Emerging technologies: What is the future of cartilage restoration?

Introduction Injury to articular cartilage injury is a common and challenging diagnosis, often resulting in substantial morbidity for patients. A treatment strategy typically includes simple debridement, microfracture, osteochondral autograft or allograft transplantation or cell-based therapy such as autologous chondrocyte implantation. We review cell-based cartilage repair technologies currently in the early phases of clinical application and highlight the promise and limitations in this rapidly advancing area of musculoskeletal medicine. Conclusion Cartilage restoration is a field that is currently growing at a fast pace. We reviewed new cartilage restoration technologies; many of these have shown promise but have relatively limited long-term outcome data to guide clinicians. Future research will help improve our understanding, and more effective techniques can become available. Introduction Despite substantial progress on basic science and clinical fronts over the last few decades, articular cartilage injury remains an enormous challenge for musculoskeletal physicians. The diagnosis is unfortunately quite common–in a review of over 25,000 knee arthroscopies performed over a 15-year period, the incidence of chondral lesions was noted to be 60%1. Chondral injuries often cause substantial morbidity for patients, including significant time lost from work and sport2. Furthermore, while the natural history of the various types of chondral lesions is not yet fully understood3, a long-term concern is development of progressive degenerative joint disease. The disease burden for both patients and physicians is large, and given the complexity of the issues involved, treatment dilemmas often exist. Algorithms for operative treatment of symptomatic chondral lesions vary, but guidelines for choosing between currently available treatments have been offered4,5. These include evaluation and treatment of any associated joint pathologies including systemic disorders, limb malalignment, meniscal deficiency and ligamentous instability. A thorough assessment of the size, thickness and location of the chondral lesion is also required. Based on lesion and patient characteristics, a treatment strategy is chosen. In current practice, this typically includes one of the following options: simple debridement, microfracture, osteochondral autograft or allograft transplantation or cellbased therapy such as autologous chondrocyte implantation (ACI). Each of these strategies has relative merits and limitations, but no currently available technique meets all requirements for an ‘ideal’ treatment option. As described by Gomoll and Farr, an ideal cartilage repair technique would be (1) cost-efficient, (2) easily available or of-the-shelf, (3) implantable through a singlestage, minimally invasive technique, (4) produce physiologically stratified, fully integrated (basilar and marginal) hyaline repair tissue and (5) allow for quick return to activity6. While current options–with varying degrees of efficacy–may ameliorate symptoms, the broader goal of restoring a durable, smooth, hyaline tissue that effectively transmits shear and compressive loads from the cartilage to the bone remains elusive7. A recapitulation of the multilayered nature of hyaline cartilage, including the normal bone–cartilage interface, appears to be fundamental to this endeavor7. The goal of this critical review is to provide an overview of cell-based cartilage repair technologies currently in the early phases of clinical application and highlight the promise and limitations in this rapidly advancing area of musculoskeletal medicine. Discussion Restoration techniques based on chondrocyte transplantation ACI ACI (Sanofi Bioservices, Cambridge, MA) was the first technique developed to treat chondral defects with chondrocyte transplantation. ACI was pioneered in Sweden in the mid1980s and was the subject of a landmark clinical report by Peterson and Brittberg in 19948. The technology received FDA approval for use in the United States in 19956. The concept involves a two-stage procedure in which a small sample of healthy, articular cartilage is biopsied and undergoes enzymatic digestion followed by cultivation and expansion of chondrocytes in a laboratory setting over a several week period. The resulting cell culture is treated with trypsin and placed in liquid suspension * Corresponding author: Email: David.Flanigan@osumc.edu Cartilage Restoration Program, OSU Sports Medicine, Sports Health and Performance Institute, Department of Orthopaedics, The Ohio State University, Columbus, OH


Introduction
Despite substantial progress on basic science and clinical fronts over the last few decades, articular cartilage injury remains an enormous challenge for musculoskeletal physicians.The diagnosis is unfortunately quite common-in a review of over 25,000 knee arthroscopies performed over a 15-year period, the incidence of chondral lesions was noted to be 60% 1 .Chondral injuries often cause substantial morbidity for patients, including significant time lost from work and sport 2 .Furthermore, while the natural history of the various types of chondral lesions is not yet fully understood 3 , a long-term concern is development of progressive degenerative joint disease.The disease burden for both patients and physicians is large, and given the complexity of the issues involved, treatment dilemmas often exist.
Algorithms for operative treatment of symptomatic chondral lesions vary, but guidelines for choosing between currently available treatments have been offered 4,5 .These include evaluation and treatment of any associated joint pathologies including systemic disorders, limb malalignment, meniscal deficiency and ligamentous instability.A thorough assessment of the size, thickness and location of the chondral lesion is also required.Based on lesion and patient characteristics, a treatment strategy is chosen.In current practice, this typically includes one of the following options: simple debridement, microfracture, osteochondral autograft or allograft transplantation or cellbased therapy such as autologous chondrocyte implantation (ACI).
Each of these strategies has relative merits and limitations, but no currently available technique meets all requirements for an 'ideal' treatment option.As described by Gomoll and Farr, an ideal cartilage repair technique would be (1) cost-efficient, (2) easily available or of-the-shelf, (3) implantable through a singlestage, minimally invasive technique, (4) produce physiologically stratified, fully integrated (basilar and marginal) hyaline repair tissue and (5) allow for quick return to activity 6 .While current options-with varying degrees of efficacy-may ameliorate symptoms, the broader goal of restoring a durable, smooth, hyaline tissue that effectively transmits shear and compressive loads from the cartilage to the bone remains elusive 7 .A recapitulation of the multilayered nature of hyaline cartilage, including the normal bone-cartilage interface, appears to be fundamental to this endeavor 7 .
The goal of this critical review is to provide an overview of cell-based cartilage repair technologies currently in the early phases of clinical application and highlight the promise and limitations in this rapidly advancing area of musculoskeletal medicine.

Discussion
Restoration techniques based on chondrocyte transplantation ACI ACI (Sanofi Bioservices, Cambridge, MA) was the first technique developed to treat chondral defects with chondrocyte transplantation.ACI was pioneered in Sweden in the mid-1980s and was the subject of a landmark clinical report by Peterson and Brittberg in 1994 8 .The technology received FDA approval for use in the United States in 1995 6 .7][18][19] , and three recent studies have been published with MACI versus osteochondral autograft 20 , ACI with collagen membrane 21 and microfracture 22 .In all three studies, MACI showed improved clinical results over the alternative restorative techniques.

Hyalograft C
Hyalograft C (Fidia Advanced Biopolymers Laboratories, Padova, Italy) is a tissue engineered scaffold (Figure 1), whose main component -HYAFF11 -is an esterified derivative of hyaluronic acid (HA) 23 .HA is a prominent component of normal cartilage matrix.A cartilage sample is obtained from an initial arthroscopy, and the chondrocytes are harvested and seeded onto the HA scaffold.This scaffold is comprised of a network of 20-micron thick fibres.
It is believed that the scaffold promotes matrix production and limits dedifferentiation of cells expressing the chondrocyte phenotype 4 .The graft can be implanted arthroscopically with application of gentle pressure to allow fit into the lesion bed 23 .
The scaffold is designed to take advantage of the natural adhesive properties of the complex sugars in the matrix and allows for implantation without adjunctive fixation for implantation at a second-stage surgery.The cellular implantation requires an open surgery in which the chondral lesion is carefully prepared and a periosteal (or collagen) patch is sutured in place over the lesion to create a watertight seal.The cellular suspension is then delivered into the lesion bed below the patch 8 .By implanting expanded chondrocytes into the lesion, the goal is to ultimately fill the defect with a mature hyaline-like cartilage, with wear and load transmission properties more closely approximating native cartilage 4 .Since its introduction, ACI has gained widespread acceptance as a viable cartilage repair strategy.In addition, generally favourable clinical results have been reported in numerous studies 4,[8][9][10][11][12] , and ACI remains a valuable tool for many cartilage restoration surgeons.However, there are limitations to the technique.These include the overall cost of the procedure, the two-stage surgical technique, lengthy and intensive rehab and complications attendant to an extensive surgical procedure 4,13 .This has limited the widespread use of ACI.
To address some of these potential problems and limitations with the original ACI method, numerous variations on the original concept have been developed in the past decade..The size of the hydrogel plug can be manufactured to meet the size requirements of the defect being treated.The hydrogel plug is manufactured to a predetermined diameter, and at implantation the lesion is drilled to a depth of 4 mm and a diameter corresponding to the size of the implant.The implant is then pressfit into the defect without adjunctive fixation.A multicentre case series of 17 patients with 2-year outcome data has been reported for Cartipatch 30 .

Emerging cartilage restoration technologies-two-stage techniques
The series demonstrated significantly improved IKDC scores over baseline.
.NeoCart is currently undergoing a phase III trial 27 .

BioCart II
BioCart II (ProChon BioTech, Rehovot, Israel) is a two-stage autologous chondrocyte technique that utilizes autologous serum with additional growth factors to expand the chondrocytes and seed them onto a fibrin/HA-based scaffold (Figure 5) 28 .
The scaffold has a three-dimensional open pore design, which promotes chondrocyte growth.A recent case series reported on 31 patients at an average of 17-month follow-up and demonstrated significantly improved IKDC scores as well as MRI T2-mapping values 28 .

CaReS
CaReS (Ars Arthro, Esslingen, Germany) utilizes a three-dimensional hydrogel based on rat-tail-derived type I collagen to promote growth of harvested autologous chondrocytes.The chondrocyte-gel mixture is cultured with autologous serum for 2 weeks and is then implanted into the chondral defect and secured with fibrin glue.The three-dimensional framework is believed to decrease the potential for chondrocyte dedifferentiation 29 .In addition, the hydrogel can be manufactured to meet surgeon-requested size specifications, and due to its water content it can be moulded intra-operatively to conform to the unique shape of each lesion.A multicentre case series reported on 116 patients treated with CaReS with average follow-up of 30 months and showed substantially improved IKDC, SF-36 and pain scores 29 .The graft is minced into small pieces and implanted in a single stage into a chondral lesion and secured with fibrin glue.Juvenile donor cartilage is chosen based on the concept that juvenile chondrocytes have greater capacity for cell multiplication and anabolic activity than adult chondrocytes 34 .The juvenile minced cartilage graft is considered allograft tissue and is therefore not formally regulated by the FDA.DeNovo NT is currently being studied in several on-going postmarket trials 35 .DeNovo ET (Engineered Tissue) (ISTO, St. Louis, MO) like DeNovo NT is derived from juvenile human donor cartilage; however, the ET product undergoes expansion in culture to produce a hyaline-like graft that can be trimmed to size and implanted with fibrin glue 6 .DeNovo ET is the subject of an on-going phase III clinical trial 36 .Currently published clinical outcome data for DeNovo NT and ET are limited to case reports 37 .

Autologous matrix-induced chondrogenesis (AMIC)
AMIC is a novel approach to cartilage restoration that combines microfracture with a porcine-derived collagen type I/III patch (Chondro-Gide, Geistlich Pharma AG, Wolhusen, Switzerland).In contrast to other techniques that have been discussed, no allogenic or autologous chondrocytes are implanted into the defect.In theory, the application of the collagen patch overtop of the microfracture bed can stabilize the clot and provide an enhanced three-dimensional framework for cell growth and expansion.In addition, AMIC has the advantage of being a one-stage procedure.The technique requires preparation and microfracture of the chondral defect in a standard fashion.This is followed by fixation of a collagen patch with suture or fibrin glue over top

Emerging cartilage restoration technologies-one-stage techniques
Cartilage autograft implantation system (CAIS) CAIS (Depuy Mitek, Raynham, MA) involves arthroscopic harvest of healthy cartilage tissue, followed by mechanical digestion of the cartilage with a specialized instrument to create 1 to 2 mm chondral fragments.The fragments are secured to a synthetic scaffold (comprised of a 35% polycaprolactone, 65% polyglycolic acid copolymer and polydioxanone mesh) with fibrin glue.The scaffold is trimmed to the desired size and shape and implanted via a miniarthrotomy into the defect, with the chondral fragments facing the subchondral bone and then secured with two or more bioabsorbable staples 31 .Initial results of a prospective randomized trial of CAIS versus microfracture followed 29 patients at 2-year follow up.The CAIS group showed statistically improved outcome scores for IKDC and KOOS but no difference in SF-36 compared with the microfracture group.MRI data revealed increased number of intralesional osteophytes in the microfracture group 31 .Clinical trials of CAIS are on-going in the United States 32 (no longer enrolling patients) and Singapore (actively enrolling) 33 .

Conclusion
Cartilage restoration is a vast field currently experiencing rapid growth.

Conflict of interests
David C. Flanigan, MD, is a consultant for Sanofi and Smith and Nephew.

Abbreviations list
Cartipatch (Tissue Bank of France, Lyon, France) also uses a threedimensional hydrogel scaffold for Licensee OA Publishing London 2013.Creative Commons Attribution License (CC-BY) For citation purposes: JM Ryan, DC Flanigan.Emerging technologies: What is the future of cartilage restoration?Hard Tissue 2013 Feb 26;2(2):12 Competing interests: none declared.Conflict of interests: declared in the article.All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.DeNovo DeNovo NT (Natural Tissue) Graft (Zimmer, Inc., Warsaw, IN) consists of allogenic cartilage tissue obtained from juvenile human donor joints.

Figure 3 :
Figure 3: BioSeed C scaffold seeded with 2 × 10 6 autologous chondrocytes (a).Vicryl sutures are then placed at every corner to serve as a pulley (b).The sutures are then fixed transosseously using 1.7-mm k-wires in an inside-out technique (c).The graft as a result fits smoothly into the defect (d).The graft is now securely fixed via a press-fit technique (e).Reprinted with permission from Erggelet C, Kreuz PC, Mrosek EH, Schagemann JC, Lahm A, Ducommun PP, Ossendorf C. Autologous chondrocyte implantation versus ACI using 3D-bioresorbable graft for the treatment of large full-thickness cartilage lesions of the knee.Arch Orthop Trauma Surg.2010 Aug;130(8):957-64.

Table 1 Characteristics of selected scaffolds used in emerging cartilage restoration techniques Product name Scaffold type Adjunct with MFx? Trials Cell free?
For citation purposes: JM Ryan, DC Flanigan.Emerging technologies: What is the future of cartilage restoration?Hard Tissue 2013 Feb 26;2(2):12 Competing interests: none declared.Conflict of interests: declared in the article.All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.