Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.

https://escholarship.org/content/qt76m4g3q5/qt76m4g3q5.pdf?t=oe66jy

Repair and tissue engineering techniques for articular cartilage

Injuries to articular cartilage and menisci can lead to cartilage degeneration that ultimately results in arthritis. Different forms of arthritis affect ~50 million people in the USA alone, and it is therefore crucial to identify methods that will halt or slow the progression to arthritis, starting with the initiating events of cartilage and meniscus defects. The surgical approaches in current use have a limited capacity for tissue regeneration and yield only short-term relief of symptoms. Tissue engineering approaches are emerging as alternatives to current surgical methods for cartilage and meniscus repair. Several cell-based and tissue-engineered products are currently in clinical trials for cartilage lesions and meniscal tears, opening new avenues for cartilage and meniscus regeneration. This Review provides a summary of surgical techniques, including tissue-engineered products, that are currently in clinical use, as well as a discussion of state-of-the-art tissue engineering strategies and technologies that are being developed for use in articular cartilage and meniscus repair and regeneration. The obstacles to clinical translation of these strategies are also included to inform the development of innovative tissue engineering approaches.

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Surgical and tissue engineering strategies for articular cartilage and meniscus repair.

Fighting bacterial resistance is one of the concerns in modern days, as antibiotics remain the main resource of bacterial control. Data shows that for every antibiotic developed, there is a microorganism that becomes resistant to it. Natural polymers, as the source of antibacterial agents, offer a new way to fight bacterial infection. The advantage over conventional synthetic antibiotics is that natural antimicrobial agents are biocompatible, non-toxic, and inexpensive. Chitosan is one of the natural polymers that represent a very promising source for the development of antimicrobial agents. In addition, chitosan is biodegradable, non-toxic, and most importantly, promotes wound healing, features that makes it suitable as a starting material for wound dressings. This paper reviews the antimicrobial properties of chitosan and describes the mechanisms of action toward microbial cells as well as the interactions with mammalian cells in terms of wound healing process. Finally, the applications of chitosan as a wound-dressing material are discussed along with the current status of chitosan-based wound dressings existing on the market.

Chitosan as a Wound Dressing Starting Material: Antimicrobial Properties and Mode of Action

Background:Randomized controlled trials studying the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes (MACI) versus microfracture (MFX) for treating cartilage defects are limited.Purpose:To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee.Study Design:Randomized controlled clinical trial; Level of evidence, 1.Methods:Patients enrolled in the SUMMIT (Demonstrate the Superiority of MACI implant to Microfracture Treatment) trial had ≥1 symptomatic focal cartilage defect (Outerbridge grade III or IV; ≥3 cm2) of the femoral condyles or trochlea, with a baseline Knee Injury and Osteoarthritis Outcome Score (KOOS) pain value <55. The co–primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years. Histological evaluation and magnetic resonance imaging (MRI) assessments of structural repair tissue, treatment failure, the remaining 3 KOOS subscales,...

http://journals.sagepub.com/doi/pdf/10.1177/0363546518756976

Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture Two-Year Follow-up of a Prospective Randomized Trial

Context:Isolated chondral and osteochondral defects of the knee are a difficult clinical challenge, particularly in younger patients for whom alternatives such as partial or total knee arthroplasty are rarely advised. Numerous surgical techniques have been developed to address focal cartilage defects. Cartilage treatment strategies are characterized as palliation (eg, chondroplasty and debridement), repair (eg, drilling and microfracture [MF]), or restoration (eg, autologous chondrocyte implantation [ACI], osteochondral autograft [OAT], and osteochondral allograft [OCA]).Evidence Acquisition:PubMed was searched for treatment articles using the keywords knee, articular cartilage, and osteochondral defect, with a focus on articles published in the past 5 years.Study Design:Clinical review.Level of Evidence:Level 4.Results:In general, smaller lesions (<2 cm2) are best treated with MF or OAT. Furthermore, OAT shows trends toward greater longevity and durability as well as improved outcomes in high-demand pati...

/pdf/knee-articular-cartilage-repair-and-restoration-techniques-a-3yb6x6cpm5.pdf

Knee Articular Cartilage Repair and Restoration Techniques: A Review of the Literature

Background: Microfracture, the standard of care, is recognized to be an incomplete solution for cartilage damage. BST-CarGel, a chitosan-based medical device, is mixed with autologous whole blood and is applied to a microfractured cartilage lesion in which it physically stabilizes the clot and guides and enhances marrow-derived repair. An international, multicenter, randomized controlled trial was conducted to evaluate BST-CarGel treatment compared with microfracture alone in the repair of cartilage lesions in the knee.

Methods: Eighty patients between the ages of eighteen and fifty-five years with a single, symptomatic focal lesion on the femoral condyles were randomized to BST-CarGel and microfracture treatment (n = 41) or microfracture treatment alone (n = 39). The primary end points of repair tissue quantity and quality at twelve months were assessed by quantitative three-dimensional magnetic resonance imaging measuring the degree of lesion filling and T2 relaxation time with use of standardized one and twelve-month posttreatment scans. The secondary end point at twelve months was clinical benefit determined with the Western Ontario and McMaster Universities Osteoarthritis Index. The tertiary end point was quality of life determined by the Short Form-36. Safety was assessed through the recording of adverse events.

Results: Patient baseline characteristics were similar in the two groups, although baseline lesion areas were slightly larger on quantitative magnetic resonance imaging for the BST-CarGel group compared with the microfracture group. Blinded quantitative magnetic resonance imaging analysis demonstrated that, at twelve months, when compared with microfracture treatment alone, BST-CarGel treatment met both primary end points by achieving statistical superiority for greater lesion filling (p = 0.011) and more hyaline cartilage-like T2 values (p = 0.033). The lesion filling values were 92.8% ± 2.0% for the BST-CarGel treatment group and 85.2% ± 2.1% for the microfracture treatment group, and the mean T2 values were 70.5 ± 4.5 ms for the BST-CarGel treatment group and 85.0 ± 4.9 ms for the microfracture treatment group. Western Ontario and McMaster Universities Osteoarthritis Index subscales for pain, stiffness, and function yielded equivalent improvement for both groups at twelve months, which were significant (p < 0.0001) from baseline. Treatment safety profiles were considered comparable.

Conclusions: At twelve months, BST-CarGel treatment resulted in greater lesion filling and superior repair tissue quality compared with microfracture treatment alone. Clinical benefit was equivalent between groups at twelve months, and safety was similar.

Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Novel scaffold-based BST-CarGel treatment results in superior cartilage repair compared with microfracture in a randomized controlled trial.

ObjectiveThe efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter randomized controlled trial in the knee. This report was undertaken to investigate 5-year structural and clinical outcomes.DesignThe international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. Patients were randomized to receive BST-CarGel® treatment or microfracture alone, and followed standardized 12-week rehabilitation. Co-primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling (%) and T2 relaxation times. Secondary endpoints were clinical benefit measured with WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires and safety. General estimating equations were used for longitudinal statistical analysis of repeated measures.ResultsBlinded MRI analysis ...

BST-CarGel® Treatment Maintains Cartilage Repair Superiority over Microfracture at 5 Years in a Multicenter Randomized Controlled Trial.

Purpose: Cartilage repair clinical trials should evaluate repair tissue structure as well as clinical benefit to assess biomechanical function of the repair and the potential for long term durability. Newer MRI techniques offer non-invasive quantification of both quantity and quality of repair. A standardized quantitative 3-dimensional (3D) MRI was used as the primary endpoint (repair tissue quantity and quality) of a cartilage repair RCT comparing BST-CarGel® (Piramal Healthcare (Canada) Ltd.) treatment to the microfracture control. Materials and Methods: A multicenter trial comparing BST-CarGel® treatment[1] to microfracture enrolled 80 patients (BST-CarGel® n=41, MFX n=39), with grade III/IV focal lesions on the femoral condyles. Standardized MRI scans were obtained from each patient using 3D fat-suppressed SPGR and 3D-GRE for morphological analysis, and fat-suppressed Dual Echo Spin Echo for T2 mapping. Condyles were reconstructed in 3D with semi-automated (radiologist corrected) morphological segmentation using an anatomical atlas and validated methodologies.[2] Co-registration of 1 month to 12 month scans permitted Lesion % Fill to be calculated from the ratio of new repair tissue volume at 12-months to the baseline cartilage lesion volume at 1-month post-treatment. Average T2 values at 12 months, which reflect collagen macromolecular content, organization and tissue hydration, were derived from the entire repair tissue volume as well as from separate zones representing the top and bottom halves of the repair tissue. Histological sections from 13-month elective osteochondral biopsies (BST-CarGel® n=21, MFX n=17) were evaluated using a validated PLM score[3-4] for collagen architecture and zonal stratification. Pre-specified linear and non-linear statistical models were applied to investigate potential associations between matched T2, PLM scores and Lesion % Fill. International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine 9 th Biennial ISAKOS Congress • May 12-16, 2013 • Toronto, Canada ISAKOS

Quantitative 3D MRI as a Valid Endpoint for Randomized Clinical Trials in Cartilage Repair and its Correlation with Repair Tissue Collagen Architecture

Introduction: An international, multicenter randomized clinical trial was conducted to evaluate the efficacy and safety of BSTCarGel® (Piramal Healthcare, Laval, Canada), for the repair of articular cartilage lesions, compared to microfracture alone. BST-CarGel® is a device composed of the biomaterial chitosan (polyglucosamine) which is applied over a microfractured lesion. Materials and Methods: 80 patients at international sites (Canada, Spain, South Korea) were randomized (1:1) to either BST-CarGel® +microfracture or microfracture alone. Enrolled patients were aged 18 to 55, with BMIs=30 and had a single, symptomatic, grade III or IV lesion on their femoral condyles. They followed standardized 12 week post-operative rehabilitation. Quantity and quality of cartilage repair tissue was assessed at 12 months using quantitative MRI techniques. Supplemental structural data (ICRS I and II Histology Scoring and Polarized Light Microscopy (PLM) scoring) was also obtained from elective osteochondral biopsies taken at an average of 13 months from 38 consenting patients. Clinical improvement was measured at 12 months using WOMAC and SF-36 questionnaires, and safety was evaluated by monitoring adverse events. Results: Blinded MRI analysis demonstrated that BST-CarGel® met both primary endpoints by achieving statistical superiority for BST-CarGel® in greater % Lesion Fill (p=0.0105) and more cartilage-like repair tissue T2 values (p=0.0330) when compared with microfracture alone. WOMAC assessments for pain, stiffness and function yielded equivalent improvement for both groups at 12 months, which were statistically significant (p<0.0001) from baseline. Safety was comparable for both groups. When compared to microfracture, BST-CarGel® repair tissue showed improved ICRS macroscopic grading (p=0.0002) at second-look arthroscopy, superior collagen organization by PLM (p=0.0003), and improvements in most histological parameters (4/6 ICRS-I and 10/14 ICRS-II, with 8 at (p<0.05) or near significance International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine 9 th Biennial ISAKOS Congress • May 12-16, 2013 • Toronto, Canada ISAKOS

An International Randomized Clinical Trial Evaluating Bst-Cargel®, A Novel Scaffold For Cartilage Repair, Demonstrates Superiority of Repair When Compared with Microfracture Alone Treatment

Jacques Desnoyers

Papers

Novel scaffold-based BST-CarGel treatment results in superior cartilage repair compared with microfracture in a randomized controlled trial.

BST-CarGel® Treatment Maintains Cartilage Repair Superiority over Microfracture at 5 Years in a Multicenter Randomized Controlled Trial.

Quantitative 3D MRI as a Valid Endpoint for Randomized Clinical Trials in Cartilage Repair and its Correlation with Repair Tissue Collagen Architecture

An International Randomized Clinical Trial Evaluating Bst-Cargel®, A Novel Scaffold For Cartilage Repair, Demonstrates Superiority of Repair When Compared with Microfracture Alone Treatment