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CARTILAGE REPAIR - SHOWING SIGNS OF PROMISE

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CARTILAGE REPAIR - SHOWING SIGNS OF PROMISE

By Sharon O’Reilly

Regenerating hyaline cartilage is one of the most elusive and highly sought after goals facing researchers in the orthopaedic industry today. Attempts over the last two decades to regenerate “true” hyaline cartilage using both cell-based and, more recently, cell-free approaches have fallen short. This is not due to lack of trying or investment in this space. At the ICRS 2013, 11th World Congress of the International Cartilage Repair Society, held in Izmir, Turkey in from September 15 – 18, it appears that progress in this field has finally turned a corner and strides in basic research are being made to unravel the potential reparability of the tissue covering the articular surface of joints.

Interest in cartilage regeneration remains high since the general consensus is that an injury to the articular cartilage is the first step in the joint degenerative process. However, the reality is that not all cartilage injures progress onto osteoarthritis although the risk is higher for larger lesions. Another misconception is that an articular cartilage injury results in pain. However, not all cartilage lesions are painful (cartilage has no neural innervations) or need to be treated unless they are symptomatic. So questions arise as to what makes a cartilage lesion painful and what makes a lesion predisposed to osteoarthritis?

Presentations at ICRS not only focused on the underlying mechanisms for cartilage regeneration but also shed light on the role of subchondral bone in articular cartilage repair. The presence of bone bruises or bone marrow edema resulting from a traumatic injury or chronic abnormal joint loading was raised as a potential source for pain associated with a cartilage injury. In fact, microfracture of the underlying subchondral bone—a common first line of treatment for chondral defects—has shown to negatively impact certain cartilage repair techniques such as autologous chondrocyte implantation (ACI).

Also highlighted at the meeting were new imaging technologies such as functional MRI with T2 mapping that have the capability of detecting abnormalities in cartilage composition before structural degeneration occurs. Though, an important criteria yet to be addressed is a method besides biopsy for detecting the “type” of cartilage that forms after an implant is placed in humans with many studies reporting the “percent defect filled” on MRI without specificity on whether it is filled with Type 1 fibro cartilage or Type II hyaline cartilage. All of these findings provide revealing “clues” on requirements for successful technology development in this arena.

Numerous Products & Wide Open Market

It was 20 years ago when Genzyme (today Sanofi) broke ground with its autologous chondrocyte implantation (ACI) technique and, today, Carticel remains the only FDA approved cartilage repair product on the US market. Since that time, researchers have investigated countless ways for restoring the structure and function of articular cartilage. Starting with cell transplantation techniques (autologous cells, juvenile cells, stem cells) and osteochondral grafts moving onto bioactive factors and biophasic constructs to cell-free scaffolds as adjuncts to microfracture—almost every conceivable biomaterial (e.g., collagen, polymers, polyurethanes, chitosan, hyaluronic acid, fibrin glue, hydrogels, ceramics, carbon fibre and combinations thereof have been tried. According to BioMedGPS’ SmartTRAK Business Intelligence, there are more than 80 products from 60+ companies on the worldwide stage seeking a solution for cartilage regeneration. Even though the field appears crowded, the market is wide open for a technology that reliably reproduces Type II hyaline cartilage.

The worldwide market for cartilage repair was projected to reach over $100 million in 2013, according to SmartTRAK Cartilage module. While Europe has long been the testing ground for new cartilage technologies, surprisingly, the US accounts for two-thirds of the overall global market— even though there is only one product approved on the market. Despite numerous attempts, only a handful of cartilage products have been granted an approved IDE by the FDA to commence human trials in the US. According to SmartTRAK, there are five products currently in IDE trials in the US: ISTO’s RevaFlex (formerly DeNovo ET), Histogenics’ NeoCart, DePuy Synthes’ CAIS, Medipost’s Cartistem, and TissueGene’s TG-C growth factor technology.

Most Action in Europe

Unlike the US where osteochondral allografts and variations thereof are widely used since they qualify as Human Tissue products and are not considered a device by FDA, most products in Europe on the market or under development for cartilage repair are cell-based or cell-free products. However, recent EMEA regulations governing cell-based approaches have forced companies such as TiGenix, Sanofi, co.don, among others, to conduct rigorous PMA-like studies to keep their products on the EU market. Earlier this year, Sanofi MACI, a matrix-induced ACI, became the third cell-based product approved as an Advanced Therapy Medicinal Product by the EMEA and the second cartilage repair technology after TiGenix’ ChondroCelect, which was the first EMEA approved product in 2009.

Adjuncts to Microfracture

With attention shifting away from expensive cell-based approaches, many companies have developed cell-free options that function as adjuncts to microfracture and can be approved as a device via a CE Mark. The rationale behind these technologies is that drilling into the subchondral bone during microfracture releases autologous bioactive factors (e.g., stem cells and growth factors) from the bleeding site. These factors penetrate the implant and differentiate into hyaline cartilage producing cells. Unfortunately, the typical result is the generation of “hyaline-like” tissue rather than the real deal—Type II hyaline cartilage.

Among the microfracture adjuncts on the OUS market exhibited at ICRS World Congress 2013 include Geistlich with the Chondro-Gide, a high-strength resorbable bilayered Type I/III porcine collagen membrane, which forms a secure clot over a microfractured site capturing growth factors and stem cells that differentiate into “hyaline-like” tissue. Piramal Life Sciences with BST-Cargel, a chitosan-glycerol phosphate that when dispersed with fresh autologous whole blood causes the blood to clot when placed within a cartilage lesion. Piramal’s BST-CarGel received additional press when results of an 80-patient randomized controlled study was published in the September issue of Journal of Bone and Joint Surgery that showed BST-CarGel treatment resulted in greater lesion filling and superior repair tissue quality versus microfracture alone. However, clinical benefit was equivalent between the two groups at 12 months. A commentary on the study entitled, “Augmented Microfracture: Is This the Holy Grail That We Have Been Searching for in the Treatment of Cartilage Injuries?” concluded that while results were short, this technique may provide a reasonable alternative to more expensive 2-stage autologous chondrocyte transplantation procedures.

Arthrex exhibited two cartilage repair technologies at ICRS: BioMatrix, a cell-free composite implant, and BioCartilage, a minced cartilage allograft mixed with platelet rich plasma that is implanted in a microfractured defect arthroscopically and held in place with fibrin glue. Other products exhibited at ICRS were Regentis’ GelrinC, a PEG hydrogel forms a dense gel following exposure to UV light functioning as a biosynthetic blood clot and attracting cells into a microfractured defect. CellCoTec’s INSTRUCT, which combines chondrocytes and bone marrow cells isolated from biopsies using a cell processor that are seeded on a 3D biodegradable polymer scaffold. Finceramica’s MaioRegen, a tri-layered 3D matrix that corresponds to the three layers of an osteochondral defect has clinical results reaching 5 years. Amedrix with ChondroFiller Gel, Anika with Hyalofast, and BMI Biomedical Implants with carbon fiber CHOPIN Pins.

While not an exhibitor, CartiHeal presented long term results from preclinical studies evaluating the safety and performance of Agili-C, a cell-free implant composed of modified aragonite and hyaluronic acid. A well-funded Israeli start-up, CartiHeal, plans to invest in the research required to fully understand Agili-C’s underlying mechanism of action for hyaline cartilage regeneration. This year, Cartiheal received Israel’s prestigious “Incubator Company Excellence Award” for 2012 in recognition of its groundbreaking cartilage regeneration technology platform.

Subchondroplasty

With increased attention placed on the subschondral bone as the source of knee pain, one technology to watch is Zimmer’s Subchondroplasty. This simple, low cost minimally invasive procedure involves injecting a bone cement-like material into the area of bruised bone as detected by T2 mapping on MRI stabilizing the site and alleviating pain. While the results are still early, Subchondroplasty may prove to be an effective solution to a challenging problem for so many OA patients with knee pain.
 

Autor

Dr Adriano Karpstein

Dr Adriano Karpstein

Medicina Esportiva, Ortopedista e Traumatologista

Especialização em Cirurgia de Joelho, Traumatologia Esportiva e Cirurgia Artroscópica no(a) Hospital de Clínicas - Universidade Federal do Paraná.