™ system from InGeneron GmbH. The cells were then injected under fluoroscopic control in the periarticular fat. Follow-up examinations were performed at one week 1 and 5 years. Results: Every patient reported improved VAS pain at any follow-up (1 week, 1, and 5 years) with ADRCs compared to the baseline. Conclusion: Our observational data indicate that facet joint syndrome patients treated with unmodified adipose tissue-derived regenerative cells experience improved quality of life in the long term.

Currently, there are no pharmacological treatments able to reverse nigral degeneration in Parkinson’s disease (PD), hence the unmet need for the provision of neuroprotective agents. Cannabis-derived phytocannabinoids (CDCs) and resveratrol (RSV) may be useful neuroprotective agents for PD due to their anti-oxidative and anti-inflammatory properties. To evaluate this, we undertook a systematic review of the scientific literature to assess the neuroprotective effects of CDCs and RSV treatments in pre-clinical in vivo animal models of PD. The literature databases MEDLINE, EMBASE, PsychINFO, PubMed and Web of Science core collection were systematically searched to cover relevant studies. A total of 1034 publications were analyzed, of which 18 met the eligibility criteria for this review. Collectively, the majority of neurotoxin-induced PD rodent studies demonstrated that treatment with CDCs or RSV produced a significant improvement in motor function and mitigated the loss of dopaminergic neurons. Biochemical analysis of rodent brain tissue suggested that neuroprotection was mediated by anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms. This review highlights the neuroprotective potential of CDCs and RSV for in vivo models of PD, and therefore suggests their potential translation to human clinical trials to either ameliorate PD progression and/or be implemented as a prophylactic means to reduce the risk of development of PD.

This paper aims to review the challenges, toxicity, and routes of synthesis and usage of silver nanoparticles in different applications but also highlighting their sustainability from both medical and environmental issues. Regarding their toxicity, it is known that silver nanoparticles can destroy over 650 microorganisms comparing with antibiotics. Supplementary, will be presented in a comparative manner some conventional synthesis routes (physical and chemical methods) and green synthesis routes using plant extracts. The approach using plant extracts have various advantages comparing with physical, chemical and microbial synthesis methods because there is no need to use chemicals, wasteful purifications and high energy requirements. The paper presents an overview on “green nanotechnology” focused on using either biological micro-organisms or plant extracts as an alternative to the classical chemical and physical methods. An important issue discussed in the paper is an overview of the synthesis routes of silver nanoparticles, some expected applications of silver based active agents and their toxicity and challenges that must be overcome. Also, it needs to focus our attention on the dismissal of silver nanoparticles into the environment and especially in water systems, fact which suggests that this issue must be fully understood and applied the law.

Extracellular vesicles (EVs) represent a heterogeneous population of small vesicles, consisting of a phospholipidic bilayer surrounding a soluble interior cargo. Almost all cell types release EVs, thus they are naturally present in all body fluids. Among the several potential applications, EVs could be used as drug delivery vehicles in disease treatment, in immune therapy because of their immunomodulatory properties and in regenerative medicine. In addition to general markers, EVs are characterized by the presence of specific biomarkers (proteins, miRNAs) that allow the identification of their cell- or tissue-origin. For these features, they represent a potential powerful diagnostic tool to monitor state and progression of specific diseases. As regards, a large body of studies supports the idea that endothelial derived (EMPs) together with platelet-derived microparticles (PMPs) are deeply involved in the pathogenesis of diseases characterized by micro- and macrovascular damages, including diabetes. Existing literature suggests that the detection of circulating EMPs and PMPs and their specific miRNA profile may represent a very useful non-invasive signature to achieve informations about the onset of peculiar disease manifestations. In this Review, we discuss the possible utility of EVs in the early diagnosis of diabetes-associated microvascular complications, specifically related to kidney.

Vertical and horizontal bone augmentation is one of the most challenging techniques in bone engineering. The use of barrier membranes and scaffolds in guided bone regeneration (GBR) procedures is a common approach for the treatment of lost bone around teeth and dental implants. The aim of this study was to estimate the barrier effects of a synthetic poly (lactic acid/caprolactone) [P(PA/CL)] bilayer membrane for GBR, compared to a porcine collagen bilayer membrane, in the vertical augmentation model on 10–12-months old rat skull without periosteum. The HAp block (diameter: 4 mm, height: 3 mm, porosity:75%, average pore size:150 μm) was placed on the rat skull without a periosteum. The P(LA/CL) membrane (solid layer: 25 μm, porous layer: 175 μm) or the collagen membrane (solid layer, porous layer) was applied onto the HAp block. At 3, 6, and 12 weeks after the surgery, the incised tissues were fixed, decalcified, and stained with hematoxylin and eosin for histological evaluation. The P(LA/CL) membrane remained until 12 weeks and could achieve barrier effects to inhibit cellular invasion from the repositioned soft tissues. Local bone formation occurred in the interconnected pores of HAp at 6 weeks. On the other hand, the collagen membrane did not inhibit cellular invasion for its expansion until 3 weeks, and was absorbed until 6 weeks. The results indicated that the P(LA/CL) membrane might be effective in GBR as occlusive absorbable membrane.

Background: Antibiotic-containing carrier systems are one option that offers the advantage of releasing active ingredients over a longer period of time. In vitro sustained drug release from a carrier system consisting of microporous β-TCP ceramic and alginate has been reported in previous works. Alginate dialdehyde (ADA) gelatin gel showed both better mechanical properties when loaded into a β-TCP ceramic and higher biodegradability than pure alginate. Methods: Dual release of daptomycin and BMP-2 was measured on days 1, 2, 3, 6, 9, 14, 21, and 28 by HPLC and ELISA. After release, the microbial efficacy of the daptomycin was verified and the biocompatibility of the composite was tested in cell culture. Results: Daptomycin and the model compound FITC protein A (n=30) were released from the composite over 28 days. A Daptomycin release above the minimum inhibitory concentration (MIC) by day 9 and a burst release of 71.7 ± 5.9 % were observed in the loaded ceramics. Low concentrations of BMP-2 were released from the loaded ceramics over 28 days.

Bone is the second most frequent site of metastases from differentiated thyroid carcinoma (DTC). Bone metastases (BM) occurs in about 10% of all patients with DTC. They are more frequently observed in follicular thyroid carcinoma (FTC) (7-28%), than in thyroid papillary carcinoma (PTC) (1-7%) [1,2] and are associated to unfavorable clinical out-comes, mainly related to skeletal related events (SREs), such as pathologic fractures, bone pain, spinal cord compressions and hypercalcemia, which impair the quality of life and reduce life expectancy. BM from DTC require multimodal and comprehensive treatment, including radioiodine therapy (RAI), palliative treatment, surgical treatment, external beam radiation and target drug therapy. RAI is the first line treatment, but about two thirds of DTC patients with distant metastases are not definitively cured. This treatment is considered less effective in BM particularly in case of large metastases. The different response to RAI treatment alone or associated to BM focal treatment depends to RAI avidity of lesions [3]. We report the rare case of an excellent response to RAI of a metachronous bone metastasis of skull from FTC, in a 72 yrs old woman, diagnosed 15 years after the first treatment, followed by a complete regression of radioiodine up-taking area with persistence of excellent response to the treatment six years after it. This case confirms that the complete BM response to RAI treatment depends to the degree of dedifferentiation of cancers cells and enforce the concept of a long- life follow-up of FTC patients.

Introduction: Silver nanoparticles have been extensively investigated in dental and orthopedic materials. However, the impregnation of bone graft with silver nanoparticles has been poorly investigated. Objectives: The aim of this study was to evaluate the in vitro antibiofilm activity of a bovine bone impregnated with silver nanoparticles. Methods: Bone scaffolds from cancellous bovine femur were used for the tests and impregnated with silver nanoparticles (50nm) by physical adsorption. Silver nitrate minimal inhibitory and bactericidal concentration were performed Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Enterococcus faecalis, Acinetobacter baumannii, and Escherichia coli. Disc diffusion tests for silver nanoparticles susceptibility and quantification of biofilm production on plate and bone with sessile cell count were also performed. Results: All pathogens were susceptible to silver with low minimal inhibitory concentration (0.25 – 4 mg/L). The scaffold impregnated with silver nanoparticles presented a significant reduction in the biofilm cells for all microorganisms with a reduction of more than 3 logs in colony forming units count. Conclusion: Bone scaffolds impregnated with silver nanoparticles can significantly reduce biofilm, and it can be a strategical material to be used as an implant for different approaches.

Background: Electrical conductivity of trabecular bone at 100 kHz was recently reported as a good predictor of bone volume fraction. However, to quantify its relationship with the free water (or physiological solution) content and between the conductivities of its constituents, is still unclear. Methods: In this contribution, in silico models inspired by microCT images of trabecular bovine samples were used to build realistic geometries. Finite Element Method was applied to solve the electrical problem and to robustly fit the conductivity of the constituents with literature data. The obtained effective electrical conductivity was compared to Bruggeman three media mixture model: physiological solution, bone marrow and bone matrix. Results: The values for physiological solution plus bone marrow and bone matrix that captured better the bone volume fraction in the two media Finite Element model were: σps+bm = 298.4 mS/m and σb = 21.0 mS/m, respectively. Additionally, relative good results were obtained by a three media Bruggeman mixture model with σbm= 103 mS/m, σb= 21.0 mS/m, and σps= 1200 mS/m. Simple linear relationships between the proportions of constituents depending on bone volume fraction were tested. Degree of anisotropy and fractal dimension do not show detectable changes in effective conductivity. Conclusions: These results provided some useful findings for simulation purposes: first, a higher value of electrical conductivity of bone marrow has to be used in order to obtain similar values to those experimental published data. Second, anisotropy is not detectable by conductivity measurements for small trabecular samples (cube 5 mm). Finally, the simulations presented here showed a relatively good fitting of the mixture Bruggeman model which potentially would allow both, accounting for the free water content and re-scaling the model for whole bone electrical simulations.

Osteitis fibrosa cystica (OFC) and Brown Tumour are two related but distinct types of bone lesions that result from overactivity of osteoclasts most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because of their rare prevalence and variability in their clinical manifestation. Canonically, OFC and Brown Tumours are caused by secondary hyperparathyroidism in CKD. Recent literature showed that multiple factors such as hyperactivation of the renin-angiotensin-aldosterone system and chronic inflammation may also contribute to the occurrence of these diseases through osteoclast activation. Moreover, hotspot KRAS mutations were identified in these lesions placing them in the spectrum of RAS-MAPK-driven neoplasms, while until recently thought to be reactive lesions. Some risk factors contributed to the occurrence of OFC and Brown Tumour such as age, gender, comorbidities, and certain medications. The diagnosis of OFC and Brown Tumour includes clinical symptoms involving chronic bone pain and laboratory finding of hyperparathyroidism. In radiological imaging, the X-ray and Computed tomography (CT) scan could show lytic or multi-lobular cystic alterations. Histologically both lesions are characterized by clustered osteoclast in a fibrotic hemorrhagic background. Based on the latest understanding of the mechanism of OFC, this review elaborates on the manifestation, diagnosis, and available therapies that can be leveraged to prevent the occurrence of OFC and Brown Tumour.

A potential association between hematopoietic stem cell status in the bone marrow and the surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes deriving from bone marrow mononuclear cells and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

We investigated the diagnostic capacity of selected circulating biomarkers (CBMs) for the early detection of bone metastasis (BMets) in patients with pancreatic neuroendocrine neoplasms (PanNENs). 115 patients with PanNENs and 40 controls were enrolled. We measured the serum levels of ferritin, cytokeratin 18 (CY18), CA19-9, CA125, AFP, CEA, and beta-2 microglobulin (B2M). 8 PanNENs patients developed BMets, and 107 remained BMets-free. We observed a significantly higher level of CA125 and CY18 in BM-PanNENs patients vs. non-BM-PanNENs patients (p = 0.01 and p = 0.04, respectively). CA125, CY18, and B2M area under receiver operator characteristic (AUROC) analyses differentiated BM-PanNENs from non-BM-PanNENs patients; CA125 area under the curve (AUC) 0.77, p < 0.01; CY18 AUC data were 0.72, p = 0.03, and B2M AUC 0.67, p = 0.02. Based on CBMs metrics in both subgroups, we reached a sensitivity/specificity for CA125 of 75/76%; for CY18 of 75/69%, for B2M of 100/50%, for CA125 and CY18 combination 93/90%, respectively. The useful CBMs for BM-PanNENs patients detection were CA125, CY18, and B2M. They seem to have the diagnostic capacity as a fair single biomarker and CA125&CY18 combination panel for the detection of BMets.

ABSTRACT: Understanding the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, including the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA pathophysiology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms has been characterized as underlying causes of pain chronicity. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. This review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insight on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

The number of patients with bone metabolic disorders including osteoporosis is increasing worldwide. These disorders often facilitate bone fractures, which seriously impact the patient’s quality of life and could lead to further health complications. Bone homeostasis is tightly regulated to balance bone resorption and formation. However, many anti-osteoporotic agents are broadly categorized as either bone forming or anti-resorptive, and their therapeutic use is often limited due to unwanted side effects. Therefore, safe and effective therapeutic agents are needed for osteoporosis. This study aims to clarify the bone protecting effects of oat bran water extract (OBWE) and its mode of action. OBWE inhibited RANKL-induced osteoclast differentiation by blocking c-Fos/NFATc1 through the alteration of I-κB. Furthermore, we found that OBWE enhanced BMP-2-stimulated osteoblast differentiation by the induction of Runx2 via Smad signaling molecules. In addition, the anti-osteoporotic activity of OBWE was also evaluated using an in vivo model. OBWE significantly restored ovariectomy-induced bone loss. These in vitro and in vivo results showed that OBWE has the potential to combat bone metabolic disorders including osteoporosis

Objective: Regeneration of bone defects remains a challenge for maxillofacial and reparative surgeons. The purpose of this histological study was to assess the osteogenic potential of octacalcium phosphate (OCP) and bone matrix gelatin (BMG) alone and in combination in artificially created mandibular bone defects in rats. The quality of the newly formed bone was also evaluated. Methods: Thirty-six male Sprague Dawley rats (6-8 weeks old with 120-150 g weight) were randomly divided into four groups. Defects (3 mm in diameter and 2 mm in depth) were created in the mandible of rats and filled with 6 mg of OCP, BMG or a combination of both (1/4 ratio), respectively. Defects were left unfilled in the control group. To assess osteoinduction and bone regeneration and determine the quality of the newly formed bone, tissue specimens were harvested at seven, 14, and 21 days post-implantation. The specimens were processed, stained with hematoxylin and eosin (H&E) and histologically analyzed under light microscopy. Results: In the experimental groups, new bone formation was initiated at the margins of defects from seventh day after implantation. At the end of the study period, the amount of the newly formed bone increased and the bone was relatively mature. Osteoinduction and new bone formation were greater in OCP/BMG group. In the control group, slight amount of new bone had been formed at the defect margins (next to host bone) on day 21. Conclusion: Combination of OCP/BMG may serve as an optimal biomaterial for treatment of mandibular bone defects.

Currently, drug screening is primarily based on human cell culture for initial high-throughput screening, and subsequently, rodent model to confirm the biological effects. However, the mammalian system is known for time-consuming and highly-cost to be difficult to perform high-throughput drug screening, which exists a critical gap between in vitro cell-based models and the in vivo mammalian models. Therefore, the zebrafish could bridge this gap in preclinical toxicity screening along the drug development pipeline because of its efficiency. We aimed to develop an in vivo zebrafish platform for rapid drug screening. Zebrafish, due to its high genomic conservation with mammals and rapid development and differentiation, it has many advantages, such as short life span, large number of offspring and low cost, easy manipulation for generating transgenic species, to serve as animal model for disease-based research. In 96-well microplates, zebrafish embryos were incubated with small molecular compounds that affected bone mineralization. The level of osteogenic mineralization was evaluated by fluorescent dye staining and quantified by image analysis software. Quantitative real time-PCR (qRT-PCR) was performed to evaluate the biological pathways involved in bone metabolism at the molecular level. The system was validated by demonstrating that response to alendronate and Dorsomorphin in zebrafish. In our study, we screened for 24 compounds within the CYCU-1120~1152 chemical library and identified 3 compounds, pentamidine (CYCU-1140), BML-267 (CYCU-1147), and alendronate (CYCU-1152), increased embryonic mineralization; while 6 compounds, RWJ-60475 (CYCU-1126), levamisole HCL (CYCU-1128), tetramisole HCL (CYCU-1129), fenvalerate (CYCU-1132), NSC-663284 (CYCU-1138), and BML-267ester (CYCU-1148), were inhibitory to bone mineralization. We also found that alendronate enhanced the level of bone mineralization by inhibiting osteoclast-related genes. To sum up, our research showed that zebrafish may have potential to be a drug-screening and mechanism-analysis platform for bone mineralization.

The study aimed to evaluate implant success and bone height variations after transcrestal sinus floor elevation (tSFE) using the osseodensification technique (OD) combined with beta-tricalcium phosphate (β-TCP), as bone graft material and simultaneous implant placement. Thirteen patients requiring the placement of one implant in the upper posterior maxilla, with a residual bone height of

Background: Nutritional rickets is still considered as a global health problem especially in low-resource countries and immigrant societies of developed countries. Generalized skeletal deformities including angular knee deformities as genu varum and genu valgum are prominent features of nutritional rickets. Angular knee deformities can cause gait difficulties. However, the true remodelling potential of the healed knee deformities is largely unknown to the pediatric and orthopedic community. Aims: The primary objective of this study protocol is to investigate the natural history of disease in regard to the remodelling potential of angular knee deformities in children and adolescents with healed nutritional rickets. And determine the potential patient- and deformity-related factors that are associated with a favorable deformity remodelling as age and sex of patients and type, severity, laterality of deformities etc. Methods: This will be a prospective observational analytical cohort natural history of disease study. A minimum of at least 140 knees with healed nutritional rickets and angular knee deformities will be observed at regular three-monthly intervals over a period of at least one year. We will report two outcome variables namely; clinical and radiological tibio-femoral angle. And independent patient and deformity-related variables as age, sex, deformity type, severity and laterality. Inferential statistics namely bivariate and multivariate analysis will be employed accordingly to identify the relation between outcome variables and the different independent variables. Ethics and dissemination: This protocol study has been approved by the institutional research ethics committee. Results will be presented at conferences and submitted to relevant international and society publications. Authors will also communicate the results to their scholarly networks and post them on scholarly networking sites. Conclusions: This study has the potential for improving the decision-making process as to which patients deserve conservative treatment and which deserve surgical deformity correction. Results are expected to have an impact on the clinical practice of pediatricians, orthopedic surgeons and family physicians alike.

Titanium micro-scale topography results in excellent osteoconductivity and bone-implant integration. However, the biological effects of sub-micron topography are unknown. We compared osteoblastic phenotypes and in vivo bone and implant integration abilities between titanium surfaces with micro- (1–5 µm) and sub-micro-scale (0.1–0.5 µm) topographies and machined titanium. Average roughness was 12.5 ± 0.65 nm, 123 ± 6.15 nm, and 24 ± 1.2 nm for machined, micro-rough, and sub-micro-rough surfaces, respectively. The micro-rough surface showed the fewest cells attaching during the initial stage and the lowest proliferation. Calcium deposition and expression of osteoblastic genes were highest on the sub-micro-rough surface and lowest on the machined surface. Bone-to-implant integration was strongest for the micro-rough surface, consistent with it having the greatest ability to retain cells in vitro. Thus, the biological effects of titanium surfaces are not necessarily proportional to the degree of roughness in osteoblastic cultures or in vivo. Sub-micro-rough titanium ameliorates the disadvantage of micro-rough titanium by restoring cell attachment and proliferation and enhances the rate of osteoblastic differentiation over that of micro-rough titanium; however, bone integration and the ability to retain cells are compromised due to its lower interfacial mechanical locking compared to that of micro-rough titanium.

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge dealing with patients diagnosed with bone metastases. The management have improved significantly in the past years, however fraught with lack of evidences, approach to these patients held out hope for more systematic and tailored treatment—and some patients can achieve impressive gains. Nevertheless, in real-life practice the outlook at the beginning of the take in charge of SMUP is decidedly more somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidences and highlighted three key points that emerge. The characterization of the SMUP biologic profile is essential to drive clinical decisions, integrating genetic and molecular profile into a multi-step diagnostic work-up. Nonetheless, pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials within. This review argues that greater efforts are required to face the unmet need dealing with SMUP patients in oncology. Finally, we provide an original functional network analysis, identifying novel therapeutic targets.

Lathyrane-type diterpenes have a wide range of biological activities. Among them, euphoboetirane A (1) exerts neurogenesis-promoting activity. In order to increase the structural diversity of this type of lathyranes to explore their potential use in neurodegenerative disorders, the biotransformation of 1 by Streptomyces puniceus BC-5GB.11 has been investigated. The strain BC-5GB.11, isolated from surface sediments collected from the intertidal zone of the inner Bay of Cadiz, was identified as Streptomyces puniceus, as determined by phylogenetic analysis using 16S rRNA gene sequence. Biotransformation of 1 by BC-5GB.11 afforded five products (3-7), all of them reported here for the first time. The main biotransformation pathways involved regioselective oxidation at non-activated carbons (3-5) and isomerization of the D^12,13 double bond (6). In addition, a cyclopropane-rearranged compound was found (7). The structures of all compounds were elucidated on the basis of extensive NMR and HRESIMS spectroscopic studies.

Current methodologies for developing patient-derived xenografts (PDX) in humanized mice in preclinical trials to test response to immune-based therapies are limited by graft versus host disease. Here we compared two approaches for establishing PDX tumors in humanized mice: 1) PDX are first established in immune-deficient mice; 2) PDX are initially established in humanized mice, before transplanting established PDX’s to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Pre-clinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with limited infiltration of CD8+ T cell into the tumor. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in the presence of human immune cells before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

3D bioprinting is the process of manipulating cell-laden bioinks to fabricate living structures. 3D bioprinting techniques have brought considerable innovation in biomedicine, especially in the field of tissue engineering, allowing the production of 3D organ and tissue models for in vivo transplantation purposes or for in-depth and precise in vitro analyses. Natural-derived hydrogels, especially those obtained from the decellularization of biological tissues, are promising bioinks for 3D printing purposes, as they present the best biocompatibility characteristics. Despite this, many natural hydrogels do not possess the necessary mechanical properties to allow a simple and immediate application in the 3D printing process. In this review, we focus on the bioactive and mechanical characteristics that natural hydrogels may possess to allow efficient production of organs and tissues for biomedical applications, emphasizing the reinforcement techniques to improve their biomechanical properties.

High density polyethylene (HDPE) and poly(lactic) acid (PLA) blends with different ratios of both polymers, namely 30:70, 50:50 and 70:30, were produced. Polyethylene grafted maleic anhydride and a random copolymer of ethylene and glycidyl methacrylate, were also proposed as compatibilizers to modify HDPE-PLA optimal blends and were added in the amounts of 1, 3 and 5 wt.%. Blends properties have been evaluated through different aspects by performing tensile tests, scanning electron microscopy to analyze blend morphology and interfaces, and thermomechanical analysis through differential scanning calorimetry, thermo-gravimetric analyses and infrared spectroscopy. The second blend, the one with equal amounts of HDPE and PLA seems to represent a good balance between high amount of bio-derived charge and acceptable mechanical properties. This suggests a good potential of these blends, which would be a good starting point for the production of composites with lingo-cellulosic fillers.

Objective: To evaluate the clinical efficacy of antibiotic bone cement plus lateral bone repositioning for severe diabetic foot and its impact on wound healing rate. Methods: Sixty patients with hemodialysis anemia admitted to the endocrinology department of our hospital from July 2020 to July 2021 were included and randomly assigned to receive antibiotic bone cement plus lateral bone repositioning (observation group) or vacuum sealing drainage (VSD) (control group). Outcome measures included skin temperature of the affected limb, ankle-brachial index, sensory threshold, foot wound healing, dorsalis pedis artery hemodynamics, lower limb function and clinical efficacy. Results: Antibiotic bone cement plus lateral bone repositioning resulted in significantly higher treatment efficiency and transcutaneous partial pressure of oxygen, smaller wound, and lower trauma pH versus VSD, suggesting that antibiotic bone cement plus lateral bone repositioning contributes to potentiating the treatment efficacy and reducing the foot ulcer trauma, thereby facilitating rapid recovery. Patients given antibiotic bone cement plus lateral bone repositioning had larger vascular internal diameter and blood flow and better sensory conduction velocity of the common peroneal nerve and the motor conduction velocity of the tibial nerve versus those given VSD, indicating its vascular and neurological benefits. Conclusion: Antibiotic bone cement plus lateral bone repositioning enhances the treatment efficiency, boosts trauma healing, and promotes postoperative functional recovery of patients.

This review summarises the complex relationship between medications used to treat type 2 diabetes, and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density, thus we analysed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, as well as GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control and potential medication-related effects on bone.

3D Printing (3DP) technology has revolutionized the field of the use of bioceramics for maxillofacial and periodontal applications, offering unprecedented control over the shape, size, and structure of bioceramic implants. In addition, bioceramics have become attractive materials for these applications due to their biocompatibility, biostability, and favorable mechanical properties. However, despite their advantages, bioceramic implants are still associated with inferior biological performance issues after implantation, such as slow osseointegration, inadequate tissue response, and increased risk of implant failure. To address these challenges, researchers have been developing strategies to improve the biological performance of 3D printed bioceramic implants. The purpose of this review is to provide an overview of 3DP techniques and strategies for bioceramic materials designed for bone regeneration. The review also addresses the use and incorporation of active biomolecules in 3D printed bioceramic constructs to stimulate bone regeneration. By controlling the surface roughness, and chemical composition of the implant, the construct can be tailored to promote osseointegration and reduce the risk of adverse tissue reactions. Additionally, growth factors, such as bone morphogenic proteins (rhBMP-2) and pharmacologic agent (dipyridamole), can be incorporated to promote the growth of new bone tissue. Incorporating porosity into bioceramic constructs can improve bone tissue formation and the overall biological response of the implant. As such, by employing surface modification, combining with other materials, and incorporation of 3DP workflow can lead to better patient healing outcomes.

The phytonutraceutical Ormona® is a product composed of: purified oil of Bixa orellana Linné; dry extract of Myrciaria dubia McVaugh; dry extract of Trifolium pratense L. and dry extract of Euterpe oleracea Mart. obtained using Evolve® technology. This study evaluated the effects of Ormona® on Wistar rats affected by ovariectomy-induced osteoporosis. Pre-treatment was conducted for 15 days before surgery and continued for a further 45 days after the surgical procedure. The experimental design consisted of 5 groups (n=5): OVW: treated with distilled water (1 mL/ kg, p.o); ADS: alendronate sodium (4 mg/ kg p.o); EST: conjugated estrogen (2 ug/ kg, p.o); ORM: Ormona® (20 mg/kg, p.o); ORM + EST: Ormona® (20 mg/kg + conjugated estrogen 2 ug/ kg, p.o. Biochemical and hormonal parameters, along with bone histopathology and trabecular and femoral diaphysis size, were evaluated through Scanning Electron Microscopy (SEM) and bone calcium quantification by atomic absorption spectrophotometry. The results show that ovariectomy caused bone alterations such as loss of femoral microarchitecture, decreased bone homeostasis parameters, and changes in the lipid profile. Estrogen supplementation reduced parameters such as cholesterol, LDL, and Ca2+ concentration. However, Ormona® showed higher serum estradiol levels (p&lt; 0.01), effects on the lipid profile, including parameters that estrogen replacement and alendronate sodium did not affect, with an increase in HDL, and positive modulation of bone metabolism, increasing osteocytes and the presence of osteoblasts. Ormona®, therefore, produced better results than the groups treated with estrogen and alendronate sodium.

Abstract: The centrepiece of this analytical review is the metabolism of hydroxyapatite in its natural, bone, and synthetic forms, where the mitochondria-mediated mechanism may serve as the leading mechanism. The possibility that osteoblast mitochondria play an important role in the initial stages of bone mineralisation is discussed. Furthermore, the paper highlights the key role of mitochondria in the metabolism of synthetic hydroxyapatite.Differences between the results of in vivo and in vitro studies using synthetic hydroxyapatite of different morphologies are also detailed. It is noted that long-term infiltration with immune cells and in vivo studies are necessary to adequately evaluate hydroxyapatite as a bone-plastic material.Particular attention is given to the interaction of hydroxyapatite with immune cells and its ability to affect the ribosomes and mitochondria of cells. Due to its mechanical properties, scalability and potential use for the treatment of extensive bone defects of tumor origin, hydroxyapatite is a promising material.This study also highlights the importance of further development of in vitro research methods in the context of their biomimeticity. Overall, this work offers a theoretical direction for future studies of hydroxyapatite as a bone grafting material and emphasises the value of in vivo studies.

Estimating age at death is essential to establish a biological profile from human skeletal remains in both forensic and archeological settings. Imaging studies of skeletal age changes in adults have described metamorphosis of trabecular bone structure and bone loss in the proximal femur , as well as changes in morphology during different stages of life. This study aims to assess the utility of a digital representation of conventional X-ray films of the proximal femur for the estimation of age at death in a sample of 91 adult individuals (47 females and 44 males) of the Coimbra Identified Skeletal Collection. The proposed approach showed a root mean squared error (RMSE) of 17.32 years (and mean absolute error of 13.47 years) for females and an RMSE of 14.06 years (mean absolute error of 11.08 years) for males. The main advantage of this approach is the consistency in the feature detection and extraction, as X-ray images projected on the femora space will always produce the same set features to be analyzed for age estimation while more traditional methods rely heavily on operator experience which can lead to inconsistent age estimates among experts.

Cadmium, an environmental toxin, is associated with a range of adverse health effects due to increased Reactive Oxygen Species production, including decreased bone mineral density and osteoporosis. Notably, cadmium is found at concentrations 4-5x higher in the blood of smokers versus non-smokers. Experiments performed in human cancer cells indicate that melatonin may directly protect against cadmium-induced tissue damage via regulation of mitochondrial activity. Further, recent evidence has demonstrated that melatonin can improve bone health for individuals with osteoporosis and partially protect against cadmium-associated inhibition of bone repair. Here we review this data and propose supplementation with melatonin as a strategy to protect against the negative impacts of cadmium exposure on bone mineral density within individuals regularly exposed to cadmium via cigarette smoking.

Consumption of prunes has been shown to slow bone loss after menopause in American women but there is no data on its effects in Asian women. 135 postmenopausal Korean women with osteopenia were randomized to 100g/day of prunes or no prunes with 600U vitamin D and 800mg of calcium for 12 months. Bone density was measured at baseline and 12 months in the lumbar spine, both hips and the L forearm. Serum levels of CTX and P1NP and vitamin D calcium and phosphate were measured at baseline, 6 and 12 months. PTH was measured at baseline if vitamin D was low Four women dropped out of each group over the 12 months. There was no difference between groups in blood measures or bone density in any region over the 12 month trial., In conclusion 100g/day of prunes has no effect in Korean woman on bone density or bone markers.

This review provides a comprehensive overview of two major advancements in hearing loss treatment: the middle ear implant (MEI) and bone conduction implants (BCIs). MEI, surgically inserted in the middle ear, directly stimulate the ossicles, and are primarily employed to treat sensorineural, conductive, or mixed hearing losses. BCIs work via bone conduction, bypassing the outer and middle ear to deliver sound vibrations to the inner ear, beneficial especially for conductive or mixed hearing losses and single-sided deafness. The decision to opt for these devices is a multifaceted process, considering audiological criteria, surgical feasibility, and patient expectations. The review also details the portfolio of available devices, their functioning, and audiological usage indications. While both MEI and BCIs prove beneficial for patients, the review emphasizes the need for careful preoperative planning and counselling, considering factors such as potential complications, surgical challenges, and patient suitability. Overall, the two types of implants, despite their individual complexities, provide an effective alternative to traditional hearing aids, offering a path to improved sound clarity and quality for patients with various types of hearing loss.

Based on previous studies of our group in which we demonstrated that dalbavancin loaded in bone cement had good elution capacity for the treatment of biofilm-related periprosthetic infections, we now assess the anti-biofilm activity of dalbavancin and compare it with that of vancomycin up to a 3-month period. We performed an in vitro model based on calculation of percentage reduction of log cfu/ml counts of sonicated steel discs contaminated with Staphylococci and further exposed to bone cement discs loaded with 2.5% or 5% vancomycin and dalbavancin at each study period (24 hours, 48 hours, 1 week, 2 weeks, 6 weeks, 3 months). In addition, we tested the anti-biofilm activity of eluted vancomycin and dalbavancin at each study period based on a 96-well plate model assessing percentage reduction of metabolic activity. Overall, dalbavancin showed a significant concentration decrease from 2 weeks of incubation and maintain its anti-biofilm activity up to 3 months, whereas, despite vancomycin showed a significant decrease at 1w and then it gradually increased, its anti-biofilm activity was significantly lower. Dalbavancin percentage reduction cfu/ml counts were higher than those of vancomycin, both at 2.5% and 5% concentrations. Reduction of log cfu/ml counts were higher for S. epidermidis than for S. aureus, being more notable for 5% dalbavancin at month 3. In addition, percentage reduction of metabolic activity also decreased at 3 months in 5% dalbavancin and 5% vancomycin, being more notable in the last.

Nano/micron-sized bioactive glass (BG) particles are attractive candidates for both soft and hard tissue engineering. They can chemically bond to the host tissues, enhance new tissue formation, activate cell proliferation, stimulate the genetic expression of proteins, and trigger unique an-ti-bacterial, anti-inflammatory, and anti-cancer functionalities. Recently, composites based on bi-opolymers and BG particles have been developed with various state-of-the-art techniques for tis-sue engineering. Gelatin, a semi-synthetic biopolymer, has attracted the attention of researchers because it is derived from the most abundant protein in the body, viz., collagen. It is a polymer that can be dissolved in water and processed to acquire different configurations, such as hydro-gels, fibers, films, scaffolds, etc. Searching "bioactive glass gelatin" in the tile on Scopus renders 80 highly relevant articles published in the last ~10 years, which signifies the importance of such composites. First, this review addresses the basic concepts of soft and hard tissue engineering, in-cluding the healing mechanisms and limitations ahead. Then, current knowledge on gelatin/BG composites including composition, processing and properties is summarized and discussed both for soft and hard tissue applications. This review explores physical, chemical and mechanical features and ion-release effects of such composites concerning osteogenic and angiogenic respons-es in vivo and in vitro. Additionally, recent developments of BG/gelatin composites using 3D/4D printing for tissue engineering are presented. Finally, the perspectives and current challenges in developing desirable composites for the regeneration of different tissues are outlined.

Mandibular critical size defect (CSD) due to pathological conditions, trauma, and congenital disease can not heal spontaneously and predominantly filled with fibrous tissue. Therefore, a Guided Bone Regeneration (GBR) combined with bone grafting can be performed. The researchers considered using Demineralized Dentin Material Membrane (DDMM) from bovine dentine as an alternative GBR. This study aimed to determine the amount of fibroblast and collagen density after DDMM and bone graft implantation on CSD. Thirty-six Rattus norvegicus rats were used as samples. Mandibular bone defect 5x5 mm was made, then filled with bone graft and covered with Bovine Pericardium Collagen Membrane (BPCM) in the control group and DDMM in the treatment group. Six samples were sacrificed on 7, 14, and 21 days post-surgical for histology examination. There were no significant differences in the amount of fibroblast and collagen density (p-value > 0,05). The amount of fibroblast is lower and the collagen density is higher in treatment group. DDMM has microporosity to prevent connective tissue ingrowth and dentine tubules to allow growth factors release. DDMM and bone graft implantation can reduce the amount of fibroblasts and increase collagen density of CSD which potentially being used as a CSD alternative treatment for bone regeneration.

Using the headphone jack of a mobile phone, the proposed device connects mobile music playback through a customized red laser pointer that is cascaded to batteries and the 3.5-mm stereo plug. The red laser pointer flashes according to the frequency of the music currently playing on the mobile phone. The self-made laser pointer which wavelength is 630–650 nm and maximum output is 5 mw and it will light up when the smart phone’s music starts playing at a music frequency matching the light frequency. The frequency signal of the light received by a solar panel is converted to an electrical analog signal, and the analog current signal is amplified through the energy conversion panel and then output to the direct current motor. The motor shaft does not rotate under a small current, but rather only slightly vibrates according to the magnitude of the currents’ analog frequency. Through gripping the motor shaft with teeth, users can transmit audio to the auditory ossicles (i.e., malleus, incus, and stapes) through the dentary bones. After receiving a music signal, the auditory ossicles enable people with congenital or acquired hearing loss to access external audio.

Three-dimensional (3D) printing techniques have received considerable focus in the area of bone engineering due to its precise control in the fabrication of complex structures with customizable shapes, internal and external architectures, mechanical strength, and bioactivity. In this study, we design a new composition biomaterial consisting of polylactic acid (PLA), and halloysite nanotubes (HNTs) loaded with zinc nanoparticles (PLA+H+Zn). The hydrophobic surface of the 3D printed scaffold was coated with two layers of fetal bovine serum (FBS) on the sides and one layer of NaOH in the middle. Additionally, a layer of gentamicin was coated on the outermost layer against bacterial infection. Scaffolds were cultured in standard cell culture medium without the addition of osteogenic medium. This surface modification strategy improved material hydrophilicity and enhanced cell adhesion. Pre-osteoblasts cultured on these scaffolds differentiated into osteoblasts and proceeded to produce a type I collagen matrix and subsequent calcium deposition. 3D printed scaffolds formed from this composition possessed high mechanical strength and showed an osteoinductive potential. Furthermore, the external coating of antibiotics not only preserved the previous osteogenic properties of the 3D scaffold but also significantly reduced bacterial growth. Our surface modification model enabled the fabrication of a material surface that was hydrophilic and antibacterial, simultaneously, with an osteogenic property. The designed PLA+H+Zn may be a viable candidate for the fabrication of customized bone implants.

The regeneration of bone tissue is a main purpose of most therapies in dental medicine. For bone regeneration, calcium phosphate (CaP)-based substitute materials based on natural (allo- and xenografts) and synthetic origins (alloplastic materials) are applied for guiding the regeneration processes. The optimal bone substitute has to act as a substrate for bone ingrowth into a defect, while it should be resorbed even in the time frame needed for complete regeneration up to the condition of restitution ad integrum. In this context, the modes of action of CaP-based substitute materials have been frequently investigated and it has been shown that such materials strongly influence regenerative processes such as osteoblast growth or differentiation and also on osteoclastic resorption due to different physicochemical properties of the materials. However, the material characteristics needed for the required ratio between the formation of new bone tissue and material degradation has not been found until now. The addition of different substances such as collagen or growth factors and also of different cell types have already been tested but did not allow for sufficient or prompt application. Moreover, metals or metal ions are differently used as basis or as supplement for different materials in the field of bone regeneration. Moreover, it has already been shown that different metal ions are integral components of bone tissue playing functional roles in the physiological cellular environment as well as in the course of bone healing. The present review focuses on frequently used metals as integral parts of materials designated for bone regeneration with the aim to give an overview of currently existing knowledge about the effects of metals in the field of bone regeneration.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

Cell junction that is usually associated with dynamic cytoskeletons is essential for a wide range of cellular activities such as cell migration, cell communication, barrier function and signal transduction. Real-time observation of cell junction facilitates understanding of the mechanisms by which cell junction regulate relevant cellular activities. In this study, we examined the binding capacity of a modified tridecapeptide from Cx43 to cell junction protein ZO-1 and sought to create a fluorescent peptide that could be used to label cell junction. To introduce the fluorescent peptide into the cells, a cell-penetrating peptide was linked to the modified tridecapeptide and synthesized. The binding of the modified tridecapeptide was tested using pull down and immunoprecipitation assay. The ability of the peptide to label cell junction was assessed by adding it to fixed or cultured Caco-2 cells. Testing assay revealed that the Cx43-derived peptide can bind to ZO-1. Besides, the peptide was able to label cell junction of fixed cell, although no obvious cell junction labeling was observed clearly in living cells, probably due to the inadequate affinity. These results indicate that a peptide-based strategy for labeling cell junction may be feasible, and efforts to improve its affinity are warranted in the future.

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to its inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The previous COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances when vaccination is not accessible or in individuals with compromised immune systems, drugs can give additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds including anti-viral. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Epigenetic modifications in the genome can affect gene expression without altering DNA sequence. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses have recruited cellular epi transcriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we are exploring the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing modulation processes and anti-viral effects on DNA and RNA viruses, and addressing future research objectives in this rapidly emerging field.

The concept of targeted drug delivery can be described in terms of the drug’s ability to mimic the other biological objects’ property to localize to target cells or tissues. For example, drug delivery systems based on red blood cells or mimicking some of their useful features, such as long circulation in stealth mode, have been known for decades. On the contrary, therapeutic strategies based on macrophages have gained very limited attention until recently. Here we review two biomimetic strategies associated with macrophages, that can be used to develop new therapeutic modalities: First, the mimicry of certain types of macrophages (i.e., the use of macrophages, including tumor-associated, or macrophage-like particles as a carrier for targeted delivery of therapeutic agents); and Second, the mimicry of ligands, naturally absorbed by macrophages (i.e., the use of therapeutic agents specifically targeted at macrophages). We discuss potential applications of biomimetic systems involving macrophages for the new advancements in treatment of infections, inflammatory diseases, and cancer.

Chronic wounds are associated with considerable patient morbidity and present a significant economic burden to the healthcare system. Often, chronic wounds are in a state of persistent in-flammation and unable to progress to the next phase of wound healing. Placental-derived bio-materials are recognized for their biocompatibility, biodegradability, angiogenic, an-ti-inflammatory, anti-microbial, anti-fibrotic, immunomodulatory, and immune privileged prop-erties. As such, placental-derived biomaterials have been used in wound management for more than a century. Placental-derived scaffolds are composed of an extracellular matrix (ECM) that can mimic the native tissue, creating a reparative environment to promote ECM remodeling, cell migration, proliferation, and differentiation. Reliable evidence exists throughout the literature to support the safety and effectiveness of placental-derived biomaterials in wound healing. How-ever, differences in source (i.e., anatomical regions of the placenta), preservation techniques, decellularization status, design, and clinical application have not been fully evaluated. This re-view provides an overview of wound healing and placental-derived biomaterials, summarizes the clinical results of placental-derived scaffolds in wound healing, and suggests directions for future work.

The SiBOC precursor ceramics were fabricated by polymer-derived method SiBOC precursors with different B/Si molar ratios were synthesized by controlling monomer content. The effects of different process conditions on SiBOC ceramics and the oxidation resistance of SiBOC ceramics at a high temperature (1400 ℃) were studied. The SiBOC precursor’s bonds of Si-O-C, Si-O-Si, and Si-O-B were detected by FTIR. The precursor is converted to a rigid ceramic material that has an 85.3 wt % ceramic yield of SiBOC ceramics with B/Si=0.4 by TG-DSC. The results of SEM analysis show that the SiBOC ceramics surface bulges and folds increase with the increase of boric acid content. With the increase of pyrolysis temperature and pyrolysis time, the size and number of pores on the surface of SiBOC ceramics also increase. Static oxidation tests show that SiBOC ceramics with B/Si=0.4 have better oxidation resistance under other conditions being the same.

In the present day and age, cancer is still a life-limiting factor whose one of the therapeutic strategies is immunotherapy with vaccines. This research aims to prepare and characterize nanoliposomal vaccine formulation attached to HER2/neu-derived peptide (AE36) with or without CpG-ODN, and to evaluate its immunological responses to the therapy using BALB/c mice with HER2 overexpressing breast cancer. Methods: AE36 was conjugated to the liposomes containing DOTAP, DOPE and Cholesterol. Such formulations are able to produce CD8+ and CD4+ responses and induce synthesis of cytokines detectable via Enzyme-linked immunosorbent assay kits, cytotoxicity testing and intracellular cytokine staining combined with flow cytometry. Therapeutic and prophylactic effectiveness were evaluated through the formulation in samples. The highest effectiveness was found in DDC-peptide + CpG-ODN in both prophylactic and therapeutic studies, which decreased the size of tumors significantly and increased time of survival. These nanoliposomes linked to AE36 could be regarded as an appropriate candidate for the treatment and also for prophylaxis of HER2+ breast cancer; however further studies are needed.

Forensic anthropologists play a key role in skeletal trauma analysis and commonly use macroscopic features to distinguish between trauma types. However, this approach can be challenging, particularly in cases of highly comminuted or incompletely recovered fractures. Histological analysis of microscopic fracture characteristics in fractured bones may thus help provide additional information on trauma type and bone fracture biomechanics in general. This study analysed the extent of microcrack damage to osteons in long bones with blunt force trauma (BFT) and gunshot trauma (GST), from both traumatic death cases and post-mortem experimental fractures. We identified four types of osteonal damage (OD). In traumatic death cases, OD affecting the inside of the osteon and compromising the Haversian canal (type 1) was found to be indicative of BFT. Moreover, OD affecting the cement line (type 3) and interstitial lamellae (type 4) was more common in the GST samples. OD affecting the inside of the osteon without compromising the Haversian canal (type 2) was not found to be indicative of either trauma type. In cases of experimental fractures, our study revealed that post-mortem fractures in dry bone samples featured the highest amount of OD, particularly of type 4. This study also found that the experimentally produced GST featured similar OD pattern to GST death cases. These findings support our hypothesis that there are distinct osteonal damage patterns in human long bones with BFT and GST, which are of relevant value for trauma analysis in forensic anthropology.

This study aimed to assess the response of 3D printed PLA scaffolds biomimetically coated with apatite on human primary osteoblast spheroids and evaluate the biological response to its association with Bone Morphogenetic Protein 2 (rhBMP-2) in rat calvaria. PLA scaffolds were produced via 3D printing, soaked in simulated body fluid (SBF) solution, and characterized by physical-chemical, morphological, and mechanical properties. The in vitro biological response was assessed with human primary osteoblast (HOb) spheroids. The in vivo analysis was conducted through the implantation of 3D printed PLA scaffolds either alone, covered by apatite (PLA-CaP) or PLA-CaP loaded with rhBMP-2 (PLA-CaP+rhBMP-2) on critical-sized defects (8 mm) of rat calvaria. Increased cell adhesion and in vitro release of growth factors (PDGF, bFGF, VEGF) was observed for PLA-CaP scaffolds when pre-treated with FBS. PLA-CaP+BMP2 presented higher values of newly formed bone (NFB) than other groups at all experimental periods (p&lt;0.05), attaining 44.85% of NFB after 6 months. These findings indicate that functionalization of PLA scaffolds with biomimetic apatite can improve its biological properties in the presence of complex biological media. Its association with BMP2 may enhance bone repair, suggesting this strategy as a promising candidate for bone tissue engineering.

The loss or dysfunction of skeletal tissue often necessitates surgical intervention, particularly in cases involving trauma, tumors, or abnormal development leading to critical-sized defects. Despite autografts being considered the gold standard for bone grafts, their limitations and complications prompt the exploration of alternative approaches for bone repair and regeneration. Current advancements in bone tissue engineering have led to innovative strategies aiming to regenerate injured bone structures, providing viable alternatives to traditional autografts or allografts. Among these strategies, Hydrogel Microparticles (HMPs) have emerged as promising scaffolds due to their notable characteristics, including high porosity and mechanical tunability. HMPs play an important role in facilitating vasculature formation, mineral deposition, and overall bone tissue regeneration. HMPs, fabricated through various techniques, exhibit versatility in functions such as drug and cell delivery, structural scaffolding, and bioinks for 3D printing. In addition, these microgels can be injected for minimally invasive delivery and can display modular properties with different designs and configurations. This review exclusively focuses on the advancements in HMPs for bone regeneration, delving into synthesis and functionalization techniques while highlighting their diverse applications documented in the literature. Our aim is to shed light on the unique benefits and potential of HMPs in the intricate field of engineering bone tissue.

Background: The aim of the present investigation was to evaluate the clinical success of horizontal ridge augmentation in the severely atrophic maxilla (Cawood and Howell class IV) using freeze-dried custom made bone harvested from cadaver donors tibial hemiplateau and to analyze the marginal bone level gain prior dental implants placement at 9 months after bone grafting and before prosthetic rehabilitation. Methods: A 52-year-old woman received custom made bone grafts. Patient underwent CT scans 2 weeks prior and 9 months after surgery for graft volume and density analysis. Results: The clinical and radiographic bone observations showed a very low rate of resorption after bone graft and implant placement. Conclusions: The custom-made allograft material was a highly effective modality for restoring the alveolar horizontal ridge, resulting in this way to reduce the need to obtain autogenous bone from a secondary site with predictable procedure. Further studies are needed to investigate its behavior at longer time points.

Pesticides are chemical products are used to protect crops to prevent or eliminate undesirable organisms. Pesticides can contaminate continental waters, air, soil and food products. The presence of pesticide residues must therefore be monitored in water and food using sensitive, reliable and broad-spectrum analytical methods, as there is a huge variety of pesticides. Biosensors are one of the screening methods with great potential for detecting residues below the maximum residue limits. The different sensing principles of enzymatic biosensors for pesticide analysis will be described. This review highlights the great potential of colorimetric, enzymatic biosensors for detecting pesticide residues in water and food. Moreover the development of dual colorimetric and fluorimetric sensors during the past years is presented. These methods are most often based on the enzyme acetylcholinesterase, whose activity is inhibited by pesticides. The different approaches used in the development of these biosensors will be detailed, based on different chemical substrates, fluorophores and nanomaterials. The advantages and disadvantages of each approach will be discussed. Finally, the development prospects for improving these biosensors will be presented.

Human pluripotent stem cells (hPSCs) have become a powerful tool to generate various kinds of cell types comprising the human body. Recently, organoid technology emerged as a platform to build a physiologically relevant tissue-like structure from the PSCs, which provides a more relevant three-dimensional microenvironment to the actual human body than the conventional monolayer culture system for transplantation, disease modeling, and drug development. Although it holds so many advantages, the organoid culture system still has various problems related to culture methods, which became a challenge to get similar physiological properties to their original tissue counterparts. Here, we discuss the current development of organoid culture methods, including the problem that may arise from the currently available culture systems as well as the possible approach to overcoming the current limitation and improving their optimum utilization for translational application purposes.

Development of supervised AI algorithms requires a large amount of labeled images. Image labelling is both time-consuming and expensive. Therefore, we explored the value of e-learning derived annotations for AI algorithm development in medical imaging. Methods We have developed an e-learning platform that involves image-based single click labelling as part of the educational learning process. Ten radiology residents, as part of their residency training, trained the recognition of pneumothorax on 1161 chest X-rays in posterior-anterior projection. Using this data, multiple AI algorithms for detecting pneumothorax were developed. Classification and localization performance of the models was tested on an independent internal testing dataset and on the public NIH ChestX-ray14 dataset. Results The AI models F1 scores on the internal and the NIH dataset were 0.87 and 0.44, respectively. Sensitivity was 0.85 and 0.80 for classification and specificity 0.96 and 0.48 for classification. F1 scores were 0.72 and 0.66, sensitivity 0.72 and 0.72. False positive rate was 0.36 and 0.32 for localisation. Conclusion Our results demonstrated that e-learning derived annotations are a valuable data source for algorithm development. Further work is needed to include additional parameters such as user performance, consensus of diagnosis, and quality control in the development pipeline.

The microtubule-associated protein TAU is sorted into the axon in healthy brain neurons. Somatodendritic missorting of TAU is a pathological hallmark of many neurodegenerative diseases called tauopathies, including Alzheimer’s Disease (AD). Cause, consequence, and (patho)physiological mechanisms of TAU sorting and missorting are understudied, in part also due to the lack of readily available human neuronal model systems. The human neuroblastoma cell line SH-SY5Y is widely used for studying TAU physiology and TAU-related pathology in AD and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons) using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for i) investigating intracellular TAU sorting in general, and ii) with respect to neuron subtype-specific TAU vulnerability. I) SH-SY5Y-derived neurons show pronounced axodendritic polarity, high levels of axonally localized TAU protein, expression of all six major human brain isoforms, and TAU phosphorylation similar to the human brain. As proliferative cells, SH-SY5Y cells are readily accessible for genetic engineering, stable transgene integration and leading-edge genome editing are valuable and promising tools for TAU-related studies. II) Depending on the used differentiation procedure, SH-SY5Y-derived neurons resemble cells of distinct subcortical nuclei, i.e. the Locus coeruleus (LC), Nucleus basalis (NB) and Substantia nigra (SN), all of which early affected in many tauopathies. This allows to analyse neuron-specific TAU isoform expression and intracellular localization, also in the context of vulnerability to TAU pathology. Limitations are e.g. the lack of mimicking age-related tauopathy risk factors and the difficulty to define the exact neuronal subtype of SH-SY5Y-derived neurons. In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU (mis)sorting mechanisms and neuron-specific TAU vulnerability in disease paradigms.

Patient derived model systems are important tools for studying novel anti-cancer therapies. Patient derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient derived models for radiation research including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and T10 vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, IL-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL6, CSF3, and IL8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these up-regulated genes, IL8 expression in NSCLC tissues was associated with worse prognosis and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.

Osteoporosis (OP), a prevalent skeletal disorder characterized by compromised bone strength and increased susceptibility to fractures, poses a significant public health concern. This review aims to provide a comprehensive analysis of the current state of research in the field, focusing on the application of proteomic techniques to elucidate diagnostic markers and therapeutic targets for OP. The integration of cutting-edge proteomic technologies has enabled the identification and quantification of proteins associated with bone metabolism, leading to a deeper understanding of the molecular mechanisms underlying OP. In this review, we systematically examine recent advancements in proteomic studies related to OP, emphasizing the identification of potential biomarkers for OP diagnosis and the discovery of novel therapeutic targets. Additionally, we discuss the challenges and future directions in the field, highlighting the potential impact of proteomic research in transforming the landscape of OP diagnosis and treatment.

Background: To investigate the safety and efficacy of palliative arterial embolization for metastases of the scapula. Materials and Methods: We studied the files of the patients who underwent palliatrive arterial embolization for metastases of the scapula from January 2016 to January 2023, 15 patients (8 M, and 7 F) with a mean age of 62 years (SD 10.2) with two patients receiving a second procedure, for a total of 17 embolizations. Data on technical and clinical success, as well as changes in tumor size, were collected. All embolization-related complications were evaluated according to the CIRSE classification system for complications. Results: The average follow-up was 18 months (Range 6-36 months). The main primary tumor were renal, lung and breast cancer. The primary arteries embolized were the circumflex scapular artery, the dorsal scapular artery, and the thoracoacromial trunk. A mixture of Glubran and Lipiodol in a 1:2 ratio was used for embolization, with an average of 1.1 mL (Range 0.5-1.5 mL) used per procedure. The efficacy of embolization was measured using the Visual Analogue Scale (VAS), with values recorded at baseline, at 1, 3, 6, and 12 months post-embolization, and at 6-month intervals after. Baseline VAS scores averaged 7.2 (SD 1.5), decreasing to 2.8 (SD 0.9) at one month. Progressive reduction was observed at 3, 6, and 12 months with scores of 2.3 (SD 0.8), 1.9 (SD 0.7), and 1.6 (SD 0.6) respectively. Metastatic tumor size was reduced from a mean of 192.2 cm3 (range 38.7 to 480.1 cm3) pre-embolization to a mean of 177.3 cm3 (range 37.2 to 455.5 cm3) at the 12-month follow-up (p

Localized jawbone invasion is a milestone in the progression of oral squamous cell carcinoma (OSCC). The factors that promote this process are not well understood. Sclerostin is known to be involved in bone metabolism and there are preliminary reports of its involvement in bone tumors and metastasis. To identify a possible involvement of sclerostin in the bone invasion process of OSCC, sclerostin expression was analyzed in vitro in two different human OSCC tumor cell lines by qRT-PCR, and the effect of recombinant human (rh)-sclerostin treatment on tumor cell capabil-ities was evaluated using proliferation, migration, and invasion assays. Undifferentiated human mesenchymal stem cells (hMSCs) were osteogenically differentiated and co-cultured with OSCC tumor cells to demonstrate potential interactions on migration characteristics. Sclerostin expres-sion was evaluated in clinical cases by immunohistochemistry at the OSCC jawbone interface in a cohort of 15 patients. Sclerostin expression was detected in both OSCC tumor cell lines in vitro and was also detected at the OSCC jawbone interface in clinical cases. Tumor cell proliferation rate, migration and invasion ability were increased by rh-sclerostin treatment. The migration rate of tumor cells co-cultured with osteogenically differentiated hMSCs was increased. The re-sults presented are the first data suggesting a possible involvement of sclerostin in the bone inva-sion process of OSCC, which needs to be further investigated

Critical sized bone defects and articular cartilage injuries resulting from trauma, osteonecrosis or age-related degeneration are often nonhealing by the physiological repairing mechanisms, thus representing a clinic issue due to the relevant epidemiological incidence. Current treatment approaches consist of autologous or allogenic grafting, which are associated with painfulness, morbidity, risk of infections and rejection. Novel tissue-engineering approaches, aiming at the reconstruction of damaged tissues, have been proposed as alternative solutions to these conven-tional methods. These approaches are based on the combination of three fundamental compo-nents: autologous or allogenic cells, a scaffold and growth-stimulating signals, which are gener-ally referred to as the tissue engineering triad. Three-dimensional polymer networks are fre-quently used as scaffolds to allow cell proliferation and tissue regeneration. In this scenario, cryogels are giving promising results as cell scaffolds over other polymer networks, thanks to their peculiar properties. In particular, cryogels possess an interconnected porous structure and a typical sponge-like behaviour, which facilitate the cellular infiltration and ingrowth. Their properties can be appropriately adjusted to match the requirements of the specific tissue or or-gan that it is intended to regenerate. In this review it is reported the state of the art on the fabri-cation and employment of cryogels in supporting osteo or chondro-genic differentiation for the re-building of more organized tissues. Moreover, it will highlight current progress and future perspectives in the implementation of this technology in the clinical practice.

In this presented case, a 77 years old woman suffering from ongoing knee pain underwent a bone scan using 99mTc-hydroxydiphosphonate (HDP) in suspicious for bone infection. An incidental finding from this scan revealed diffuse cardiac uptake, necessitating further diagnostic procedures to exclude the possibility of cardiac amyloidosis. In the subsequent 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan and SPECT images, no perceptible cardiac uptake was observed at all. Upon retrospective review of the patient’s medical records, she had received 1000mg of ferric carboxymaltose for iron-deficient anemia, the day before the 99mTc-HDP bone scan. Therefore, it is assumed that the diffuse and temporary cardiac activity was due to the transient iron overload. We present and share this bone scan images in order to avoid possible future misinterpretation of cardiac amyloidosis.

Exosomes are membrane-bound, biologically active nanovesicles of size 30-200 nm produced by many cell types, such as both mammalian and plant cells. They are wrapped in a phospholipid bilayer and play a significant role in intercellular communications. The ease in their isolation and the ability of plant-derived exosome-like nanovesicles (PDEVs) to efficiently deliver bioactive constituents into mammalian cells have made them popular in contemporary research. PDEVs share many characteristics with mammalian EVs (MEVs), including shape, size, surface charge, and consist of bioactive molecules like lipids, proteins, nucleic acids, and tiny metabolites. However, the chemical composition profile of PDEVs and their biogenesis mechanism differ significantly from those of MEVs. They have been widely explored as potential therapeutic agents and are considered as good alternatives to act as a carrier for drug delivery. The present work elucidates the isolation of exosome-like-nanovesicles (henceforth exosomes) from the culture supernatants of an in vitro cultured callus tissue derived from a bone healing plant known for its osteogenic activity, i.e., Cissus quadrangularis. The physical and biological properties of exosomes were successfully studied using different characterization techniques. To assess their therapeutic potential, we studied the internalisation of calcein-AM labeled exosomes by human derived mesenchymal stromal cells (hMSCs). Additionally, we evaluated the potential of exosomes in the migration of cells in a cell scratch assay with hMSCs and their effect on amelioration of oxidative stress was investigated on preosteoblast MC3T3-E1 cells that were pre-treated with these exosomes. Furthermore, we investigated their proliferation and differentiation to osteoblasts like cells with the help of resazurin assay and alkaline phosphatase assay (ALP). The obtained results provide a primary justification for the use of Cissus quadrangularis-derived exosomes as a nanocarrier for drug molecules for various therapeutic bone applications.

Background: Antibiofilm activity of silver nanoparticles has been extensively investigated in common bacteria. Metallo-β-lactamase producing Gram-negative bacteria are hard-to-treat microorganisms with few therapeutic options, and silver nanoparticles were not evaluated on the biofilm of these bacteria. Objectives: The aim of this study was to evaluate the antibiofilm activity of a bone scaffold impregnated with silver nanoparticles in NDM-producing Gram-negative bacilli. Methods: Bone scaffolds from bovine femur were used for the tests and impregnated with silver nanoparticles (50 nm) by physical adsorption. Silver nitrate minimal inhibitory and bactericidal concentrations (MIC and MBC) were performed on NDM-producing Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Disc diffusion tests for silver nanoparticles susceptibility and quantification of biofilm production on plate and bone with sessile cell count were performed. Results: The MIC results demonstrated that silver nitrate had an antimicrobial effect on all microorganisms, inactivating the growth of isolates from a concentration of 8 µg/mL. MBC results showed that E. coli 16.211 was the only isolate to present MIC different from MBC, with a value of 16 µg/mL. Conclusion: Bone scaffolds impregnated with silver nanoparticles can significantly reduce biofilm, and it can be a strategic material to be used as an implant for different approaches.

The purpose of this study was to evaluate the outcomes of implants placed in horizontally augmented alveolar ridges using porcine bone grafts and to investigate the long-term stability of the porcine bone grafts. A retrospective analysis was conducted on 55 sites that underwent horizontal ridge augmentation using porcine bone grafts and implant placement with a follow-up period longer than 5 years. Furthermore, additional analysis was conducted on 24 sites where porcine bone grafts were used exclusively and implants were placed simultaneously with horizontal ridge augmentation. The mean follow-up period after prosthesis loading was 67.3 months, with a mean marginal bone loss of 0.18 mm at 1 year and a cumulative mean marginal bone loss of 0.37 mm over the entire follow-up period. Of the 55 implants, 2 were lost and 4 did not meet the success criteria, resulting in a survival rate of 96.4% and a success rate of 89.1%. In 24 sites, the mean marginal bone loss was 0.22 mm at 1 year and 0.40 mm at 65.8 months, with 100% survival and success rates. Porcine bone grafts can be successfully used in horizontal ridge augmentation for implant placement in cases of ridges with insufficient horizontal width.

The injectable hydrated calcium phosphate bone-like paste (hCPP) have been developed with suitable nanoscale characteristics and unindered injection through 23G standard needles. In vitro assays showed the cytocompatibility of hCPP with mesenchymal embryonic C3H10T1/2 cell cultures. The hCPPs were identified to be composed of aggregated nano-sized particles with sphere-like shapes with low crystallinity. The ability of serum proteins (FBS) to adsorb on hCPP particles was also studied. The hCPP demonstrated high protein adsorption capacity, thereby indicating its potential in various biomedical applications. The results of the in vivo assay upon subcutaneous injection in Wistar rats indicated the nontoxicity and biocompatibility of experimental hCPP, as well as the gradual resorption of hCPP, comparable to the period of bone regeneration. The data obtained are of great interest for the development of commercial highly effective osteoplastic materials for bone tissue regeneration and augmentation.

Mild impacts to the head, particularly when repetitive in nature, are increasingly recognized to have a range of significant negative implications for brain health. Much of the ongoing research in the field is focused on the neurological consequences of these injuries, and the relationship between head impacts and long-term neurodegenerative conditions such as chronic traumatic encephalopathy and Alzheimer’s disease. However, our understanding of the complex relationship between applied mechanical force at impact, brain pathophysiology, and neurological function, remains incomplete. Past research has shown that mild head impacts, even below the threshold that results in cranial fracture, induce changes in cranial bone structure and morphology. These structural and physiological changes likely have implications for the transmission of mechanical force into the underlying brain parenchyma. Here, we review this evidence in the context of the current understanding of bone mechanosensitivity and the consequences of traumatic brain injuries or concussions. We postulate that heterogeneity of the calvarium including differing bone thickness due to prior impacts, age, or individual variability, may be a modulator of outcomes following subsequent head impacts. We advocate for greater consideration of cranial responses to head injury in both experimental and computer modeling of impact biomechanics, and raise the hypothesis that calvarial bone thickness represents a novel biomarker of brain injury vulnerability after head trauma.

Background: Painful spinal bone metastases (PSBMs) patients regularly receive palliative radiation therapy (RT) with response rates in about 2 of 3 patients. In this exploratory study, we evaluated the value of machine learning (ML) models based on radiomic, semantic and clinical features to predict complete pain response. Methods: Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomic, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation.Results: The best radiomic classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01).Conclusions: We could demonstrate that radiomic and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results.

The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2, are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA) -, gastrin-releasing peptide receptor (GRPR) -, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.