Biodegradable oxygen-evolving metalloantibiotics for spatiotemporal sono-metalloimmunotherapy against orthopaedic biofilm infections.

Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.

Bispherical metal augment improved biomechanical stability in severe acetabular deficiency reconstruction: a comparative finite element analysis.

BACKGROUND: This study used finite element analysis (FEA) to compare the biomechanical stability of bispherical metal augment (BA) and wedge-shaped trabecular-metal augment (TA) in different acetabular defect reconstruction models, thereby explaining the application value of this novel bispherical augment in complex hip revision. METHODS: Three different acetabular defect pelvis models originating from three representative patients with different types of severe acetabular defects (Paprosky IIC, IIIA, and IIIB) were constructed and reconstruction with BA and TA technique was simulated. Based on the FEA models, the displacement of reconstruction implants, relative displacement of bone implants, and hemi-pelvic von Mises stress were investigated under static loads. RESULTS: BA acquired smaller reconstruction system displacement, less relative displacement of bone implants, and lower pelvic von Mises stress than TA in all Paprosky IIC, IIIA, and IIIB defect reconstructions. CONCLUSION: The FEA results show that BA could acquire favourable biomechanical stability in severe acetabular defect reconstruction. This technique is a reliable method in complex hip revision.

Honeycomb-inspired ZIF-sealed interface enhances osseointegration via anti-infection and osteoimmunomodulation.

Implant-associated infections (IAIs) pose a significant threat to orthopedic surgeries. Bacteria colonizing the surface of implants disrupt bone formation-related cells and interfere with the osteoimmune system, resulting in an impaired immune microenvironment and osteogenesis disorders. Inspired by nature, a zeolitic imidazolate framework (ZIF)-sealed smart drug delivery system on Ti substrates (ZSTG) was developed for the "natural-artificial dual-enzyme intervention (NADEI)" strategy to address these challenges. The subtle sealing design of ZIF-8 on the TiO2 nanotubes ensured glucose oxidase (GOx) activity and prevented its premature leakage. In the acidic infection microenvironment, the degradation of ZIF-8 triggered the rapid release of GOx, which converted glucose into H2O2 for disinfection. The Zn2+ released from degraded ZIF-8, as a DNase mimic, can hydrolyze extracellular DNA, which further enhances H2O2-induced disinfection and prevents biofilm formation. Importantly, Zn2+-mediated M2 macrophage polarization significantly improved the impaired osteoimmune microenvironment, accelerating bone repair. Transcriptomics revealed that ZSTG effectively suppressed the inflammatory cascade induced by lipopolysaccharide while promoting cell proliferation, homeostasis maintenance, and bone repair. In vitro and in vivo results confirmed the superior anti-infective, osteoimmunomodulatory, and osteointegrative capacities of the ZSTG-mediated NADEI strategy. Overall, this smart bionic platform has significant potential for future clinical applications to treat IAIs.

Micheliolide prevents estrogen deficiency-induced bone loss via inhibiting osteoclast bone resorption.

Osteoporosis is one of the major health problems characterized by decreased bone density and increased risk of fractures. Nowadays, the treating strategies against osteoporosis are efficient, but still have some drawbacks. Micheliolide, a guaianolide sesquiterpene lactone isolated from Michelia compressa and Michelia champac, has been reported to have anti-inflammatory effects. Here, our data suggest that Micheliolide could protect mice from ovariectomy induced bone loss. According to the Micro-CT scan and histomorphometry quantification data, Micheliolide treatment inhibits excessive osteoclast bone resorption without affecting bone formation in estrogen deficiency mice. Consistently, our data suggest that Micheliolide could inhibit osteoclastogenesis in vitro. Additionally, we confirmed that Micheliolide inhibits osteoclasts formation via inhibiting P38 MAPK signaling pathway, and P79350 (a P38 agonist) could rescue this effect. In summary, our data suggest that Micheliolide could ameliorate estrogen deficiency-induced bone loss via attenuating osteoclastogenesis. Hence, Micheliolide could be used as a novel anti-resorptive agent against osteoporosis.

CircFam190a: a critical positive regulator of osteoclast differentiation via enhancement of the AKT1/HSP90ß complex.

The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90ß, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.

Mechanism of YAP1 in the senescence and degeneration of endplate chondrocytes induced by intermittent cyclic mechanical tension.

BACKGROUND: This study aimed to investigate the potential mechanism of YAP1 in the senescence and degeneration of endplate chondrocytes induced by intermittent cyclic mechanical tension (ICMT). METHODS: According to the Pfirrmann grade evaluation classification, 30 human endplate cartilage tissues were divided into the lumbar vertebra fracture (LVF) group and lumbar disc herniation (LDH) group. Then, quantitative reverse transcription polymerase chain reaction, western blot, flow cytometry, hematoxylin-eosin staining, and senescence-associated ß-galactosidase staining were performed. The difference in extracellular matrix expression between LVF and LDH endplate cartilage was detected. Second, the effect of ICMT on endplate chondrocytes degeneration was observed. Finally, the key regulatory role of YAP1 in ICMT-induced endplate cartilage degeneration was further verified. RESULTS: In degraded human endplate cartilage and tension-induced degraded endplate chondrocytes, the expression of YAP1, COL-2A, and Sox9 was decreased. Conversely, the expression of p53 and p21 was increased. By regulating YAP1 in vivo and in vitro, we can achieve alleviation of ICMT-induced senescence of endplate chondrocytes and effective treatment of disc degeneration. CONCLUSIONS: ICMT could induce senescence and degeneration of endplate chondrocytes, and ICMT-induced senescence and degeneration of endplate chondrocytes could be alleviated by regulating YAP1 expression.

Primary cilia: The central role in the electromagnetic field induced bone healing.

Primary cilia have emerged as the cellular "antenna" that can receive and transduce extracellular chemical/physical signals, thus playing an important role in regulating cellular activities. Although the electromagnetic field (EMF) is an effective treatment for bone fractures since 1978, however, the detailed mechanisms leading to such positive effects are still unclear. Primary cilia may play a central role in receiving EMF signals, translating physical signals into biochemical information, and initiating various signalingsignaling pathways to transduce signals into the nucleus. In this review, we elucidated the process of bone healing, the structure, and function of primary cilia, as well as the application and mechanism of EMF in treating fracture healing. To comprehensively understand the process of bone healing, we used bioinformatics to analyze the molecular change and associated the results with other studies. Moreover, this review summarizedsummarized some limitations in EMFs-related research and provides an outlook for ongoing studies. In conclusion, this review illustrated the primary cilia and related molecular mechanisms in the EMF-induced bone healing process, and it may shed light on future research.

Excessive sulfur oxidation in endoplasmic reticulum drives an inflammatory reaction of chondrocytes in aging mice.

Osteoarthritis, as a common joint disease among middle-aged and elderly people, has many problems, such as diverse pathogenesis, poor prognosis and high recurrence rate, which seriously affects patients' physical and mental health and reduces their quality of life. At present, the pathogenesis of osteoarthritis is not completely clear, and the treatment plan is mainly to relieve symptoms and ensure basic quality of life. Therefore, it is particularly urgent to explore the pathogenesis of osteoarthritis. Protein, as organic macromolecule which plays a major role in life activities, plays an important role in the development of disease. Through protein omics, this study found that with the increase of age, excessive sulfur oxidation occurred in endoplasmic reticulum of chondrocytes, which then drove the occurrence of inflammatory reaction, and provided a direction for the follow-up molecular targeted.

Decellularized Nucleus Pulposus Matrix/Chitosan Hybrid Hydrogels for Nucleus Pulposus Tissue Engineering.

STUDY DESIGN: Basic research. OBJECTIVE: To prepared 3 DNPM/chitosan hybrid hydrogels and chose the best DNPM/chitosan hybrid hydrogel for NP tissue engineering. METHODS: Three DNPM/chitosan hybrid hydrogels were fabricated by changing the ratio of the decellularized NP matrix to chitosan and crosslinking with genipin. NP stem cells (NPSCs) were cultured on the hybrid hydrogels and their proliferation, morphology, and gene expression were evaluated. Finally, an in vivo experiment was performed to evaluate the immune response to the hydrogels. RESULTS: The adhered NPSCs proliferated well on the hybrid hydrogel. The gene expression of NP-related collagen type II, aggrecan, and Sox-9 from NPSCs cultured on DNPM/chitosan hybrid hydrogel-1 was greater than from cells cultured on DNPM/chitosan hybrid hydrogel-2 and DNPM/chitosan hybrid hydrogel-3. Few inflammatory cells were observed during the in vivo experiment with DNPM/chitosan hybrid hydrogel-1. CONCLUSIONS: DNPM/chitosan hybrid hydrogel-1 is a potential candidate scaffold for NP tissue engineering.

Acidity-Activatable Nanoparticles with Glucose Oxidase-Enhanced Photoacoustic Imaging and Photothermal Effect, and Macrophage-Related Immunomodulation for Synergistic Treatment of Biofilm Infection.

The pH-responsive theragnostics exhibit great potential for precision diagnosis and treatment of diseases. Herein, acidity-activatable nanoparticles of GB@P based on glucose oxidase (GO) and polyaniline are developed for treatment of biofilm infection. Catalyzed by GO, GB@P triggers the conversion of glucose into gluconic acid and hydrogen peroxide (H2 O2 ), enabling an acidic microenvironment-activated simultaneously enhanced photothermal (PT) effect/amplified photoacoustic imaging (PAI). The synergistic effects of the enhanced PT efficacy of GB@P and H2 O2 accelerate biofilm eradication because the penetration of H2 O2 into biofilm improves the bacterial sensitivity to heat, and the enhanced PT effect destroys the expressions of extracellular DNA and genomic DNA, resulting in biofilm destruction and bacterial death. Importantly, GB@P facilitates the polarization of proinflammatory M1 macrophages that initiates macrophage-related immunity, which enhances the phagocytosis of macrophages and secretion of proinflammatory cytokines, leading to a sustained bactericidal effect and biofilm eradication by the innate immunomodulatory effect. Accordingly, the nanoplatform of GB@P exhibits the synergistic effects on the biofilm eradication and bacterial residuals clearance through a combination of the enhanced PT effect with immunomodulation. This study provides a promising nanoplatform with enhanced PT efficacy and amplified PAI for diagnosis and treatment of biofilm infection.

Fabrication of Tissue-Engineered Cartilage Using Decellularized Scaffolds and Chondrocytes.

In this paper, we aim to explore the application value of tissue engineering for the construction of artificial cartilage in vitro. Chondrocytes from healthy porcine articular cartilage tissue were seeded on articular cartilage extracellular matrix (ACECM) scaffolds and cultivated. Type II collagen immunofluorescent staining was used to assess secretion from the extracellular matrix. Chondrocytes, which were mainly polygonal and cobblestone-shaped, were inoculated on ACECM-oriented scaffolding for 7 days, and the neo-tissue showed translucent shape and toughness. Using inverted and fluorescence microscopy, we found that chondrocytes on the scaffolds performed well in terms of adhesion and growth, and they secreted collagen type II. Moreover, the porcine ACECM scaffolds had good biocompatibility. The inflammatory cell detection, cellular immune response assay and humoral immune response assay showed porcine ACECM scaffolds were used for xenotransplantation without significant immune inflammatory response. All these findings reveal that ACECM-oriented scaffold is an ideal natural biomaterial for cartilage tissue engineering.

Conversion of a Fused or Ankylosed Hip to Total Hip Arthroplasty: Is the Direct Anterior Approach in the Lateral Decubitus Position an Ideal Solution?

BACKGROUND: Total hip arthroplasty (THA) using the direct anterior approach (DAA) is becoming increasingly popular due to its potential benefits over the posterolateral approach (PLA). However, few studies have compared the efficacies of these two surgical approaches in hip fusion treatment. This study compared early clinical direct anterior and posterolateral THA outcomes in hip fusion treatment. METHODS: Here, 127 hips (65 DAA, 62 PLA) were retrospectively evaluated. Early postoperative functional outcomes of DAA and PLA groups were assessed using Harris score and Oxford Hip Score (OHS) and standard anteroposterior hip radiographs. Surgical characteristics, perioperative results, and complications within 6 months postoperatively were recorded. RESULTS: Though baseline values were similar, Harris and OHS scores were better in the DAA group than in the PLA group at 1 and 3 months postoperatively. The average cup anteversion angle was significantly greater in the DAA group than in the PLA group (12.7° vs. 11.1°). More hips undergoing DAA were successfully orientated in both inclination and anteversion angles (46 vs. 32). Early postoperative hip function predictors were preoperative fused hip position, surgical approach, and range of motion. DAA was associated with reduced postoperative blood loss and shorter hospital stays. Furthermore, 14 vs. 8 complications occurred in the DAA vs. PLA group. Lateral femoral cutaneous nerve injuries were observed in eight hips (12.3%) of the DAA group. CONCLUSION: For fused or ankylosed hips, THA using DAA in the lateral decubitus position may result in excellent prosthesis positioning and faster postoperative recovery throughout early follow-up vs. PLA.

Modular revision strategy with bispherical augments in severe acetabular deficiency reconstruction.

PURPOSE: Reconstruction of severe acetabular deficiency is extremely challenging in total hip arthroplasty (THA) revisions. Novel bispherical augments were designed to fill acetabular bone loss and facilitate restoration of hip center of rotation (HCOR). Current study aims to compare the outcomes of bispherical augments and tantalum augments. METHODS: Between July 2017 and December 2018, bispherical augments (BA group) were implanted in 25 patients (25 hips) and 22 patients (22 hips) underwent porous tantalum augments (TA group) reconstruction in revision THA. Clinical and radiographic results were evaluated for 25 hips in BA group and 20 hips in TA group at the final follow-up. The mean duration of follow-up was 2.9 years (range, 2.2 ~ 3.7) in BA group and 2.9 years (range, 2.3 ~ 3.8) in TA group. RESULTS: Harris hip scores, HCOR, and leg length discrepancy (LLD) correction did not differ between the treatment groups. The bispherical augments were located more closer to the medial-superior part (zone II) of acetabular shell while the majority of tantalum augments were located at the lateral-superior part (zone I) (P = 0.010). More screws were used in the BA group for augment fixation (mean 2.1 vs. 1.3) (P = 0.000). There was no evidence of loosening or migration in all hips. Only one dislocation occurred in BA group and treated with closed reduction, no recurrence of instability up to the final follow-up. CONCLUSION: The clinical and radiological outcomes of bispherical augments were comparable with tantalum augments; this technique was a reliable alternative method in severe acetabular deficiency reconstruction.

Long non-coding RNA KRT8P41/miR-193a-3p/FUBP1 axis modulates the proliferation and invasion of chordoma cells.

Chordomas are low-grade malignancies accounting for 1-4% of primary bone malignancies. Moreover, local recurrences increase the rate of metastasis. Our previous study identified the far upstream element (FUSE)-binding protein 1 (FUBP1) as a biomarker and potential therapeutic target for chordoma. In this study, lncRNA KRT8P41 was identified as a lncRNA positively correlated with FUBP1. In chordoma patients, higher lncRNA KRT8P41 expression was correlated with a poorer prognosis. LncRNA KRT8P41 silencing significantly inhibited chordoma cell proliferation and invasion. miR-193a was negatively correlated with lncRNA KRT8P41 and FUBP1; lncRNA KRT8P41 inhibited miR-193a expression, and miR-193a inhibited FUBP1 expression. Furthermore, miR-193a directly bound to lncRNA KRT8P41 and FUBP1 and lncRNA KRT8P41 competed with FUBP1 for miR-193a binding and relieved miR-193a-mediated FUBP1 inhibition. LncRNA KRT8P41 silencing inhibited, whereas miR-193a inhibition promoted chordoma cell proliferation and invasion; the inhibition of miR-193a attenuated the roles of lncRNA KRT8P41. Within chordoma tissues, the expression of miR-193a was decreased, and the expression of FUBP1 increased compared to normal control tissues. LncRNA KRT8P41 exhibited a positive correlation with FUBP1 and a negative correlation with miR-193a in vivo. Therefore, it was concluded that lncRNA KRT8P41, miR-193a-3p, and FUBP1 form a lncRNA-miRNA-mRNA axis, modulating the proliferation and invasion of chordoma cells.

Microbiology of Periprosthetic Hip and Knee Infections in Surgically Revised Cases from 34 Centers in Mainland China.

BACKGROUND AND AIM: Periprosthetic joint infection (PJI) is one of the most devastating complications after total joint arthroplasty (TJA). However, the antibiotic resistance of infecting pathogens can significantly vary in different parts of the country. In the current study, we analyzed the demographic and microbiological profiles of knee and hip PJI over three years and compared the microbiological differences between them. METHODS: A multicenter retrospective study of PJI patients in 34 referral medical centers in mainland China from January 2015 to November 2017 was performed. RESULTS: A total of 925 PJI patients were recruited, 452 were identified as knee PJIs, and 473 were hip PJIs. The most common causative pathogens were Staphylococcus aureus (26.5%) and coagulase-negative staphylococci (14.3%). Methicillin-resistant staphylococci were involved in 25.6% (237/925) of all PJI cases. Mycobacterium and fungus only accounted for 6.5% (61) of all cases. Enteric gram-negative bacilli, anaerobes, and polymicrobial pathogens were more common in hip joint prostheses than in knee PJI (P = 0.014; P = 0.006; P = 0.002, respectively). CONCLUSION: While the majority of causative pathogens in PJI cases are staphylococcal species, the prevalence of atypical organisms and resistant pathogens should also be given attention and warrant the need for empiric antibiotic treatment.

Repair of articular cartilage defect using adipose-derived stem cell-loaded scaffold derived from native cartilage extracellular matrix.

The purpose of this study was to investigate the feasibility of adipose-derived stem cells (ADSCs) as the seed cells of cartilage tissue engineering. ADSCs were isolated from adipose tissue that was harvested under sterile conditions from the inguen fold of porcines and cultured in vitro. Acellular cartilage extracellular matrix (ACECM) scaffolds of pigs were then constructed. Moreover, inflammatory cells, as well as cellular and humoral immune responses, were detected using hematoxylin and eosin staining staining, immunohistochemical staining, and western blot analysis. The results showed that the cartilage complex constructed by ADSCs and ACECM through tissue engineering successfully repaired the cartilage defect of the pig knee joint. The in vivo repair experiment showed no significant difference between chondrocytes, ADSCs, and induced ADSCs, indicating that ADSCs do not require in vitro induction and have the potential for chondrogenic differentiation in the environment around the knee joint. In addition, pig-derived acellular cartilage scaffolds possess no obvious immune inflammatory response when used in xenotransplantation. ADSCs may serve as viable seed cells for cartilage tissue engineering.

Modified minimally invasive-transforaminal lumbar interbody fusion under microscopic view to achieve bilateral decompression and fusion through a single approach to treat developmental lumbar spinal stenosis.

PURPOSE: To describe a modified minimally invasive spine (MIS) procedure to treat lumbar developmental spinal stenosis (DSS) to achieve complete decompression and fusion. The method preserves the muscles, ligaments, and most of the bony structures. DSS is not considered a good indication for MIS procedures and few reports discuss alternative treatments. Because MIS has the advantages of low blood loss, rapid recovery, and short hospital stay, it would be ideal for DSS. METHODS: After confirming the screw positions, we placed a tube retractor in the facet joint on the decompressed side. The inferior facet joint and part of the superior joint of the lower segment were removed, the spinal canal was carefully exposed under a microscopic view, and fusion was performed through Kambin's triangle. Next, the operation table was rotated to the contralateral side and angled to approximately 15-20 degrees. We then tilted the tube retractor in the facet joint toward the operation side by 15-20 degrees, which provided access to the contralateral canal for decompression. The ligament flavum was carefully removed and the dural sac was gently retracted to expose the lateral recess on the other side. We then examined the nerve root on the contralateral side to ensure there was no compression. RESULTS: Eight patients with lumbar DSS were treated using this method. Patients' neurological symptoms improved greatly without complications and patients were able to walk the day after surgery. The inner plate of the contralateral lamina and muscle as well as most of the ligaments that contribute to stability were preserved. CONCLUSION: This modified MIS decompression procedure successfully treated DSS by providing spinal canal decompression and preserving most of the stabilizing structures.

A novel redox-responsive ursolic acid polymeric prodrug delivery system for osteosarcoma therapy.

Ursolic acid (UA), found widely in nature, exerts effective anti-tumoral activity against various malignant tumors. However, the low water solubility and poor bioavailability of UA have greatly hindered its translation to the clinic. To overcome these drawbacks, a simple redox-sensitive UA polymeric prodrug was synthesized by conjugating UA to polyethylene glycol using a disulfide bond. This formulation can self-assemble into micelles (U-SS-M) in aqueous solutions to produce small size micelles (∼62.5 nm in diameter) with high drug loading efficiency (∼16.7%) that exhibit pH and reduction dual-sensitivity. The cell and animal studies performed using the osteosarcoma MG-63 cell line and MG-63 cancer xenograft mice as the model systems consistently confirmed that the U-SS-M formulation could significantly prolong the circulation in blood and favor accumulation in tumor tissue. Targeted accumulation allows the U-SS-M to be effectively internalized by cancer cells, where the rapid release of UA is favored by a glutathione-rich and acidic intracellular environment, and ultimately achieves potent antitumor efficacy.

Promoting osteoblasts responses in vitro and improving osteointegration in vivo through bioactive coating of nanosilicon nitride on polyetheretherketone.

OBJECTIVE: To enhance the bioactivity of polyetheretherketone (PEEK) while maintain its mechanical strengths. METHODS: Suspension coating and melt bonding. RESULTS: Silicon nitride (Si3N4, SN) coating lead to higher surface roughness, hydrophilicity and protein absorption; SN coating could slowly release Si ion into simulated body fluid (SBF), which caused weak alkaline of micro-environment owing to the slight dissolution of SN; SN coating resulted in the improvements of adhesion, proliferation, differentiation and gene expressions of MC3T3-E1 cells in vitro; SN coating of PEEK with bioactive SN coating (CSNPK) obviously promoted bone regeneration and osseointegration in vivo. CONCLUSIONS: CSNPK with SN coating as bone implant might be a promising candidate for orthopedic implants. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The silicon nitride-coated polyetheretherketone (CSNPK) prepared in this article could induce MC3T3-E1 cells adhesion, proliferation and differentiation in vitro; it could also induce bone regeneration in bone defect in vivo, which indicate its good cytocompatibility and biocompatibility. If the raw materials are medical grade, and preparation process as well as production process of this article are further improved, it will have great translational potential.

Effects of infrapatellar fat pad preservation versus resection on clinical outcomes after total knee arthroplasty in patients with knee osteoarthritis (IPAKA): study protocol for a multicentre, randomised, controlled clinical trial.

INTRODUCTION: The infrapatellar fat pad (IPFP) is commonly resected during total knee arthroplasty (TKA) for better exposure. However, our previous studies have suggested that IPFP size was protective against, while IPFP signal intensity alteration was detrimental on knee symptoms and structural abnormalities. We hypothesise that an IPFP with normal qualities, rather than abnormal qualities, should be preserved during TKA. The aim of this study is to compare, over a 1-year period, the postoperative clinical outcomes of IPFP preservation versus resection after TKA in patients with normal or abnormal IPFP signal intensity alteration on MRI. METHODS AND ANALYSIS: Three hundred and sixty people with end-stage knee osteoarthritis and on the waiting list for TKA will be recruited and identified as normal IPFP quality (signal intensity alteration score ≤1) or abnormal IPFP quality (signal intensity alteration score ≥2). Patients in each hospital will then be randomly allocated to IPFP resection group or preservation group. The primary outcomes are the summed score of self-reported Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS subscales assessing function in daily activities and function in sport and recreation. Secondary endpoints will be included: KOOS subscales (pain, symptoms and quality of life), Knee Society Score, 100 mm Visual Analogue Scale (VAS) Pain, timed up-and-go test, patellar tendon shortening, 100 mm VAS self-reported efficacy of reduced pain and increased quality of life, and Insall-Salvati index assessed on plain X-ray. Adverse events will be recorded. Intention-to-treat analyses will be used. ETHICS AND DISSEMINATION: The study is approved by the local Medical Ethics Committee (Zhujiang Hospital Ethics Committee, reference number 2017-GJGBK-001) and will be conducted according to the principle of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard, and in compliance with the Medical Research Involving Human Subjects Act . Data will be published in peer-reviewed journals and presented at conferences, both nationally and internationally. TRIAL REGISTRATION NUMBER: This trial was registered at Clinicaltrial.gov website on 19 October 2018 with identify number NCT03763448.