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Bone & Joint Open
Vol. 5, Issue 12 | Pages 1067 - 1071
2 Dec 2024
Salzmann M Kropp E Prill R Ramadanov N Adriani M Becker R

Aims. The transepicondylar axis is a well-established reference for the determination of femoral component rotation in total knee arthroplasty (TKA). However, when severe bone loss is present in the femoral condyles, rotational alignment can be more complicated. There is a lack of validated landmarks in the supracondylar region of the distal femur. Therefore, the aim of this study was to analyze the correlation between the surgical transepicondylar axis (sTEA) and the suggested dorsal cortex line (DCL) in the coronal plane and the inter- and intraobserver reliability of its CT scan measurement. Methods. A total of 75 randomly selected CT scans were measured by three experienced surgeons independently. The DCL was defined in the coronal plane as a tangent to the dorsal femoral cortex located 75 mm above the joint line in the frontal plane. The difference between sTEA and DCL was calculated. Descriptive statistics and angulation correlations were generated for the sTEA and DCL, as well as for the distribution of measurement error for intra- and inter-rater reliability. Results. The external rotation of the DCL to the sTEA was a mean of 9.47° (SD 3.06°), and a median of 9.2° (IQR 7.45° to 11.60°), with a minimum value of 1.7° and maximum of 16.3°. The measurements of the DCL demonstrated very good to excellent test-retest and inter-rater reliability coefficients (intraclass correlation coefficient 0.80 to 0.99). Conclusion. This study reveals a correlation between the sTEA and the DCL. Overall, 10° of external rotation of the dorsal femoral cortical bone to the sTEA may serve as a reliable landmark for initial position of the femoral component. Surgeons should be aware that there are outliers in this study in up to 17% of the measurements, which potentially could result in deviations of femoral component rotation. Cite this article: Bone Jt Open 2024;5(12):1067–1071


Bone & Joint Research
Vol. 10, Issue 10 | Pages 677 - 689
1 Oct 2021
Tamaddon M Blunn G Xu W Alemán Domínguez ME Monzón M Donaldson J Skinner J Arnett TR Wang L Liu C

Aims. Minimally manipulated cells, such as autologous bone marrow concentrates (BMC), have been investigated in orthopaedics as both a primary therapeutic and augmentation to existing restoration procedures. However, the efficacy of BMC in combination with tissue engineering is still unclear. In this study, we aimed to determine whether the addition of BMC to an osteochondral scaffold is safe and can improve the repair of large osteochondral defects when compared to the scaffold alone. Methods. The ovine femoral condyle model was used. Bone marrow was aspirated, concentrated, and used intraoperatively with a collagen/hydroxyapatite scaffold to fill the osteochondral defects (n = 6). Tissue regeneration was then assessed versus the scaffold-only group (n = 6). Histological staining of cartilage with alcian blue and safranin-O, changes in chondrogenic gene expression, microCT, peripheral quantitative CT (pQCT), and force-plate gait analyses were performed. Lymph nodes and blood were analyzed for safety. Results. The results six months postoperatively showed that there were no significant differences in bone regrowth and mineral density between BMC-treated animals and controls. A significant upregulation of messenger RNA (mRNA) for types I and II collagens in the BMC group was observed, but there were no differences in the formation of hyaline-like cartilage between the groups. A trend towards reduced sulphated glycosaminoglycans (sGAG) breakdown was detected in the BMC group but this was not statistically significant. Functional weightbearing was not affected by the inclusion of BMC. Conclusion. Our results indicated that the addition of BMC to scaffold is safe and has some potentially beneficial effects on osteochondral-tissue regeneration, but not on the functional endpoint of orthopaedic interest. Cite this article: Bone Joint Res 2021;10(10):677–689


Bone & Joint Research
Vol. 5, Issue 3 | Pages 80 - 86
1 Mar 2016
Scott G Imam MA Eifert A Freeman MAR Pinskerova V Field RE Skinner J Banks SA

Objectives. Throughout the 20th Century, it has been postulated that the knee moves on the basis of a four-bar link mechanism composed of the cruciate ligaments, the femur and the tibia. As a consequence, the femur has been thought to roll back with flexion, and total knee arthroplasty (TKA) prostheses have been designed on this basis. Recent work, however, has proposed that at a position of between 0° and 120° the medial femoral condyle does not move anteroposteriorly whereas the lateral femoral condyle tends, but is not obliged, to roll back – a combination of movements which equates to tibial internal/ femoral external rotation with flexion. The aim of this paper was to assess if the articular geometry of the GMK Sphere TKA could recreate the natural knee movements in situ/in vivo. Methods. The pattern of knee movement was studied in 15 patients (six male: nine female; one male with bilateral TKAs) with 16 GMK Sphere implants, at a mean age of 66 years (53 to 76) with a mean BMI of 30 kg/m. 2. (20 to 35). The motions of all 16 knees were observed using pulsed fluoroscopy during a number of weight-bearing and non-weight-bearing static and dynamic activities. Results. During maximally flexed kneeling and lunging activities, the mean tibial internal rotation was 8° (standard deviation (. sd. ) 6). At a mean 112° flexion (. sd. 16) during lunging, the medial and lateral condyles were a mean of 2 mm (. sd. 3) and 8 mm (. sd. 4) posterior to a transverse line passing through the centre of the medial tibial concavity. With a mean flexion of 117° (. sd. 14) during kneeling, the medial and lateral condyles were a mean of 1 mm (. sd. 4) anterior and 6 mm (. sd. 4) posterior to the same line. During dynamic stair and pivoting activities, there was a mean anteroposterior translation of 0 mm to 2 mm of the medial femoral condyle. Backward lateral condylar translation occurred and was linearly related to tibial rotation. Conclusion. The GMK Sphere TKA in our study group shows movements similar in pattern, although reduced in magnitude, to those in recent reports relating to normal knees during several activities. Specifically, little or no translation of the medial femoral condyle was observed during flexion, but there was posterior roll-back of the lateral femoral condyle, equating to tibiofemoral rotation. We conclude that the GMK Sphere is anteroposteriorly stable medially and permits rotation about the medial compartment. Cite this article: Professor G. Scott. Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised?: A pulsed fluoroscopic investigation. Bone Joint Res 2016;5:80–86. DOI: 10.1302/2046-3758.53.2000621


Bone & Joint Research
Vol. 7, Issue 8 | Pages 511 - 516
1 Aug 2018
Beverly M Mellon S Kennedy JA Murray DW

Objectives. We studied subchondral intraosseous pressure (IOP) in an animal model during loading, and with vascular occlusion. We explored bone compartmentalization by saline injection. Materials and Methods. Needles were placed in the femoral condyle and proximal tibia of five anaesthetized rabbits and connected to pressure recorders. The limb was loaded with and without proximal vascular occlusion. An additional subject had simultaneous triple recordings at the femoral head, femoral condyle and proximal tibia. In a further subject, saline injections at three sites were carried out in turn. Results. Loading alone caused a rise in subchondral IOP from 11.7 mmHg (. sd. 7.1) to 17.9 mmHg (. sd. 8.1; p < 0.0002). During arterial occlusion, IOP fell to 5.3 mmHg (. sd. 4.1), then with loading there was a small rise to 7.6 mmHg (. sd. 4.5; p < 0.002). During venous occlusion, IOP rose to 20.2 mmHg (. sd. 5.8), and with loading there was a further rise to 26.3 mmHg (. sd. 6.3; p < 0.003). The effects were present at three different sites along the limb simultaneously. Saline injections showed pressure transmitted throughout the length of the femur but not across the knee joint. Conclusion. This is the first study to report changes in IOP in vivo during loading and with combinations of vascular occlusion and loading. Intraosseous pressure is not a constant. It is reduced during proximal arterial occlusion and increased with proximal venous occlusion. Whatever the perfusion state, in vivo load is transferred partly by hydraulic pressure. We propose that joints act as hydraulic pressure barriers. An understanding of subchondral physiology may be important in understanding osteoarthritis and other bone diseases. Cite this article: M. Beverly, S. Mellon, J. A. Kennedy, D. W. Murray. Intraosseous pressure during loading and with vascular occlusion in an animal model. Bone Joint Res 2018;7:511–516. DOI: 10.1302/2046-3758.78.BJR-2017-0343.R2


Objectives. Bioresorbable orthopaedic devices with calcium phosphate (CaP) fillers are commercially available on the assumption that increased calcium (Ca) locally drives new bone formation, but the clinical benefits are unknown. Electron beam (EB) irradiation of polymer devices has been shown to enhance the release of Ca. The aims of this study were to: 1) establish the biological safety of EB surface-modified bioresorbable devices; 2) test the release kinetics of CaP from a polymer device; and 3) establish any subsequent beneficial effects on bone repair in vivo. Methods. ActivaScrew Interference (Bioretec Ltd, Tampere, Finland) and poly(L-lactide-co-glycolide) (PLGA) orthopaedic screws containing 10 wt% β-tricalcium phosphate (β-TCP) underwent EB treatment. In vitro degradation over 36 weeks was investigated by recording mass loss, pH change, and Ca release. Implant performance was investigated in vivo over 36 weeks using a lapine femoral condyle model. Bone growth and osteoclast activity were assessed by histology and enzyme histochemistry. Results. Calcium release doubled in the EB-treated group before returning to a level seen in untreated samples at 28 weeks. Extensive bone growth was observed around the perimeter of all implant types, along with limited osteoclastic activity. No statistically significant differences between comparative groups was identified. Conclusion. The higher than normal dose of EB used for surface modification did not adversely affect tissue response around implants in vivo. Surprisingly, incorporation of β-TCP and the subsequent accelerated release of Ca had no significant effect on in vivo implant performance, calling into question the clinical evidence base for these commercially available devices. Cite this article: I. Palmer, S. A. Clarke, F. J Buchanan. Enhanced release of calcium phosphate additives from bioresorbable orthopaedic devices using irradiation technology is non-beneficial in a rabbit model: An animal study. Bone Joint Res 2019;8:266–274. DOI: 10.1302/2046-3758.86.BJR-2018-0224.R2


Bone & Joint Research
Vol. 9, Issue 11 | Pages 761 - 767
1 Nov 2020
Hada M Mizu-uchi H Okazaki K Murakami K Kaneko T Higaki H Nakashima Y

Aims. This study aims to investigate the effects of posterior tibial slope (PTS) on knee kinematics involved in the post-cam mechanism in bi-cruciate stabilized (BCS) total knee arthroplasty (TKA) using computer simulation. Methods. In total, 11 different PTS (0° to 10°) values were simulated to evaluate the effect of PTS on anterior post-cam contact conditions and knee kinematics in BCS TKA during weight-bearing stair climbing (from 86° to 6° of knee flexion). Knee kinematics were expressed as the lowest points of the medial and lateral femoral condyles on the surface of the tibial insert, and the anteroposterior translation of the femoral component relative to the tibial insert. Results. Anterior post-cam contact in BCS TKA was observed with the knee near full extension if PTS was 6° or more. BCS TKA showed a bicondylar roll forward movement from 86° to mid-flexion, and two different patterns from mid-flexion to knee extension: screw home movement without anterior post-cam contact and bicondylar roll forward movement after anterior post-cam contact. Knee kinematics in the simulation showed similar trends to the clinical in vivo data and were almost within the range of inter-specimen variability. Conclusion. Postoperative knee kinematics in BCS TKA differed according to PTS and anterior post-cam contact; in particular, anterior post-cam contact changed knee kinematics, which may affect the patient’s perception of the knee during activities. Cite this article: Bone Joint Res 2020;9(11):761–767


Bone & Joint Open
Vol. 5, Issue 7 | Pages 592 - 600
18 Jul 2024
Faschingbauer M Hambrecht J Schwer J Martin JR Reichel H Seitz A

Aims

Patient dissatisfaction is not uncommon following primary total knee arthroplasty. One proposed method to alleviate this is by improving knee kinematics. Therefore, we aimed to answer the following research question: are there significant differences in knee kinematics based on the design of the tibial insert (cruciate-retaining (CR), ultra-congruent (UC), or medial congruent (MC))?

Methods

Overall, 15 cadaveric knee joints were examined with a CR implant with three different tibial inserts (CR, UC, and MC) using an established knee joint simulator. The effects on coronal alignment, medial and lateral femoral roll back, femorotibial rotation, bony rotations (femur, tibia, and patella), and patellofemoral length ratios were determined.


Bone & Joint Research
Vol. 13, Issue 4 | Pages 137 - 148
1 Apr 2024
Lu Y Ho T Huang C Yeh S Chen S Tsao Y

Aims

Pigment epithelium-derived factor (PEDF) is known to induce several types of tissue regeneration by activating tissue-specific stem cells. Here, we investigated the therapeutic potential of PEDF 29-mer peptide in the damaged articular cartilage (AC) in rat osteoarthritis (OA).

Methods

Mesenchymal stem/stromal cells (MSCs) were isolated from rat bone marrow (BM) and used to evaluate the impact of 29-mer on chondrogenic differentiation of BM-MSCs in culture. Knee OA was induced in rats by a single intra-articular injection of monosodium iodoacetate (MIA) in the right knees (set to day 0). The 29-mer dissolved in 5% hyaluronic acid (HA) was intra-articularly injected into right knees at day 8 and 12 after MIA injection. Subsequently, the therapeutic effect of the 29-mer/HA on OA was evaluated by the Osteoarthritis Research Society International (OARSI) histopathological scoring system and changes in hind paw weight distribution, respectively. The regeneration of chondrocytes in damaged AC was detected by dual-immunostaining of 5-bromo-2'-deoxyuridine (BrdU) and chondrogenic markers.


Bone & Joint Research
Vol. 12, Issue 12 | Pages 734 - 746
12 Dec 2023
Chen M Hu C Hsu Y Lin Y Chen K Ueng SWN Chang Y

Aims

Therapeutic agents that prevent chondrocyte loss, extracellular matrix (ECM) degradation, and osteoarthritis (OA) progression are required. The expression level of epidermal growth factor (EGF)-like repeats and discoidin I-like domains-containing protein 3 (EDIL3) in damaged human cartilage is significantly higher than in undamaged cartilage. However, the effect of EDIL3 on cartilage is still unknown.

Methods

We used human cartilage plugs (ex vivo) and mice with spontaneous OA (in vivo) to explore whether EDIL3 has a chondroprotective effect by altering OA-related indicators.


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.


Bone & Joint Research
Vol. 13, Issue 12 | Pages 695 - 702
1 Dec 2024
Cordero García-Galán E Medel-Plaza M Pozo-Kreilinger JJ Sarnago H Lucía Ó Rico-Nieto A Esteban J Gomez-Barrena E

Aims

Electromagnetic induction heating has demonstrated in vitro antibacterial efficacy over biofilms on metallic biomaterials, although no in vivo studies have been published. Assessment of side effects, including thermal necrosis of adjacent tissue, would determine transferability into clinical practice. Our goal was to assess bone necrosis and antibacterial efficacy of induction heating on biofilm-infected implants in an in vivo setting.

Methods

Titanium-aluminium-vanadium (Ti6Al4V) screws were implanted in medial condyle of New Zealand giant rabbit knee. Study intervention consisted of induction heating of the screw head up to 70°C for 3.5 minutes after implantation using a portable device. Both knees were implanted, and induction heating was applied unilaterally keeping contralateral knee as paired control. Sterile screws were implanted in six rabbits, while the other six received screws coated with Staphylococcus aureus biofilm. Sacrifice and sample collection were performed 24, 48, or 96 hours postoperatively. Retrieved screws were sonicated, and adhered bacteria were estimated via drop-plate. Width of bone necrosis in retrieved femora was assessed through microscopic examination. Analysis was performed using non-parametric tests with significance fixed at p ≤ 0.05.


Bone & Joint Research
Vol. 12, Issue 1 | Pages 58 - 71
17 Jan 2023
Dagneaux L Limberg AK Owen AR Bettencourt JW Dudakovic A Bayram B Gades NM Sanchez-Sotelo J Berry DJ van Wijnen A Morrey ME Abdel MP

Aims

As has been shown in larger animal models, knee immobilization can lead to arthrofibrotic phenotypes. Our study included 168 C57BL/6J female mice, with 24 serving as controls, and 144 undergoing a knee procedure to induce a contracture without osteoarthritis (OA).

Methods

Experimental knees were immobilized for either four weeks (72 mice) or eight weeks (72 mice), followed by a remobilization period of zero weeks (24 mice), two weeks (24 mice), or four weeks (24 mice) after suture removal. Half of the experimental knees also received an intra-articular injury. Biomechanical data were collected to measure passive extension angle (PEA). Histological data measuring area and thickness of posterior and anterior knee capsules were collected from knee sections.


Bone & Joint Research
Vol. 12, Issue 8 | Pages 497 - 503
16 Aug 2023
Lee J Koh Y Kim PS Park J Kang K

Aims

Focal knee arthroplasty is an attractive alternative to knee arthroplasty for young patients because it allows preservation of a large amount of bone for potential revisions. However, the mechanical behaviour of cartilage has not yet been investigated because it is challenging to evaluate in vivo contact areas, pressure, and deformations from metal implants. Therefore, this study aimed to determine the contact pressure in the tibiofemoral joint with a focal knee arthroplasty using a finite element model.

Methods

The mechanical behaviour of the cartilage surrounding a metal implant was evaluated using finite element analysis. We modelled focal knee arthroplasty with placement flush, 0.5 mm deep, or protruding 0.5 mm with regard to the level of the surrounding cartilage. We compared contact stress and pressure for bone, implant, and cartilage under static loading conditions.


Bone & Joint Open
Vol. 5, Issue 2 | Pages 101 - 108
6 Feb 2024
Jang SJ Kunze KN Casey JC Steele JR Mayman DJ Jerabek SA Sculco PK Vigdorchik JM

Aims

Distal femoral resection in conventional total knee arthroplasty (TKA) utilizes an intramedullary guide to determine coronal alignment, commonly planned for 5° of valgus. However, a standard 5° resection angle may contribute to malalignment in patients with variability in the femoral anatomical and mechanical axis angle. The purpose of the study was to leverage deep learning (DL) to measure the femoral mechanical-anatomical axis angle (FMAA) in a heterogeneous cohort.

Methods

Patients with full-limb radiographs from the Osteoarthritis Initiative were included. A DL workflow was created to measure the FMAA and validated against human measurements. To reflect potential intramedullary guide placement during manual TKA, two different FMAAs were calculated either using a line approximating the entire diaphyseal shaft, and a line connecting the apex of the femoral intercondylar sulcus to the centre of the diaphysis. The proportion of FMAAs outside a range of 5.0° (SD 2.0°) was calculated for both definitions, and FMAA was compared using univariate analyses across sex, BMI, knee alignment, and femur length.


Bone & Joint Open
Vol. 4, Issue 7 | Pages 523 - 531
11 Jul 2023
Passaplan C Hanauer M Gautier L Stetzelberger VM Schwab JM Tannast M Gautier E

Aims

Hyaline cartilage has a low capacity for regeneration. Untreated osteochondral lesions of the femoral head can lead to progressive and symptomatic osteoarthritis of the hip. The purpose of this study is to analyze the clinical and radiological long-term outcome of patients treated with osteochondral autograft transfer. To our knowledge, this study represents a series of osteochondral autograft transfer of the hip with the longest follow-up.

Methods

We retrospectively evaluated 11 hips in 11 patients who underwent osteochondral autograft transfer in our institution between 1996 and 2012. The mean age at the time of surgery was 28.6 years (8 to 45). Outcome measurement included standardized scores and conventional radiographs. Kaplan-Meier survival curve was used to determine the failure of the procedures, with conversion to total hip arthroplasty (THA) defined as the endpoint.


Bone & Joint Open
Vol. 5, Issue 11 | Pages 992 - 998
6 Nov 2024
Wignadasan W Magan A Kayani B Fontalis A Chambers A Rajput V Haddad FS

Aims

While residual fixed flexion deformity (FFD) in unicompartmental knee arthroplasty (UKA) has been associated with worse functional outcomes, limited evidence exists regarding FFD changes. The objective of this study was to quantify FFD changes in patients with medial unicompartmental knee arthritis undergoing UKA, and investigate any correlation with clinical outcomes.

Methods

This study included 136 patients undergoing robotic arm-assisted medial UKA between January 2018 and December 2022. The study included 75 males (55.1%) and 61 (44.9%) females, with a mean age of 67.1 years (45 to 90). Patients were divided into three study groups based on the degree of preoperative FFD: ≤ 5°, 5° to ≤ 10°, and > 10°. Intraoperative optical motion capture technology was used to assess pre- and postoperative FFD. Clinical FFD was measured pre- and postoperatively at six weeks and one year following surgery. Preoperative and one-year postoperative Oxford Knee Scores (OKS) were collected.


Bone & Joint Research
Vol. 13, Issue 6 | Pages 306 - 314
19 Jun 2024
Wu B Su J Zhang Z Zeng J Fang X Li W Zhang W Huang Z

Aims

To explore the clinical efficacy of using two different types of articulating spacers in two-stage revision for chronic knee periprosthetic joint infection (kPJI).

Methods

A retrospective cohort study of 50 chronic kPJI patients treated with two types of articulating spacers between January 2014 and March 2022 was conducted. The clinical outcomes and functional status of the different articulating spacers were compared. Overall, 17 patients were treated with prosthetic spacers (prosthetic group (PG)), and 33 patients were treated with cement spacers (cement group (CG)). The CG had a longer mean follow-up period (46.67 months (SD 26.61)) than the PG (24.82 months (SD 16.46); p = 0.001).


Bone & Joint Research
Vol. 12, Issue 1 | Pages 22 - 32
11 Jan 2023
Boschung A Faulhaber S Kiapour A Kim Y Novais EN Steppacher SD Tannast M Lerch TD

Aims

Femoroacetabular impingement (FAI) patients report exacerbation of hip pain in deep flexion. However, the exact impingement location in deep flexion is unknown. The aim was to investigate impingement-free maximal flexion, impingement location, and if cam deformity causes hip impingement in flexion in FAI patients.

Methods

A retrospective study involving 24 patients (37 hips) with FAI and femoral retroversion (femoral version (FV) < 5° per Murphy method) was performed. All patients were symptomatic (mean age 28 years (SD 9)) and had anterior hip/groin pain and a positive anterior impingement test. Cam- and pincer-type subgroups were analyzed. Patients were compared to an asymptomatic control group (26 hips). All patients underwent pelvic CT scans to generate personalized CT-based 3D models and validated software for patient-specific impingement simulation (equidistant method).


Aims

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

Methods

In this study, 60 rats were included in a titanium rod implantation model and underwent subsequent guanylate cyclase treatment. Imaging, histology, and biomechanics were used to evaluate the osseointegration of rats in each group. First, the impact of VIT on bone integration in aged rats with iron overload was investigated. Subsequently, VIT was employed to modulate the differentiation of MC3T3-E1 cells and RAW264.7 cells under conditions of iron overload.


Bone & Joint Open
Vol. 5, Issue 11 | Pages 1013 - 1019
11 Nov 2024
Clark SC Pan X Saris DBF Taunton MJ Krych AJ Hevesi M

Aims

Distal femoral osteotomies (DFOs) are commonly used for the correction of valgus deformities and lateral compartment osteoarthritis. However, the impact of a DFO on subsequent total knee arthroplasty (TKA) function remains a subject of debate. Therefore, the purpose of this study was to determine the effect of a unilateral DFO on subsequent TKA function in patients with bilateral TKAs, using the contralateral knee as a self-matched control group.

Methods

The inclusion criteria consisted of patients who underwent simultaneous or staged bilateral TKA after prior unilateral DFO between 1972 and 2023. The type of osteotomy performed, osteotomy hardware fixation, implanted TKA components, and revision rates were recorded. Postoperative outcomes including the Forgotten Joint Score-12 (FJS-12), Tegner Activity Scale score, and subjective knee preference were also obtained at final follow-up.