Osteoarthritis Pain.

Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the current intervention strategy for OA pain cannot provide satisfactory pain relief, and the chronic use of the drugs for pain management is often associated with significant side effects and toxicities. These observations suggest that the mechanisms of OA-related pain remain undefined. The current review mainly focuses on the characteristics and mechanisms of OA pain. We evaluate pathways associated with OA pain, such as nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA), calcitonin gene-related peptide (CGRP), C-C motif chemokine ligands 2 (CCL2)/chemokine receptor 2 (CCR2) and tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß), the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, and the Wnt/ß-catenin signaling pathway. In addition, animal models currently used for OA pain studies and emerging preclinical studies are discussed. Understanding the multifactorial components contributing to OA pain could provide novel insights into the development of more specific and effective drugs for OA pain management.

Metformin Hydrochloride Encapsulation by Alginate Strontium Hydrogel for Cartilage Regeneration by Reliving Cellular Senescence.

Cartilage lesion is a common tissue defect and is challenging in clinical practice. Trauma-induced cellular senescence could decrease the chondrocyte capability of maintaining cartilage tissue regeneration. A previous investigation showed that, by controlling the cellular senescence, the cartilage regeneration can be significantly accelerated. Based on this finding, we design a novel hydrogel, Alg/MH-Sr, that combines metformin, an established drug for inhibiting senescence, and strontium, an effective anti-inflammatory material for cartilage tissue engineering. A RT-PCR test suggests the significant inhibitory effect of the hydrogel on senescent, apoptotic, oxidative, and inflammatory genes' expression. Histological examinations demonstrate that the Alg/MH-Sr hydrogel accelerated cartilage repairment, and chondrocyte senescence was significantly inhibited. Our study demonstrates that the Alg/MH-Sr hydrogel is effective for cartilage defect treatment and provides a new clue in accelerating tissue repairment by inhibiting the senescence of cells and tissues.

Levels of neuropeptide Y in synovial fluid relate to pain in patients with knee osteoarthritis.

BACKGROUND: The precise etiology of knee osteoarthritis (KOA) pain remains highly controversial and there is no known effective treatment. Due to the known and suggested effects of neuropeptide Y (NPY) on pain, we have sought to investigate the relationship between the concentration of NPY in synovial fluid of knee, pain of KOA, and structural severity of KOA. METHODS: One hundred KOA patients and twenty healthy participants (control group) were recruited. The pain and the radiographic grade of KOA were assessed separately by Hideo Watanabe's pain score and Tomihisa Koshino's scoring system. Synovial fluid of knee from all participants was collected with arthrocentesis. Radioimmunoassay was used to examine the concentration of NPY in synovial fluid of knee. RESULTS: Concentrations of NPY in synovial fluid were significantly higher in KOA patients (124.7 ± 33.4 pg/mL) compared with controls (64.8 ± 26.3 pg/mL) (p = 0.0297). According to Hideo Watanabe's pain score, 100 KOA patients were divided into 5 subgroups: no pain (n = 12), mild pain (n = 25), moderate pain (n = 37), strong pain (n = 19) and severe pain (n = 7). Within the KOA group, significantly higher concentrations of NPY were found in each subgroup as pain intensified (no pain 81.4 ± 11.7 pg/mL, mild pain 99.1 ± 23.2 pg/mL, moderate pain 119.9 ± 31.5 pg/mL, strong pain 171.2 ± 37.3 pg/mL and severe pain 197.3 ± 41.9 pg/mL). Meanwhile, according to Tomihisa Koshino's scoring system, 100 KOA patients were divided into 3 subgroups: early stage (n = 30), middle stage (n = 53), advanced stage (n = 17). Concentrations of NPY in middle and advanced stage groups of KOA patients were significant higher than early stage group of KOA patients (early stage 96.4 ± 27.1 pg/mL, middle stage 153.3 ± 16.9 pg/mL, advanced stage 149.5 ± 36.7 pg/mL) (p = 0.0163, p = 0.0352). Concentrations of NPY in advanced stage group of KOA patients has no significant difference compare with middle stage group of KOA patients (p = 0. 2175). CONCLUSIONS: This study demonstrated the presence and variation of concentrations of NPY in the KOA joint fluid, suggesting a role for NPY as a putative regulator of pain transmission and perception in KOA pain.

Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells.

Radiation therapy can result in bone injury with the development of fractures and often can lead to delayed and nonunion of bone. There is no prevention or treatment for irradiation-induced bone injury. We irradiated the distal half of the mouse left femur to study the mechanism of irradiation-induced bone injury and found that no mesenchymal stem cells (MSCs) were detected in irradiated distal femora or nonirradiated proximal femora. The MSCs in the circulation doubled at 1 week and increased fourfold after 4 wk of irradiation. The number of MSCs in the proximal femur quickly recovered, but no recovery was observed in the distal femur. The levels of free radicals were increased threefold at 1 wk and remained at this high level for 4 wk in distal femora, whereas the levels were increased at 1 wk and returned to the basal level at 4 wk in nonirradiated proximal femur. Free radicals diffuse ipsilaterally to the proximal femur through bone medullary canal. The blood vessels in the distal femora were destroyed in angiographic images, but not in the proximal femora. The osteoclasts and osteoblasts were decreased in the distal femora after irradiation, but no changes were observed in the proximal femora. The total bone volumes were not affected in proximal and distal femora. Our data indicate that irradiation produces free radicals that adversely affect the survival of MSCs in both distal and proximal femora. Irradiation injury to the vasculatures and the microenvironment affect the niches for stem cells during the recovery period.

Effect of tibial drill-guide angle on the mechanical environment at bone tunnel aperture after anatomic single-bundle anterior cruciate ligament reconstruction.

PURPOSE: The tibial drill-guide angle in anterior cruciate ligament (ACL) reconstruction influences the tunnel placement and graft-tunnel force, and is potentially associated with post-operative tunnel widening. This study aimed to examine the effect of the drill-guide angle on the stress redistribution at the tibial tunnel aperture after anatomic single-bundle ACL reconstruction. METHODS: A validated finite element model of human knee joint was used. The tibial tunnel with drill-guide angle ranging from 30° to 75° was investigated. The post-operative stress redistribution in tibia under the compressive, valgus, rotational and complex loadings was analysed. RESULTS: Compressive loading played a leading role on the stress redistribution at intra-articular tibial tunnel aperture. After ACL reconstruction, stress concentration occurred in the anterior and posterior regions of tunnel aperture while stress reduction occurred in the lateral and posteromedial regions under the compressive loading. Stress redistribution was partially alleviated by using the drill-guide angle ranging from 55° to 65°. CONCLUSIONS: The present study quantified the effect of bone tunnel drill-guide angle on the post-operative stress redistribution. This phenomenon potentially contributed to tunnel widening. A tunnel drill-guide angle ranging from 55° to 65° was proposed based on the biomechanical rationale. It could serve as a helpful surgical guide for ACL reconstruction.

3D Bioprinting of Artificial Skin Substitute with Improved Mechanical Property and Regulated Cell Behavior through Integrating Patterned Nanofibrous Films.

Three-dimensional (3D) bioprinting has advantages for constructing artificial skin tissues in replicating the structures and functions of native skin. Although many studies have presented improved effect of printing skin substitutes in wound healing, using hydrogel inks to fabricate 3D bioprinting architectures with complicated structures, mimicking mechanical properties, and appropriate cellular environments is still challenging. Inspired by collagen nanofibers withstanding stress and regulating cell behavior, a patterned nanofibrous film was introduced to the printed hydrogel scaffold to fabricate a composite artificial skin substitute (CASS). The artificial dermis was printed using gelatin-hyaluronan hybrid hydrogels containing human dermal fibroblasts with gradient porosity and integrated with patterned nanofibrous films simultaneously, while the artificial epidermis was formed by seeding human keratinocytes upon the dermis. The collagen-mimicking nanofibrous film effectively improved the tensile strength and fracture resistance of the CASS, making it sewable for firm implantation into skin defects. Meanwhile, the patterned nanofibrous film also provided the biological cues to guide cell behavior. Consequently, CASS could effectively accelerate the regeneration of large-area skin defects in mouse and pig models by promoting re-epithelialization and collagen deposition. This research developed an effective strategy to prepare composite bioprinting architectures for enhancing mechanical property and regulating cell behavior, and CASS could be a promising skin substitute for treating large-area skin defects.

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow.

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.

Bidirectional control of parathyroid hormone and bone mass by subfornical organ.

Parathyroid hormone (PTH) is one of the most important hormones for bone turnover and calcium homeostasis. It is unclear how the central nervous system regulates PTH. The subfornical organ (SFO) lies above the third ventricle and modulates body fluid homeostasis. Through retrograde tracing, electrophysiology, and in vivo calcium imaging, we identified the SFO as an important brain nucleus that responds to serum PTH changes in mice. Chemogenetic stimulation of GABAergic neurons in SFO induces decreased serum PTH followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in the SFO promoted serum PTH and bone mass. Moreover, we found that the blockage of different PTH receptors in the SFO affects peripheral PTH levels and the PTH's response to calcium stimulation. Furthermore, we identified a GABAergic projection from the SFO to the paraventricular nucleus, which modulates PTH and bone mass. These findings advance our understanding of the central neural regulation of PTH at cellular and circuit level.

A Unified Therapeutic-Prophylactic Tissue-Engineering Scaffold Demonstrated to Prevent Tumor Recurrence and Overcoming Infection toward Bone Remodeling.

Osteosarcoma occurs in children and adolescents frequently and leads to a high fatality rate. Although surgical resection is the most common methods in clinic, patients always suffer from tumor metastasis and recurrence and it is difficult for them to self-repair large bone defects. Furthermore, the postoperative infection from bacteria triggers an inflammatory response and hinders the bone-repair process. This work demonstrates a gadolinium (Gd)-complex and molybdenum sulfide (MoS2 ) co-doped N-acryloyl glycinamide (NAGA)/gelatin methacrylate (Gel-MA) multifunctional hydrogel (GMNG). The combination between NAGA and Gel-MA endows the GMNG with attractive mechanical properties and controllable degradation ability. The MoS2 improves the hydrogel system, which has excellent photothermal ability to kill tumor cells and inhibit bacterial infection both in vitro and in vivo. Based on the Gd-complex, the magnetic resonance imaging (MRI) effect can be used to monitor the position and degradation situation of the hydrogel. Notably, accompanied by the degradation of GMNG hydrogel, the gradually released Gd3+ from the hydrogel exhibits osteogenic property and could promote new bone formation efficiently in vivo. Therefore, this strategy supplies a method to prepare multifunctional bone-defect-repair materials and is expected to represent a significant guidance and reference to the development of biomaterials for bone tissue engineering.

Distribution of bone voids in the thoracolumbar spine in Chinese adults with and without osteoporosis: A cross-sectional multi-center study based on 464 vertebrae.

Bone void is a novel intuitive morphological indicator to assess bone quality but its use in vertebrae has not been described. This cross-sectional and multi-center study aimed to investigate the distribution of bone voids in the thoracolumbar spine in Chinese adults based on quantitative computed tomography (QCT). A bone void was defined as a trabecular net region with extremely low bone mineral density (BMD) (<40 mg/cm3), detected by an algorithm based on phantom-less technology. A total of 464 vertebrae from 152 patients (51.8 ± 13.4 years old) were included. The vertebral trabecular bone was divided into eight sections based on the middle sagittal, coronal, and horizontal planes. Bone void of the whole vertebra and each section were compared between healthy, osteopenia, and osteoporosis groups and between spine levels. Receiver operator characteristic (ROC) curves were plotted and optimum cutoff points of void volume between the groups were obtained. The total void volumes of the whole vertebra were 124.3 ± 221.5 mm3, 1256.7 ± 928.7 mm3, and 5624.6 ± 3217.7 mm3 in healthy, osteopenia, and osteoporosis groups, respectively. The detection rate of vertebrae with bone voids was higher and the normalized void volume was larger in the lumbar than in thoracic vertebrae. L3 presented the largest void (2165.0 ± 3396.0 mm3), while T12 had the smallest void (448.9 ± 699.4 mm3). The bone void was mainly located in the superior-posterior-right section (40.8 %). Additionally, bone void correlated positively with age and increased rapidly after 55 years. The most significant void volume increase was found in the inferior-anterior-right section whereas the least increase was found in the inferior-posterior-left section with aging. The cutoff points were 345.1 mm3 between healthy and osteopenia groups (sensitivity = 0.923, specificity = 0.932) and 1693.4 mm3 between osteopenia and osteoporosis groups (sensitivity = 1.000, specificity = 0.897). In conclusion, this study demonstrated the bone void distribution in vertebrae using clinical QCT data. The findings provide a new perspective for the description of bone quality and showed that bone void could guide clinical practice such as osteoporosis screening.

Cultural Validation of the Chinese Central Sensitization Inventory in Patients with Chronic Pain and its Predictive Ability of Comorbid Central Sensitivity Syndromes.

BACKGROUND: Central sensitization (CS) is frequently reported in chronic pain, and the central sensitization inventory (CSI) is popularly used to assess CS. However, a validated Chinese CSI is lacking and its predictive ability for the comorbidity of central sensitivity syndromes (CSSs) remains unclear. Hence, this study aimed to generate the Chinese CSI (CSI-C) with cultural adaptation and examine its psychometric properties. METHODS: The CSI-C was formulated through forward and backward translation, panel review and piloting and then validated among patients with chronic pain (n = 235). Its internal consistency, test-retest reliability, and concurrent validity were measured. An exploratory factor analysis (EFA) was performed for the construct validity. Receiver operating characteristic (ROC) analysis was employed to determine the discriminative ability in the presence of comorbidity of CSSs. RESULTS: About 70% of the participants in the study experienced at least mild CS symptoms. CSI-C demonstrates a high internal consistency (Cronbach's alpha = 0.896) and excellent test-retest reliability (ICC = 0.932). CSI-C scoring was significantly correlated with pain intensity (r = 0.188), EQ-5D index (r = -0.375), anxiety (r=0.525), and depression (r = 0.467). The EFA generated a 5-factor model, including physical symptoms, emotional distress, hypersensitivity syndromes and so on. An CSI cutoff of 42 had a sensitivity of 71.4% and a specificity of 70% for identifying chronic pain patients with ≥2 CSSs. CONCLUSION: The CS manifestations are prevalent in those with persistent pain. CSI-C is a reliable and valid instrument for measuring CS. A CSI score ≥42 may predict the comorbidity of 2 or above CSSs in patients with chronic pain.

Infiltration from Suspension Systems Enables Effective Modulation of 3D Scaffold Properties in Suspension Bioprinting.

Bioprinting is a biofabrication technology which allows efficient and large-scale manufacture of 3D cell culture systems. However, the available biomaterials for bioinks used in bioprinting are limited by their printability and biological functionality. Fabricated constructs are often homogeneous and have limited complexity in terms of current 3D cell culture systems comprising multiple cell types. Inspired by the phenomenon that hydrogels can exchange liquids under the infiltration action, infiltration-induced suspension bioprinting (IISBP), a novel printing technique based on a hyaluronic acid (HA) suspension system to modulate the properties of the printed scaffolds by infiltration action, was described in this study. HA served as a suspension system due to its shear-thinning and self-healing rheological properties, simplicity of preparation, reusability, and ease of adjustment to osmotic pressure. Changes in osmotic pressure were able to direct the swelling or shrinkage of 3D printed gelatin methacryloyl (GelMA)-based bioinks, enabling the regulation of physical properties such as fiber diameter, micromorphology, mechanical strength, and water absorption of 3D printed scaffolds. Human umbilical vein endothelial cells (HUVEC) were applied as a cell culture model and printed within cell-laden scaffolds at high resolution and cell viability with the IISBP technique. Herein, the IISBP technique had been realized as a reliable hydrogel-based bioprinting technique, which enabled facile modulation of 3D printed hydrogel scaffolds properties, being expected to meet the scaffolds requirements of a wide range of cell culture conditions to be utilized in bioprinting applications.

Which is the preferred revision technique for loosened iliac screw? A novel technique of boring cement injection from the outer cortical shell.

STUDY DESIGN: An in vitro biomechanical cadaver study. OBJECTIVES: To evaluate the pull-out strength after 5000 cyclic loading among 4 revision techniques for the loosened iliac screw using corticocancellous bone, longer screw, traditional cement augmentation, and boring cement augmentation. SUMMARY OF BACKGROUND DATA: Iliac screw loosening is still a clinical problem for lumbo-iliac fusion. Although many revision techniques using corticocancellous bone, larger screw, and polymethylmethacrylate (PMMA) augmentation were applied in repairing pedicle screw loosening, their biomechanical effects on the loosened iliac screw remain undetermined. METHODS: Eight fresh human cadaver pelvises with the bone mineral density values ranging from 0.83 to 0.97 g/cm were adopted in this study. After testing the primary screw of 7.5 mm diameter and 70 mm length, 4 revision techniques were sequentially established and tested on the same pelvis as follows: corticocancellous bone, longer screw with 100 mm length, traditional PMMA augmentation, and boring PMMA augmentation. The difference of the boring technique from traditional PMMA augmentation is that PMMA was injected into the screw tract through 3 boring holes of outer cortical shell without removing the screw. On an MTS machine, after 5000 cyclic compressive loading of -200∼-500 N to the screw head, axial maximum pull-out strengths of the 5 screws were measured and analyzed. RESULTS: The pull-out strengths of the primary screw and 4 revised screws with corticocancellous bone, longer screw and traditional and boring PMMA augmentation were 1167 N, 361 N, 854 N, 1954 N, and 1820 N, respectively. Although longer screw method obtained significantly higher pull-out strength than corticocancellous bone (P<0.05), the revised screws using these 2 techniques exhibited notably lower pull-out strength than the primary screw and 2 PMMA-augmented screws (P<0.05). Either traditional or boring PMMA screw showed obviously higher pull-out strength than the primary screw (P<0.05); however, no significant difference of pull-out strength was detected between the 2 PMMA screws (P>0.05). CONCLUSIONS: Wadding corticocancellous bone and increasing screw length failed to provide sufficient anchoring strength for a loosened iliac screw; however, both traditional and boring PMMA-augmented techniques could effectively increase the fixation strength. On the basis of the viewpoint of minimal invasion, the boring PMMA augmentation may serve as a suitable salvage technique for iliac screw loosening.

A biomechanical study on the effect of lengthening magnitude on spine off-loading in magnetically controlled growing rod surgery: Implications on lengthening frequency.

Purpose: To assess whether the magnitude of lengthening in magnetically controlled growing rod (MCGR) surgeries has an immediate or delayed effect on spinal off-loading. Methods: 9 whole porcine spines were instrumented using two standard MCGRs from T9 to L5. Static compression testing using a mechanical testing system (MTS) was performed at three MCGR lengthening stages (0 mm, 2 mm, and 6 mm) in each spine. At each stage, five cycles of compression at 175N with 25 min of relaxation was carried out. Off-loading was derived by comparing the load sustained by the spine with force applied by the MTS to the spine. Micro-CT imaging was subsequently performed. Results: The mean load sustained by the vertebral body before lengthening was 39.69N, and immediately after lengthening was 25.12N and 19.91N at 2 mm and 6 mm lengthening, respectively; decreasing to 10.07N, 8.31N, and 8.17N after 25 minutes of relaxation, at 0 mm, 2 mm, and 6 mm lengthening stages, respectively. There was no significant difference in off-loading between 2 mm and 6 mm lengthening stages, either instantaneously (p = 0.395) or after viscoelastic relaxation (p = 0.958). CT images showed fractures/separations at the level of pedicle screws in six spines and in the vertebral body's growth zone in five spines after 6 mm MCGR lengthening. Conclusion: This study demonstrated MCGRs cause significant off-loading of the spine leading to stress shielding. 6 mm of lengthening caused tissue damage and microfractures in some spines. There was no significant difference in spine off-loading between 2 mm and 6 mm MCGR lengthening, either immediately after lengthening or after viscoelastic relaxation.

Clay-based nanocomposite hydrogel with attractive mechanical properties and sustained bioactive ion release for bone defect repair.

Although clay-based nanocomposite hydrogels have been widely explored, their instability in hot water and saline solution inhibits their applications in biomedical engineering, and the exploration of clay-based nanocomposite hydrogels in bone defect repair is even less. In this work, we developed a stable clay-based nanocomposite hydrogel using 4-acryloylmorpholine as the monomer. After UV light illumination, the obtained poly(4-acryloylmorpholine) clay-based nanocomposite hydrogel (poly(4-acry)-clay nanocomposite hydrogel) exhibits excellent mechanical properties due to the hydrogen bond interactions between the poly(4-acryloylmorpholine) chains and the physical crosslinking effect of the nanoclay. Besides good biocompatibility, the sustainable release of intrinsic Mg2+ and Si4+ from the poly(4-acry)-clay nanocomposite hydrogel endows the system with excellent ability to promote the osteogenic differentiation of primary rat osteoblasts (ROBs) and can promote new bone formation effectively after implantation. We anticipate that these kinds of clay-based nanocomposite hydrogels with sustained release of bioactive ions will open a new avenue for the development of novel biomaterials for bone regeneration.

Types of vertebral fractures could influence the selection of clinical bone mineral measures to predict biomechanical properties.

Areal and volumetric BMD (aBMD and vBMD) measured by DXA and quantitative CT (QCT), respectively, are usually employed to predict vertebral fracture risks. In this study, we induced compression and wedge vertebral fractures to test if the types of fracture could influence the selection of bone mineral measures to predict biomechanical properties of vertebral bodies. DXA and QCT were employed to scan twenty-four male cadaveric vertebral bodies of humans for bone mineral content (BMC) and aBMD measures, and vBMD measures, respectively. We computed vBMD measures from three kinds of volumes of interest: intact structures (vertebral body, cortical compartment, and trabecular core), axially middle sections (1.250-1.875 cm height) of the intact structures, and clinically used elliptical regions of trabecular bone. We loaded vertebral bodies to failure for properties of strength (Pu), failure displacement (δu), and stiffness (K). Thirteen vertebral bodies sustained compression fractures and the remaining sustained wedge fractures. Linear and power regression models were used to test bone mineral predictions for Pu, δu, and K. We also did equality tests of correlation coefficients. Our results showed aBMD, BMC, and vBMD of the middle section of trabecular bone had the strongest correlations with Pu (R2 = 0.6420, p < 0.001), δu (R2 = 0.4619, p < 0.001), and K (R2 = 0.5992, p < 0.001) in power regression models, respectively when compression and wedge fractures were mixed. Considering compression fractures only, vBMD of the intact vertebral body displayed the strongest correlations with both Pu (R2 = 0.6529, p < 0.001) and K (R2 = 0.6354, p < 0.001) while BMC showed the strongest correlation with δu (R2 = 0.4376, p < 0.001) in linear regression models. When only wedge fractures were analyzed, vBMD of the elliptical regions of trabecular bone exhibited the strongest correlations with both Pu (R2 = 0.5845, p < 0.001) and K (R2 = 0.6420, p < 0.001) in power regression models, however, no bone mineral measure could significantly correlate with δu. These results may suggest the type of fracture could influence the determination of bone mineral measures to predict biomechanical properties of vertebral bodies.

Lingzhi and San-Miao-San with hyaluronic acid gel mitigate cartilage degeneration in anterior cruciate ligament transection induced osteoarthritis.

OBJECTIVE: To investigate the mitigate efficacy of Chinese medicine Lingzhi (LZ) and San-Miao-San (SMS) combined with hyaluronic acid (HA)-gel in attenuating cartilage degeneration in traumatic osteoarthritis (OA). METHODS: The standardized surgery of anterior cruciate ligament transection (ACLT) was made from the medial compartment of right hind limbs of 8-week-old female SD rats and resulted in a traumatic OA. Rats (n â€‹= â€‹5/group) were treated once intra-articular injection of 50 â€‹µl HA-gel, 50 â€‹µl HA-gel+50 â€‹µg LZ-SMS, 50 â€‹µl of saline+50 â€‹µg LZ-SMS and null (ACLT group) respectively, except sham group. Limbs were harvested for µCT scan and histopathological staining 3-month post-treatment. Inflammatory cytokines from plasma and synovial fluid were detected using Immunology Multiplex Assay kit. The putative targets of active compounds in LZ-SMS and known therapeutic targets for OA were combined to construct protein-protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was adopted to predict the potential targets and signaling pathway of LZ-SMS in OA through the tool of DAVID Bioinformatics. RESULTS: In vivo, HA-gel â€‹+ â€‹LZ-SMS treatment resulted in a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (total volume of cartilage), compared to ACLT and HA-gel groups. In addition, histological results showed the elevated cartilage matrix, chondrogenic and osteoblastic signals in HA-gel â€‹+ â€‹LZ-SMS treatment. Treatment also significantly altered subchondral bone (SCB) structure including an increase in BV/TV, Tb.Th, BMD, Conn.Dn, Tb.N, and DA, as well as a significant decrease in Tb.Sp and Po(tot), which implied a protective effect on maintaining the stabilization of tibial SCB microstructure. Furthermore, there was also a down-regulated inflammatory cytokines and upregulated anti-inflammatory cytokine IL-10 in HA+LZ-SMS group. Finally, 64 shared targets from 37 active compounds in LZ-SMS related to the core genes for the development of OA. LZ-SMS has a putative role in regulating inflammatory circumstance through influencing the MAPK signaling pathway. CONCLUSION: Our study elucidated a protective effect of HA-gel â€‹+ â€‹LZ-SMS in mitigating cartilage degradation and putative interaction with targets and signaling pathway for the development of traumatic OA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our results provide a biological rationale for the use of LZ-SMS as a potential candidate for OA treatment.

Rapid external erosion of coral substrate in subtropical Hong Kong waters.

Erosion of coral substrate plays a crucial role in reef calcium carbonate budget, but little is known about erosion in subtropical corals. In a 2-year study of coral substrate erosion, we deployed Porites skeletal blocks at nine sites across subtropical Hong Kong waters. External erosion varied from 0.05 to 3.07 kg m-2 yr-1 and accounted for 23.4-99.2% of the total erosion. More than half of the study sites had substantial external erosion (> 1 kg m-2 yr-1), and the values were positively correlated with density of the sea urchin Diadema setosum. Excluding urchins from access to the skeletal blocks using cages reduced external erosion by more than 90%. Overall, our study revealed that external erosion caused by urchin grazing contributed predominantly to the total coral skeletal loss in Hong Kong waters. Control of sea urchin population is needed to reduce coral erosion in places with high urchin density. (149 words).

3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model.

Osteochondral defect repair in osteoarthritis (OA) remains an unsolved clinical problem due to the lack of enough seed cells in the defect and chronic inflammation in the joint. To address this clinical need, we designed a bone marrow-derived mesenchymal stem cell (BMSC)-laden 3D-bioprinted multilayer scaffold with methacrylated hyaluronic acid (MeHA)/polycaprolactone incorporating kartogenin and ß-TCP for osteochondral defect repair within each region. BMSC-laden MeHA was designed to actively introduce BMSCs in situ, and diclofenac sodium (DC)-incorporated matrix metalloproteinase-sensitive peptide-modified MeHA was induced on the BMSC-laden scaffold as an anti-inflammatory strategy. BMSCs in the scaffolds survived, proliferated, and produced large amounts of cartilage-specific extracellular matrix in vitro. The effect of BMSC-laden scaffolds on osteochondral defect repair was investigated in an animal model of medial meniscectomy-induced OA. BMSC-laden scaffolds facilitated chondrogenesis by promoting collagen II and suppressed interleukin 1ß in osteochondral defects of the femoral trochlea. Congruently, BMSC-laden scaffolds significantly improved joint function of the injured leg with respect to the ground support force, paw grip force, and walk gait parameters. Therefore, this research demonstrates the potential of 3D-bioprinted BMSC-laden scaffolds to simultaneously inhibit joint inflammation and promote cartilage defect repair in OA joints.

Multifunctional fibrous scaffolds for bone regeneration with enhanced vascularization.

Due to the structural similarity to the extracellular matrix of human tissue and the ultra-high surface area-to-volume ratio, three dimensional electrospun fibrous structures have been increasingly used as tissue engineering scaffolds. Given that successful bone regeneration requires both good osteogenesis and vascularization, producing scaffolds that have both osteogenic and angiogenic potential is highly desirable. In this investigation, tricomponent fibrous scaffolds simultaneously incorporated with recombinant human vein endothelial growth factor (rhVEGF), recombinant human bone morphogenetic protein-2 (rhBMP-2) and bioactive calcium phosphate (Ca-P) nanoparticles are produced through a novel multi-source multi-power electrospinning method, and sequential growth factor release with a quick rhVEGF release and a steady rhBMP-2 release is achieved. The enhanced human umbilical vein endothelial cell (HUVEC) migration and tube formation, and up-regulated human bone marrow derived mesenchymal stem cell (hBMSC) osteogenic differentiation and mineralization demonstrate that tricomponent scaffolds have balanced angiogenic-osteogenic properties in vitro. 8 weeks after the scaffold implantation into the cranial defects of mice, obvious new bone regeneration and newly formed capillaries are observed in tricomponent scaffolds, suggesting that the tricomponent scaffolds enhance osteogenesis in vivo with required vascularization, which shows the great potential of the tricomponent scaffolds in bone tissue regeneration.