Purpose

To evaluate the morphological and biochemical quality of cartilage transplants and surrounding articular cartilage of patients 25 years after perichondrium transplantation (PT) and autologous chondrocyte transplantation (ACT) as measured by ultra-high field 7 Tesla (7T) Magnetic Resonance Imaging (MRI) and to present these findings next to clinical outcome.

Methods and Materials

Seven PT patients and five ACT patients who underwent surgery on the femoral condyle between 1986 and 1996 were included. Patient reported outcome measures (PROMs) were assessed by the clinical questionnaires: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) and Visual Analogue Scale (VAS) for knee pain). The morphological (MOCART score) and biochemical quality (glycosaminoglycans (GAGs) content and collagen integrity) of cartilage transplants and surrounding articular cartilage were analyzed by 7T MRI. The results of the PT and ACT patients were compared. Finally, a detailed morphological analysis of the grafts alone was performed.

Results

No statistically significant difference was found for the PROMs and MOCART scores of PT and ACT patients. Evaluation of the graft alone showed poor repair tissue quality and high prevalence of intralesional osteophyte formation in both the PT and ACT patients. Penetration of the graft surface by the intralesional osteophyte (calcification thickness score 1) was related to biochemically damaged opposing tibial cartilage; GAG content was significantly lower in patients with an osteophyte penetrating the graft surface.

Figure 1.

Figure 2. MTR asymmetry values (A) and global T2 relaxation times (B) for the 6 different ROIs. The regions in the femur are displayed on the left side of the dotted line, regions in the tibia are presented on the right side of the dotted line.

Conclusion

Both PT and ACT patients have a high incidence of intralesional osteophyte formation 25 years after surgery. The resulting biochemical damage to the opposing tibial cartilage might be dependent on osteophyte morphology.

Purpose

The goal of this study was to identify the effect of cartilage thickness mismatches between a graft and the surrounding native bone on cartilage tissue deformation in a human patellar osteochondral allograft model.

Methods and Materials

Two types of finite element models were used to quantify the effect of mismatches in the subchondral bone surface: a simplified 2D model and patient-specific 3D models. In the 2D models, the thickness of the graft cartilage in the graft region was varied from 0.33x the thickness of native cartilage to 3x the thickness of native cartilage, which was set to 2 mm. Ten 3D models were created from nano-CT scans of 16mm cadaveric patellar OCA transplants. A 1 MPa pressure was applied to the cartilage surface, and the patellar surface was fixed for all models.

Results

3D models highlighted which geometric features produced high stress regions in the patellar cartilage and where those stresses occurred. Furthermore, the 3D models provided ranges for the parameter sweeps that were conducted with 2D models. 2D models revealed that larger thickness mismatches with thicker recipient cartilage caused higher stresses. Compared to patellae with donor cartilage that was thicker than recipient cartilage, patellae with donor cartilage than was thinner than recipient cartilage had lower stresses when the recipient cartilage thickness was <4 mm. This trend reversed for recipient cartilage >4 mm. Surface curvature increased stresses when donor cartilage was thicker than recipient cartilage and decreased stresses when donor cartilage was thinner than recipient cartilage.

Conclusion

Mismatches in the subchondral bone can produce stress increases large enough to cause local chondrocyte death near the subchondral bone surface, highlighting that future monitoring of cartilage transplants should include full-thickness imaging techniques and that allografts should be matched based on cartilage thickness.

Purpose

Osteoarthritis (OA) is typically diagnosed by history of joint pain associated with decreased movement and radiographic assessment. Putative biomarkers have been characterized as potential indicators of OA pathogenesis, however, there are currently no reliable biomarkers that are quantifiable diagnostic or prognostic signatures of OA. Senescent T-cells have been linked to conditions such as frailty, rheumatoid arthritis, and bone loss. The purpose of this study was to measure levels of circulating senescent T-cells in OA patients vs healthy controls as a potentially novel biomarker.

Methods and Materials

Data was obtained from 2 clinical studies investigating OA and senescence in healthy patients. OA patients (KL: II-IV) were ambulatory between 40-85 years. Peripheral Blood Mononuclear Cells (PBMCs) were collected by density gradient centrifugation and CD3+ T-cells were isolated using RosetteSep^TM. Senescence was determined using C₁₂FDG (flow cytometry) and serum biomarkers were analyzed using multiplex immunoassays.

Results

Patient PBMCs displayed a distribution of two distinct populations of moderate C₁₂FDG signal (“dim”) and high C₁₂FDG signal (“bright”) cells (Fig. 1A) significantly correlating with age (Fig. 1B). Increases in bright %PBMCs and total (bright+dim) %PBMCs were observed in OA compared to healthy patients (Fig. 1C). However, in T-cells specifically, overt increases were found in bright and total %T-cells (Fig. 1D). Significant associations were also found in OA patients between senescent T-cells and serum biomarkers elevated during OA (CS846, IL-Ra, IL-15) and aging/senescence (SOST, VEGF), suggesting senescent T-cells to be predictive of OA (Fig. 2). Finally, we found correlative trends between senescent T-cells and functional performance and pain scores in OA patients.

Conclusion

These studies are clinically significant given we combined a simple stain (C₁₂FDG) using flow cytometry to rapidly measure senescent T-cells in blood of OA patients significantly correlated to OA serum biomarkers. Thus, detection of senescent T-cells may offer diagnostic insight for OA or evaluate efficacy of therapeutics.

Purpose

No high-level studies investigated the potential of micro-fragmented adipose tissue (MF-AT) over other biological products like platelet-rich plasma (PRP). The aim of this randomized controlled trial (RCT) was to compare a single injection of MF-AT to PRP in terms of clinical outcome and disease-modifying properties in patients with symptomatic knee OA.

Methods and Materials

A total of 118 knee OA patients were randomly assigned to a single intra-articular MF-AT vs PRP injection and evaluated before the injection and at 1-3-6-12- 24 months with the IKDC subjective score, KOOS subscales, EQ-VAS, EQ-5D, and VAS pain. The treated knees were also evaluated at baseline and at 6-12-24 months of follow-up with radiographs and high-resolution MRI with the WORMS.

Results

Both MF-AT and PRP provided a statistically significant improvement up to the last follow-up of 24 months. No differences were found between MF-AT and PRP groups in terms of adverse events (18.9%vs10.9%), failures (15.1%vs25.5%), and all clinical outcomes at all follow-ups. Radiographs and MRI findings did not show significant changes after the injection, neither as improvement, nor as disease progression, with no intergroup difference. Patients with moderate/severe OA treated with MF-AT showed a significantly higher IKDC improvement at 6 months compared to PRP (15.7±19.0 vs 8.6±14.2, p=0.041). Similarly, more patients with moderate/severe OA treated with MF-AT reached the MCID for the IKDC subjective score at 6 months compared to the PRP group (75.0%vs34.6%, p=0.005).

Conclusion

A single intra-articular injection of both MF-AT and PRP provided a significant clinical improvement up to 24 months in patients with symptomatic knee OA. Both treatments showed a comparable low number of failures and adverse events, without signs of disease progression. Overall, no differences could be documented in both clinical and imaging results between the two biological approaches. Compared with PRP, MF-AT provided a higher clinical improvement at 6 months in moderate-severe OA.

Purpose

To compare the effectiveness of Arthrosamid^® with that of Synvisc-One^® by assessing changes from baseline in transformed WOMAC pain, stiffness and physical function subscale scores (0-100 score where 100 was worst).

Methods and Materials

This was a prospective, double-blind multicentre study (3 sites in Denmark) where 239 subjects were randomised 1:1 to receive a single intra-articular injection of either 6 mL Arthrosamid (n=119) or 6 mL Synvisc-One (n=120). The study was approved by the Capital Region’s Committee on Health Research Ethics. All patients provided informed consent prior to study activities. Injections were given by an experienced investigator, who was not involved further with the patients. Patients could continue analgesics (except 48 hours prior to visits) and non-pharmacologic therapy, but topical (on target knee) and systemic corticosteroids or additional injections were not allowed. This abstract presents data from the 52-week follow-up visit.

The statistical analyses were based on the least squares means for the treatment-by-week interaction effect using a mixed model for repeated measurement with a restricted maximum likelihood-based approach. The estimated mean treatment difference based on this model was reported with two-sided symmetric 95 % CI and the corresponding p-value.

(ClinicalTrials.gov Identifier: NCT04045431)

Results

Demographic and baseline characteristics were similar between groups (Table 1).

There were clinically relevant decreases in the 3 WOMAC subscale scores from baseline to 52 weeks in both groups (Table 2). Treatment differences in favour of Arthrosamid compared to Synvisc-One were measured in the WOMAC pain, stiffness and physical function subscales, but the differences did not reach statistical significance.

Conclusion

At 52 weeks after treatment, the effectiveness of Arthrosamid was numerically superior to Synvisc‑One but not statistically significantly different, as measured by the WOMAC pain, stiffness and physical function subscales.

Purpose

LNA043 is a modified human angiopoietin-like-3 (ANGPTL3) protein with chondro-anabolic properties. A first-in-human trial showed a favorable safety profile and modulation of pathways involved in osteoarthritis. The primary objective of this trial (NCT 03334812) was to assess the efficacy of a single intra-articular (i.a.) injection of LNA043 in regenerating hyaline cartilage at the donor site in patients undergoing autologous chondrocyte implantation (ACI).

Methods and Materials

This randomized, placebo-controlled, double-blind, proof-of-mechanism study included 14 subjects who received an i.a. LNA043 injection (randomization 2:1) at the end of the cartilage-harvesting procedure. Cartilage regeneration in the full-thickness defect at the ACI donor and index lesion was assessed via lesion-volume changes and glycosaminoglycan content (GAG) at Day 3 (baseline), Weeks 4 (primary endpoint), 12 and 28, using 7T magnetic resonance imaging (MRI), and histology of biopsies (second surgery, Week 4).

Results

LNA043 treatment resulted in a 65±8% refilling (vs placebo: 38±11%, p=0.04) of the donor site after 4 weeks (Figure 1), and increased to 86±11% at Week 28 (vs placebo: 63±14%, p=0.12). The index lesion showed partial repair at Week 4 (change from baseline-volume of the defect-encompassing sub-region: LNA043: +128±97mm³ vs placebo: +16±30mm³, p=0.03). Sodium-MRI demonstrated increased GAG-content of the regenerated donor site (sodium signal-increase of 26±5%, 16±6% and 38±7% for LNA043 vs. -2±12% (p=0.12), 13±10% (p=0.51) and 8±21% (p=0.15) for placebo at Weeks 4, 12 and 28) (Figure 2). Histology and immunohistochemistry confirmed the presence of hyaline cartilage. LNA043 was rapidly distributed into the circulation, no drug-related adverse events (AEs) or serious AEs were reported. No binding anti-LNA043 antibodies were detected.

Conclusion

A single i.a. injection of LNA043 at 20 mg promoted refilling of the donor site in patients undergoing ACI. The newly formed tissue showed hyaline-like quality, LNA043 displayed a favorable safety profile without significant drug related safety signals or immunogenicity.

Purpose

The purpose of this study was: 1) to assess trochlear width, depth, and sulcus angle via magnetic resonance imaging (MRI) in patients without patellofemoral problems and 2) to determine whether bench measurements of donor femurs can better match donors and patients.

Methods and Materials

An analysis was performed on 209 deidentified MRIs. Trochlear width and depth were measured 15 mm and 20 mm distal to the most proximal articular surface. MRI’s were classified into three groups based on trochlear depth (Group 1: 0-4.0 mm; Group 2: 4.1-6.0 mm; 16 Group 3: > 6.0 mm). Difference in trochlear depth at the two distances was calculated. The same protocol was performed on 23 cadaveric knees.

Results

209 MRIs (ages 12-57, average age: 25.8 years) were included in the review. Mean trochlear depths at 15mm and 20mm were significantly different between the groups. Group 3 had significantly larger trochlear widths than Groups 1 and 2. All MRIs showed an increase in trochlear depth between 15 and 20 mm (mean increase: 1.31 ± 0.78 mm). There was no significant difference in trochlear depths between MRI and cadaveric groups. For MRI groups at 15 mm, the resultant apex decreased 10° between Groups 1 and 2 and decreased 7.4° between Groups 2 and 3.

Conclusion

Tibial width has historically been used to assess OCA transplantation but does not consider trochlear depth nor does it guarantee suitable pairings. Assuming trochleae are perfect isosceles triangles, one can measure trochlear width and cartilage sulcus angle via MRI to assess trochlear depth. Additionally, trochlear data was distributed into three independent groups. Consideration of trochlear depth and its distribution may enable more accurate OCA matching.

Purpose

The purpose of this study is to determine the safety and effectiveness of a single injection of nSTRIDE® APS for unilateral knee osteoarthritis (NCT02905240).

Methods and Materials

This study was conducted as an Investigational Device Exemption (IDE-17069) with the FDA. Subjects with knee OA Kellgren-Lawrence 2-4 (n=332) were randomized to receive a single intra-articular injection of APS or saline under ultrasound guidance. The primary endpoint was the change in WOMAC pain from baseline to 12-months post-injection. Secondary endpoints included functional status, knee stiffness, and quality of life. Injection safety and anatomical changes were evaluated by MRI and radiographs 12 months post-injection.

Results

APS treatment showed a significant improvement in WOMAC Pain compared to baseline (51.8±36.2% improvement [95% CI 46.0, 57.7]) 12 months after a single injection, however, no significant difference in treatment effect between APS and saline was observed. No statistical differences in adverse event reporting between groups occurred. There was significant improvement at 12 months from baseline in function, stiffness, VAS pain, and EQ-5D for both groups. No major changes in joint morphology were shown for either group, as assessed by x-ray and MRI. By 12-months post-injection, saline subjects took more rescue medication, restricted medication, and exited due to knee pain at almost twice the rate of APS subjects. A novel post hoc pain responder criteria was created that accounted for medication usage and study exit rate, which demonstrated a statistically significant difference in responder rates(p=0.0239)(Figure 1).

Conclusion

Treatment with a single, intra-articular injection of APS in subjects with knee osteoarthritis can be considered safe, and was found to reduce pain and improve function up to 12 months when compared to baseline. A novel responder criterion incorporating medication usage was developed that could be used in future studies as a method to help mitigate the high placebo response typically observed in knee OA studies.

Purpose

This study aims to compare the medial compartment cartilage condition in patients implanted with a NUsurface to non-surgical controls, on a 2-year follow-up MRI.

Methods and Materials

Population: 242 subjects with a history of partial meniscectomy of at least 6 months, suffering from knee pain (176 NUsurface implanted, 66 non-surgical care). Methods: A randomized controlled superiority trial compared the medial compartment cartilage condition in NUsurface patients and controls on a 2-year follow-up MRI. Evaluation of the cartilage was obtained using a Outerbridge method¹. Cartilage lesions were classified to full-thickness and non-full-thickness lesions (partial thickness defects or no morphological cartilage defects). Statistical analysis was conducted using Fisher’s exact test.

Results

At 2-year follow-up 17/116 (14.7%) NUsurface patients and 14/32 (43.8%) controls deteriorated from non-full thickness to full-thickness lesions in the medial compartment (P=0.001). At baseline, both groups presented similar proportions of full-thickness cartilage defects in the medial femoral condyle (MFC) (26.6% vs 25.6%) (p>0.05) and at 2-years follow-up full-thickness defects were seen in 33/158 (20.9%) of implanted patients vs 24/43 (55.8%) in controls. After 2-years, improvement in the MFC cartilage was significantly higher in implanted patients vs controls (26/42 (61.9%):1/11 (9.1%), respectively (p=0.002)). There was no significant difference in the MTP results.

Conclusion

Two-year results from the FDA-regulated clinical trial demonstrate that the NUsurface implant provides superior protection of the medial compartment cartilage, specifically the MFC, in post meniscectomy patients, when compared to non-surgical care. By reducing or slowing cartilage deterioration, utilizing a replaceable synthetic meniscus, total knee arthroplasty may be delayed.