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The Bone & Joint Journal
Vol. 101-B, Issue 7_Supple_C | Pages 108 - 114
1 Jul 2019
Ji G Xu R Niu Y Li N Ivashkiv L Bostrom MPG Greenblatt MB Yang X

Aims. It is increasingly appreciated that coordinated regulation of angiogenesis and osteogenesis is needed for bone formation. How this regulation is achieved during peri-implant bone healing, such as osseointegration, is largely unclear. This study examined the relationship between angiogenesis and osteogenesis in a unique model of osseointegration of a mouse tibial implant by pharmacologically blocking the vascular endothelial growth factor (VEGF) pathway. Materials and Methods. An implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (n = 38). Mice received anti-VEGF receptor-1 (VEGFR-1) antibody (25 mg/kg) and VEGF receptor-2 (VEGFR-2) antibody (25 mg/kg; n = 19) or an isotype control antibody (n = 19). Flow cytometric (n = 4/group) and immunofluorescent (n = 3/group) analyses were performed at two weeks post-implantation to detect the distribution and density of CD31. hi. EMCN. hi. endothelium. RNA sequencing analysis was performed using sorted CD31. hi. EMCN. hi. endothelial cells (n = 2/group). Osteoblast lineage cells expressing osterix (OSX) and osteopontin (OPN) were also detected with immunofluorescence. Mechanical pull-out testing (n = 12/group) was used at four weeks post-implantation to determine the strength of the bone-implant interface. After pull-out testing, the tissue attached to the implant surface was harvested. Whole mount immunofluorescent staining of OSX and OPN was performed to determine the amount of osteoblast lineage cells. Results. Flow cytometry revealed that anti-VEGFR treatment decreased CD31. hi. EMCN. hi. vascular endothelium in the peri-implant bone versus controls at two weeks post-implantation. This was confirmed by the decrease of CD31 and endomucin (EMCN) double-positive cells detected with immunofluorescence. In addition, treated mice had more OPN-positive cells in both peri-implant bone and tissue on the implant surface at two weeks and four weeks, respectively. More OSX-positive cells were present in peri-implant bone at two weeks. More importantly, anti-VEGFR treatment decreased the maximum load of pull-out testing compared with the control. Conclusion. VEGF pathway controls the coupling of angiogenesis and osteogenesis in orthopaedic implant osseointegration by affecting the formation of CD31. hi. EMCN. hi. endothelium. Cite this article: Bone Joint J 2019;101-B(7 Supple C):108–114


Orthopaedic Proceedings
Vol. 102-B, Issue SUPP_9 | Pages 70 - 70
1 Oct 2020
Staats K Sosa BR Kuyl E Niu Y Suhardi VJ Turajane K Windhager R Greenblatt MB Ivashkiv L Bostrom MP Yang X
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Introduction. Initial post-operative implant instability leads to impaired osseointegration, one of the most common reasons for aseptic loosening and revision surgery. In this study, we developed a novel murine model of implant instability and demonstrated the anabolic effect of immediate and delayed intermittent Parathyroid Hormone (iPTH) treatment in the setting of instability-induced osseointegration failure. Methods. 3D-printed titanium implants were inserted in an oversized drill-hole in the tibia of C57Bl/6 mice (n=54). After implantation, the mice were randomly divided in 3 treatment groups (control: PBS-vehicle; iPTH; delayed iPTH). Radiographic analysis was performed to confirm signs of implant loosening. Peri-implant tissue formation was assessed through histology. Osseointegration was assessed through µCT and biomechanical pullout testing. Results. Immediate iPTH treatment reduced radiolucencies and induced a distinct pedestal sign distal to the implant stem (white arrow Fig 1A). The PBS treated mice had fibrous tissue implant encapsulation, whereas new mineralized tissue and no fibrous tissue was observed with immediate iPTH treatment (Fig 1E). Delayed iPTH treatment was also able to exhibit significant peri-implant bone mineralization, osteoblasts, angiogenesis, and a reduction of fibrous tissue (Fig 2A-B). iPTH treatment increased the force required to pull out the implant significantly from 8.41 ± 8.15N in the PBS group to 21.49 ± 10.45N and 23.68 ± 8.99N, in the immediate and delayed iPTH treatment groups, respectively (Fig 2D). PBS vehicle resulted in a bone volume/trabecular volume (BV/TV) of 0.23 ± 0.03, while immediate and delayed iPTH treatment increased BV/TV significantly to 0.46 ± 0.07 and 0.34 ± 0.10, respectively (Fig 2E). Conclusion. Immediate iPTH treatment prevents peri-implant fibrous tissue formation and enhances peri-implant bone formation in our murine model of mechanical instability. Delayed iPTH treatment was able to resolve the peri-implant fibrous tissue and stimulate bone formation. This study potentially addresses a leading cause of aseptic loosening by demonstrating that initial implant instability can be rescued by iPTH even with delayed start of treatment. For any figures or tables, please contact authors directly


Bone & Joint Research
Vol. 13, Issue 2 | Pages 66 - 82
5 Feb 2024
Zhao D Zeng L Liang G Luo M Pan J Dou Y Lin F Huang H Yang W Liu J

Aims

This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA.

Methods

Six sets of gene expression profiles were obtained from the Gene Expression Omnibus database. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), and multiple machine-learning algorithms were used to screen crucial genes in osteoarthritic cartilage, and genome enrichment and functional annotation analyses were used to decipher the related categories of gene function. Single-sample gene set enrichment analysis was performed to analyze immune cell infiltration. Correlation analysis was used to explore the relationship among the hub genes and immune cells, as well as markers related to articular cartilage degradation and bone mineralization.


The Bone & Joint Journal
Vol. 104-B, Issue 4 | Pages 444 - 451
1 Apr 2022
Laende EK Mills Flemming J Astephen Wilson JL Cantoni E Dunbar MJ

Aims

Thresholds of acceptable early migration of the components in total knee arthroplasty (TKA) have traditionally ignored the effects of patient and implant factors that may influence migration. The aim of this study was to determine which of these factors are associated with overall longitudinal migration of well-fixed tibial components following TKA.

Methods

Radiostereometric analysis (RSA) data over a two-year period were available for 419 successful primary TKAs (267 cemented and 152 uncemented in 257 female and 162 male patients). Longitudinal analysis of data using marginal models was performed to examine the associations of patient factors (age, sex, BMI, smoking status) and implant factors (cemented or uncemented, the size of the implant) with maximum total point motion (MTPM) migration. Analyses were also performed on subgroups based on sex and fixation.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_12 | Pages 44 - 44
1 Oct 2018
Ji G Xu R Niu Y Turajane K Li N Greenblatt MB Yang X Bostrom M
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Introduction. Poor osseointegration of cementless implants is the leading clinical cause of implant loosening, subsidence, and replacement failure, which require costly and technically challenging revision surgery. The mechanism of osseointegration requires further elucidation. We have recently developed a novel titanium implant for the mouse tibia that maintains in vivo knee joint function and allows us to study osseointegration in an intra-articular, load-bearing environment. Vascular endothelial growth factor (VEGF) is one of the most important growth factors for regulation of vascular development and angiogenesis. It also plays critical roles in skeletal development and bone repair and regeneration. A specialized subset of vascular endothelium, CD31. hi. EMCN. hi. cells displaying high cell surface expression of CD31 and Endomucin, has been reported to promote osteoblast maturation and may be responsible for bone formation during development and fracture healing. Because of their potential role in osseointegration, the aim of this study was to use our mouse implant model to investigate the role of VEGF and CD31. hi. EMCN. hi. endothelium in osseointegration. Methods. Under an IACUC-approved protocol, the implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (N = 38). The mice were then randomized into 2 groups: Control group (N=19) and Anti-VEGFR group (N=19). A cocktail of VEGFR-1 antibody (25mg/kg) and VEGFR-2 antibody (25mg/kg) was given to the mice in the Anti-VEGFR group by intraperitoneal injection every third day starting immediately after surgery until euthanasia. An equivalent amount of an isotype control antibody was given to the control group. Flow cytometric (N = 4/group) and immunofluorescencent (N = 3/group) analyses were performed at 2 weeks post-implantation to detect the distribution and density of CD31. hi. EMCN. hi. endothelium in the peri-implant bone. Pull-out testing was used at 4 weeks post-implantation to determine the strength of the bone-implant interface. Results. Flow cytometry revealed that Anti-VEGFR treatment decreased CD31. hi. EMCN. hi. vascular endothelium percentage in the peri-implant bone vs. control (p = 0.039) at 2 weeks post-implantation (Fig. 1). This was confirmed by the decrease of CD31 and EMCN double positive cells detected with immunofluorescence at the same time point (Fig. 2). More importantly, anti-VEGFR treatment decreased the maximum load of pullout testing compared with control (p = 0.042) (Fig. 3). Conclusion. VEGF is a key mediator of osseointegration and the development of CD31. hi. EMCN. hi. endothelium. This may provide a new drug target for the enhancement of osseointegration. We have also developed a system to run flow cytometric analysis and perform fluorescent staining on the limited tissue around the implant in this mouse model. This will be a powerful platform for future mechanistic studies on osseointegration. For any figures or tables, please contact authors directly


Bone & Joint Research
Vol. 11, Issue 2 | Pages 91 - 101
1 Feb 2022
Munford MJ Stoddart JC Liddle AD Cobb JP Jeffers JRT

Aims

Unicompartmental and total knee arthroplasty (UKA and TKA) are successful treatments for osteoarthritis, but the solid metal implants disrupt the natural distribution of stress and strain which can lead to bone loss over time. This generates problems if the implant needs to be revised. This study investigates whether titanium lattice UKA and TKA implants can maintain natural load transfer in the proximal tibia.

Methods

In a cadaveric model, UKA and TKA procedures were performed on eight fresh-frozen knee specimens, using conventional (solid) and titanium lattice tibial implants. Stress at the bone-implant interfaces were measured and compared to the native knee.


Bone & Joint Open
Vol. 2, Issue 6 | Pages 414 - 421
1 Jun 2021
Kim SK Nguyen C Avins AL Abrams GD

Aims

The aim of this study was to screen the entire genome for genetic markers associated with risk for anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injury.

Methods

Genome-wide association (GWA) analyses were performed using data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. ACL and PCL injury cases were identified based on electronic health records from KPRB and the UK Biobank. GWA analyses from both cohorts were tested for ACL and PCL injury using a logistic regression model adjusting for sex, height, weight, age at enrolment, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNPs). The data from the two GWA studies were combined in a meta-analysis. Candidate genes previously reported to show an association with ACL injury in athletes were also tested for association from the meta-analysis data from the KPRB and the UK Biobank GWA studies.


The Bone & Joint Journal
Vol. 103-B, Issue 6 Supple A | Pages 185 - 190
1 Jun 2021
Kildow BJ Patel SP Otero JE Fehring KA Curtin BM Springer BD Fehring TK

Aims

Debridement, antibiotics, and implant retention (DAIR) remains one option for the treatment of acute periprosthetic joint infection (PJI) despite imperfect success rates. Intraosseous (IO) administration of vancomycin results in significantly increased local bone and tissue concentrations compared to systemic antibiotics alone. The purpose of this study was to evaluate if the addition of a single dose of IO regional antibiotics to our protocol at the time of DAIR would improve outcomes.

Methods

A retrospective case series of 35 PJI TKA patients, with a median age of 67 years (interquartile range (IQR) 61 to 75), who underwent DAIR combined with IO vancomycin (500 mg), was performed with minimum 12 months' follow-up. A total of 26 patients with primary implants were treated for acute perioperative or acute haematogenous infections. Additionally, nine patients were treated for chronic infections with components that were considered unresectable. Primary outcome was defined by no reoperations for infection, nor clinical signs or symptoms of PJI.


Bone & Joint Research
Vol. 10, Issue 4 | Pages 269 - 276
1 Apr 2021
Matsubara N Nakasa T Ishikawa M Tamura T Adachi N

Aims

Meniscal injuries are common and often induce knee pain requiring surgical intervention. To develop effective strategies for meniscus regeneration, we hypothesized that a minced meniscus embedded in an atelocollagen gel, a firm gel-like material, may enhance meniscus regeneration through cell migration and proliferation in the gel. Hence, the objective of this study was to investigate cell migration and proliferation in atelocollagen gels seeded with autologous meniscus fragments in vitro and examine the therapeutic potential of this combination in an in vivo rabbit model of massive meniscus defect.

Methods

A total of 34 Japanese white rabbits (divided into defect and atelocollagen groups) were used to produce the massive meniscus defect model through a medial patellar approach. Cell migration and proliferation were evaluated using immunohistochemistry. Furthermore, histological evaluation of the sections was performed, and a modified Pauli’s scoring system was used for the quantitative evaluation of the regenerated meniscus.


The Bone & Joint Journal
Vol. 98-B, Issue 7 | Pages 867 - 873
1 Jul 2016
Dalury DF

As the number of younger and more active patients treated with total knee arthroplasty (TKA) continues to increase, consideration of better fixation as a means of improving implant longevity is required. Cemented TKA remains the reference standard with the largest body of evidence and the longest follow-up to support its use. However, cementless TKA, may offer the opportunity of a more bone-sparing procedure with long lasting biological fixation to the bone. We undertook a review of the literature examining advances of cementless TKA and the reported results.

Cite this article: Bone Joint J 2016;98-B:867–73.


The Bone & Joint Journal
Vol. 96-B, Issue 12 | Pages 1637 - 1643
1 Dec 2014
Yang Z Liu H Xie X Tan Z Qin T Kang P

Total knee replacement (TKR) is an effective method of treating end-stage arthritis of the knee. It is not, however, a procedure without risk due to a number of factors, one of which is diabetes mellitus. The purpose of this study was to estimate the general prevalence of diabetes in patients about to undergo primary TKR and to determine whether diabetes mellitus adversely affects the outcome. We conducted a systematic review and meta-analysis according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The Odds Ratio (OR) and mean difference (MD) were used to represent the estimate of risk of a specific outcome. Our results showed the prevalence of diabetes mellitus among patients undergoing TKR was 12.2%. Patients with diabetes mellitus had an increased risk of deep infection (OR = 1.61, 95% confidence interval (CI), 1.38 to 1.88), deep vein thrombosis (in Asia, OR = 2.57, 95% CI, 1.58 to 4.20), periprosthetic fracture (OR = 1.89, 95% CI, 1.04 to 3.45), aseptic loosening (OR = 9.36, 95% CI, 4.63 to 18.90), and a poorer Knee Society function subscore (MD = -5.86, 95% CI, -10.27 to -1.46). Surgeons should advise patients specifically about these increased risks when obtaining informed consent and be meticulous about their peri-operative care.

Cite this article: Bone Joint J 2014;96-B:1637–43.


The Journal of Bone & Joint Surgery British Volume
Vol. 87-B, Issue 8 | Pages 1073 - 1076
1 Aug 2005
Cross MJ Parish EN

We prospectively reviewed 1000 consecutive patients who underwent a cementless, hydroxyapatite-coated, stemless, total knee replacement over a period of nine years. Regular post-operative clinical follow-up was performed using the Knee Society score. The mean pre-operative score was 96, improving to 182 and 180 at five and ten years, respectively. To date, there have been seven (0.5%) cases which required revision, primarily for septic loosening (four cases), with low rates of other post-operative complications. The cumulative survival at ten years with revision as the end-point, was 99.14% (95% confidence interval 92.5 to 99.8). These results support the use of hydroxyapatite in a cementless total knee replacement since it can give reliable fixation with an excellent clinical and functional outcome.