Elizaveta Kon

Arthroscopic Collagen Meniscus Implantation for Partial Lateral Meniscal Defects A 2-Year Minimum Follow-up Study

Background: Loss of knee meniscal tissue often leads to increased pain and decreased function. Hypothesis: At a minimum 2-year follow-up, patients receiving a lateral collagen meniscus implant (CMI) would show improved knee function and decreased pain compared with their preoperative status. Study Design: Case series; Level of evidence, 4. Methods: Twenty-four patients with irreparable lateral meniscal tears (n = 7) or previous partial lateral meniscectomy (n = 17) underwent arthroscopic lateral collagen meniscus implantation. Clinical evaluation was performed preoperatively, at 6 months, and at a minimum 2-year follow-up with Lysholm, visual analog scale (VAS) for pain, Tegner, objective International Knee Documentation Committee (IKDC), and EuroQol 5 dimensions (EQ-5D) scores. A magnetic resonance imaging (MRI) evaluation was performed preoperatively and at final follow-up using the modified Yulish score for cartilage and the Genovese score for implant size and signal intensity. Results: All clinical scores significantly improved from preoperative evaluation to final follow-up. Average Lysholm scores improved from 64.0 ± 16.2 to 92.7 ± 13.8 (P < .0001), VAS for pain from 55.2 ± 29.4 to 19.5 ± 25.6 (P < .0001), Tegner from 3 (interquartile range, 2-4) to 5 (interquartile range, 4-7) (P = .0062), objective IKDC from 6A, 14B, 4C to 20A, 3B, 1D (P = .0002), and EQ-5D from 0.58 ± 0.28 to 0.89 ± 0.14 (P < .0001). Good to excellent (A + B) objective IKDC scores improved from 83% preoperatively to 96% at 2-year follow-up. The Tegner index (the percentage of the lost activity level that was regained as a result of the treatment intervention) was 47% at 6-month follow-up and 79% at 2-year follow-up: this improvement was statistically significant (P = .0062). The MRI evaluations for tibial and femoral modified Yulish scores for cartilage remained similar over the course of the study; 87.5% of implants were reduced in size, and in 3 cases (12.5%), they were completely resorbed; 50% of the implants had a slightly hyperintense signal (relative to the normal meniscus), and signal intensity changes suggested that full maturation had occurred in 37.5% at final follow-up (based on the Genovese scores). Conclusion: The lateral CMI demonstrated that it was safe in this population study, with decreased pain and improved knee function in 96% of patients with excellent/good Lysholm results in 87% of patients at a minimum 2-year follow-up. The MRI scans demonstrated a decreased implant size relative to a normal meniscus.

Scaffolds for cartilage repair of the ankle joint: The impact on surgical practice

BACKGROUND Ideal management of osteochondral lesions in the ankle joint is still theme of debate. Scaffold-based repair is emerging as a new approach for regenerative treatment. METHODS Articles published in PubMed from 2000 to January 2012 addressing cartilage scaffold-based treatment were identified, including levels I-IV evidence clinical trials with measures of functional, clinical or imaging outcome. RESULTS The analysis showed a progressively increasing number of articles from 2000. The number of selected papers was 19:15 focusing on two-step and 4 on one-step procedures; no randomized studies, 3 comparative studies, 11 case series and 5 case reports were identified. CONCLUSIONS Regenerative surgical approach with scaffold-based procedures is emerging as a potential therapeutic option for the treatment of chondral lesions of the ankle. One step treatments simplify the procedure and the results reported are very close to the previous techniques. However, well-designed studies are lacking, and randomized long-term trials are necessary to confirm the potential of these techniques. LEVEL OF EVIDENCE Review - IV.

Ribose mediated crosslinking of collagen-hydroxyapatite hybrid scaffolds for bone tissue regeneration using biomimetic strategies

This study explores for the first time the application of ribose as a highly biocompatible agent for the crosslinking of hybrid mineralized constructs, obtained by bio-inspired mineralization of self-assembling Type I collagen matrix with magnesium-doped-hydroxyapatite nanophase, towards a biomimetic mineralized 3D scaffolds (MgHA/Coll) with excellent compositional and structural mimicry of bone tissue. To this aim, two different crosslinking mechanisms in terms of pre-ribose glycation (before freeze drying) and post-ribose glycation (after freeze drying) were investigated. The obtained results explicate that with controlled freeze-drying, highly anisotropic porous structures with opportune macro-micro porosity are obtained. The physical-chemical features of the scaffolds characterized by XRD, FTIR, ICP and TGA demonstrated structural mimicry analogous to the native bone. The influence of ribose greatly assisted in decreasing solubility and increased enzymatic resistivity of the scaffolds. In addition, enhanced mechanical behaviour in response to compressive forces was achieved. Preliminary cell culture experiments reported good cytocompatibility with extensive cell adhesion, proliferation and colonization. Overall, scaffolds developed by pre-ribose glycation process are preferred, as the related crosslinking technique is more facile and robust to obtain functional scaffolds. As a proof of concept, we have demonstrated that ribose crosslinking is cost-effective, safe and functionally effective. This study also offers new insights and opportunities in developing promising scaffolds for bone tissue engineering.

One-Step Treatment for Patellar Cartilage Defects With a Cell-Free Osteochondral Scaffold: A Prospective Clinical and MRI Evaluation:

Background: The treatment of symptomatic cartilage defects of the patella is particularly challenging, and no gold standard is currently available. Purpose: To evaluate the clinical results of a biphasic cell-free collagen-hydroxyapatite scaffold and to evaluate osteochondral tissue regeneration with magnetic resonance imaging (MRI). Study Design: Case series; Level of evidence, 4. Methods: Thirty-four patients (18 men and 16 women; mean ± SD: age, 30.0 ± 10 years) were treated by scaffold implantation for knee chondral or osteochondral lesions of the patella (area, 2.1 ± 1 cm2). The clinical evaluation was performed prospectively at 12 and 24 months via the IKDC (International Knee Documentation Committee; objective and subjective) and Tegner scores. MRI evaluation was performed at both follow-ups in 18 lesions through the MOCART score (magnetic resonance observation of cartilage repair tissue) and specific subchondral bone parameters. Results: A statistically significant improvement in all the scores was observed at 12- and 24-month follow-up as compared with the basal evaluation. The IKDC subjective score improved from 39.5 ± 14.5 to 61.9 ± 14.5 at 12 months (P > .0005) with a further increase to 67.6 ± 17.4 at 24 months of follow-up (12-24 months, P = .020). The MRI evaluation showed a stable value of the MOCART score between 12 and 24 months, with a complete filling of the cartilage in 87.0% of the lesions, complete integration of the graft in 95.7%, and intact repair tissue surface in 69.6% at final follow-up. The presence of osteophytes or more extensive bony overgrowth was documented in 47.8% of the patients of this series, but no correlation was found between MRI findings and clinical outcome. Conclusion: The implantation of a cell-free collagen-hydroxyapatite osteochondral scaffold provided a clinical improvement at short-term follow-up for the treatment of patellar cartilage defects. Women had lower outcomes, and the need for realignment procedures led to a slower recovery. MRI evaluation showed some abnormal findings with the presence of bone overgrowth, but no correlation has been found with the clinical outcome.

Evaluation of different crosslinking agents on hybrid biomimetic collagen-hydroxyapatite composites for regenerative medicine.

This study focuses on the development of novel bone-like scaffolds by bio-inspired, pH-driven, mineralization of type I collagen matrix with magnesium-doped hydroxyapatite nanophase (MgHA/Coll). To this aim, this study evaluates the altered modifications in the obtained composite due to different crosslinkers such as dehydrothermal treatment (DHT), 1,4-butanediol diglycidyl ether (BDDGE) and ribose in terms of morphological, physical-chemical and biological properties. The physical-chemical properties of the composites evaluated by XRD, FTIR, ICP and TGA demonstrated that the chemical mimesis of bone was effectively achieved using the in-lab biomineralization process. Furthermore, the presence of various crosslinkers greatly promoted beneficial enzymatic resistivity and swelling ability. The morphological results revealed highly porous and fibrous micro-architecture with total porosity above 85% with anisotropic pore size within the range of 50-200μm in all the analysed composites. The mechanical behaviour in response to compressive forces demonstrated enhanced compressive modulus in all crosslinked composites, suggesting that mechanical behaviour is largely dependent on the type of crosslinker used. The biomimetic compositional and morphological features of the composites elicited strong cell-material interaction. Therefore, the results showed that by activating specific crosslinking mechanisms, hybrid composites can be designed and tailored to develop tissue-specific biomimetic biomaterials for hard tissue engineering.

Treatment of Knee Osteochondritis Dissecans With a Cell-Free Biomimetic Osteochondral Scaffold: Clinical and Imaging Findings at Midterm Follow-up.

Background: Osteochondritis dissecans (OCD) is a developmental condition of subchondral bone that may result in secondary separation and instability of the overlying articular cartilage, which in turn may lead to degeneration of the overall joint and early osteoarthritis. Biphasic scaffolds have been developed to address defects of the entire osteochondral unit by reproducing the different biological and functional requirements and guiding the growth of both bone and cartilage. Purpose: To evaluate midterm clinical and imaging results after cell-free osteochondral scaffold implantation for the treatment of knee OCD. Study Design: Case series; Level of evidence, 4. Methods: Twenty-seven patients (8 women, 19 men; mean age, 25.5 ± 7.7 years) were treated for knee OCD, with International Cartilage Repair Society (ICRS) grade 3 to 4 lesions with a mean size of 3.4 ± 2.2 cm2 (range, 1.5-12 cm2), and prospectively evaluated for up to 5 years using the ICRS classification system and the Tegner score. Eighteen patients underwent magnetic resonance imaging (MRI) at 24 and 60 months of follow-up, and the graft was evaluated using the magnetic resonance observation of cartilage repair tissue (MOCART) score for the cartilage layer, while a specific score was used for subchondral bone. Results: All patients significantly improved their clinical scores at each follow-up until their final evaluation. The mean International Knee Documentation Committee (IKDC) subjective score improved from 48.4 ± 17.8 to 82.2 ± 12.2 at 2 years (P < .0005), and it then remained stable for up to 5 years postoperatively (90.1 ± 12.0). The mean Tegner score increased from 2.4 ± 1.7 preoperatively to 4.4 ± 1.6 at 2 years (P = .001), with a further increase up to 5.0 ± 1.7 at 5 years of follow-up (P < .0005 vs preoperatively), reaching almost the preinjury level (5.7 ± 2.2). The MOCART score showed stable results between 24 and 60 months, whereas the subchondral bone status significantly improved over time. No correlation was found between MRI findings and clinical outcomes. Conclusion: This 1-step cell-free scaffold implantation procedure showed good and stable results for up to 60 months of follow-up for the treatment of knee OCD. MRI showed abnormalities, in particular at the subchondral bone level, but there was an overall improvement of features over time. No correlation was found between imaging and clinical findings.

Cell-based cartilage repair using the hyalograft transplant

Autologous chondrocyte implantation (ACI) is an effective means of treating symptomatic articular cartilage defects. This two-stage cartilage repair strategy relies on the cultured expansion of harvested chondrocytes; these cells are subsequently reimplanted into the host defect and covered (periosteum, collagen patch). The ACI technique has been shown by many authors to result in improved clinical outcomes by facilitating the creation of a hyaline-like cartilage repair tissue. However, it has been demonstrated that defect fill can be variable, and that the procedure itself is technically demanding. Over the past few years, so called “second generation” ACI techniques have been available for clinical use in many parts of the world. These second generation techniques rely on the combination of autologous chondrocytes with absorbable scaffolds. It is believed that the addition of a stable matrix scaffold facilitates the creation of a more hyaline-like cartilage repair tissue. We describe, herein, such a technique. The Hyalograft C implant has been used to treat symptomatic cartilage defects at our institution for many years. This implant consists of autologous chondrocytes that are seeded on a hyaluronan-based scaffold. Implantation of the Hyalograft C scaffold simplifies the method by which autologous chondrocytes may be used to repair a cartilage defect. Moreover, we believe this is the first method by which autologous chondrocytes may be implanted using minimally invasive arthroscopic techniques. The Hyalograft C implant effectively treats symptomatic cartilage defects in a manner that is less morbid, simpler, and more predictable than first-generation ACI methods.

Clinical Outcomes of Knee Osteoarthritis Treated With an Autologous Protein Solution Injection: A 1-Year Pilot Double-Blinded Randomized Controlled Trial

Background: Osteoarthritis (OA) is a debilitating disease resulting in substantial pain and functional limitations. A novel blood derivative has been developed to concentrate both growth factors and antagonists of inflammatory cytokines, with promising preliminary findings in terms of safety profile and clinical improvement. Purpose: To investigate if one intra-articular injection of autologous protein solution (APS) can reduce pain and improve function in patients affected by knee OA in a multicenter, randomized, double-blind, saline-controlled study. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Forty-six patients with unilateral knee OA (Kellgren-Lawrence 2 or 3) were randomized into the APS group (n = 31), which received a single ultrasound-guided injection of APS, and the saline (control) group (n = 15), which received a single saline injection. Patient-reported outcomes and adverse events were collected at 2 weeks and at 1, 3, 6, and 12 months through visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), Short Form–36 (SF-36), Clinical Global Impression of Severity/Change (CGI-S/C), Patient Global Impression of Severity/Change (PGI-S/C), and Outcome Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) responder rate. Imaging evaluation was also performed with radiograph and magnetic resonance imaging (MRI) before and after treatment (12 months and 3 and 12 months, respectively). Results: The safety profile was positive, with no significant differences in frequency and severity of adverse events between groups. The improvement from baseline to 2 weeks and to 1, 3, and 6 months was similar between treatments. At 12 months, improvement in WOMAC pain score was 65% in the APS group and 41% in the saline group (P = .02). There were no significant differences in VAS pain improvement between groups. At 12 months, APS group showed improved SF-36 Bodily Pain subscale (P = .0085) and Role Emotional Health subscale (P = .0410), as well as CGI-C values (P = .01) compared with saline control. Significant differences between groups were detected in change from baseline to 12 months in bone marrow lesion size as assessed on MRI and osteophytes in the central zone of the lateral femoral condyle, both in favor of the APS group (P = .041 and P = .032, respectively). There were no significant differences between APS and control groups in other measured secondary endpoints. Conclusion: This study provides evidence to support the safety and clinical improvement at 1-year follow-up of a single intra-articular injection of APS in patients affected by knee OA. Treatment with APS or a saline injection provided significant pain relief over the course of the study with differences becoming apparent at between 6 and 12 months after treatment. Trial Registration: NCT02138890 (ClinicalTrials.gov identifier)

“Bone Morphogenic Protein augmentation for long bone healing” response to “Clinical need for bone morphogenetic protein”

We take advantage of the comments of Dr. Vukicevic et al. to clarify that the study focus did not include other diseases and locations than long bones; in this light, the articles that Dr. Vukicevic mentioned could not be selected. We would like to recognize the key contribution of Urist and the nice tribute of the International Orthopaedics heritage section on the BMPs discovery. While we could not refer to the latter, published after our search, we put emphasis on the steps of important discoveries that made BMPs available for clinical use, a road that started in 1965, when Urist showed that new bone formation could be induced by demineralized bone matrix, later identified as BMPs, and purified in the next three decades. In the past years, BMPs have been studied in several pre-clinical models. As this was not the focus of this systematic clinical review, only some pre-clinical papers were cited, aiming at underlining important aspects, such as the relationship between dosage and bone formation and the delivery material, which could influence BMPs release and effect, key factors requiring further studies to optimize BMPs augmentation, as mentioned in the discussion. While our article does not present the methodological strength of a meta-analysis, and while it was not possible to summarize the entire extensive literature on BMPs, we hope that our review could be useful to summarize the available evidence in terms of both BMPs augmentation potential and complications for the treatment of long bones affected by fractures, non-union, and osteonecrosis.

3D porous collagen scaffolds reinforced by glycation with ribose for tissue engineering application

In this study, ribose was proposed as a promising, non-toxic, low-cost crosslinker to enhance the structural integrity and stiffness of type I collagen matrices. The main objective was to determine the optimal conditions of glycation by ribose to fabricate 3D porous collagen scaffolds and to verify their effectiveness for use as scaffolds for cartilage tissue engineering, by physicochemical and biological characterization. Two different crosslinking strategies were investigated including variation in the amount of ribose and the time of reaction: pre-crosslinking (PRE) and post-crosslinking (POST). All ribose-glycated collagen scaffolds demonstrated good swelling properties and interconnected porous microstructure suitable for cell growth and colonization. The POST samples were superior to PRE, in terms of porosity, degree of crosslinking, fluid uptake ability, and resistance to enzymatic digestion. Moreover, the mechanical properties of the scaffolds were significantly improved upon glycation when compared to non-crosslinked collagen, manifesting the best performance for POST matrices crosslinked for 5 d and in the highest amount of sugar. In vitro studies analyzing cell-material interactions revealed scaffold cytocompatibility with higher cell viability and cell proliferation as well as higher glycosaminoglycan secretion for POST scaffolds with respect to PRE. This report demonstrated the feasibility of developing 3D collagen scaffolds by ribose glycation and highlighted the POST-crosslinking strategy as being more favorable than the PRE-crosslinking to achieve scaffolds suitable for cartilage regeneration.