Functional response and predation rate of Cryptolaemus montrouzieri (Coleoptera: Coccinellidae) to Paracoccus marginatus (Hemiptera: Pseudococcidae) at different temperatures.

The ladybug, Cryptolaemus montrouzieri (Mulsant) (Coleoptera: Cocccinellidae)(Mulsant)(Coleoptera: Cocccinellidae), is a highly efficient predator in controlling mealybug populations and is considered an effective agent for controlling the papaya mealybugs (Paracoccus marginatus) (Williams & Granara de Willink) (Hemiptera: Pseudococcidae). Various criteria have been proposed for evaluating predator effectiveness, with the consumption rate of prey by individual predators, specifically the functional response, emerging as a common and crucial metric. This study evaluated the functional responses of third- and fourth-instar larvae, as well as male and female adults (<48 h old) of C. montrouzieri to adult females of P. marginatus at 3 different temperatures (22 °C, 28 °C, and 35 °C) with 70% ±â€…5% RH and a 12L:12D h photoperiod. Prey densities were 2, 4, 8, 16, 32, 45, or 60 papaya mealybugs per predator for all tests. The response to prey density by third- and fourth-instar larvae or both sexes of adult C. montrouzieri was a type II at all temperatures. The highest attack rate and lowest handling time were estimated at 28 °C in males and 35 °C in females, respectively. The highest daily prey consumption rate occurred at 35 °C in both the immature and adult stages of C. montrouzieri. These findings support the potential of C. montrouzieri in controlling the papaya mealybug, especially in tropical and subtropical regions, given its search efficiency at high temperatures tested in this study. However, additional field investigations are needed to ascertain the control efficacy of C. montrouzieri for this mealybug in biocontrol programs.

Chronic kidney disease: a contraindication for using biodegradable magnesium or its alloys as potential orthopedic implants?

Magnesium (Mg) has gained widespread recognition as a potential revolutionary orthopedic biomaterial. However, whether the biodegradation of the Mg-based orthopedic implants would pose a risk to patients with chronic kidney disease (CKD) remains undetermined as the kidney is a key organ regulating mineral homeostasis. A rat CKD model was established by a 5/6 subtotal nephrectomy approach, followed by intramedullary implantation of three types of pins: stainless steel, high pure Mg with high corrosion resistance, and the Mg-Sr-Zn alloy with a fast degradation rate. The long-term biosafety of the biodegradable Mg or its alloys as orthopedic implants were systematically evaluated. During an experimental period of 12 weeks, the implantation did not result in a substantial rise of Mg ion concentration in serum or major organs such as hearts, livers, spleens, lungs, or kidneys. No pathological changes were observed in organs using various histological techniques. No significantly increased iNOS-positive cells or apoptotic cells in these organs were identified. The biodegradable Mg or its alloys as orthopedic implants did not pose an extra health risk to CKD rats at long-term follow-up, suggesting that these biodegradable orthopedic devices might be suitable for most target populations, including patients with CKD.

A rabbit osteochondral defect (OCD) model for evaluation of tissue engineered implants on their biosafety and efficacy in osteochondral repair.

Osteochondral defect (OCD) is a common but challenging condition in orthopaedics that imposes huge socioeconomic burdens in our aging society. It is imperative to accelerate the R&D of regenerative scaffolds using osteochondral tissue engineering concepts. Yet, all innovative implant-based treatments require animal testing models to verify their feasibility, biosafety, and efficacy before proceeding to human trials. Rabbit models offer a more clinically relevant platform for studying OCD repair than smaller rodents, while being more cost-effective than large animal models. The core-decompression drilling technique to produce full-thickness distal medial femoral condyle defects in rabbits can mimic one of the trauma-relevant OCD models. This model is commonly used to evaluate the implant's biosafety and efficacy of osteochondral dual-lineage regeneration. In this article, we initially indicate the methodology and describe a minimally-invasive surgical protocol in a step-wise manner to generate a standard and reproducible rabbit OCD for scaffold implantation. Besides, we provide a detailed procedure for sample collection, processing, and evaluation by a series of subsequent standardized biochemical, radiological, biomechanical, and histological assessments. In conclusion, the well-established, easy-handling, reproducible, and reliable rabbit OCD model will play a pivotal role in translational research of osteochondral tissue engineering.

Canonical pathways for validating steroid-associated osteonecrosis in mice.

The present study aimed to establish and evaluate a preclinical model of steroid-associated osteonecrosis (SAON) in mice. Sixteen 24-week-old male C57BL/6 mice were used to establish SAON by two intraperitoneal injections of lipopolysaccharide (LPS), followed by three subcutaneous injections of methylprednisolone (MPS). Each injection was conducted on working day, with an interval of 24 h. Six cycles of injections were conducted. Additional twelve mice (age- and gender-matched) were used as normal controls. At 2 and 6 weeks after completing induction, bilateral femora and bilateral tibiae were collected for histological examination, micro-CT scanning, and bulk RNA sequencing. All mice were alive until sacrificed at the indicated time points. The typical SAON lesion was identified by histological evaluation at week 2 and week 6 with increased lacunae and TUNEL+ osteocytes. Micro-CT showed significant bone degeneration at week 6 in SAON model. Histology and histomorphometry showed significantly lower Runx2+ area, mineralizing surface (MS/BS), mineral apposition rate (MAR), bone formation rate (BFR/BS), type H vessels, Ki67+ (proliferating) cells, and higher marrow fat fraction, osteoclast number and TNFα+ areas in SAON group. Bulk RNA-seq revealed changed canonical signaling pathways regulating cell cycle, angiogenesis, osteogenesis, and osteoclastogenesis in the SAON group. The present study successfully established SAON in mice with a combination treatment of LPS and MPS, which could be considered a reliable and reproducible animal model to study the pathophysiology and molecular mechanism of early-stage SAON and to develop potential therapeutic approaches for the prevention and treatment of SAON.

Study on Carbonation of Porcine Blood Hydrogel in the Composite Mortar of Ancient Chinese Architectural Painting.

In the ancient Chinese recipe for composite mortar used in the construction of ground layers for architectural painting, the mixture of porcine blood and lime water is one of the constituent materials. Herein, according to the traditional recipe, the interaction between porcine blood and lime water was systematically and deeply investigated. The experimental investigation demonstrated that porcine blood mixed with lime water at the ratio found in the recipe can form a hydrogel with a hydrophobic surface. During air-drying, the lime water in porcine blood hydrogel can react with CO2 to form calcium carbonate. The crystal morphology of the formed calcium carbonate depends on the surrounding micro-environment of calcium ions in the porcine blood hydrogel. The formed morphology of calcium carbonate includes small calcite crystallites, small graininess calcite crystals with round features, calcite aggregates with layered ladder-like structures, and amorphous calcium carbonate (ACC). Interestingly, the calcium carbonate formed in the inner part of the porcine blood hydrogel exhibits lamellar distribution due to a Liesegang pattern formation. Based on the findings that the porcine blood hydrogel has surface hydrophobicity and brittleness, it can be predicted that in the preparation process of composite mortar for ancient building color painting base course, porcine blood used in the form of a hydrogel is not only easier to be dispersed in hydrophobic tung oil than in liquid porcine blood but also the affinity between porcine blood gel and tung oil is enhanced. As constituent material dispersed in the composite mortar, the layered distribution of calcium carbonate in the porcine blood hydrogel may presumably be beneficial to reduce the internal stress of the composite mortar material.

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment.

Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status - notably, obstructed fatty acid transportation - was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

Lysine-rich rice partially enhanced the growth and development of skeletal system with better skeletal microarchitecture in young rats.

Rice is the primary staple food for half of the world's population but is low in lysine content. Previously, we developed transgenic rice with enhanced free lysine content in rice seeds (lysine-rich rice), which was shown safe for consumption and improved the growth in rats. However, the effects of lysine-rich rice on skeletal growth and development remained unknown. In this study, we hypothesized that lysine-rich rice improved skeletal growth and development in weaning rats. Male weaning Sprague-Dawley rats received lysine-rich rice (HFL) diet, wild-type rice (WT) diet, or wild-type rice with various contents of lysine supplementation diet for 70 days. Bone microarchitectures were examined by microcomputed tomography, bone strength was investigated by mechanical test, and dynamics of bone growth were examined by histomorphometric analysis. In addition, we explored the molecular mechanism of lysine and skeletal growth through biochemical testing of growth hormone, bone turnover marker, and amino acid content of rat serum analysis, as well as in a cell culture system. Results indicated that the HFL diet improved rats' bone growth, strength, and microarchitecture compared with the WT diet group. In addition, the HFL diet increased the serum essential amino acids, growth hormone (insulin-like growth factor-1), and bone formation marker concentrations. The cell culture model showed that lysine deficiency reduced insulin-like growth factor-1 and Osterix expression, Akt/mammalian target of rapamycin signaling, and matrix mineralization, and inhibited osteoblast differentiation associated with bone growth. Our findings showed that lysine-rich rice improved skeletal growth and development in weaning rats. A further increase of rice lysine content is highly desirable to fully optimize bone growth and development.

Engineered biochemical cues of regenerative biomaterials to enhance endogenous stem/progenitor cells (ESPCs)-mediated articular cartilage repair.

As a highly specialized shock-absorbing connective tissue, articular cartilage (AC) has very limited self-repair capacity after traumatic injuries, posing a heavy socioeconomic burden. Common clinical therapies for small- to medium-size focal AC defects are well-developed endogenous repair and cell-based strategies, including microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), and matrix-induced ACI (MACI). However, these treatments frequently result in mechanically inferior fibrocartilage, low cost-effectiveness, donor site morbidity, and short-term durability. It prompts an urgent need for innovative approaches to pattern a pro-regenerative microenvironment and yield hyaline-like cartilage with similar biomechanical and biochemical properties as healthy native AC. Acellular regenerative biomaterials can create a favorable local environment for AC repair without causing relevant regulatory and scientific concerns from cell-based treatments. A deeper understanding of the mechanism of endogenous cartilage healing is furthering the (bio)design and application of these scaffolds. Currently, the utilization of regenerative biomaterials to magnify the repairing effect of joint-resident endogenous stem/progenitor cells (ESPCs) presents an evolving improvement for cartilage repair. This review starts by briefly summarizing the current understanding of endogenous AC repair and the vital roles of ESPCs and chemoattractants for cartilage regeneration. Then several intrinsic hurdles for regenerative biomaterials-based AC repair are discussed. The recent advances in novel (bio)design and application regarding regenerative biomaterials with favorable biochemical cues to provide an instructive extracellular microenvironment and to guide the ESPCs (e.g. adhesion, migration, proliferation, differentiation, matrix production, and remodeling) for cartilage repair are summarized. Finally, this review outlines the future directions of engineering the next-generation regenerative biomaterials toward ultimate clinical translation.

Acupuncture Ameliorated Behavioral Abnormalities in the Autism Rat Model via Pathways for Hippocampal Serotonin.

Purpose: Acupuncture can improve symptoms of autism spectrum disorder (ASD), but the potential mechanisms remain undefined. So, we aimed to explore the behavioral improvement of autism rat model after acupuncture and to describe the potential molecular mechanism underlying these changes. Patients and Methods: Wistar rats were intraperitoneally injected with VPA 12.5 days after conception, and their offspring were considered as good models of autism. Experimental rats were divided into three groups (wild-type (WT), n = 10; VPA, n = 10; and VPA_acupuncture, n = 10). VPA_acupuncture group rat received 4 weeks of acupuncture treatment (Shéntíng (GV24), and Bilateral Benshén (GB13)) on the 23rd day after birth. All rats were subjected to behavioral tests, including social interaction, open field, and Morris water maze tests. Afterwards, hippocampal tissues (left side) were removed and subjected to RNA sequencing (RNA-seq) analysis; ELISA was also used to detect the associated serotonin levels in the hippocampus. Results: Behavioral tests showed that acupuncture treatment improved spontaneous activity, aberrant social interaction, and alleviated impaired learning and memory in the VPA-induced rat model. Differentially expressed genes (DGEs) analysis showed 142 significantly differentially expressed genes between WT and VPA groups, and 282 between VPA and VPA_acupuncture rats. Htr2c and Htr1a, 5-HT receptor genes, were up-regulated in the VPA group compared with WT group. Additionally, Tph1, a rate-limiting enzyme gene of 5-HT synthesis, was up-regulated after acupuncture. These genes were confirmed to have the same trend of expression obtained by RT-qPCR and RNA seq. Furthermore, the concentration of serotonin in the hippocampus in the VPA group was significantly lower than the WT and VPA_acupuncture groups. Conclusion: Acupuncture improved abnormal behavioral symptoms in the VPA-induced rat model. Further experiments showed that the improvement of the serotonin system may be one of the main regulatory mechanisms of acupuncture for treating ASD.

Effects of Elevated CO2 on the Fitness Parameters of Individually- and Group-Reared Agasicles hygrophila (Coleoptera: Chrysomelidae).

Agasicles hygrophila Selman and Vogt (Coleoptera: Chrysomelidae) is a natural enemy of Alternanthera philoxeroides (Mart.) Griseb (Amaranthaceae: Alternanthera), a worldwide invasive weed. Elevated atmospheric CO2 concentrations may have significant impacts plants, herbivorous insects, and natural enemies. To assess the concurrent effect of elevated CO2 on the development time, fecundity, and population parameters of A. hygrophila, the age-stage, two-sex life table was used to understand the fitness and population parameters of individually-reared and group-reared A. hygrophila under elevated CO2 concentration. In individually-reared population, the development time of preadults, adult pre-oviposition period, and total pre-oviposition period of A. hygrophila in the elevated CO2 (eCO2, 750 ppm) treatment were shorter than those in the ambient CO2 (aCO2, 420 ppm) treatment. In group-reared population, the developmental time of preadults, female adult longevity, female proportion, adult pre-oviposition period, and total pre-oviposition period of A. hygrophila in eCO2 were longer than those in aCO2. Additionally, in both individually-reared and group-reared population, fecundity and oviposition days of A. hygrophila in eCO2 were higher than those in aCO2, and a higher intrinsic rate of increase, finite rate of increase, and the net reproductive rate of A. hygrophila were observed at eCO2. Moreover, shorter preadult development time, adult pre-oviposition period, total pre-oviposition period, male adult longevity, and higher fecundity were found in group-reared cohort at both aCO2 and eCO2. The results indicates that elevated CO2 has effects on the growth and reproduction of A. hygrophila, and the population growth rate of group-reared was faster and produced more offspring.

Controlled Release of Bone Morphogenetic Protein-2 Augments the Coupling of Angiogenesis and Osteogenesis for Accelerating Mandibular Defect Repair.

Reconstruction of a mandibular defect is challenging, with high expectations for both functional and esthetic results. Bone morphogenetic protein-2 (BMP-2) is an essential growth factor in osteogenesis, but the efficacy of the BMP-2-based strategy on the bone regeneration of mandibular defects has not been well-investigated. In addition, the underlying mechanisms of BMP-2 that drives the bone formation in mandibular defects remain to be clarified. Here, we utilized BMP-2-loaded hydrogel to augment bone formation in a critical-size mandibular defect model in rats. We found that implantation of BMP-2-loaded hydrogel significantly promoted intramembranous ossification within the defect. The region with new bone triggered by BMP-2 harbored abundant CD31+ endomucin+ type H vessels and associated osterix (Osx)+ osteoprogenitor cells. Intriguingly, the new bone comprised large numbers of skeletal stem cells (SSCs) (CD51+ CD200+) and their multi-potent descendants (CD51+ CD105+), which were mainly distributed adjacent to the invaded blood vessels, after implantation of the BMP-2-loaded hydrogel. Meanwhile, BMP-2 further elevated the fraction of CD51+ CD105+ SSC descendants. Overall, the evidence indicates that BMP-2 may recapitulate a close interaction between functional vessels and SSCs. We conclude that BMP-2 augmented coupling of angiogenesis and osteogenesis in a novel and indispensable way to improve bone regeneration in mandibular defects, and warrants clinical investigation and application.

Sublethal and Transgenerational Toxicities of Chlorfenapyr on Biological Traits and Enzyme Activities of Paracoccus marginatus (Hemiptera: Pseudococcidae).

Papaya mealybug, Paracoccus marginatus Williams and Granara de Willink (Hemiptera: Pseudococcidae), is an economically important, invasive insect that is now distributed worldwide. Chlorfenapyr has been demonstrated to have a significant control effect on P. marginatus. In order to evaluate the sublethal and transgenerational effects of chlorfenapyr on P. marginatus, the life table data of three consecutive generations were collected and analyzed by the age stage, two-sex life table method, and the enzyme activities were assayed using a spectrophotometer. The results showed that exposure to the insecticide had significant effects on the biological traits of subsequent generations of P. marginatus, and a higher intrinsic rate of increase (r), finite rate of increase (λ), net reproductive rate (R0), and a shorter mean generation time (T) were observed in the chlorfenapyr-treated F1 mealybugs. Enzyme activity assays showed that chlorfenapyr significantly inhibited the activities of catalase (CAT) and peroxidase (POD) while activating the activities of superoxide dismutase (SOD), which suggested that SOD, CAT, and POD may play an important role in the self-defense of P. marginatus against chlorfenapyr. These results conclusively demonstrated that exposure of P. marginatus to sublethal concentrations of chlorfenapyr induced hormetic effects on the F1 generation while having negative effects on the F0 and F3 generations.

Fitness of the Papaya Mealybug, Paracoccus marginatus (Hemiptera: Pseudococcidae), after Transferring from Solanum tuberosum to Carica papaya, Ipomoea batatas, and Alternanthera philoxeroides.

The papaya mealybug, Paracoccus marginatus Williams and Granara de Willink (Hemiptera: Pseudococcidae), is a polyphagous invasive pest in China. The effect that the shifting of the host plant has on the fitness of a polyphagous pest is critical to its prevalence and potential pest control. In order to assess the fitness changes of P. marginatus after transferal from potato (Solanum tuberosum (Tubiflorae: Solanaceae)) to papaya (Carica papaya (Parietales: Caricacea)), sweet potato (Ipomoea batatas (Tubiflorae: Convolvulaceae)), and alligator weed (Alternanthera philoxeroides (Centrospermae: Amaranthaceae)), the life table data of three consecutive generations were collected and analyzed using the age-stage, two-sex life table method. The results showed that when P. marginatus was transferred from S. tuberosum to papaya, a higher intrinsic rate of increase (r) and finite rate of increase (λ) were observed. Paracoccus marginatus individuals transferred to I. batatas had the significantly lower population parameters than those on C. papaya; however, the fitness recovered for those on I. batatas after two generations. Paracoccus marginatus individuals were unable to complete development on A. philoxeroides. Our results conclusively demonstrate that P. marginatus individuals can readily adapt to C. papaya and I. batatas even after host plant shifting, and are capable of causing severe damage to these hosts.

De Novo Transcription Responses Describe Host-Related Differentiation of Paracoccus marginatus (Hemiptera: Pseudococcidae).

Paracoccus marginatus (Hemiptera: Pseudococcidae) is an invasive pest with a diverse host range, strong diffusion, and high fecundity. It has been observed that P. marginatus feeding on Carica papaya have a higher survival rate, fecundity, and longer lifespan than P. marginatus feeding on Solanum tuberosum, indicating their successful adaptation to C. papaya; however, the mechanisms underlying host plant adaptation remain unclear. Therefore, RNA-seq was performed to study the transcriptional responses of P. marginatus feeding on C. papaya and S. tuberosum plants. A total of 408 genes with significant differential expression were defined; most of them were downregulated in S. tuberosum, including those of digestive enzymes, detoxifying enzymes, ribosomes, and reproductive-related genes, which may result from the adaptation of the host to nutritional needs and changes in toxic chemical levels. Enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes showed that lysosome and longevity regulating pathways related to digestion, detoxification, and longevity were enriched. We suggest that C. papaya is a more suitable host than S. tuberosum, and downregulated target genes may have important effects on the adaptation of P. marginatus to host transfer.

Infection of Metarhizium anisopliae Ma6 and defense responses of host Phyllotreta striolata adults.

Entomopathogenic fungus as biological control agent plays a crucial role in the integrated management of insect pests. Metarhizium anisopliae Ma6 has been identified as a highly pathogenic strain against Phyllotreta striolata (Fabricius) (Coleoptera: Chrysomelidae), one of the most economically important and dominant insect pests damaging Brassica plants. The infection of M. anisopliae Ma6 on P. striolata was observed under stereomicroscopy and scanning electron microscopy (SEM), and biochemical defense responses of P. striolata adults after infection were investigated. The changes in total amino acids and free fatty acids, and the activities of protective enzymes, including catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), in P. striolata adults were measured. In stereomicroscopy and SEM observations, a large number of mycelia were observed on the body surface of P. striolata on the 5th day after treatment by M. anisopliae. Many conidia were germinated and covered the body of P. striolata on the 7th day after treatment. The free fatty acid, total amino acid, CAT, POD, and SOD activities all showed an increased and then decreased trend. These results suggest that entomopathogenic fungal infection triggers the defense response of hosts, which induces changes in nutrients and antioxidant enzymes in P. striolata adults. Our findings provide useful information for understanding the potential for using M. anisopliae Ma6 as a biocontrol agent.

Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis.

Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. Here, we report that macrophages in eWAT are a main source of osteopontin, which selectively circulates to the bone marrow and promotes the degradation of the bone matrix by activating osteoclasts, as well as modulating bone marrow-derived macrophages (BMDMs) to engulf the lipid droplets released from adipocytes in the bone marrow of mice. However, the lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes. Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. These results provide an avenue for developing therapeutic strategies to mitigate obesity-related bone disorders.

Quaternary Alloy Quantum Dots as Fluorescence Probes for Total Acidity Detection of Paper-Based Relics.

Traditionally, the acidity of paper-based relics was determined by an extraction method and using a pH meter. This method could not obtain the total acidity of the paper-based relics because it only detected the concentration of free protons in the aqueous soaking solution. To overcome this defect, a new method for determining the total acidity of paper-based relics has been established by using quaternary alloy quantum dots. The quantum dots, CdZnSeS, modified by p-Aminothiophenol (pATP) were prepared, and their composition and structure were characterized. The fluorescence behavior of prepared quantum dots with acidity was investigated. The following results were obtained. The fluorescence of CdZnSeS-pATP quantum dots could decrease with increases in acidity because pATP dissociated from the surfaces of the quantum dots due to protons or undissociated weak acids. Based on this feature, a method for determining the acidity of paper-based relics was constructed, and this method was used to evaluate the acidity of actual paper-based relics. Obviously, for a given paper sample, since both free protons and bound protons can be determined by this method, the acidity measured by this method is more reasonable than that by pH meter.

Nanoparticle-Cartilage Interaction: Pathology-Based Intra-articular Drug Delivery for Osteoarthritis Therapy.

Osteoarthritis is the most prevalent chronic and debilitating joint disease, resulting in huge medical and socioeconomic burdens. Intra-articular administration of agents is clinically used for pain management. However, the effectiveness is inapparent caused by the rapid clearance of agents. To overcome this issue, nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents. Given the therapeutic programs are inseparable from pathological progress of osteoarthritis, an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders. In this review, we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release. Then, we review the interactions of nanoparticles with cartilage microenvironment and the rational design. Furthermore, we highlight advances in the therapeutic schemes according to the pathology signals. Finally, armed with an updated understanding of the pathological mechanisms, we place an emphasis on the development of "smart" bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals. We anticipate that the exploration of nanoparticles by balancing the efficacy, safety, and complexity will lay down a solid foundation tangible for clinical translation.

Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis.

Critical size bone defects are frequently caused by accidental trauma, oncologic surgery, and infection. Distraction osteogenesis (DO) is a useful technique to promote the repair of critical size bone defects. However, DO is usually a lengthy treatment, therefore accompanied with increased risks of complications such as infections and delayed union. Here, we demonstrated that magnesium (Mg) nail implantation into the marrow cavity degraded gradually accompanied with about 4-fold increase of new bone formation and over 5-fold of new vessel formation as compared with DO alone group in the 5 mm femoral segmental defect rat model at 2 weeks after distraction. Mg nail upregulated the expression of calcitonin gene-related peptide (CGRP) in the new bone as compared with the DO alone group. We further revealed that blockade of the sensory nerve by overdose capsaicin blunted Mg nail enhanced critical size bone defect repair during the DO process. CGRP concentration-dependently promoted endothelial cell migration and tube formation. Meanwhile, CGRP promoted the phosphorylation of focal adhesion kinase (FAK) at Y397 site and elevated the expression of vascular endothelial growth factor A (VEGFA). Moreover, inhibitor/antagonist of CGRP receptor, FAK, and VEGF receptor blocked the Mg nail stimulated vessel and bone formation. We revealed, for the first time, a CGRP-FAK-VEGF signaling axis linking sensory nerve and endothelial cells, which may be the main mechanism underlying Mg-enhanced critical size bone defect repair when combined with DO, suggesting a great potential of Mg implants in reducing DO treatment time for clinical applications.

Biodegradable magnesium pins enhanced the healing of transverse patellar fracture in rabbits.

Displaced fractures of patella often require open reduction surgery and internal fixation to restore the extensor continuity and articular congruity. Fracture fixation with biodegradable magnesium (Mg) pins enhanced fracture healing. We hypothesized that fixation with Mg pins and their degradation over time would enhance healing of patellar fracture radiologically, mechanically, and histologically. Transverse patellar fracture surgery was performed on thirty-two 18-weeks old female New Zealand White Rabbits. The fracture was fixed with a pin made of stainless steel or pure Mg, and a figure-of-eight stainless steel band wire. Samples were harvested at week 8 or 12, and assessed with microCT, tensile testing, microindentation, and histology. Microarchitectural analysis showed that Mg group showed 12% higher in the ratio of bone volume to tissue volume at week 8, and 38.4% higher of bone volume at week 12. Tensile testing showed that the failure load and stiffness of Mg group were 66.9% and 104% higher than the control group at week 8, respectively. At week 12, Mg group was 60.8% higher in ultimate strength than the control group. Microindentation showed that, compared to the Control group, Mg group showed 49.9% higher Vickers hardness and 31% higher elastic modulus at week 8 and 12, respectively. At week 12, the new bone of Mg group remodelled to laminar bone, but those of the control group remained woven bone-like. Fixation of transverse patellar fracture with Mg pins and its degradation enhanced new bone formation and mechanical properties of the repaired patella compared to the Control group.