Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy.

Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1+/-) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1R1783W) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant ß-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a ß-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.

A novel allogeneic acellular matrix scaffold for porcine cartilage regeneration.

BACKGROUND: Cartilage defects are common sports injuries without significant treatment. Articular cartilage with inferior regenerative potential resulted in the poor formation of hyaline cartilage in defects. Acellular matrix scaffolds provide a microenvironment and biochemical properties similar to those of native tissues and are widely used for tissue regeneration. Therefore, we aimed to design a novel acellular cartilage matrix scaffold (ACS) for cartilage regeneration and hyaline-like cartilage formation. METHODS: Four types of cartilage injury models, including full-thickness cartilage defects (6.5 and 8.5 mm in diameter and 2.5 mm in depth) and osteochondral defects (6.5 and 8.5 mm in diameter and 5 mm in depth), were constructed in the trochlear groove of the right femurs of pigs (n = 32, female, 25-40 kg). The pigs were divided into 8 groups (4 in each group) based on post-surgery treatment differences. was assessed by macroscopic appearance, magnetic resonance imaging (MRI), micro-computed tomography (micro-CT), and histologic and immunohistochemistry tests. RESULTS: At 6 months, the ACS-implanted group exhibited better defect filling and a greater number of chondrocyte-like cells in the defect area than the blank groups. MRI and micro-CT imaging evaluations revealed that ACS implantation was an effective treatment for cartilage regeneration. The immunohistochemistry results suggested that more hyaline-like cartilage was generated in the defects of the ACS-implanted group. CONCLUSIONS: ACS implantation promoted cartilage repair in full-thickness cartilage defects and osteochondral defects with increased hyaline-like cartilage formation at the 6-month follow-up.

Self-Cascade Uricase/Catalase Mimics Alleviate Acute Gout.

Uricase-based therapies are limited for gout partially due to the accumulation of H2O2 in an arthrosis environment with slow metabolism. To tackle this limitation, previous studies adopted a cascade reaction between the degradation of uric acid (UA) and timely elimination of H2O2 using complicated composites of uricase and catalase (CAT)/CAT-like nanozyme. Herein, the self-cascade nanozyme Pt/CeO2 with high efficiency toward simultaneous UA degradation and H2O2 elimination is demonstrated on the basis of both uricase- and CAT-like activities in Pt, Ir, Rh, and Pd platinum-group metals. With an optimized molar ratio of Pt and CeO2, Pt/CeO2 (1/5) not only does better in degrading UA but also has excellent reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavenging activities. In monosodium urate (MSU)-induced acute gout rats, Pt/CeO2 nanozyme markedly alleviates pain along with joint edema, thus improving gait claudication and tissue inflammation. These results provide novel insights into strategies of an efficient enzyme-mimetic treatment for gout.

Multi-Pathway Microenvironment Regulation for Atherosclerosis Therapy Based on Beta-Cyclodextrin/L-Arginine/Au Nanomotors with Dual-Mode Propulsion.

Most of the current non-pharmacological treatment strategies for atherosclerosis (AS) suffer from poor penetration into the plaque and only aim at a certain factor in its formation process, resulting in limited therapeutic effect. Herein, a kind of nanomotor with dual-mode propulsion is constructed, which is sensitive to higher reactive oxygen species (ROS) at the AS site and near-infrared (NIR) laser by the covalent binding and self-assembly of ß-cyclodextrin (ß-CD) and L-arginine (LA) with immobilization of Au nanoparticles. NIR laser irradiation can be used as a driving force and to ablate inflammatory macrophages through the photothermal effect. The nitric oxide (NO) released by the nanomotors can be used as another driving force and a therapeutic agent to promote endothelial repair in the plaque site. LA can eliminate ROS in the inflammatory site, and ß-CD can promote the removal of cholesterol from foam cells. In particular, the two driving modes of nanomotors synergistically promote their aggregation and penetration in the plaque. This kind of nanomotor can regulate the microenvironment of AS in multiple ways, including combination therapy for endothelial repair, lipid clearance, and reducing ROS, which is expected to become a potential non-pharmacological strategy in the treatment of AS.

Methylene blue prevents osteoarthritis progression and relieves pain in rats via upregulation of Nrf2/PRDX1.

Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA.

Trehalose reduces bone loss in experimental biliary cirrhosis rats via ERK phosphorylation regulation by enhancing autophagosome formation.

Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG/receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.

A C-Met chemical inhibitor promotes fracture healing through interacting with osteogenic differentiation via the mTORC1 pathway.

Currently, HGF/C-Met signaling inhibitors are being investigated to determine if they are useful for enhancing progenitor cell differentiation into osteoblasts, and one of them, BMS-777607, has been utilized to treat osteoporosis and bone loss in several types of diseases. However, whether BMS-777607 could be a potential treatment during fracture healing remains elusive. Here, we examined the therapeutic effects of BMS-777607 on bone fracture healing in a mouse model. In vivo radiological analysis showed that fractures treated with BMS-777607 exhibited accelerated osteotylus formation during the early stage of bone healing. Thereafter, the Safranin O staining evaluation indicated that the structure of the external callus in the Treatment group was larger than that in the Vehicle group at week 2. Furthermore, cellular proliferation of MC3T3-E1 was not significantly affected by low concentrations of BMS-777607. In addition, stimulation of osteoblast differentiation and mineralization was a result of BMS-777607 inducing the expression of Runx2 and Col1, and this osteogenic ability, at least in part, was mediated through the mammalian target of rapamycin complex 1 (mTORC1) signaling in vitro. Conclusively, BMS-777607 has been identified as a therapeutic agent to improve bone formation during fracture healing, and its osteogenic effects on osteoblast differentiation were mediated via the mTORC1 signaling pathway.

Prevalence and Risk Factors of Preoperative Deep Vein Thrombosis in Patients with End-Stage Knee Osteoarthritis.

BACKGROUND: The purpose of this study is to determine the prevalence and the risk factors of DVT in end-stage OA patients. METHODS: From March 2015 to June 2017, 521 patients with knee degenerative osteoarthritis undergoing knee arthroplasty were enrolled; 458 patients (87.9%) were admitted for primary total knee arthroplasty and 63 patients (12.1%) were admitted for unicompartmental knee arthroplasty. Parameters were compared using χ2 or t-test for both the groups. Binary logistic regression analysis was used to determine risk factors. RESULTS: The incidence of preoperative DVT was 6.7% (n = 35). Age in preoperative DVT group was significantly more than the non-DVT group (72.54 ± 6.53 vs. 68.65 ± 7.35, P = 0.002). Preoperative D-dimer >0.5 µg/mL (P < 0.001) was also associated with preoperative DVT in knee osteoarthritis patients. The incidence increased with age significantly (2.17% in <65 years, 6.86% in ≥65 <75 years, and 12.26% in ≥75 years) (P = 0.008). Thus, age (P = 0.041, OR 1.075, 95% CI [1.002-1.110]) and D-dimer >0.5 µg/mL (P < 0.001, OR 4.441, 95% CI [1.942-10.153]) were the independent risk factors for preoperative DVT in knee osteoarthritis patients. CONCLUSIONS: The incidence of DVT in end-stage osteoarthritis was 6.7%. The results suggest that older people aged over 75 and D-dimer > 0.5 µg/mL were risk factors for DVT among patients admitted to the hospital for total knee arthroplasty. Instrumental screening should be encouraged, especially in subgroups at higher risk for preoperative DVT.

A genome-wide association study identifies new genes associated with developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is one of the most common congenital malformations and covers a spectrum of hip disorders from mild dysplasia to irreducible dislocation. The pathological mechanisms of DDH are poorly understood, which hampers the development of diagnostic tools and treatments. To gain insight into its disease mechanism, we explored the potential biological processes that underlie DDH by integrating pathway analysis tools and performing a genome-wide association study (GWAS). A total of 406 DDH-associated genes (P < 0.001) were identified by our GWAS using a Chinese Han cohort consisting of 386 DDH cases and 500 healthy controls (Set A). We verified the significant loci (P < 10-5 ) in another Chinese Han cohort consisting of 574 DDH patients and 569 healthy controls (Set B). An intronic Single Nucleotide Polymorphism (SNP) (rs61930502) showed significant association in Set A and Set B (P = 2.65 × 10-7 and 2.0 × 10-4 , respectively). The minor allele, rs61930502-A, which tended to prevent DDH showed a dominant effect. Heat shock 70 kDa protein 8 (HSPA8) showed the most direct interactions with other proteins which were coded by DDH-associated genes in the protein-protein interaction analysis. Interestingly, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested a relation between DDH and the genes involved in type II diabetes mellitus pathway (P = 0.0067). Our genetic and protein interaction evidence could open avenues for future studies of DDH.

Prevalence of patellofemoral pain and knee pain in the general population of Chinese young adults: a community-based questionnaire survey.

BACKGROUND: Previous studies that have described the prevalence of patellofemoral pain (PFP) have been limited to samples of military personnel or sporting populations, and convincing data in the general Chinese population are lacking. The present study defined the prevalence of PFP and knee pain in the general population of Chinese young adults and evaluated whether gender, age, or body mass index (BMI) were associated with PFP. METHODS: An anonymous online questionnaire survey was open to the general public in China. A self-report questionnaire was used to specifically identify PFP. The population aged 18-40 years was enrolled in the study and completed the questionnaire. The prevalence of PFP and knee pain in the overall sample and in subgroups stratified by sex, age, and BMI was estimated. Logistic regression analysis was conducted to determine if there was a significant association between PFP and sex, age, or BMI. RESULTS: A total of 1153 participants were enrolled in the study. The prevalence of PFP in the overall sample and among the male and female participants was 20.7, 20.3, and 21.2%, respectively. The prevalence of the knee pain in the overall sample and among the male and female participants was 35.6, 38.2, and 33.7%, respectively. The prevalence of PFP in the subgroups stratified by age and BMI did not differ significantly between the groups. Gender, age, and BMI did not have significant associations with the prevalence of PFP. CONCLUSION: PFP is common in the general Chinese population. Clinicians should direct more attention toward the early diagnosis of and interventions for PFP.

Quantitative efficacy of topical administration of tranexamic acid on postoperative bleeding in total knee arthroplasty.

AIMS: Topical tranexamic acid (TXA) is used in patients undergoing total knee arthroplasty to reduce perioperative blood loss. However, the optimal dosing regimen remains undetermined. The aim of the present study was to quantitatively evaluate the effect of topical TXA on the reduction of postoperative drainage, and identify the dosing regimen factors affecting the efficacy of topical TXA. METHODS: Model-based meta-analysis was used to evaluate the efficacy of topical TXA and the dosing regimen factors influencing clinical efficacy. Data from a systemic literature search was identified and used to build a time-effect model for placebo and TXA in treating perioperative blood loss. RESULTS: Fourteen studies containing 16 TXA-control groups of drainage volume data were included for MBMA modelling. The model described the postoperative drainage-time profiles adequately. According to the model estimation, TXA can finally reduce the postoperative drainage by about 41.7%, and 10.9 h was needed to reach 50% of the maximal drainage volume. Covariate analysis indicated that both dose and contact time alone did not correlate well with clinical efficacy. However, when considered together, they can dramatically improve fitting of the data. Simulation showed that increasing dose or contact time extensively would produce a plateau-like effect: 2-3 g TXA with contact time of 1-2 h would yield >60% reduction in the drainage volume. CONCLUSIONS: Dose and contact time together determined the efficacy of TXA. Extensively large dose or long contact time seems unnecessary. These findings may further guide the clinical practice on the topical TXA regimen optimization.

Evaluation of posterior lateral femoral condylar hypoplasia using axial MRI images in patients with complete discoid meniscus.

PURPOSE: Hypoplasia of the lateral femoral condyle has been reported in discoid lateral meniscus patients, but associated imaging findings in the axial plane have not been characterized. In this study, we aimed to identify differences in the lateral femoral condyle between patients with discoid lateral meniscus and those with normal menisci using axial MRI images. METHODS: Twenty-three patients (24 knees) with complete discoid lateral meniscus, 43 (45 knees) with incomplete discoid lateral meniscus, and 50 with normal menisci (50 knees) were enrolled and distributed into three groups. Two new angles, posterior lateral condylar angle (PLCA) and posterior medial condylar angle (PMCA), were measured on axial MRI images; the posterior condylar angle (PCA) was also measured. Differences between the three groups in the PLCA, PMCA, PCA, and PLCA/PMCA were analysed. The predictive value of PLCA and PLCA/PMCA for complete discoid lateral meniscus was assessed. RESULTS: In the complete discoid lateral meniscus group, PLCA and PLCA/PMCA were significantly smaller compared with the normal meniscus group and the incomplete discoid lateral meniscus group (P < 0.001). A significantly larger PCA was identified in the complete discoid lateral meniscus group compared with the incomplete discoid lateral meniscus group (P < 0.05) and normal meniscus group (P < 0.05). Both PLCA and PLCA/PMCA showed excellent predictive value for complete discoid lateral meniscus. CONCLUSIONS: Hypoplasia of the posterior lateral femoral condyle is typically seen in patients with complete discoid lateral meniscus. PLCA and PLCA/PMCA can be measured from axial MRI images and used as excellent predictive parameters for complete discoid lateral meniscus. LEVEL OF EVIDENCE: Diagnostic study, Level III.

A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis.

Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.

A panel of microRNAs as a new biomarkers for the detection of deep vein thrombosis.

Deep vein thrombosis is one of the common complications of orthopedic surgery, and pulmonary embolism which is one of its lethal complications can lead to mortality. Numerous efforts have been made to identify reliable and predictive biomarkers to detect the early signs of deep vein thrombosis. These studies have, however, not delivered any more informative candidates than the D-dimer that have been available. Cell-free microRNAs are present in a range of body fluids and have recently been shown to be useful biomarkers in many diseases. Therefore, the purpose of present study was to identify potential microRNA biomarkers of deep vein thrombosis that are present in serum. Serum samples were taken from 18 deep vein thrombosis patients and 20 age- and sex-matched controls. TaqMan microRNA array was used for an initial screening. Real-time PCR assay was implemented to confirm the concentrations of candidate microRNAs. We found that the serum levels of miR-582, miR-195 and miR-532 of deep vein thrombosis patients were higher than those of controls. miR-582 yielded an AUC (the areas under the ROC curve) of 0.959, and the other two microRNAs yielded an AUC of 1.000 in discriminating deep vein thrombosis from controls. These data hint that serum miR-582, miR-195 and miR-532 might have potential to be a novel noninvasive biomarkers for detection of DVT. And this is the first study suggesting that serum microNRAs might be used as biomarkers for deep vein thrombosis.

Diffusion tensor imaging of the anterior cruciate ligament graft after reconstruction: repeatability and diffusion tensor imaging metrics.

PURPOSE: The purpose of the study was to explore the feasibility and repeatability of diffusion tensor imaging and diffusion tractography on the anterior cruciate ligament graft after reconstruction and determine the fractional anisotropy and mean apparent diffusion coefficient values. MATERIALS AND METHODS: Twenty-two patients who underwent anterior cruciate ligament reconstruction operation were scanned at 3-T clinical magnetic resonance scanner. The fiber tracking and other postprocessing steps were carried out twice by a radiologist on the workstation and repeated by another radiologist. Diffusion tensor metrics of different parts of the grafts were determined with region of interest- and fiber tractography-based measurements, and the intraobserver and interobserver measurement variances were calculated. RESULTS: Tractography illustrated nicely the 3-dimensional courses of the graft in all 22 cases. The mean fractional anisotropy value of the intratunnel part was significantly higher than that of the intra-articular part, whereas the mean apparent diffusion coefficient value of the intratunnel part was lower when compared with that of the intra-articular part. According to the 2-sided paired samples Student t test, the intraobserver and interobserver measurements correlated well. CONCLUSIONS: Diffusion tensor imaging and diffusion tractography can be used to visualize the anterior cruciate ligament grafts and can provide additional information over standard morphologic magnetic resonance imaging.

Diffusion tensor imaging for anatomical and quantitative evaluation of the anterior cruciate ligament and ACL grafts: a preliminary study.

PURPOSE: The aim of this study was to evaluate whether anterior cruciate ligament (ACL) and ACL graft could be imaged using diffusion tensor imaging (DTI) and to provide the DTI metrics for ACL and grafts. MATERIALS AND METHODS: Magnetic resonance imaging and DTI were performed in 40 healthy volunteers and 15 patients with ACL reconstruction. Fiber tracking and other postprocessing steps were performed on the workstation. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of ACL and grafts were determined. RESULTS: The courses of ACL and grafts were analyzed quantitatively using FA and ADC, and tractography illustrated nicely the 3-dimensional courses of the fiber bundles and corresponded well to the known anatomy. There was no significant difference in the mean FA and ADC values of the sexes. CONCLUSIONS: Diffusion tensor imaging can be used to image and visualize the structure of ACL and ACL grafts.

Incidence of symptomatic and asymptomatic venous thromboembolism after elective knee arthroscopic surgery: a retrospective study with routinely applied venography.

PURPOSE: The purpose of this study was to assess the incidence of total venous thromboembolism (VTE) after knee arthroscopy with routinely applied venography. METHODS: We reviewed 537 consecutive patients undergoing arthroscopic knee surgery from March 2012 to July 2013. The surgical procedure was categorized as simple anterior cruciate ligament reconstruction (ACLR), posterior cruciate ligament reconstruction (PCLR), or reconstruction of both cruciate ligaments. All patients having arthroscopy in our institution were routinely examined with venography on the third postoperative day. Clinical signs of DVT were checked and recorded before venography. RESULTS: Eighty (14.9%) of 537 patients were diagnosed with VTE by venography. Of the 80 detected cases of VTE, only 20 (3.7%) patients presented with clinical signs of DVT, indicating that there were 60 (11.2%) asymptomatic cases. No patient died or presented with a clinically suspected pulmonary embolism (PE). Sex, body mass index (BMI), operative time, and duration of tourniquet application were not significant risk factors for DVT. Patient age (P < .0001) is a strongly significant risk factor for deep venous thrombosis (DVT). Compared with patients who underwent simple arthroscopic procedures, complex procedures-the reconstruction of 1 (P < .005) or both knee cruciate ligaments (P < .0005)-led to a significantly higher postoperative incidence of DVT. CONCLUSIONS: The total incidence of VTE diagnosed with venography after arthroscopic knee surgery was 14.9%, of which only 3.7% of cases were symptomatic, indicating 11.2% cases of silent VTE. Advanced age and complex arthroscopic surgery are strongly associated with VTE. LEVEL OF EVIDENCE: Level IV, prognostic case series.

Deep venous thrombosis after knee arthroscopy: a systematic review and meta-analysis.

PURPOSE: To establish a contemporary literature-based estimate of the incidence of deep venous thrombosis (DVT) after knee arthroscopic surgery. METHODS: We performed a systematic review and meta-analysis of the English language literature to assess the efficacy of prophylaxis to prevent DVT after knee arthroscopic surgery. Only randomized controlled trials (RCTs) or prospective studies were considered. Studies were excluded if they were not original prospective studies concerning DVT detected by imaging after knee arthroscopic surgery. We calculated pooled proportions of postoperative DVT and proximal DVT. RESULTS: Nine prospective uncontrolled studies and 4 RCTs were retrieved. Within them, the populations given low-molecular-weight heparin (LMWH) to prevent DVT had a 0.1% to 11.9% incidence of DVT, with an overall 36 DVTs identified (4 proximal), averaging 1.8%. One hundred thirty-six DVTs (29 proximal) were indicated in the populations without prophylaxis, and the DVT incidence varied from 1.8% to 41.2%, averaging 6.8%. Of the RCTs, the pooled risk ratio for DVT to develop was 0.180 (range, 0.065 to 0.499) for those who had LMWH as prophylaxis. An absolute risk reduction of 1.2%--from 1.5% to 0.3%--for the development of proximal DVT was observed. CONCLUSIONS: Compared with patients who did not receive prophylaxis, the pooled risk ratio for the development of DVT was 0.18 for those who had LMWH prophylaxis. The incidence of proximal DVT is very low after arthroscopic surgery regardless of receiving prophylaxis (4 of 2,184) or not (29 of 1,814). The rate of proximal DVT in total DVT occurrence can be markedly reduced from 21.3% (29 of 136) to 11.1% (4 of 36). LEVEL OF EVIDENCE: Level IV. This study is a meta-analysis of RCTs and a systematic review of Level IV studies.

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.