Graphene Quantum Dots Reduce Hypertrophic Scar by Inducing Myofibroblasts To Be a Quiescent State.

Contrary to the initial belief that myofibroblasts are terminally differentiated cells, myofibroblasts have now been widely recognized as an activation state that is reversible. Therefore, strategies targeting myofibroblast to be a quiescent state may be an effective way for antihypertrophic scar therapy. Graphene quantum dots (GQDs), a novel zero-dimensional and carbon-based nanomaterial, have recently garnered significant interest in nanobiomedicine, owing to their excellent biocompatibility, tunable photoluminescence, and superior physiological stability. Although multiple nanoparticles have been used to alleviate hypertrophic scars, a GQD-based therapy has not been reported. Our in vivo studies showed that GQDs exhibited significant antiscar efficacy, with scar appearance improvement, collagen reduction and rearrangement, and inhibition of myofibroblast overproliferation. Further in vitro experiments revealed that GQDs inhibited α-SMA expression, collagen synthesis, and cell proliferation and migration, inducing myofibroblasts to become quiescent fibroblasts. Mechanistic studies have demonstrated that the effect of GQDs on myofibroblast proliferation blocked cell cycle progression by disrupting the cyclin-CDK-E2F axis. This study suggests that GQDs, which promote myofibroblast-to-fibroblast transition, could be a novel antiscar nanomedicine for the treatment of hypertrophic scars and other types of pathological fibrosis.

Netrin-1 co-cross-linked hydrogel accelerates diabetic wound healing in situ by modulating macrophage heterogeneity and promoting angiogenesis.

Diabetic wounds, characterized by prolonged inflammation and impaired vascularization, are a serious complication of diabetes. This study aimed to design a gelatin methacrylate (GelMA) hydrogel for the sustained release of netrin-1 and evaluate its potential as a scaffold to promote diabetic wound healing. The results showed that netrin-1 was highly expressed during the inflammation and proliferation phases of normal wounds, whereas it synchronously exhibited aberrantly low expression in diabetic wounds. Neutralization of netrin-1 inhibited normal wound healing, and the topical application of netrin-1 accelerated diabetic wound healing. Mechanistic studies demonstrated that netrin-1 regulated macrophage heterogeneity via the A2bR/STAT/PPARγ signaling pathway and promoted the function of endothelial cells, thus accelerating diabetic wound healing. These data suggest that netrin-1 is a potential therapeutic target for diabetic wounds.

JAM-A Overexpression in Human Umbilical Cord-Derived Mesenchymal Stem Cells Accelerated the Angiogenesis of Diabetic Wound By Enhancing Both Paracrine Function and Survival of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) is promising in promoting wound healing mainly due to their paracrine function. Nonetheless, the transplanted MSCs presented poor survival with cell dysfunction and paracrine problem in diabetic environment, thus limiting their therapeutic efficacy and clinical application. JAM-A, an adhesion molecule, has been reported to play multi-functional roles in diverse cells. We therefore investigated the potential effect of JAM-A on MSCs under diabetic environment and explored the underlying mechanism. Indeed, high-glucose condition inhibited MSCs viability and JAM-A expression. However, JAM-A abnormality was rescued by lentivirus transfection and JAM-A overexpression promoted MSCs proliferation, migration and adhesion under hyperglycemia. Moreover, JAM-A overexpression attenuated high-glucose-induced ROS production and MSCs apoptosis. The bio-effects of JAM-A on MSCs under hyperglycemia were confirmed by RNA-seq with enrichment analyses. Moreover, Luminex chip results showed JAM-A overexpression dramatically upregulated PDGF-BB and VEGF in the supernatant of MSCs, which was verified by RT-qPCR and western blotting. The supernatant was further found to facilitate HUVECs proliferation, migration and angiogenesis under hyperglycemia. In vivo experiments revealed JAM-A overexpression significantly enhanced MSCs survival, promoted wound angiogenesis, and thus accelerated diabetic wound closure, partially by enhancing PDGF-BB and VEGF expression. This study firstly demonstrated that JAM-A expression of MSCs was inhibited upon high-glucose stimulation. JAM-A overexpression alleviated high-glucose-induced MSCs dysfunction, enhanced their anti-oxidative capability, protected MSCs from hyperglycemia-induced apoptosis and improved their survival, thus strengthening MSCs paracrine function to promote angiogenesis and significantly accelerating diabetic wound healing, which offers a promising strategy to maximize MSCs-based therapy in diabetic wound.

Withdrawal Notice: CircRNA circPRKCI is upregulated in osteoporosis and sponges miR-103 to suppress the apoptosis of osteoblast induced by Lipopolysaccharide (LPS)

Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Pb Transfer Preference of Arbuscular Mycorrhizal Fungus Rhizophagus irregularis in Morus alba under Different Light Intensities.

Arbuscular mycorrhizal (AM) fungi can improve the lead (Pb) tolerance of host plants and accumulate intensive Pb in mycorrhizal roots. However, the detailed contribution of AM fungal extraradical hyphae to the plants' Pb uptake remains unknown. In this study, mulberry (Morus alba) colonized by the AM fungus (Rhizophagus irregularis) with light treatments were linked by fungal extraradical hyphae using a three-compartment system (pot test), and their differences in responding to Pb application were compared. Shading inhibited mulberry photosynthesis and the growth of mulberry. In this study, Pb application did not affect the colonization of R. irregularis when symbiosis had already formed as the root was not exposed to Pb during the colonization and formation of the AM fungal hyphae network. The R. irregularis preferred to transfer more Pb to the unshaded mulberry than to the shaded mulberry, a condition capable of providing more C supply for fungal survival than to low-light mulberry. The Pb transferred through the mycorrhizal pathway to mulberry had low mobility and might be compartmented in the root by R. irregularis until exceeding a threshold. The relatively high expressions of MaABCG16 with high Pb concentrations in plants suggest that MaABCG16 might play an important role in Pb translocation.

The Osteoarthritis Natural Progress and Changes in Intraosseous Pressure of the Guinea Pig Model in Different Degeneration Stages.

OBJECTIVE: Articular cartilage and subchondral bone changes during the pathological progress of knee osteoarthritis (KOA) is a key event marking the development of the disease. The age varying alteration patterns within entire osteochondral unit remains poorly understood. The purpose of this study was to find a reasonable age range of the Dunkin-Hartley guinea pig model for the studying of KOA pathological process, and to investigate Intraosseous pressure (IOP) in the process during different degeneration stages of KOA. METHODS: Male Dunkin-Hartley guinea pigs were selected and divided into groups of 3, 6, 9, 12, 18 months old by age, 10 in each group. All knees underwent imaging examination including X-ray, Micro-CT and MRI. Observed the imaging findings with the use of Kellgren-Lawrence (K-L) classification and knee osteoarthritis MRI scores. Measured the IOP of distal femur (DF) and proximal tibia (PT) in each group, and observed the differences of bilateral tibiofemoral articular cartilage in histological and immunohistochemistry, staining results were evaluated by using Mankin's score. Analysis of variance (ANOVA) and t-tests were used to compare the differences indicators between groups. RESULTS: With the increase of age, changes in X-ray, Micro-CT and MRI imaging findings and pathological staining results of articular cartilage in all stages were consistent with the changing of degenerative KOA process. The IOP of DF and PT increased gradually with age, and reached its peak in 12-month age group, and then gradually decreased, there was a statistically significant difference of IOP between each group. The IOP of DF was slightly higher than that of PT, but the difference was not statistically significant. CONCLUSION: Dunkin-Hartley guinea pigs can be used as an animal model to study different pathological stages of KOA. There might be a correlation between the changes of IOP and the pathological progress of articular cartilage and subchondral bone in DF and PT.

Clinical Outcomes of the Central Third Patellar Tendon Versus Four-strand Hamstring Tendon Autograft Used for Anterior Cruciate Ligament Reconstruction: A Systematic Review and Subgroup Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The most frequently used auto-grafts for ACL reconstruction (ACLR) are bone-patellar tendon-bone (BPTB) and four-strand hamstring tendon (4S-HT), but significant controversy exists about which graft is better. This study aimed to compare the knee outcomes following ACLR with BPTB and 4S-HT autografts. METHODS: Subgroup meta-analyses were performed basing on available randomised controlled trials (RCTs) according to different follow-up intervals. 23 RCTs were eligible for inclusion, involving 933 participants in each treatment group. RESULTS: Only short-term (≤2 years) knee anteroposterior and rotational stability were significantly poorer with 4S-HT when compared to BPTB autograft, as judged by side-to-side difference on knee laxity (WMD=-0.50, 95%CI -0.81~-0.18, p=0.002) and pivot-shift test (OR=0.58, 95%CI 0.39~0.88, p=0.010), respectively. The IKDC objective grade was evident to be in favour of 4S-HT group in mid-term (3-5 years) follow-up (OR=0.63, 95%CI 0.43~0.92, p=0.017). Several donor-site related complications, including anterior knee pain, pain with kneeling and extension deficit, were more frequent in BPTB autograft group, while lower short-term iskinetic peak flexion torques both at 60°/S (WMD=8.93, 95%CI 7.88~9.99, p<0.001) and 240°/S (WMD=11.63, 95%CI 9.92~13.34, p<0.001) were caused by HT harvesting. CONCLUSION: BPTB was associated with inferior mid- to long-term (>5 years) knee functional outcomes, and increased frequency of donor-site complications. In contrast, only short-term knee laxity was increased for 4S-HT autograft, which is expected to be improved by providing more conservative rehabilitation protocol and aperture fixation methods.

Outcomes of Intercalary Prosthetic Reconstruction for Pathological Diaphyseal Femoral Fractures Secondary to Metastatic Tumors.

OBJECTIVE: To evaluate the clinical outcomes and complications of segmental prosthetic reconstruction for pathological diaphyseal femoral fractures secondary to metastatic tumors. METHODS: Between 2011 and 2015, we retrospectively evaluated 16 patients (6 men and 10 women; 64.5 ± 11.4 years old at diagnosis) who underwent prosthetic reconstruction after segmental resection of diaphyseal femoral fractures due to metastatic lesions. Visual analog scale (VAS), functional outcomes, implant-related complications, and Mean postoperative Musculoskeletal Tumor Society (MSTS) score for each patient were collected. RESULTS: The mean length of bone defect was 10.2 ± 2.6 cm (range, 8-16 cm); follow-up was 9 ± 6.8 months (range, 2-25 months) for all patients, and 24 months (23 and 25 months) for the 2 patients still alive. At final follow-up, 14 patients were dead, indicating a mean survival of 6.9 ± 3.6 months (range, 2-14 months). Mean preoperative VAS score was 8.5 ± 1.0, which decreased to 2.5 ± 1.3 at day 2 postoperatively, indicating significant pain relief (P < 0.05). The MSTS score for lower extremities was 84.6% (range, 73%-90%). The range of motion and function of adjacent joints was within the normal limits in all cases. Three patients (33%) developed complications, including aseptic loosening because of disease progression (1), infection (1), and peri-prosthesis fracture (1). CONCLUSION: These findings demonstrated that this approach greatly relieves pain, and yields satisfactory functional outcomes with fewer complications in patients with pathological femoral fractures secondary to metastatic tumors; however, survival was not significantly improved.

[Application of temporary balloon blocking technique in bone tumors surgery under the aid of CT angiography].

OBJECTIVE: To study the value of CT angiography (CTA) in the surgical treatment of bone tumors with the temporary balloon blocking technique. METHODS: A retrospective analysis was made on the clinical data of 36 bone tumor patients between April 2008 and October 2013. There were 22 males and 14 females, aged from 25 to 83 years (mean, 46 years). The tumor located at the sacrococcygeal region in 17 cases, at the ilium in 12 cases, at the pubis in 5 cases, and at the proximal femur in 2 cases. Before surgery, CTA was performed to measure the external diameter of aortaventralis and arteria iliac communis, and the distance between the low renal artery and the abdominal aortic bifurcation as well as mark the anatomical relationship between the low renal artery, the abdominal aortic bifurcation and bony landmarks of vertebral body. According to these data, suitable balloon was chosen and the balloon positioning was guided in the surgery to completely excise tumor assisted by balloon blocking technique. RESULTS: The CTA results showed that the external diameter of aortaventralis and arteria iliaca communis was (1.545 ± 0.248) cm and (1.060 ± 0.205) cm respectively, and the distance between the low renal artery and the abdominal aortic bifurcation was (10.818 ± 1.165) cm. The three-dimensional reconstruction showed that the opening of the low renal artery was mainly located at L1 (16/36, 44.4%) and the abdominal aortic bifurcation mainly located at L4 (22/36, 61.1%). Effective block of abdomial aorta was performed; the blood pressure obviously increased in 3 cases after balloon inflation, and pulse of the left dorsal artery of the foot decreased in 1 case after removal of balloon, which were relieved after expectant treatment. The operation time was 118-311 minutes; the intraoperative blood loss was 200-1800 mL, 21 patients were given blood transfusion, and the amount of blood transfusion was 400-1200 mL; and the aortic clamping time was 40-136 minutes. All patients were followed up 5-44 months (mean, 21 months). According to Enneking standard, the results were excellent in 9 cases, good in 20 cases, fair in 5 cases, and poor in 2 cases at 3 months after operation. There were 10 cases of dysfunction of urination and defecation, 2 cases of tumor recurrence, and 3 cases of death after surgery. CONCLUSION: CTA and three-dimensional reconstructions technique can accurately measure the external diameter of aortaventralis and arteria iliaca communis and the distance between low renal artery and abdominal aortic bifurcation and offer great help to choose appropriate balloon and locate the balloon during surgery. The balloon blocking technique under the assistance of CTA can obviously reduce intraoperative blood loss and tumor recurrence, supply a clear view in surgery and shorten the operation time.

Management of great vessels and nerves in limb-salvage surgery for bone and soft tissue tumors.

In recent years, limb-salvage surgery has gradually replaced amputations and become one of the main treatment strategies for patients with bone and soft tissue tumors of the extremities. The goals of tumor resection in limb-salvage surgery are to reduce the recurrence rate and preserve as much limb function as possible. However, depending on the size and specific location of the tumor, large neurovascular bundles may be involved. In addition, management of large nerves and vessels can make wide marginal resection more difficult. Sites where these problems commonly arise include the sciatic and tibial common peroneal nerve, artery and vein in the lower limbs.

Tissue-engineered calcium phosphate cement in rabbit femoral condylar bone defects.

BACKGROUND: Calcium phosphate cement (CPC) is a favorable bone-graft substitute, with excellent biocompatibility and osteoconductivity. However, its reduced osteoinductive ability may limit the utility of CPC. To increase its osteoinductive potential, this study aimed to prepare tissue-engineered CPC and evaluate its use in the repair of bone defects. The fate of transplanted seed cells in vivo was observed at the same time. METHODS: Tissue-engineered CPC was prepared by seeding CPC with encapsulated bone mesenchymal stem cells (BMSCs) expressing recombinant human bone morphogenetic protein-2 (rhBMP-2) and green fluorescent protein (GFP). Tissue-engineered CPC and pure CPC were implanted into rabbit femoral condyle bone defects respectively. Twelve weeks later, radiographs, morphological observations, histomorphometrical evaluations, and in vivo tracing were performed. RESULTS: The radiographs revealed better absorption and faster new bone formation for tissue-engineered CPC than pure CPC. Morphological and histomorphometrical evaluations indicated that tissue-engineered CPC separated into numerous small blocks, with active absorption and reconstruction noted, whereas the residual CPC area was larger in the group treated with pure CPC. In the tissue-engineered CPC group, in vivo tracing revealed numerous cells expressing both GFP and rhBMP-2 that were distributed in the medullar cavity and on the surface of bony trabeculae. CONCLUSION: Tissue-engineered CPC can effectively repair bone defects, with allogenic seeded cells able to grow and differentiate in vivo after transplantation.