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Osteoarthritis (OA) is a common degenerative joint disease which currently lacks of effective agents. It is therefore urgent and necessary to seek an effective approach that can inhibit inflammation and promote cartilage matrix homeostasis. Cartilage progenitor cells (CPCs) are identified as a cell population of superficial zone in articular cartilage which possess strong migration ability, proliferative capacity, and chondrogenic potential. Recently, the application of CPCs may represent a novel cell therapy strategy for OA treatment. There is growing evidence that extracellular vesicles (EVs) are primary mediators of the benefits of stem cell-based therapy. In this study, we explored the protective effects of CPCs-derived EVs (CPCs-EVs) on IL-1β-induced chondrocytes. We found CPCs-EVs exhibited chondro-protective effects in vitro. Furthermore, our study demonstrated that CPCs-EVs promoted matrix anabolism and inhibited inflammatory response at least partially via blocking STAT3 activation. In addition, liquid chromatography-tandem mass spectrometry analysis identified 991 proteins encapsulated in CPCs-EVs. By bioinformatics analysis, we showed that STAT3 regulatory proteins were enriched in CPCs-EVs and could be transported to chondrocytes. To promoting the protective function of CPCs-EVs in vivo, CPCs-EVs were modified with cationic peptide ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD) for surface charge reverse. In posttraumatic OA mice, our results showed PPD modified CPCs-EVs (PPD-EVs) effectively inhibited extracellular matrix catabolism and attenuated cartilage degeneration. Moreover, PPD-EVs down-regulated inflammatory factors expressions and reduced OA-related pain in OA mice. In ex-vivo cultured OA cartilage explants, PPD-EVs successfully promoted matrix anabolism and inhibited inflammation. Collectively, CPCs-EVs-based cell-free therapy is a promising strategy for OA treatment. [ABSTRACT FROM AUTHOR]

Background: Kashin–Beck disease (KBD) is an endemic, chronic osteoarthropathy that seriously affects joint function and can lead to severe knee deformity. Osteotomy is considered to be one of the effective methods for the treatment of this disease. Therefore, we designed a novel type of osteotomy named combined proximal tibial osteotomy (CPTO), which combines the characteristics of opening‐wedge high tibial osteotomy and tibial condylar valgus osteotomy. Case presentation: We report the case of a 48‐year‐old male with knee pain and varus deformity who was diagnosed with KBD and varus knee osteoarthritis (Kellgren–Lawrence stage IV). Considering the patient's relatively young age, a varus deformity of the right knee of 16.79°, and an intra‐articular instability, we performed a CPTO treatment. In this procedure, we performed an L‐shaped osteotomy from the medial edge of the proximal tibia to the intercondylar eminence and an osteotomy from the medial side of the proximal tibia to the lateral side through the same incision, to adjust the leg alignment and the congruity of the joint by valgus correction. At 29 months follow‐up, this patient achieved satisfactory results, with a varus right knee of 2.87°. There was significant improvement in his right knee function, pain, and joint stability. Conclusions: CPTO may be an acceptable treatment for KBD patients with severe knee varus deformity and intra‐articular instability. It can be considered as an alternative treatment, especially for patients with advanced osteoarthritis needing knee preservation. [ABSTRACT FROM AUTHOR]

Complex-valued neural network is a kind of learning model which can deal with problems in complex domain. Fully complex extreme learning machine (CELM) is a much faster training algorithm than the complex backpropagation (CBP) scheme. However, it is at the cost of using more hidden nodes to obtain the comparable performance. An upper-layer-solution-aware algorithm has been proposed for training single-hidden layer feedforward neural networks, which performs much better than its counterparts, pseudo-inverse learning (PIL)/extreme learning machine and gradient decent-based backpropagation neural networks. Consequently, there exist two challenges that need to be dealt with: 1) How to combine the advantages of CBP and CELM to develop a novel complex learning algorithm? and 2) What is the convergent behavior of the presented algorithm? In this article, an input weights dependent complex-valued (IWDCV) learning algorithm based on Wirtinger calculus has been proposed, which effectively solves the nonanalytic problem of the common activation functions during training neural networks. In addition, the monotonicity of the error function and the deterministic convergence of the proposed model have been strictly proved, which theoretically guarantee the efficiency and effectiveness of the given model, IWDCV. Finally, for real and complex-valued problems, a variety of simulations have been done to demonstrate the comparable performance of the proposed algorithm which support the theoretical observations as well. [ABSTRACT FROM AUTHOR]

This brief proposes an enhanced fractional derivative that can prevent the tap weight coefficients from destroying the gradient information, solve the problem caused by the fractional extreme point, and improve the convergence speed with the help of error estimation information and Sign function. Based on this fractional derivative, an enhanced fractional least mean square (EFLMS) filter algorithm is proposed. We analyze the influence of unknown system vector on the convergence performance of the EFLMS algorithm. The computational complexity of the proposed algorithm is also analyzed. Simulation experiments show that the EFLMS algorithm achieves better performance in system identification than the classic least mean square (LMS) algorithm and the existing algorithms based on fractional calculus. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell‐derived small extracellular vesicles (MSC‐sEVs) possess a great therapeutical potential for osteoarthritis (OA) treatment. However, the steric and electrostatic hindrance of cartilage matrix leads to very limited distribution of MSC‐sEVs in cartilage and low bioavailability of MSC‐sEVs after intra‐articular injection. To overcome this, a strategy to reverse the surface charge of MSC‐sEVs by modifying the MSC‐sEVs with a novel cationic amphiphilic macromolecule namely ε‐polylysine‐polyethylene‐distearyl phosphatidylethanolamine (PPD) was developed in this study. Through incubation with 100 μg/ml PPD, positively charged MSC‐sEVs (PPD‐sEVs) were obtained, and the modification process showed nearly no disturbance to the integrity and contents of sEVs and exhibited good stability under the interference of anionic macromolecules. A more effective cellular uptake and homeostasis modulation ability of PPD‐sEVs than unmodified MSC‐sEVs to chondrocytes was demonstrated. More importantly, PPD‐sEVs demonstrated significantly enhanced cartilage uptake, cartilage penetration, and joint retention capacity as compared to MSC‐sEVs. Intra‐articular injection of PPD‐sEVs into a mouse OA model showed significantly improved bioavailability than MSC‐sEVs, which resulted in enhanced therapeutic efficacy with reduced injection frequency. In general, this study provides a facile and effective strategy to improve the intra‐articular bioavailability of MSC‐sEVs and has a great potential to accelerate the clinical practice of MSC‐sEVs based OA therapy. [ABSTRACT FROM AUTHOR]

Platelet aggregates, such as PRP, PRF, and CGF, have been used alone or in combination with other grafting materials to enhance restoration outcomes. The process for preparing these autografting materials requires two-step centrifugation or specific centrifuges. In this study, we obtained an injectable fibrin scaffold (IFS) rich in growth factors by one-step centrifugation of whole blood from rabbits. The purpose of this study is to introduce some characteristics of IFS. This scaffold was characterized using various techniques, including Masson's trichrome staining, scanning electron microscopy, porosity measurements, and cell counting. The sustained release of growth factors, including PDGF, VEGF, TGF-β1, IGF, FGF, and EGF, was quantified using ELISA assay. The obtained IFS was tested for its effects on cell proliferation, extracellular matrix deposition, and full-thickness skin defect repair. The prepared IFS is characterized by a loose fibrin network structure with white blood cells and platelets that slowly release growth factors and can promote the healing of skin defects via the promotion of cell proliferation, collagen deposition, and tissue revascularization. In addition, its liquid properties and porous structure are conducive to its application as a therapeutic component in tissue engineering. [ABSTRACT FROM AUTHOR]

We propose three different methods to determine the optimal number of hidden nodes based on L1 regularization for a multilayer perceptron network. The first two methods, respectively, use a set of multiplier functions and multipliers for the hidden-layer nodes and implement the L1 regularization on those, while the third method equipped with the same multipliers uses a smoothing approximation of the L1 regularization. Each of these methods begins with a given number of hidden nodes, then the network is trained to obtain an optimal architecture discarding redundant hidden nodes using the multiplier functions or multipliers. A simple and generic method, namely, the matrix-based convergence proving method (MCPM), is introduced to prove the weak and strong convergence of the presented smoothing algorithms. The performance of the three pruning methods has been tested on 11 different classification datasets. The results demonstrate the efficient pruning abilities and competitive generalization by the proposed methods. The theoretical results are also validated by the results. [ABSTRACT FROM AUTHOR]

Background. Platelet-rich plasma (PRP) has been shown to be a promising therapeutic agent against osteoarthritis (OA), whereas its chondroprotection mechanism is not fully elucidated. Autophagy is considered an important biological process throughout the development of OA. Therefore, the objective of the present study is to investigate the role of autophagy in the chondroprotection and compare the effects of releasate between L-PRP and P-PRP. Methods. PRP were prepared from rat blood. Rat chondrocytes pretreated in the presence or absence of interleukin-1 beta (IL-1β) were incubated with PRP releasate. The expressions of OA-related genes and autophagy-related genes were determined by RT-PCR and western blot, respectively. Autophagic bodies were assessed by transmission electron microscopy and the autophagy flux was monitored under the confocal microscopy. The effect of PRP on autophagy was further investigated in the milieu of autophagy activator, rapamycin, or autophagy inhibition by downregulation of Atg5. The effect of PRP on cartilage repair and autophagy was also evaluated in an OA rat model. Results. In vitro, PRP releasate increased the expression of the anabolic genes, COL2 and Aggrecan, and decreased the expression of the catabolic genes, whereas the expression of autophage markers, Atg5 and Beclin-1, as well as the ratio of LC3 II/LC3 I, was not significantly altered in normal or IL-1β-treated chondrocytes. Similar expression pattern was found following the activation (rapamycin) or inhibition (Atg5 silencing) of autophagy. In vivo, PRP releasate ameliorated posttraumatic cartilage degeneration while the expression of LC3 was comparable to that in the vehicle treatment group. Conclusions. PRP releasate promoted the anabolic gene expression, relieved inflammatory stress in chondrocytes, and ameliorated cartilage degeneration, but autophagy was independent of these processes. [ABSTRACT FROM AUTHOR]

Background: High levels of pro-inflammatory cytokines in leukocyte- and platelet-rich plasma (L-PRP) may activate the nuclear factor κB (NF-κB) pathway to counter the beneficial effect of the growth factors on bone regeneration. However, to date, no relevant studies have substantiated this.Methods: L-PRP and pure platelet-rich plasma (P-PRP) were isolated. The in vitro effects of L-PRP and P-PRP on the proliferation, viability and migration of human bone marrow-derived mesenchymal stem cells (HBMSCs) and EaHy926, tube formation of EaHy926, and osteogenic differentiation of HBMSCs were assessed by cell counting, flow cytometry, scratch assay, tube formation assay, and real-time quantitative polymerase chain reaction (RT-PCR), western blotting and Alizarin red staining, respectively. The in vitro effects of L-PRP and P-PRP on the nuclear translocation of NF-κB p65, mRNA expression of inducible nitric oxide synthase and cyclooxygenase-2, and production of prostaglandin E2 and nitric oxid were assessed by western blotting, RT-PCR, enzyme-linked immunosorbent assay and Griess reaction, respectively. The in vivo effects of L-PRP or P-PRP preprocessed β-tricalcium phosphate (β-TCP) on the calvarial defects in rats were assessed by histological and immunofluorescence examinations.Results: P-PRP, which had similar platelet and growth factors concentrations but significantly lower concentrations of leukocytes and pro-inflammatory cytokines compared with L-PRP, promoted the proliferation, viability and migration of HBMSCs and EaHy926, tube formation of EaHy926 and osteogenic differentiation of HBMSCs in vitro, compared with L-PRP. The implantation of P-PRP preprocessed β-TCP also yielded better histological results than the implantation of L-PRP preprocessed β-TCP in vivo. Moreover, L-PRP treatment resulted in the activation of the NF-κB pathway in HBMSCs and EaHy926 in vitro while the postoperative delivery of caffeic acid phenethyl ester, an inhibitor of NF-κB activation, enhanced the histological results of the implantation of L-PRP preprocessed β-TCP in vivo.Conclusions: Leukocytes in L-PRP may activate the NF-κB pathway via the increased pro-inflammatory cytokines to induce the inferior effects on bone regeneration of L-PRP compared with P-PRP. Hence, P-PRP may be more suitable for bone regeneration compared with L-PRP, and the combined use of P-PRP and β-TCP represents a safe, simple, and effective alternative option for autogenous bone graft in the treatment of bone defects. [ABSTRACT FROM AUTHOR]

Background: Traditionally, acute undisplaced or minimally-displaced scaphoid fractures are treated by casting in short- or long-arm casts. Although reports have shown that operative treatment is safe, effective and produces satisfactory results, outcomes from current studies comparing these two methods are questionable. The aim of this meta-analysis was to evaluate the effects of operative versus non-operative treatment for acute undisplaced or minimally-displaced scaphoid fractures in adults. Methods: Computerized searches were performed without language restrictions and all randomized controlled studies providing information on the effects of operative versus non-operative treatment on the outcomes of acute undisplaced or minimally-displaced scaphoid fractures were included. The weighted and standard mean difference (WMD and SMD) or the relative risk (RR) were calculated for continuous or dichotomous data respectively. Results: A total of six studies reported in seven publications were included, representing data on 340 fractures. Meta-analysis indicated that operative treatment resulted in significantly better functional outcomes in the short term when compared with non-operative treatment. Consistently, patients who accepted surgery had a more rapid return to work. Further, surgery was advantageous in preventing delayed union of the fractures, a finding supported by the results of analysis of the time to fracture union. A number-needed-to-treat analysis revealed that more than 20 patients would have to undergo operative treatment to prevent one delayed union. Conclusion: Acute undisplaced or minimally-displaced scaphoid fractures demonstrate faster recovery with operative treatment; however, the current meta-analysis does not provide evidence supporting the routine use of operative treatment for all acute undisplaced or minimally-displaced scaphoid fractures. [ABSTRACT FROM AUTHOR]

Background and purpose There is no consensus on the difference in effects of internal fixation (IF) and external fixation (EF) on outcomes for the treatment of distal radius fractures. We performed a meta-analysis of randomized clinical studies. Methods We searched the literature and included studies that compared the effects of IF and EF on the treatment of distal radius fractures. Statistically, we pooled patient data using standard meta-analytic methods. For the continuous variables, the weighted mean difference (WMD) was used. For dichotomous data, the relative risk (RR) was calculated. Results 10 studies were eligible for data extraction. The pooled data showed that compared with EF, IF led to statistically significantly better Disabilities of the Arm, Shoulder, and Hand (DASH) scores at 12 months postoperatively, recovery of forearm supination at 3 months, and restoration of volar tilt and radial inclination. IF using volar locking plates resulted in better DASH scores than EF at 3 and 6 months, but the trend diminished over time; at 12 months postoperatively, the scores were not statistically significant. Compared with EF, IF led to fewer minor surgical complications. Interpretation For surgical treatment of distal radius fractures, IF yields better functional outcomes, forearm supination, restoration of anatomic volar tilt and radial inclination, and fewer minor complications. The patients who received IF using volar locking plates for the treatment of distal radius recovered more quickly than did patients who received EF. [ABSTRACT FROM AUTHOR]

Background: Anterior cruciate ligament (ACL) tears are commonly seen with concomitant injuries to the posterolateral tibial plateau, while the occurrence of ACL injuries in posterolateral tibial plateau fractures (PTPFs) remains unclear., Purpose: To (1) explore the incidence of knee ligament (anterior or posterior cruciate ligament, medial or lateral collateral ligament) and medial or lateral meniscus injuries in patients with PTPF and (2) find reliable PTPF-related parameters to predict the risk of knee ligament and meniscal injuries., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Patients diagnosed with PTPF who had computed tomography and magnetic resonance imaging (MRI) data were identified. Morphological parameters of the PTPF were measured on sagittal computed tomography images. Knee ligament and meniscal injuries were assessed using MRI. The association of ACL injuries with meniscal injuries was analyzed. Receiver operating characteristic (ROC) analysis was used to determine the value and cutoff point of the PTPF morphological parameters for diagnosing complete in-substance ACL tears., Results: Overall, 113 patients with PTPF were included. ACL injuries were present in 94 (83.2%) patients, including 43 (38.1%) avulsion fractures and 28 (24.8%) complete in-substance tears. Patients with in-substance ACL tears had a higher incidence of lateral meniscus posterior horn tears compared with the other patients ( P Bonferroni < .001). ROC analysis revealed that both the fracture depression angle (cutoff point, 25.5°) and the posterior articular surface loss percentage (cutoff point, 37.5%) had a sensitivity >90% and a specificity >80% for the diagnosis of complete in-substance ACL tears., Conclusion: ACL injuries were seen in 83.2% of the study patients. Complete in-substance ACL tears were associated with an increased incidence of lateral meniscus posterior horn tears. Among PTPF parameters, fracture depression angle and posterior articular surface loss percentage showed a high predictive value for the presence of complete in-substance ACL tears, thereby reducing delays in diagnosis and treatment., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from the Ethics Committee of Shanghai Sixth People's Hospital (reference No. 2023-033)., (© The Author(s) 2024.)

Background: The surgical treatment of posterolateral tibial plateau fractures involves a challenging and diverse set of considerations, one of which is the lack of proper and satisfactory internal fixations to purchase posterolateral fragments. Evaluating the configuration of internal fixations is often overlooked, despite it being important to outcomes of fracture fixation. This study aimed to (I) propose a new digital methodology of internal fixation evaluation that based on actual fracture cases and (II) evaluate the fixation effectiveness of four commercially available proximal tibial lateral plate-screw constructs for posterolateral fragments., Methods: Tibial plateau fractures involving the posterolateral column were retrospectively reviewed. The reconstructed three-dimensional (3D) fracture models were virtually reduced, and targeted internal fixations were modeled digitally in specialized software. Four implants from three manufacturers (DePuy Synthes, Westchester, NY, USA; Zimmer, Warsaw, IN, USA; and Biomet, Warsaw, IN, USA) were placed on each fracture in an optimal position to simulate surgical fixation and quantitatively evaluate fixation effectiveness. The fragment was considered to be "captured" if it was purchased by at least two screws. The 3D fracture maps and heat maps were created by graphically superimposing all uncaptured fracture fragments onto a tibia template., Results: This study included 144 posterolateral tibial plateau fractures. When not using screws in a variable angle (VA) manner, the fixation effectiveness for posterolateral fragments was 58.3% for the DePuy Synthes locking compression plates (LCP), 47.9% for the DePuy Synthes VA-LCP, 50.7% for the Zimmer plate, and 43.8% for the Biomet plate. In contrast, the capturing rates boosted to 76.4% and 71.5% when utilizing VA screws in the DePuy Synthes VA-LCP and the Biomet plate. The high-frequency uncaptured areas tended to concentrate on the rim of the posterolateral wall and were mainly distributed in the posterior 1/2 to 3/4 of the parallel position of the fibula head., Conclusions: The proposed new digital methodology was demonstrated feasible and may improve the quantitative evaluation of the implants and optimize the design of implants. The commercially available proximal tibial lateral plate-screw constructs were insufficient in capturing posterolateral fragments, and design-improved or additional implants may be necessitated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-750/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Distal femur fractures are complex injuries with a high rate of fracture healing problems. Since the widespread of computed tomographic imaging in the diagnosis of distal femur fractures, many fracture characteristics have been discovered. This study aimed to depict the location and frequency of distal femur fracture lines and further analyze the morphological characteristics using the 3-dimensional computed tomography (CT) mapping technique, thus providing more information to solve this challenging clinical problem., Methods: In total, 217 distal femur fractures in 216 patients were retrospectively reviewed. Fracture fragments on CT were digitally reconstructed and virtually reduced to match a template model. The contour of every fracture fragment was then marked with smooth curves, and the overlap of all fracture lines allowed for the creation of 3-dimensional fracture maps and heat maps. Fracture characteristics were summarized based on these maps., Results: This study included 114 left knee injuries, 101 right knee injuries, and 1 case with bilateral injury. Distal femur fractures were most likely to occur among patients aged 61 to 70 years. On the heat map of all 217 fractures, fracture line hot zones were mainly concentrated around the metaphysis, the lateral part of the intercondylar notch, and the patellofemoral joint. Distal femur fractures with three Arbeitsgemeinschaft für Osteosynthesefragen Foundation/Orthopaedic Trauma Association (AO/OTA) types demonstrated distinct fracture characteristics. In total, there were 58 coronal plane fractures (41.1%) in 141 intercondylar fractures., Conclusions: The intercondylar fracture patterns in AO/OTA type B and type C fractures were similar, while the supracondylar characteristics in AO/OTA type A and type C were different. The findings in this study can help orthopaedic surgeons better understand the fracture morphology on the basis of AO/OTA classification. Further studies are needed to establish a standard biomechanical fracture model and new fixation strategy for better clinical outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4591/coif). The authors report that this study was granted by AO Innovation Translation Center of the AO Foundation to reveal the morphologic details of the distal femur fractures (AO/OTA types 33A, 33B, and 33C). The authors have no other conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Multi-fragmentary patella fractures (MFPFs) are common patella fracture type. Low-profile plate fixation seems to be promising advancement in the treatment of such difficult fractures. There is no systematic morphologic study specifically for MFPFs to provide objective reference for the improvement of future implants and biomechanical models. This study aimed to delineate and quantify the location and spatial frequency of fracture lines, comminution zones, and coronal plane fragments in MFPFs using three-dimensional (3D) CT mapping technique., Methods: A total of 187 MFPFs were retrospectively reviewed and analyzed. Fractures were digitally reconstructed from CT data, and fracture lines, comminution zones, and coronal fragments were graphically overlaid onto a 3D patella template. Fracture characteristics were summarized qualitatively based on the fracture maps and quantitatively on the counts and volume of each fragment. Furthermore, according to the classic fracture patterns concerning MFPFs, subgroup analysis was conducted., Results: On average, we observed 7 fragments in each fracture, 3 of which were <1 cm 3 . Most fractures (81.2%) had coronal fragments on the anterior and/or posterior patella surfaces. We identified three classic patella fracture patterns: transverse with comminution, stellate, and "displaced comminuted" in 104, 54, and 29 knees, respectively. 3D maps demonstrated distinct distribution fracture patterns of fracture lines, comminution zones, and coronal fragments., Conclusions: Supero-medial corner of the patella was seldomly involved, and might be used as the cornerstone for fixation. Coronal fragments were common on both anterior and posterior patella surfaces, justifying the application of anterior plate osteosynthesis characterized by multi-planar fixation. Comminution areas mainly concentrated in the lower half of the patella, potentially suitable for an implant in combination with sutures or circumferential cerclage wiring. The described 3D features of MFPFs could provide reference for the design of future implants and biomechanical models., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1814). The authors report that this study was granted by AOTrauma Asia Pacific of the AO Foundation to reveal the morphologic details of the multi-fragmentary patella fracture (AO/OTA-34C3)., (2021 Annals of Translational Medicine. All rights reserved.)

We propose three different methods to determine the optimal number of hidden nodes based on L 1 regularization for a multilayer perceptron network. The first two methods, respectively, use a set of multiplier functions and multipliers for the hidden-layer nodes and implement the L 1 regularization on those, while the third method equipped with the same multipliers uses a smoothing approximation of the L 1 regularization. Each of these methods begins with a given number of hidden nodes, then the network is trained to obtain an optimal architecture discarding redundant hidden nodes using the multiplier functions or multipliers. A simple and generic method, namely, the matrix-based convergence proving method (MCPM), is introduced to prove the weak and strong convergence of the presented smoothing algorithms. The performance of the three pruning methods has been tested on 11 different classification datasets. The results demonstrate the efficient pruning abilities and competitive generalization by the proposed methods. The theoretical results are also validated by the results.

The development of multifunctional biomaterials to repair bone defects after neoplasm removal and inhibit tumor recurrence remained huge clinical challenges. Here, we demonstrate a kind of innovative and multifunctional magnetic mesoporous calcium sillicate/chitosan (MCSC) porous scaffolds, made of M-type ferrite particles (SrFe 12 O 19 ), mesoporous calcium silicate (CaSiO 3 ) and chitosan (CS), which exert robust anti-tumor and bone regeneration properties. The mesopores in the CaSiO 3 microspheres contributed to the drug delivery property, and the SrFe 12 O 19 particles improved photothermal therapy (PTT) conversion efficacy. With the irradiation of NIR laser, doxorubicin (DOX) was rapidly released from the MCSC/DOX scaffolds. In vitro and in vivo tests demonstrated that the MCSC scaffolds possessed the excellent anti-tumor efficacy via the synergetic effect of DOX drug release and hyperthermia ablation. Moreover, BMP-2/Smad/Runx2 pathway was involved in the MCSC scaffolds promoted proliferation and osteogenic differentiation of human bone marrow stromal cells (hBMSCs). Taken together, the MCSC scaffolds have the ability to promote osteogenesis and enhance synergetic photothermal-chemotherapy against osteosarcoma, indicating MCSC scaffolds may have great application potential for bone tumor-related defects.

Erythrocyte sedimentation rate (ESR), which reflects the sedimentation rate of platelets, leukocytes and erythrocytes in response to centrifugal force, may influence the cellular composition of platelet-rich plasma (PRP) obtained via centrifugation methods. However, no relevant studies have substantiated this. In the present study, blood was collected from 40 healthy volunteers and used to prepare PRP with two plasma-based preparation systems [YinPRP and Plasma Rich in Growth Factor (PRGF) systems] and two buffy coat-based systems (RegenPRP and WEGOPRP systems) in a single-donor model. Volumes of PRP and platelet-poor plasma (PPP) that were removed in the preparation process were recorded. Analyses of ESR, haematocrit, C-reaction protein, coagulation, serum glucose and serum lipid of the whole blood used for PRP preparation were performed to evaluate the levels of ESR and the factors known to influence it. Whole blood analysis was performed to evaluate the cellular composition of PRP. Results demonstrated that there were marked positive correlations between the ESR of the whole blood used for PRP preparation and PPP removal efficiencies, platelet concentrations, platelet capture efficiencies and platelet enrichment factors of PRP formulations obtained from plasma-based systems, and PRP yield efficiency of RegenPRP and PPP removal efficiency of WEGOPRP. Furthermore, there were marked negative correlations between ESR and concentrations and enrichment factors of platelets, leukocytes and erythrocytes of RegenPRP. Fibrinogen concentration of the whole blood, which had a marked positive correlation with ESR, also influenced the cellular composition of PRP. These findings may increase the understanding of PRP preparation and provide substantial evidence for the individualised optimisation of PRP preparation systems used in clinical practice.

While it has been proved that centrifugal conditions for pure platelet-rich plasma (P-PRP) preparation influence the cellular composition of P-PRP obtained, the optimal centrifugal conditions to prepare P-PRP have not yet been identified. In the present study, platelet-containing plasma (PCP) was prepared with the first-spin of different double-spin methods and P-PRP was prepared with different double-spin methods. Whole-blood analysis was performed to evaluate the cellular composition of PCP and P-PRP. The basal and ADP-induced CD62P expression rates of platelets were assessed by flow cytometry to evaluate the function of platelets in PCP and P-PRP. Enzyme-linked immune sorbent assay was performed to quantify interleukin-1β, tumor necrosis factor-α, platelet-derived growth factor AB and transforming growth factor β1 concentrations of PCP and P-PRP. Correlations between the cellular characteristics and cytokine concentrations of P-PRP were analyzed by Pearson correlation analysis. Effects of P-PRP on the proliferation, survival and migration of human bone marrow-derived mesenchymal stem cells and human articular chondrocytes were evaluated by a Cell Counting Kit-8 assay, live/dead staining and Transwell assay, respectively. The results showed that centrifugation at 160 × g for 10 min and 250 × g for 15 min successively captured and concentrated platelets and growth factors significantly more efficiently with preservation of platelet function compared with other conditions (P<0.05). The correlation analysis showed that the similar leukocyte concentrations and leukocyte-reducing efficiencies resulted in similar pro-inflammatory cytokine concentrations in P-PRP (P>0.05) and the maximization of platelet concentration, platelet enrichment factor, platelet capture efficiency and platelet function resulted in the maximization of growth factor concentrations in P-PRP obtained using the optimal conditions (P<0.05). Compared with P-PRP obtained under other conditions, P-PRP obtained under the optimal conditions significantly promoted the proliferation and migration of cells (P<0.05) and did not alter cell survival (P>0.05). Therefore, centrifugation at 160 × g for 10 min and 250 × g for 15 min successively with removal of the buffy coat as a crucial step may provide an optimal preparation system of P-PRP for clinical application.

Platelet-rich plasma (PRP) has gained growing popularity in the treatment of articular cartilage lesions in the last decade. However, the potential harmful effects of leukocytes in PRP on cartilage regeneration have seldom been studied in vitro, and not at all in vivo yet. The objective of the present study is to compare the effects of leukocyte- and platelet-rich plasma (L-PRP) and pure platelet-rich plasma (P-PRP) on cartilage repair and NF-κB pathway, in order to explore the mechanism underlying the function of leukocytes in PRP in cartilage regeneration. The constituent analysis showed that P-PRP had significantly lower concentrations of leukocytes and pro-inflammatory cytokines compared with L-PRP. In addition, cell proliferation and differentiation assays indicated P-PRP promoted growth and chondrogenesis of rabbit bone marrow mesenchymal stem cells (rBMSC) significantly compared with L-PRP. Despite similarity in macroscopic appearance, the implantation of P-PRP combining rBMSC in vivo yielded better cartilage repair results than the L-PRP group based on histological examination. Importantly, the therapeutic effects of PRP on cartilage regeneration could be enhanced by removing leukocytes to avoid the activation of the NF-κB pathway. Thus, PRP without concentrated leukocytes may be more suitable for the treatment of articular cartilage lesions.

Background: Quite a few randomized controlled trials (RCTs) investigating the efficacy of platelet-rich plasma (PRP) for treatment of knee osteoarthritis (OA) have been recently published. Therefore, an updated systematic review was performed to evaluate the temporal effect of PRP on knee pain and physical function., Methods: Pubmed, Embase, Cochrane library, and Scopus were searched for human RCTs comparing the efficacy and/or safety of PRP infiltration with other intra-articular injections. A descriptive summary and quality assessment were performed for all the studies finally included for analysis. For studies reporting outcomes concerning Western Ontario and McMaster Universities Arthritis Index (WOMAC) or adverse events, a random-effects model was used for data synthesis., Results: Fourteen RCTs comprising 1423 participants were included. The control included saline placebo, HA, ozone, and corticosteroids. The follow-up ranged from 12 weeks to 12 months. Risk of bias assessment showed that 4 studies were considered as moderate risk of bias and 10 as high risk of bias. Compared with control, PRP injections significantly reduced WOMAC pain subscores at 3, 6, and 12 months follow-up (p = 0.02, 0.004, <0.001, respectively); PRP significantly improved WOMAC physical function subscores at 3, 6, and 12 months (p = 0.002, 0.01, <0.001, respectively); PRP also significantly improved total WOMAC scores at 3, 6 and 12 months (all p < 0.001); nonetheless, PRP did not significantly increased the risk of post-injection adverse events (RR, 1.40 [95% CI, 0.80 to 2.45], I 2  = 59%, p = 0.24)., Conclusions: Intra-articular PRP injections probably are more efficacious in the treatment of knee OA in terms of pain relief and self-reported function improvement at 3, 6 and 12 months follow-up, compared with other injections, including saline placebo, HA, ozone, and corticosteroids., Review Registration: PROSPERO CRD42016045410 . Registered 8 August 2016.

Background: High levels of pro-inflammatory cytokines in leukocyte- and platelet-rich plasma (L-PRP) may activate the nuclear factor κB (NF-κB) pathway to counter the beneficial effect of the growth factors on bone regeneration. However, to date, no relevant studies have substantiated this., Methods: L-PRP and pure platelet-rich plasma (P-PRP) were isolated. The in vitro effects of L-PRP and P-PRP on the proliferation, viability and migration of human bone marrow-derived mesenchymal stem cells (HBMSCs) and EaHy926, tube formation of EaHy926, and osteogenic differentiation of HBMSCs were assessed by cell counting, flow cytometry, scratch assay, tube formation assay, and real-time quantitative polymerase chain reaction (RT-PCR), western blotting and Alizarin red staining, respectively. The in vitro effects of L-PRP and P-PRP on the nuclear translocation of NF-κB p65, mRNA expression of inducible nitric oxide synthase and cyclooxygenase-2, and production of prostaglandin E2 and nitric oxid were assessed by western blotting, RT-PCR, enzyme-linked immunosorbent assay and Griess reaction, respectively. The in vivo effects of L-PRP or P-PRP preprocessed β-tricalcium phosphate (β-TCP) on the calvarial defects in rats were assessed by histological and immunofluorescence examinations., Results: P-PRP, which had similar platelet and growth factors concentrations but significantly lower concentrations of leukocytes and pro-inflammatory cytokines compared with L-PRP, promoted the proliferation, viability and migration of HBMSCs and EaHy926, tube formation of EaHy926 and osteogenic differentiation of HBMSCs in vitro, compared with L-PRP. The implantation of P-PRP preprocessed β-TCP also yielded better histological results than the implantation of L-PRP preprocessed β-TCP in vivo. Moreover, L-PRP treatment resulted in the activation of the NF-κB pathway in HBMSCs and EaHy926 in vitro while the postoperative delivery of caffeic acid phenethyl ester, an inhibitor of NF-κB activation, enhanced the histological results of the implantation of L-PRP preprocessed β-TCP in vivo., Conclusions: Leukocytes in L-PRP may activate the NF-κB pathway via the increased pro-inflammatory cytokines to induce the inferior effects on bone regeneration of L-PRP compared with P-PRP. Hence, P-PRP may be more suitable for bone regeneration compared with L-PRP, and the combined use of P-PRP and β-TCP represents a safe, simple, and effective alternative option for autogenous bone graft in the treatment of bone defects.

Platelet-rich plasma (PRP) is an autologous concentrated cocktail of growth factors and inflammatory mediators, and has been considered to be potentially effective for cartilage repair. In addition, the fibrinogen in PRP may be activated to form a fibrin matrix to fill cartilage lesions, fulfilling the initial requirements of physiological wound healing. The anabolic, anti-inflammatory and scaffolding effects of PRP based on laboratory investigations, animal studies, and clinical trials are reviewed here. In vitro, PRP is found to stimulate cell proliferation and cartilaginous matrix production by chondrocytes and adult mesenchymal stem cells (MSCs), enhance matrix secretion by synoviocytes, mitigate IL-1β-induced inflammation, and provide a favorable substrate for MSCs. In preclinical studies, PRP has been used either as a gel to fill cartilage defects with variable results, or to slow the progression of arthritis in animal models with positive outcomes. Findings from current clinical trials suggest that PRP may have the potential to fill cartilage defects to enhance cartilage repair, attenuate symptoms of osteoarthritis and improve joint function, with an acceptable safety profile. Although current evidence appears to favor PRP over hyaluronan for the treatment of osteoarthritis, the efficacy of PRP therapy remains unpredictable owing to the highly heterogeneous nature of reported studies and the variable composition of the PRP preparations. Future studies are critical to elucidate the functional activity of individual PRP components in modulating specific pathogenic mechanisms.

Background: Bisphosphonates and parathyroid hormone (PTH) represent the antiresorptive and anabolic classes of drugs for osteoporosis treatment. Bone mineral density (BMD) is an essential parameter for the evaluation of anti-osteoporotic drugs. The aim of this study was to evaluate the effects of PTH versus bisphosphonates on BMD for the treatment of osteoporosis., Methods/principal Findings: We performed a literature search to identify studies that investigated the effects of PTH versus bisphosphonates treatment on BMD. A total of 7 articles were included in this study, representing data on 944 subjects. The pooled data showed that the percent change of increased BMD in the spine is higher with PTH compared to bisphosphonates (WMD = 5.90, 95% CI: 3.69-8.10, p<0.01,). In the hip, high dose (40 µg) PTH (1-34) showed significantly higher increments of BMD compared to alendronate (femoral neck: WMD = 5.67, 95% CI: 3.47-7.87, p<0.01; total hip: WMD = 2.40, 95%CI: 0.49-4.31, p<0.05). PTH treatment has yielded significantly higher increments than bisphosphonates with a duration of over 12 months (femoral neck: WMD = 5.67, 95% CI: 3.47-7.86, p<0.01; total hip: WMD = 2.40, 95% CI: 0.49-4.31, P<0.05) and significantly lower increments at 12 months (femoral neck: WMD = -1.05, 95% CI: -2.26-0.16, p<0.01; total hip: WMD: -1.69, 95% CI: -3.05-0.34, p<0.05). In the distal radius, a reduction in BMD was significant between PTH and alendronate treatment. (WMD = -3.68, 95% CI: -5.57-1.79, p<0.01)., Discussion: Our results demonstrated that PTH significantly increased lumbar spine BMD as compared to treatment with bisphosphonates and PTH treatment induced duration- and dose-dependent increases in hip BMD as compared to bisphosphonates treatment. This study has also disclosed that for the distal radius, BMD was significantly lower from PTH treatment than alendronate treatment.