Treatment of hallux rigidus by a novel bi-phasic aragonite-based implant: results of a two year multi-centre clinical trial.

PURPOSE: The two year results of a multi-centre clinical trial were examined to evaluate surgical treatment of hallux rigidus using a novel, bi-phasic, biodegradable, and cell-free aragonite-based scaffold (Agili-C™, CartiHeal Ltd, Israel). METHODS: Twenty patients with moderate-to-severe hallux rigidus were recruited. After thorough metatarsophalangeal joint (MTPJ-1) debridement, the scaffolds were implanted into the defect centre. Eight patients received concomitant osteotomy. Treatment outcome was followed clinically (Pain VAS, FAAM-ADL, FAAM-Sport, AOFAS-HMIS, maximum active range of extension ROM-EXT, and flexion ROM-FLEX), and by medical imaging, at six month intervals for two years. Adverse events were recorded throughout the study follow-up period. RESULTS: Significant clinical improvement over time was observed in all evaluated parameters (screening to final evaluation averages: Pain VAS 59 to 26, FAAM-ADL 57 to 77, FAAM-Sport 39 to 66, AOFAS-HMIS 51 to 81, ROM-EXT 18° to 36°), except for ROM-FLEX. Radiographs showed stable MTPJ-1 width over the two years in 17/18 cases (94%). MRI demonstrated progressive implant biodegradation, coupled with articular cartilage and subchondral bone regeneration, with a repair tissue defect fill of 75-100% in 14/17 (82%) subjects at their final visit. Revision surgery with implant removal was performed in two patients. CONCLUSION: Bi-phasic, osteochondral, biodegradable, aragonite-based scaffold demonstrated positive clinical outcome and a good safety profile in the treatment of medium-to-advanced hallux rigidus. According to the medical imaging, this implant has the potential to restore the entire osteochondral unit of metatarsal head.

Complex Osteochondral Lesions of the Talus Treated With a Novel Bi-Phasic Aragonite-based Implant.

To present initial results of a novel, bi-phasic, porous, biodegrade, and cell-free aragonite-based scaffold for treating complex osteochondral lesions of the talus (OLT). Four subjects (2 males and 2 females; 34-61 years old) were operated on their ankles due to chronic and deep OLT-Hepple grades 4 or 5 (1.8-2.2 cm2). Three subjects had OLT on the medial central trochlea, and 1 had a combined medial and lateral lesions. OLT were exposed through medial malleolus osteotomy, with an additional lateral arthrotomy in the combined lesions. Bi-phasic porous osteochondral scaffolds (single implant or 2 implants) were implanted in a press-fit manner using a designated surgical toolset. Treatment outcome was followed clinically (Foot and Ankle Outcome Score, EQ-5D 3L, Tegner activity scale) and by medical imaging (radiographs, magnetic resonance imaging) from 18 to 32 months. All Foot and Ankle Outcome Score values increased from preoperative to final follow-up values (Symptoms 62 to 71, Pain 53 to 84, ADL 60 to 89, Sport 19 to 65, and QoL 18 to 47). EQ-5D 3L increased from 0.59 to 0.76, and Tegner activity values increased from 1.5 to 3. Kellgren-Lawrence ankle radiographic scores remained stable (2 to 2). Postoperative MR evaluation demonstrated cartilage defect fill of 75% to 100% respect to the native cartilage in 3 subjects (4 OLTs), while 1 lesion was filled 25% to 50%. No graft related serious adverse events or graft failures were reported. The use of a bi-phasic osteochondral biodegradable aragonite-based scaffold in the treatment of complex OLT during the reported period presented positive and promising clinical and radiologic outcome, without serious adverse events or graft failures.

Osteogenic differentiation of human bone marrow-derived mesenchymal stem cells is enhanced by an aragonite scaffold.

Bone graft substitutes and bone void fillers are predominantly used to treat bone defects and bone fusion in orthopaedic surgery. Some aragonite-based scaffolds of coralline exoskeleton origin exhibit osteoconductive properties and are described as useful bone repair scaffolds. The purpose of this study was to evaluate the in vitro osteogenic potential of the bone phase of a novel aragonite-based bi-phasic osteochondral scaffold (Agili-C™, CartiHeal Ltd.) using adult human bone marrow-derived mesenchymal stem cells (MSCs). Analyses were performed at several time intervals: 3, 7, 14, 21, 28 and 42 days post-seeding. Osteogenic differentiation was assessed by morphological characterisation using light microscopy after Alizarin red and von Kossa staining, and scanning electron microscopy. The transcript levels of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), bone gamma-carboxyglutamate (BGLAP), osteonectin (SPARC) and osteopontin (SPP1) were determined by quantitative PCR. Proliferation was assessed by a thymidine incorporation assay and proliferating cell nuclear antigen (PCNA) immunocytochemistry. Our results demonstrate that the bone phase of the bi-phasic aragonite-based scaffold supports osteogenic differentiation and enhanced proliferation of bone marrow-derived MSCs at both the molecular and histological levels. The scaffold was colonized by differentiating MSCs, suggesting its suitability for incorporation into bone voids to accelerate bone healing, remodelling and regeneration. The mechanism of osteogenic differentiation involves scaffold surface modification with de novo production of calcium phosphate deposits, as revealed by energy dispersive spectroscopy (EDS) analyses. This novel coral-based scaffold may promote the rapid formation of high quality bone during the repair of osteochondral lesions.

Reconstruction of Large Osteochondral Defects Using a Hemicondylar Aragonite-Based Implant in a Caprine Model.

PURPOSE: To investigate the safety and regenerative potential of a hemicondylar aragonite-based scaffold in the reconstruction of large osteochondral lesions occupying an extensive portion of the medial femoral condyle in a goat model. METHODS: Eight Saanen goats were treated by the implantation of an aragonite-based scaffold (size: 19 × 8 × 8 mm) on a previously prepared hemicondylar osteochondral defect located in the right medial femoral condyle of the knee. Goats were euthanized after 12 months and the specimens underwent X-ray imaging, macroscopic, micro-computed tomography, histology, and immunohistochemistry evaluations to assess subchondral bone and cartilage regeneration. RESULTS: In all 8 goats, no adverse event or persistent inflammation was observed. The evaluations performed showed integration of the scaffold, which almost completely resorbed at 12 months. In all animals, no signs of osteoarthritis progression were seen. Concurrent regeneration of the osteochondral unit was observed, with trabecular bone tissue replacing the implant and restoring the subchondral layer, and the formation of an overlying hyaline cartilage surface, well integrated within the surrounding native tissue, also was observed. CONCLUSIONS: The use of the hemicondylar biphasic aragonite-based implant in the treatment of osteochondral defects in the goat model proved to be technically feasible and safe. The scaffold degraded and was replaced by regenerated tissue within the 12-month study period, restoring the osteochondral unit both at the level of the cartilaginous layer and the subchondral bone. CLINICAL RELEVANCE: The present animal study describes a scaffold-based procedure for the treatment of large condylar defects, which often require massive allograft or unicompartmental replacement. The aragonite-based implant promoted a regeneration of both cartilage and subchondral bone, and its use as a "biologic" unicondylar prosthesis might be feasible also in the clinical setting.

Aragonite-Based Scaffold Versus Microfracture and Debridement for the Treatment of Knee Chondral and Osteochondral Lesions: Results of a Multicenter Randomized Controlled Trial.

BACKGROUND: Lesions of the articular cartilage, with or without involvement of the subchondral bone, are a common cause of pain and dysfunction in the knee. Although several treatment options have been developed, the majority of previous clinical trials examined patients with isolated or focal midsized defects, which rarely represent the condition found in the general population. Rather, cartilage lesions are often associated with the presence of mild to moderate osteoarthritic changes. PURPOSE: The present multicenter randomized controlled trial compared the clinical and radiographic outcomes of an aragonite-based osteochondral implant with a control group (arthroscopic debridement/microfractures) in patients affected by joint surface lesions of the knee, including those with concurrent mild to moderate osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 251 patients were enrolled in 26 medical centers according to the following criteria: age 21 to 75 years, up to 3 cartilage defects of International Cartilage Regeneration & Joint Preservation Society grade 3a or above located on the femoral condyles and/or trochlea, total treatable area from 1 to 7 cm2, bony defect depth ≤8 mm, and knee osteoarthritis grade 0 to 3 according to Kellgren-Lawrence score. Patients were randomized to the aragonite-based implant or debridement/microfracture control arm in a 2:1 ratio. Evaluation was performed at 6, 12, 18, and 24 months based on overall Knee injury and Osteoarthritis Outcome Score (KOOS) as the primary endpoint, and the KOOS subscales (Pain, Quality of Life, Activities of Daily Living), percentage of responders, and International Knee Documentation Committee (IKDC) subjective score as the secondary endpoints. Patients also underwent magnetic resonance imaging evaluation at 12 and 24 months to assess defect fill grade. Failures (ie, need for any secondary treatment) and adverse events were also recorded. RESULTS: The implant group showed a statistically superior outcome in the primary endpoint and all secondary endpoints at each follow-up. The magnitude of improvement in the implant group was twice as large as that in the control group in terms of mean KOOS improvement at 2 years. Responder rate (defined as at least a 30-point improvement in overall KOOS) was 77.8% in the implant group as opposed to 33.6% in the control (P < .0001). Statistically superior results were seen in the IKDC score as well. At 24 months, 88.5% of the implanted group had at least 75% defect fill on magnetic resonance imaging as compared with 30.9% of controls (P < .0001). The failure rate was 7.2% for the implant group versus 21.4% for control. CONCLUSION: This aragonite-based scaffold was safe and effective in the treatment of chondral and osteochondral lesions in the knee, including patients with mild to moderate osteoarthritis, and provided superior outcomes as compared with the control group. REGISTRATION: NCT03299959 (ClinicalTrials.gov identifier).

Aragonite-Based Scaffold for the Treatment of Joint Surface Lesions in Mild to Moderate Osteoarthritic Knees: Results of a 2-Year Multicenter Prospective Study.

BACKGROUND: Osteoarthritis (OA) is considered a contraindication to most cartilage repair techniques. Several regenerative approaches have been attempted with the aim of delaying or preventing joint replacement, with controversial results. Currently, there is a paucity of data on the use of single-step techniques, such as cell-free biomimetic scaffolds, for the treatment of joint surface lesions (JSLs) in OA knees. PURPOSE: To present the 2-year follow-up clinical and radiological outcomes after implantation of a novel, cell-free aragonite-based scaffold for the treatment of JSLs in patients with mild to moderate knee OA in a multicenter prospective study. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 86 patients, 60 male and 26 female, with a mean age of 37.4 ± 10.0 years, mild to moderate knee OA, and a mean defect size of 3.0 ± 1.7 cm2, were recruited at 8 medical centers according to the following criteria: radiographic mild to moderate knee OA (Kellgren-Lawrence grade 2 or 3); up to 3 treatable chondral/osteochondral defects (International Cartilage Repair Society grades 3 and 4) on the femoral condyles or trochlea; a total defect size ≤7 cm2; and no concurrent knee instability, severe axial malalignment, or systemic arthropathy. All patients were evaluated at baseline and at 6, 12, 18, and 24 months after implantation using the Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) subjective score. Additionally, magnetic resonance imaging (MRI) was performed to assess the amount of cartilage defect filling at the repaired site. RESULTS: Significant improvement on all KOOS subscales was recorded from baseline (Pain: 49.6 ± 13.1; Activities of Daily Living [ADL]: 56.1 ± 18.4; Sport: 22.8 ± 18.8; Quality of Life [QoL]: 23.5 ± 16.5; Symptoms: 55.4 ± 19.9) to the 24 months' follow-up (Pain: 79.5 ± 21.1 [P < .001]; ADL: 84.1 ± 21.4 [P < .001]; Sport: 60.8 ± 31.9 [P < .001]; QoL: 54.9 ± 30.4 [P < .001]; Symptoms: 77.7 ± 21.2 [P < .001]). The IKDC subjective score showed a similar trend and improved from 37.8 ± 14.7 at baseline to 65.8 ± 23.5 at 24 months (P < .001). MRI showed a significant increase in defect filling over time: up to 78.7% ± 25.3% of surface coverage after 24 months. Treatment failure requiring revision surgery occurred in 8 patients (9.3%). CONCLUSION: The use of an aragonite-based osteochondral scaffold in patients with JSLs and mild to moderate knee OA provided significant clinical improvement at the 24-month follow-up, as reported by the patients. These findings were associated with good cartilage defect filling, as observed on MRI.

Osteochondral regeneration with a novel aragonite-hyaluronate biphasic scaffold: up to 12-month follow-up study in a goat model.

BACKGROUND: The regeneration of articular hyaline cartilage remains an elusive goal despite years of research. Recently, an aragonite-hyaluronate (Ar-HA) biphasic scaffold has been described capable of cartilage regeneration over a 6-month follow-up period. This study was conducted in order to assess the fate of the regenerated osteochondral tissue in a 12-month-long validated caprine model. HYPOTHESIS/PURPOSE: The hypothesis was that the implantation of the Ar-HA implant leads to tissue regeneration and maturation. STUDY DESIGN: A two-arm caprine model of a critical osteochondral defect compares the fate of acute osteochondral defects (group A) to Ar-HA implanted defects (group B). METHODS: Critical 6 mm in diameter and 10-mm in depth osteochondral defects were created in the load-bearing medial femoral condyle of 20 mature goats and randomized into two groups. In group A (n = 6), a blood clot spontaneously filled the defect; in group B (n = 14), a single Ar-HA implant reconstructed the defect. The animals were sacrificed after either 6 or 12 months. Parameters assessed included clinical evaluation, x-rays, micro-CT, ultrasound and histology at both time points, and specimen high-field magnetic resonance imaging with T2 mapping at the 12-month time point. RESULTS: In most group A animals, the defects were not reconstructed (1/3 at 6 months, and 0/3 at 12 months). Defects in group B were mostly reconstructed (5/7 at 6 months and 6/7 at 12 months). Group A defects were either empty or contained fibrous repair tissue; while group B filling was compatible with hyaline cartilage and normal bone. CONCLUSION: Ar-HA scaffolds implanted in critical osteochondral defects result in hyaline cartilage formation and subchondral bone regeneration. The results improved at the 12-month time point compared to the 6-month time point, indicating a continuous maturation process without deterioration of the repair tissue. CLINICAL RELEVANCE: Osteochondral defects are common in humans; the results of the current study suggest that an acellular Ar-HA scaffold might induce cartilage and subchondral bone regeneration.