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The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 1 | Pages 62 - 67
1 Jan 2012
Aurich M Hofmann GO Mückley T Mollenhauer J Rolauffs B

We attempted to characterise the biological quality and regenerative potential of chondrocytes in osteochondritis dissecans (OCD). Dissected fragments from ten patients with OCD of the knee (mean age 27.8 years (16 to 49)) were harvested at arthroscopy. A sample of cartilage from the intercondylar notch was taken from the same joint and from the notch of ten patients with a traumatic cartilage defect (mean age 31.6 years (19 to 52)). Chondrocytes were extracted and subsequently cultured. Collagen types 1, 2, and 10 mRNA were quantified by polymerase chain reaction. Compared with the notch chondrocytes, cells from the dissecate expressed similar levels of collagen types 1 and 2 mRNA. The level of collagen type 10 message was 50 times lower after cell culture, indicating a loss of hypertrophic cells or genes. The high viability, retained capacity to differentiate and metabolic activity of the extracted cells suggests preservation of the intrinsic repair capability of these dissecates. Molecular analysis indicated a phenotypic modulation of the expanded dissecate chondrocytes towards a normal phenotype. Our findings suggest that cartilage taken from the dissecate can be reasonably used as a cell source for chondrocyte implantation procedures.


The Journal of Bone & Joint Surgery British Volume
Vol. 88-B, Issue 12 | Pages 1591 - 1595
1 Dec 2006
Price AJ Oppold PT Murray DW Zavatsky AB

The Oxford medial unicompartmental knee replacement was designed to reproduce normal mobility and forces in the knee, but its detailed effect on the patellofemoral joint has not been studied previously. We have examined the effect on patellofemoral mechanics of the knee by simultaneously measuring patellofemoral kinematics and forces in 11 cadaver knee specimens in a supine leg-extension rig. Comparison was made between the intact normal knee and sequential unicompartmental and total knee replacement. Following medial mobile-bearing unicompartmental replacement in 11 knees, patellofemoral kinematics and forces did not change significantly from those in the intact knee across any measured parameter. In contrast, following posterior cruciate ligament retaining total knee replacement in eight knees, there were significant changes in patellofemoral movement and forces.

The Oxford device appears to produce near-normal patellofemoral mechanics, which may partly explain the low incidence of complications with the extensor mechanism associated with clinical use.


The Bone & Joint Journal
Vol. 102-B, Issue 11 | Pages 1527 - 1534
3 Nov 2020
Orita K Minoda Y Sugama R Ohta Y Ueyama H Takemura S Nakamura H

Aims. Vitamin E-infused highly cross-linked polyethylene (E1) has recently been introduced in total knee arthroplasty (TKA). An in vitro wear simulator study showed that E1 reduced polyethylene wear. However there is no published information regarding in vivo wear. Previous reports suggest that newly introduced materials which reduce in vitro polyethylene wear do not necessarily reduce in vivo polyethylene wear. To assist in the evaluation of the newly introduced material before widespread use, we established an in vivo polyethylene wear particle analysis for TKA. The aim of this study was to compare in vivo polyethylene wear particle generation between E1 and conventional polyethylene (ArCom) in TKA. Methods. A total of 34 knees undergoing TKA (17 each with ArCom or E1) were investigated. Except for the polyethylene insert material, the prostheses used for both groups were identical. Synovial fluid was obtained at a mean of 3.4 years (SD 1.3) postoperatively. The in vivo polyethylene wear particles were isolated from the synovial fluid using a previously validated method and examined by scanning electron microscopy. Results. The total number of polyethylene wear particles obtained from the knees with E1 (mean 6.9, SD 4.0 × 10. 7. counts/knee) was greater than that obtained from those with ArCom (mean 2.2, SD 2.6 × 10. 7. counts/knee) (p = 0.001). The particle size (equivalent circle of diameter) from the knees with E1 was smaller (mean 0.5 μm, SD 0.1) than that of knees with ArCom (mean 1.5, SD 0.3 μm) (p = 0.001). The aspect ratio of particles from the knees with E1 (mean 1.3, SD 0.1) was smaller than that with ArCom (mean 1.4, SD 0.1) (p < 0.001 ). Conclusion. This is the first report of in vivo wear particle analysis of E1. E1 polyethylene did not reduce the number of in vivo polyethylene wear particles compared with ArCom in early clinical stage. Further careful follow-up of newly introduced E1 for TKA should be carried out. Cite this article: Bone Joint J 2020;102-B(11):1527–1534


The Bone & Joint Journal
Vol. 102-B, Issue 6 Supple A | Pages 158 - 162
1 Jun 2020
Griseti Q Jacquet C Sautet P Abdel MP Parratte S Ollivier M Argenson J

Aims. The aim of this study was to compare the ability of tantalum, 3D porous titanium, antibiotic-loaded bone cement, and smooth titanium alloy to inhibit staphylococci in an in vitro environment, based on the evaluation of the zone of inhibition (ZOI). The hypothesis was that there would be no significant difference in the inhibition of methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA/MRSA) between the two groups. Methods. A total of 30 beads made of three different materials (tantalum/3D porous titanium and smooth titanium alloy) were bathed for one hour in a solution of 1 g vancomycin in 20 ml of sterile water for injection (bath concentration: 50 mg/mL). Ten 1 cm. 3. cylinders of antibiotic-loaded cement were also created by mixing standard surgical cement with 1 g of vancomycin in standardized sterile moulds. The cylinders were then placed on agar plates inoculated with MSSA and MRSA. The ZOIs were measured each day and the cylinders were transferred onto a new inoculated plate. Results. For MSSA and MRSA, no inhibitory effect was found in the control group, and antibiotic-loaded smooth titanium alloy beads showed a short inhibitory effect until day 2. For MSSA, both tantalum and 3D porous titanium beads showed significantly larger mean ZOIs than cement beads (all p < 0.01) each day until day 7 for tantalum and until day 3 for 3D porous titanium. After six days, antibiotic-loaded cement had significantly larger mean ZOIs than the 3D porous titanium (p = 0.027), but no significant difference was found with tantalum (p = 0.082). For MRSA, both tantalum and 3D porous titanium beads had significantly larger mean ZOIs than antibiotic-loaded cement each day until day 6 for tantalum (all p < 0.01) and until day 3 for 3D porous titanium (all p < 0.04). Antibiotic-loaded cement had significantly larger mean ZOIs than tantalum and 3D porous titanium from day 7 to 9 (all p < 0.042). Conclusion. These results show that porous metal implants can deliver local antibiotics over slightly varying time frames based on in vitro analysis. Cite this article: Bone Joint J 2020;102-B(6 Supple A):158–162


The Bone & Joint Journal
Vol. 101-B, Issue 7 | Pages 848 - 851
1 Jul 2019
Sautet P Parratte S Mékidèche T Abdel MP Flécher X Argenson J Ollivier M

Aims. The aims of this study were to compare the mean duration of antibiotic release and the mean zone of inhibition between vancomycin-loaded porous tantalum cylinders and antibiotic-loaded bone cement at intervals, and to evaluate potential intrinsic antimicrobial properties of tantalum in an in vitro medium environment against methicillin-sensitive Staphylococcus aureus (MSSA). Materials and Methods. Ten porous tantalum cylinders and ten cylinders of cement were used. The tantalum cylinders were impregnated with vancomycin, which was also added during preparation of the cylinders of cement. The cylinders were then placed on agar plates inoculated with MSSA. The diameter of the inhibition zone was measured each day, and the cylinders were transferred to a new inoculated plate. Inhibition zones were measured with a Vernier caliper and using an automated computed evaluation, and the intra- and interobserver reproducibility were measured. The mean inhibition zones between the two groups were compared with Wilcoxon’s test. Results. MSSA was inhibited for 12 days by the tantalum cylinders and for nine days by the cement cylinders. At day one, the mean zone of inhibition was 28.6 mm for the tantalum and 19.8 mm for the cement group (p < 0.001). At day ten, the mean zone of inhibition was 3.8 mm for the tantalum and 0 mm for the cement group (p < 0.001). The porous tantalum cylinders soaked only with phosphate buffered solution showed no zone of inhibition. Conclusion. Compared with cement, tantalum could release antibiotics for longer. Further studies should assess the advantages of using antibiotic-loaded porous tantalum implants at revision arthroplasty. Cite this article: Bone Joint J 2019;101-B:848–851


Aims

The aim of this study was to compare the migration of the femoral component, five years postoperatively, between patients with a highly cross-linked polyethylene (HXLPE) insert and those with a conventional polyethylene (PE) insert in an uncemented Triathlon fixed insert cruciate-retaining total knee arthroplasty (TKA). Secondary aims included clinical outcomes and patient-reported outcome measures (PROMs). We have previously reported the migration and outcome of the tibial components in these patients.

Methods

A double-blinded randomized controlled trial was conducted including 96 TKAs. The migration of the femoral component was measured with radiostereometry (RSA) at three and six months and one, two, and five years postoperatively. PROMs were collected preoperatively and at all periods of follow-up.


The Bone & Joint Journal
Vol. 105-B, Issue 8 | Pages 880 - 887
1 Aug 2023
Onodera T Momma D Matsuoka M Kondo E Suzuki K Inoue M Higano M Iwasaki N

Aims

Implantation of ultra-purified alginate (UPAL) gel is safe and effective in animal osteochondral defect models. This study aimed to examine the applicability of UPAL gel implantation to acellular therapy in humans with cartilage injury.

Methods

A total of 12 patients (12 knees) with symptomatic, post-traumatic, full-thickness cartilage lesions (1.0 to 4.0 cm2) were included in this study. UPAL gel was implanted into chondral defects after performing bone marrow stimulation technique, and assessed for up to three years postoperatively. The primary outcomes were the feasibility and safety of the procedure. The secondary outcomes were self-assessed clinical scores, arthroscopic scores, tissue biopsies, and MRI-based estimations.


Aims

The primary objective of this study was to compare the five-year tibial component migration and wear between highly crosslinked polyethylene (HXLPE) inserts and conventional polyethylene (PE) inserts of the uncemented Triathlon fixed insert cruciate-retaining total knee arthroplasty (TKA). Secondary objectives included clinical outcomes and patient-reported outcome measures (PROMs).

Methods

A double-blinded, randomized study was conducted including 96 TKAs. Tibial component migration and insert wear were measured with radiostereometric analysis (RSA) at three, six, 12, 24, and 60 months postoperatively. PROMS were collected preoperatively and at all follow-up timepoints.


The Bone & Joint Journal
Vol. 106-B, Issue 9 | Pages 907 - 915
1 Sep 2024
Ross M Zhou Y English M Sharplin P Hirner M

Aims

Knee osteoarthritis (OA) is characterized by a chronic inflammatory process involving multiple cytokine pathways, leading to articular cartilage degeneration. Intra-articular therapies using pharmaceutical or autologous anti-inflammatory factors offer potential non-surgical treatment options. Autologous protein solution (APS) is one such product that uses the patient’s blood to produce a concentrate of cells and anti-inflammatory cytokines. This study evaluated the effect of a specific APS intra-articular injection (nSTRIDE) on patient-reported outcome measures compared to saline in moderate knee OA.

Methods

A parallel, double-blinded, placebo-controlled randomized controlled trial was conducted, where patients with unilateral moderate knee OA (Kellgren-Lawrence grade 2 or 3) received either nSTRIDE or saline (placebo) injection to their symptomatic knee. The primary outcome was the difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12 months post-intervention. Secondary outcomes included WOMAC component scores, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analogue scale (VAS) scores at all follow-up timepoints (three, six, and 12 months).


The Bone & Joint Journal
Vol. 105-B, Issue 6 | Pages 622 - 634
1 Jun 2023
Simpson CJRW Wright E Ng N Yap NJ Ndou S Scott CEH Clement ND

Aims

This systematic review and meta-analysis aimed to compare the influence of patellar resurfacing following cruciate-retaining (CR) and posterior-stabilized (PS) total knee arthroplasty (TKA) on the incidence of anterior knee pain, knee-specific patient-reported outcome measures, complication rates, and reoperation rates.

Methods

A systematic review of MEDLINE, PubMed, and Google Scholar was performed to identify randomized controlled trials (RCTs) according to search criteria. Search terms used included: arthroplasty, replacement, knee (Mesh), TKA, prosthesis, patella, patellar resurfacing, and patellar retaining. RCTs that compared patellar resurfacing versus unresurfaced in primary TKA were included for further analysis. Studies were evaluated using the Scottish Intercollegiate Guidelines Network assessment tool for quality and minimization of bias. Data were synthesized and meta-analysis performed.


The Bone & Joint Journal
Vol. 104-B, Issue 6 | Pages 663 - 671
1 Jun 2022
Lewis E Merghani K Robertson I Mulford J Prentice B Mathew R Van Winden P Ogden K

Aims

Platelet-rich plasma (PRP) intra-articular injections may provide a simple and minimally invasive treatment for early-stage knee osteoarthritis (OA). This has led to an increase in its adoption as a treatment for knee OA, although there is uncertainty about its efficacy and benefit. We hypothesized that patients with early-stage symptomatic knee OA who receive multiple PRP injections will have better clinical outcomes than those receiving single PRP or placebo injections.

Methods

A double-blinded, randomized placebo-controlled trial was performed with three groups receiving either placebo injections (Normal Saline), one PRP injection followed by two placebo injections, or three PRP injections. Each injection was given one week apart. Outcomes were prospectively collected prior to intervention and then at six weeks, three months, six months, and 12 months post-intervention. Primary outcome measures were Knee Injury and Osteoarthritis Outcome Score (KOOS) and EuroQol five-dimension five-level index (EQ-5D-5L). Secondary outcomes included visual analogue scale for pain and patient subjective assessment of the injections.


The Bone & Joint Journal
Vol. 99-B, Issue 6 | Pages 793 - 798
1 Jun 2017
Anderson FL Koch CN Elpers ME Wright TM Haas SB Heyse TJ

Aims. We sought to establish whether an oxidised zirconium (OxZr) femoral component causes less loss of polyethylene volume than a cobalt alloy (CoCr) femoral component in total knee arthroplasty. Materials and Methods. A total of 20 retrieved tibial inserts that had articulated with OxZr components were matched with 20 inserts from CoCr articulations for patient age, body mass index, length of implantation, and revision diagnosis. Changes in dimensions of the articular surfaces were compared with those of pristine inserts using laser scanning. The differences in volume between the retrieved and pristine surfaces of the two groups were calculated and compared. Results. The loss of polyethylene volume was 122 mm. 3. (standard deviation (. sd. ) 87) in the OxZr group and 170 mm. 3. (. sd. 96) in the CoCr group (p = 0.033). The volume loss in the OxZr group was also lower in the medial (72 mm. 3 . (. sd. 67) versus 92 mm. 3 . (. sd. 60); p = 0.096) and lateral (49 mm. 3 . (. sd. 36) versus 79 mm. 3 . (. sd. 61); p = 0.096) compartments separately, but these differences were not significant. Conclusion. Our results corroborate earlier findings from in vitro testing and visual retrieval analysis which suggest that polyethylene volume loss is lower with OxZr femoral components. Since both OxZr and CoCr are hard surfaces that would be expected to create comparable amounts of polyethylene creep, the differences in volume loss may reflect differences in the in vivo wear of these inserts. Cite this article: Bone Joint J 2017;99-B:793–8


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.


The Bone & Joint Journal
Vol. 104-B, Issue 3 | Pages 376 - 385
1 Mar 2022
Gramlich Y Hofmann L Kress S Ruckes C Kemmerer M Klug A Hoffmann R Kremer M

Aims

This study compared the cobalt and chromium serum ion concentration of patients treated with two different metal-on-metal (MoM) hinged total knee arthroplasty (TKA) systems, as well as a titanium nitride (TiN)-coated variant.

Methods

A total of 63 patients (65 implants) were treated using either a MoM-coated (n = 29) or TiN-coated (n = 7) hinged TKA (GenuX mobile bearing, MUTARS; Implantcast, Germany) versus the BPKS (Brehm, Germany) hinged TKA (n = 27), in which the weight placed on the MoM hinge is diffused through a polyethylene (PE) inlay, reducing the direct load on the MoM hinge. Serum cobalt and chromium ion concentrations were assessed after minimum follow-up of 12 months, as well as functional outcome and quality of life.


The Bone & Joint Journal
Vol. 104-B, Issue 1 | Pages 34 - 44
1 Jan 2022
Beckers L Dandois F Ooms D Berger P Van Laere K Scheys L Vandenneucker H

Aims

Higher osteoblastic bone activity is expected in aseptic loosening and painful unicompartmental knee arthroplasty (UKA). However, insights into normal bone activity patterns after medial UKAs are lacking. The aim of this study was to identify the evolution in bone activity pattern in well-functioning medial mobile-bearing UKAs.

Methods

In total, 34 patients (13 female, 21 male; mean age 62 years (41 to 79); BMI 29.7 kg/m2 (23.6 to 42.1)) with 38 medial Oxford partial UKAs (20 left, 18 right; 19 cementless, 14 cemented, and five hybrid) were prospectively followed with sequential 99mTc-hydroxymethane diphosphonate single photon emission CT (SPECT)/CT preoperatively, and at one and two years postoperatively. Changes in mean osteoblastic activity were investigated using a tracer localization scheme with volumes of interest (VOIs), reported by normalized mean tracer values. A SPECT/CT registration platform additionally explored cortical tracer evolution in zones of interest identified by previous experimental research.


The Bone & Joint Journal
Vol. 103-B, Issue 6 Supple A | Pages 87 - 93
1 Jun 2021
Chalmers BP Elmasry SS Kahlenberg CA Mayman DJ Wright TM Westrich GH Imhauser CW Sculco PK Cross MB

Aims

Surgeons commonly resect additional distal femur during primary total knee arthroplasty (TKA) to correct a flexion contracture, which leads to femoral joint line elevation. There is a paucity of data describing the effect of joint line elevation on mid-flexion stability and knee kinematics. Thus, the goal of this study was to quantify the effect of joint line elevation on mid-flexion laxity.

Methods

Six computational knee models with cadaver-specific capsular and collateral ligament properties were implanted with a posterior-stabilized (PS) TKA. A 10° flexion contracture was created in each model to simulate a capsular contracture. Distal femoral resections of + 2 mm and + 4 mm were then simulated for each knee. The knee models were then extended under a standard moment. Subsequently, varus and valgus moments of 10 Nm were applied as the knee was flexed from 0° to 90° at baseline and repeated after each of the two distal resections. Coronal laxity (the sum of varus and valgus angulation with respective maximum moments) was measured throughout flexion.


The Bone & Joint Journal
Vol. 103-B, Issue 6 Supple A | Pages 13 - 17
1 Jun 2021
Park KJ Chapleau J Sullivan TC Clyburn TA Incavo SJ

Aims

Infection complicating primary total knee arthroplasty (TKA) is a common reason for revision surgery, hospital readmission, patient morbidity, and mortality. Increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern. The use of vancomycin as prophylactic agent alone or in combination with cephalosporin has not demonstrated lower periprosthetic joint infection (PJI) rates, partly due to timing and dosing of intravenous (IV) vancomycin administration, which have proven important factors in effectiveness. This is a retrospective review of a consecutive series of primary TKAs examining incidence of PJI, adverse reactions, and complications using IV versus intraosseous (IO) vancomycin at 30-day, 90-day, and one-year follow-up.

Methods

A retrospective review of 1,060 patients who underwent TKA between May 2016 to July 2020 was performed. There were 572 patients in the IV group and 488 in the IO group, with minimal 30 days of follow-up. Patients were followed up at regularly scheduled intervals (two, six, and 12 weeks). No differences between groups for age, sex, BMI, or baseline comorbidities existed. The IV group received an IV dose of 15 mg/kg vancomycin given over an hour preceding skin incision. The IO group received a 500 mg dose of vancomycin mixed in 150 ml of normal saline, injected into proximal tibia after tourniquet inflation, before skin incision. All patients received an additional dose of first generation cephalosporin. Evaluation included preoperative and postoperative serum creatinine values, tourniquet time, and adverse reactions attributable to vancomycin.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 7 | Pages 914 - 920
1 Jul 2011
Rogers BA Middleton FR Shearwood-Porter N Kinch S Roques A Bradley NW Browne M

Two-stage revision surgery for infected total knee replacement offers the highest rate of success for the elimination of infection. The use of articulating antibiotic-laden cement spacers during the first stage to eradicate infection also allows protection of the soft tissues against excessive scarring and stiffness. We have investigated the effect of cyclical loading of cement spacers on the elution of antibiotics. Femoral and tibial spacers containing vancomycin at a constant concentration and tobramycin of varying concentrations were studied in vitro. The specimens were immersed and loaded cyclically to 250 N, with a flexion excursion of 45°, for 35 000 cycles. The buffered solution was sampled at set intervals and the antibiotic concentration was established so that the elution could be calculated. Unloaded samples were used as a control group for statistical comparison. The elution of tobramycin increased proportionately with its concentration in cement and was significantly higher at all sampling times from five minutes to 1680 minutes in loaded components compared with the control group (p = 0.021 and p = 0.003, respectively). A similar trend was observed with elution of vancomycin, but this failed to reach statistical significance at five, 1320 and 1560 minutes (p = 0.0508, p = 0.067 and p = 0.347, respectively). However, cyclically loaded and control components showed an increased elution of vancomycin with increasing tobramycin concentration in the specimens, despite all components having the same vancomycin concentration. The concentration of tobramycin influences both tobramycin and vancomycin elution from bone cement. Cyclical loading of the cement spacers enhanced the elution of vancomycin and tobramycin


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 7 | Pages 864 - 869
1 Jul 2008
Amis AA Oguz C Bull AMJ Senavongse W Dejour D

Objective patellar instability has been correlated with dysplasia of the femoral trochlea. This in vitro study tested the hypothesis that trochleoplasty would increase patellar stability and normalise the kinematics of a knee with a dysplastic trochlea. Six fresh-frozen knees were loaded via the heads of the quadriceps. The patella was displaced 10 mm laterally and the displacing force was measured from 0° to 90° of flexion. Patellar tracking was measured from 0° to 130° of knee flexion using magnetic sensors. These tests were repeated after raising the central anterior trochlea to simulate dysplasia, and repeated again after performing a trochleoplasty on each specimen. The simulated dysplasia significantly reduced stability from that of the normal knee (p < 0.001). Trochleoplasty significantly increased the stability (p < 0.001), so that it did not then differ significantly from the normal knee (p = 0.244). There were small but statistically significant changes in patellar tracking (p< 0.001). This study has provided objective biomechanical data to support the use of trochleoplasty in the treatment of patellar instability associated with femoral trochlear dysplasia


The Bone & Joint Journal
Vol. 102-B, Issue 6 Supple A | Pages 59 - 65
1 Jun 2020
Kwon Y Arauz P Peng Y Klemt C

Aims

The removal of the cruciate ligaments in total knee arthroplasty (TKA) has been suggested as a potential contributing factor to patient dissatisfaction, due to alteration of the in vivo biomechanics of the knee. Bicruciate retaining (BCR) TKA allows the preservation of the cruciate ligaments, thus offering the potential to reproduce healthy kinematics. The aim of this study was to compare in vivo kinematics between the operated and contralateral knee in patients who have undergone TKA with a contemporary BCR design.

Methods

A total of 29 patients who underwent unilateral BCR TKA were evaluated during single-leg deep lunges and sit-to-stand tests using a validated computer tomography and fluoroscopic imaging system. In vivo six-degrees of freedom (6DOF) kinematics were compared between the BCR TKA and the contralateral knee.