Tissue engineering, synthetic scaffolds and other options may enhance cartilage repair

Although several articular cartilage lesion repair techniques including microfracture, autologous chondrocyte implantation and mosaicplasty have provided some improvement for patients, surgeons are looking to up-and-coming technologies that promise better tissue regeneration.

“The cartilage repair techniques that I have used during the last 15 years have preserved people’s joints and given them a high quality of life. Only 9% of them have gone on to knee replacement surgery,” Tom Minas, MD, attending orthopedic surgeon and director of the Cartilage Repair Center at Brigham & Women’s Hospital in Boston, told Orthopedics Today. “The newer tissue-engineered products are now being compared to microfracture as a standard of care, which they should not.”

Orthopedics and researchers are divided over which cartilage repair techniques are optimal and whether emerging developments will deliver on the promise of improved outcomes, according to our sources.

“It is important to put across the message that there is not one best cartilage [repair] technique,” Daniël B.F. Saris, MD, PhD, an orthopedic surgeon at University Medical Center (UMC) Utrecht and a professor of reconstructive medicine at the University of Twente, in the Netherlands, told Orthopedics Today.

New materials and procedures — especially the potential of single-step repair techniques using bone marrow stem cells or scaffolds — represent an exciting step toward solving the articular cartilage repair dilemma, he said.

Microfracture

Introduced by J. Richard Steadman, MD, in the 1980s, microfracture is considered by many to be the standard cartilage repair technique.

“It is easy to do and it is not expensive,” Minas said.

Microfracture is a bone marrow stimulation technique that highlights the body’s wound-repair response, according to Saris. The surgeon debrides damaged articular cartilage and then drills holes in the bone where the cartilage is missing to “create a sort of scar tissue,” he said. Minas said penetrating the subchondral bone with a large awl stimulates pleuripotential bone marrow cells to the surface of the wound so they can differentiate into cartilage or fibrocartilage. In the process, however, intralesional osteophytes form in one-third of patients, which are “a thin film of fibrous tissue on the surface,” he said.

“It does burn bridges for other techniques if you have a failed microfracture,” Minas said. “The reason they are made worse when they get a bone formation is it is like having a pebble in your shoe. There is always this prominent area of bone that is now your weight-bearing surface, and they still experience pain.”

“The shoulders of the defect are still bearing most of the weight and the fibrocartilage repair tissue stabilizes the lesion from progressing, so in small lesions, inferior repair tissue is okay,” he said.

Complications with microfracture

In a 2003 study of 11-year results with microfracture by Steadman and colleagues, 80% of patients rated themselves as improved at 7-years postoperatively. They reportedly had less pain and significant improvements in function, according to study findings. According to Riley J. Williams, MD, director of the Institute for Cartilage Repair at Hospital for Special Surgery, other studies show good short-term success rates for microfracture, which drop off and deteriorate in patients after 2 years. In a survival analysis published this year, Korean researchers Bae and colleagues found an 89% survival rate at 5 years for microfracture done in osteoarthritic knees, which decreased to 68% survival after 10 years.

However, other research has identified mixed results with microfracture. If the surgeon attempts an autologous chondrocyte implantation (ACI) after microfracture failure, the rate of ACI failure increases three fold, according to a study by Minas and colleagues. Minas and the researchers compared 111 joints that had previously undergone microfracture and were undergoing ACI with a control group of 214 patients who had never undergone microfracture, but were undergoing ACI. The control group had a failure rate of 8%, whereas the failure rate was 26% in the group that had previously undergone microfracture.

Conversely, Knutsen and colleagues compared microfracture and ACI in 80 patients with a single cartilage defect and found no significant differences in the results for the procedures. Five-year outcomes showed the techniques yielded satisfactory results in 77% of patients, according to the study. Minas argued this study is flawed because it had multiple surgeons and the lesions operated on measured 2 cm².

“When you look at a technique that is technique-sensitive, like autologous chondrocyte implantation is for surgeons that have not done it before, it raises suspicions as to how well it was done and how well the cells were contained,” Minas said.

ACI

Although some clinicians consider microfracture the standard, others contend that ACI with a collagen membrane (ACI-C) or matrix-induced ACI (MACI; Sanofi UK, Surrey, United Kingdom) is the leading treatment, especially for larger defects, according to George Bentley, ChM, FRCS, professor of orthopedic surgery at Royal National Orthopaedic Hospital in Stanmore, United Kingdom. Bentley is an Orthopaedics Today Europe Editorial Board member. Minas agrees with Bentley that ACI-C or MACI is the leading treatment, especially for larger defects.

During ACI, the surgeon removes a piece of cartilage and sends it to a lab so the chondrocytes can be cultured. After the cultured cells are returned several weeks later, the surgeon seals the defect with a membrane — sometimes the patient’s own periosteum — and then injects the cells behind it, close to the articular surface, Bentley said. In the related MACI technique, the cultured cells are grown or seeded on a collagen scaffold or matrix that is later used to fill the cartilage defect.

First-generation ACI used the patient’s own periosteum to cover the defect, according to Kai Mithoefer, MD, an orthopedic surgeon with Harvard Vanguard Medical Associates in Chestnut Hill, Mass and clinical instructor at Harvard medical school. The first-generation technique often resulted in hypertrophy due to cartilage overgrowth in the defect. The newer, second-generation ACI-C and MACI techniques reduced the rate of hypertrophy from 26% to 5%, Mithoefer said, and decreased the risk of reoperation and failure.

“Delamination can occur from acute shear forces generated during pivoting and cutting maneuvers associated with sport which can result in a traumatic detachment of the cartilage and peeling off effect similar to rolling up a rug” Mithoefer told Orthopedics Today. “It can cause a devastating failure with the highest risk in active patients.”

Mithoefer recommended an MRI before allowing athletes to return to pivoting activates. If any hypertrophy is present, he suggested to prophylactically shave down the proud portion of the cartilage graft before allowing the athlete to return to demanding impact activities.

The quality of the resulting tissue is impressive with chondrocyte-based methods and better than microfracture, according to Saris.

“We know that if you do this in a clearly defined culture system with high-level standards of biotechnology — good clinical practices, good manufacturing practice — then you get a reliable cartilage that has results out to 20 years now,” Saris said. “It is no longer a new and experimental innovation. Cartilage cell therapy is a proven technology with a solid place in the treatment algorithm.”

Minas and colleagues won the John Insall Award for their study, which showed a survivorship of 72% at 15 years in 210 consecutive patients.

“Only 9% of the group went on to total or partial knee replacement, and those patients who had been made worse were less than 2%,” Minas said. Similarly, excellent long-term results without deterioration of sports activity were seen after ACI in athletic patients according to a report by Mithoefer in the American Journal of Sports Medicine.

Other studies have shown arthritis of the joint, smoking and obesity negatively affect the outcomes of ACI and MACI, according to Bentley.

Indications for ACI

ACI is ideal for active patients aged 18 years to 50 years with a fresh, full-thickness cartilage defect and whose quality of life has been limited due to the defect, Saris said. The surgeon must consider patient age when selecting candidates for the procedure, Bentley said.

“You would only do this in people, say, from the age of 15 [years] to about 50 [years],” Bentley said. “If they have cartilage damage and are above the age of 50 [years], then it is nearly always due to established arthritis.”

“If you are looking to extend the biological life of a middle-aged person, [this is] something that does not require much new healing,” Williams told Orthopedics Today.

Saris recommended ACI as the best treatment for large defects. The procedure does not require removal of tissue for autografts like in osteochondral autograft transfer systems (OATS), Williams said.

Previous surgery negatively influences outcomes of cell transplantation, said Bentley, who noted results are about 5 times worse in patients with an earlier surgery. Minas’ study showed the rate of ACI failure increases three fold with previous microfracture surgery.

“Patients who have had previous surgery have had some type of procedure on the subchondral bone that causes hypertrophy or cysts and that has a deleterious effect,” Bentley said. “After several surgeries, [patients] are much less physically fit and less motivated so that their rehabilitation is often prolonged because they have more [of a] recovery to make.”

OATS

László Hangody, MD, PhD, DSc, introduced OATS (also called mosaicplasty) in the late 1990s and early 2000s.

“The OATS procedure involves moving little cylinders of normal tissue in the knee to the area that is devoid of tissue or injured,” Williams said.

Our sources agreed OATS is not a good procedure for patients with larger lesions. The procedure should not be used in patients with lesions of more than 4 cm², according to Minas. The problem is the surgeon must injure a part of the knee to fix another part of the knee, Williams said.

“You take from Peter to pay Paul and end up causing a problem someplace else,” Minas said.

The area from which the osteochondral plug is taken can cause acute or chronic donor site pain and morbidity, which is a problem for high-impact or athletic patients, Mithoefer said.

“The technique should not be done in the patella where the cartilage is thick, whereas your donor site cartilage thickness is small, and these plugs tend to resorb and collapse on the patella,” Minas said.

Our sources also agreed the technique is technically challenging. However, Williams said it can have durable results for high-demand athletes. Krych, Williams and colleagues compared OATS to microfracture in a 2012 study published in the Journal of Bone and Joint Surgery American and found patients treated with OATS had a higher level of activity than patients who underwent microfracture.

Tissue-engineered products

On the horizon is an approach where the patients’ cells are harvested, seeded on a matrix and implanted in the patient with a patch solution, according to Williams. Histogenics (Boston, Mass.) developed one such technology out of a lab at Brigham and Women’s Hospital called NeoCart, an autologous cartilage tissue implant. The technology involves a type 1 collagen matrix seeded with the patient’s cells and then placed in a pressure perfusion chamber where the chondrocytes multiply, Williams said. The matrix is then glued over the defect in the knee. Williams hopes phase 3 will be complete by the end of 2014 or 2015.

“[NeoCart] has been shown to rapidly grow normal-appearing cartilage, Minas said.

Williams and others are involved in FDA phase 1 and 2 studies that compare NeoCart with microfracture. The researchers found NeoCart as safe as microfracture for treatment of distal femoral cartilage lesions in the phase 2 study.

Scaffolds and donor cartilage

Bioabsorbable synthetic scaffolds can be loaded with healing cells that help reconstruct bone and cartilage in the defect, Williams said. One such implant is the TruFit CB osteochondral scaffold plug developed by Smith & Nephew (Fort Washington, Pa.).

Williams presented the results of a 5-year study of 500 patients who underwent either microfracture or synthetic scaffold implants for cartilage defects in the knee. They measured similar results at 2-year intervals.

“The clinical results of synthetic scaffolds far exceed those of the microfracture between 2 [years] and 5 years, and the results are much more durable on MRI,” Williams said.

Another new technology is donor cartilage harvested from healthy patients such as DeNovo (Zimmer; Warsaw, Ind.), in which cartilage microparticles collected from juvenile donors. The cells are glued into the “pothole-like” defect where they grow into new cartilage, according to Williams.

“Juvenile donors have a higher activity level and metabolic rate and produce more articular cartilage than cells from an older donor and can generate new cartilage tissue faster,” Mithoefer said.

Augmentation with synthetic hydrogel and chitosan-based scaffolds or micronized donor cartilage matrix have also been developed as second-generation microfracture techniques, according to Mithoefer.

Stem cells for focal lesions

Currently, UMC researchers are conducting the first in-human trial of an instant mesenchymal stem cell (MSC) product for use with ACI in what they call the IMPACT study. In their treatment of focal articular cartilage lesions, the investigators will assess the safety and feasibility of the MSC construct.

“In one surgical procedure, we will use the patient’s own cartilage and mix it with bone marrow from the stem cell bank,” Saris said. “You use bone-derived stem cells that can still become whatever they want, and you use chondrocytes that you do not have to culture. We are capable of doing this within one surgical procedure, which means that you get rid of all the logistics and costs of culturing. This is the next frontier in cell therapy.”

One-step procedures and those aimed at healing large cartilage defects or addressing osteoarthritis early are a few areas of research and clinical work that represent the future of articular cartilage repair.

“I am welcoming some changes in regulatory bodies to allow more rapid influx of newer technologies because our patients are expecting higher levels of function,” Minas said. “We have an aging, active society.” – by Renee Blisard Buddle and Colleen Owens

   

Do you consider cartilage repair proven or experimental medicine?

Still much to be learned

Cartilage repair is an evolving field that defies a simple answer. A number of surgical techniques, including microfracture, osteochondral autograft transfer and autologous chondrocyte implantation, have a substantial and growing body of literature. There is good evidence regarding the indications, complications and efficacy of these approaches, which are not experimental. However, there is still much to be learned, particularly about optimal rehabilitation and recovery after these surgeries and the longer-term outcomes.

Osteochondral allograft transfer has a smaller, but rapidly growing body of literature that qualifies as more established than experimental medicine, but cannot be considered proven. A wide variety of other approaches to cartilage repair are also available, with new options coming on line regularly. These techniques are more novel, with need for further study before widespread adoption. However, many of these are adaptations of the more proven approaches, so they should not necessarily be classified as experimental.

Going forward, cartilage repair will continue to evolve with greater understanding and optimization of the more proven techniques, maturation of newer approaches into proven treatment options and continued innovation with new, experimental approaches.

Robert H. Brophy, MD, is an associate professor of orthopedic surgery at Washington University School of Medicine, St. Louis.
Disclosure: Brophy is a consultant for Genzyme and ISTOS.

The field continues to advance

Articular cartilage is a resilient, connective tissue functioning to cover the ends of long bones. In a synovial joint, cartilage protects the subchondral bone and promotes a nearly frictionless surface, thereby facilitating smooth joint motion. In theory, therefore, cartilage repair should be based on the principle of aiming to restore the surface of articular cartilage closely as possible to the native joint. Presently, arthroscopic bone marrow stimulation techniques (e.g., microfracture, drilling) are the most commonly used procedures in primary cases, particularly in those of smaller lesion size. A reparative technique by definition, bone marrow stimulation produces a fibrocartilaginous repair tissue in the defect, which is predominantly composed of type I collagen. Despite good outcomes reported in the literature in several joints, type I collagen is biologically and mechanically inferior to native cartilage and may deteriorate over time. In this regard, replacement strategies of osteochondral autograft/allograft, as well as cell-based techniques (autologous chondrocyte implantation, etc.) have become popular as a means of providing a repair tissue closer to that of hyaline cartilage.

In orthopedics, we are often guilty of using subjective outcome measurements to assess our clinical results. In reality, this often leads us to believe that we are better than we really are. We must strive to use objective outcome measurements, such as quantitative MRI, optical coherence tomography and histology (via second look arthroscopy, where possible), which will ultimately tell us that we have a long way to go. The development of next generation cartilage technologies, such as early detection of injury, scaffolds and stem cells, are being developed throughout the world. This includes work performed at the University of Pittsburgh by Dr. Constance Chu with early detection using biomarkers, optical coherence tomography and 3T MRI; Dr. Rocky Tuan with nanotechnology to produce novel matrices; and Dr. Johnny Huard with stem cells and growth factors for repair. These scaffolds and other materials must be tested rigorously in the lab and then clinically. Ultimately, they must stand up to the rigorous safety requirements set forth by the FDA when evaluating potential United States market entry. These techniques are also expensive, so it is important that we ensure cost effectiveness.

The field of cartilage repair continues to advance rapidly. New technological developments and the use of objective outcome measurements will ultimately progress clinicians and researchers towards the ultimate goal — restoring native articular cartilage.

Freddie H. Fu, MD, DSc (Hon), DPs (Hon), is a Distinguished Service Professor in the Department of Orthopaedic Surgery at the University of Pittsburgh and Orthopedics Today Editorial Board member.
Disclosure: Fu has no relevant financial disclosures.