Cell therapy, biomaterials and other options may enhance cartilage repair

There are several articular cartilage repair techniques being used, including microfracture, autologous chondrocyte implantation and mosaicplasty, and orthopaedic surgeons have found they offer some improvement for patients, overall.

The physicians who spoke with Orthopaedics Today Europe discussed indications for the major techniques currently used worldwide and noted that results of each approach are somewhat mixed. From their comments it seems that orthopaedic clinicians and researchers are divided over which cartilage repair approaches are optimal and whether developments being worked on now will deliver on the promise of improved outcomes in the future.

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

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

Image: Philippi-vandeKuil A

Microfracture — gold standard

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

“It is cheap, and it is less invasive,” Gunnar Knutsen, MD, PhD, in the Department of Orthopaedic Surgery at University of Tromsø, Norway, told Orthopaedics Today Europe.

Microfracture is a bone marrow stimulation technique that highlights the body’s wound-repair response. Saris said 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.”

This not only “gives a functional restoration that lasts relatively well in a certain group of people, [but] it is simple to do and gives a good middle-term result,” he said.

Rehabilitation aids results

A proper surgical technique and appropriate postoperative rehabilitation are key components of a successful microfracture, Knutsen said, noting it works best in younger patients with smaller defects.

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 improvement in function, according to study findings.

However, other research has identified mixed results with microfracture. In their survival analysis published this year, Korean researchers Bae and colleagues found 89% survival at 5 years for microfracture done in osteoarthritic knees, which decreased to 68% survival after 10 years.

Knutsen and colleagues compared microfracture and autologous chondrocyte implantation (ACI) in 80 patients with a single cartilage defect and found results that were not significantly different for the two procedures. Five-year outcomes showed the techniques yielded satisfactory results in 77% of patients.

ACI: A leading treatment

Although some clinicians consider microfracture the gold 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 orthopaedic surgery at Royal National Orthopaedic Hospital in Stanmore, United Kingdom. Bentley is an Orthopaedics Today Europe Editorial Board member.

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, according to Bentley.

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.

The quality of the resulting tissue is impressive with these chondrocyte-based methods, according to Saris.

“The cartilage quality that is made there has been shown to be better than the tissue that is made by microfracture,” Saris told Orthopaedics Today Europe.

Clinical practices yield results

For chondrocyte-based cartilage repair, “We know now 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.”

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. It is the best treatment for large defects, Saris said.

Knutsen said the procedure is also indicated in patients with either a failed microfracture or a defect that is so large microfracture is not feasible.

Membrane vs. matrix study underway

Knutsen told Orthopaedics Today Europe he is involved in a study now to compare ACI-C with autologous matrix-induced chondrogenesis. The study design requires investigators to cover the defects in both groups with the collagen matrix Chondro-Gide membrane (Geistlich Surgery; Wolhusen, Switzerland) and then affix the membrane with stitches and fibrin glue.

So far, 30 patients with symptomatic cartilage defects are enrolled; the goal is to enroll 80 patients, with 40 patients per group. Knutsen said he and his co-investigators plan to follow up patients at 1 year, 2 years, 5 years and 10 years after the procedure.

“My hypothesis is there really should not be any difference,” Knutsen said.

Age affects outcomes

Bentley recently completed a review of 830 patients followed up after they underwent either ACI-C or MACI. His findings showed good results through 10 postoperative years.

“It is the largest review of ACI and MACI and the only one that compares the two methods over 10 years,” Bentley told Orthopaedics Today Europe. “They do show satisfactory results.”

Identifying the optimal patient is important to ACI-C and MACI outcomes, Bentley said, and the surgeon must consider patient age when selecting candidates for these procedures.

“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 above the age of 50 [years], then it is nearly always due to established arthritis.”

Surgeons should anticipate better results in younger patients, according to Bentley.

Impact of previous surgery

Previous surgery negatively influences outcomes of cell transplantation, said Bentley, who noted results are about five times worse in patients with an earlier surgery.

“Patients who have had previous surgery have usually had some type of procedure on the subchondral bone that causes hypertrophy or cysts and has a deleterious effect,” Bentley said, noting that Tom Minas, MD, of Boston, reported on this situation.

“Also, after several surgeries,” Bentley said, “[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.”

Some researchers have published findings that show that arthritis in the joint also has a negative effect on these results as do smoking and being overweight or obese. Studies with long-term results have shown that under the right indications, however, ACI and MACI can yield an 80% success rate, Bentley said.

Osteoarticular transplantation

Mosaicplasty, which László Hangody, MD, PhD, DSc, introduced for articular cartilage repair, became popular in the late 1990s and early 2000s.

“This is where you transport a little cylinder of bone with cartilage on it, and you just plug it in [the defect] like ‘Lego’ blocks,” Saris said. “Osteoarticular transplantation is a good solution for smaller defects in any age patient,” he said.

However, according to Saris, the procedure does not work well in large defects.

Hangody, of Budapest, essentially invented the mosaicplasty cartilage repair technique. He has achieved good results with it; however, in clinical practice, many other orthopaedic surgeons have been unable to reproduce his results, Martin Lind, MD, PhD, a professor in the division of sports traumatology at Aarhus University Hospital, in Denmark, said.

Although the principle of the mosaicplasty procedure is sound — fill a defect with intact bone and cartilage — some technical problems, donor site issues and poor results have decreased its popularity, Lind said.

The cartilage repair products and procedures currently being investigated may eventually answer the question of which repair technique is best.

Tissue engineering, for example, is an exciting area of research, Anthony Hollander, PhD, head of the School of Cellular and Molecular Medicine at the University of Bristol, in Bristol, United Kingdom, said. The research now underway, he said, involves growing cells on a scaffold on a piece of cartilage, which may offer the ability to treat large lesions and possibly early osteoarthritic lesions.

“The golden challenge, what I really want to contribute moving forward, is to develop a treatment for early osteoarthritis,” Hollander told Orthopaedics Today Europe. “I think it is a real unmet need.

“[We are still working on] how to integrate the mature cartilage with the surrounding natural cartilage. That remains a problem that we have to deal with,” Hollander said.

Cell selection for improved results

Regarding the potential that ACI-C and MACI hold, Bentley said investigators are studying whether it is possible to identify and use only certain cells for these treatments.

“There has been some suggestion that you could select the cartilage cells that are more likely to bring about repair than others, but that is still in its infancy,” he said. “It is the first real application of cell engineering.

Enhancing microfracture results with a scaffold or hydrogel is another exciting avenue, Lind said. It would reduce the current two-phase procedure to one phase and avoid cell culturing, saving time and money. Further, it would potentially “improve the quality of the repair tissue generated in the microfracture defect,” Lind said.

“The future will be one step [approaches],” Knutsen said, noting “the cultivation of cells and sending them to the lab and back is expensive and time consuming.”

Researchers at Harvard and Stanford Universities in the United States have developed hydrogels that could enhance microfracture treatment, he said.

Biomaterial-only treatment

One day, there may be a biomaterial-only option for cartilage repair, according to Saris.

“You do not need the cell anymore or you do not need to stimulate the bone marrow,” he said. “You can use the biomaterial as a construction scaffold.”

Although such a product is still under development, “if it develops the way people are now suggesting, it could help us solve both large and small defects,” Saris said. Furthermore, the procedure could offer a solution to the logistical issues of current cell therapy while reducing costs.

“Biomaterials can be fabricated much more easily,” Saris said. “They can be used off-the-shelf. One would expect that the cost aspect and the patient satisfaction would be a very large opportunity for the future.”

Stem cells for focal lesions

Currently, UMC Utrecht 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 treating focal articular knee cartilage lesions in that study, 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 the costs of culturing,” he said. “This is the next frontier in cell therapy.”

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

• References:
• Bae DK. Arthroscopy. 2013. doi:10.1016/j.arthro.2012.09.006.
• Knutsen G. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007;89:2105-2112.
• Smith GD. A clinical review of cartilage repair techniques. J Bone Joint Surg Br. 2005;87:445-449.
• Steadman JR. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy. 2003;19:477-484.
• Vanlauwe J. Am J Sports Med. 2011. doi:10.1177/0363546511422220.

• For more information:
• George Bentley, ChM, FRCS, can be reached at the Institute of Orthopaedics, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex, HA 4LP, United Kingdom; email: profgbentley@aol.com.
• Anthony P. Hollander, PhD, can be reached at the University of Bristol, Medical Sciences Building, Bristol BS8 1TD, United Kingdom; email: a.hollander@bristol.ac.uk.
• Gunnar Knutsen, MD, PhD, can be reached at University of Tromsø, University Hospital North Norway, 9038 Tromsø, Norway; email: gunnar.knutsen@unn.no.
• Martin Lind, MD, PhD, can be reached at Aarhus University Hospital, Tage Hansens Gade 2, 8000 Aarhus C, Denmark; email: martinlind@dadlnet.dk.
• Daniël B.F. Saris, MD, PhD, can be reached at HPN G05.228, PO Box 85500, 3508 GA Utrecht, Netherlands; email: d.saris@umcutrecht.nl.

Disclosure: Bentley has expenses paid by Genzyme/Sanofi. Hollander is chief scientific officer of Azellon Cell Therapeutics. Saris is a consultant for Smith & Nephew, Genzyme/Sanofi, Tigenix and Regentis. Knutsen and Lind have no relevant financial disclosures.

 

Do you consider cartilage repair proven or experimental medicine?

Microfracture: No longer experimental medicine

Various surgical techniques have been developed in the last 20 years for the treatment of articular cartilage defects. Microfracture (MFX), autologous chondrocyte transplantation and osteochondral transplantation have been investigated extensively with a sufficient number of validated studies and an acceptable level of evidence now available for these methods. Cartilage repair has become a valid, standardized treatment and is no longer experimental medicine. It is integrated into the daily work of orthopaedic surgeons worldwide and is often part of their training.

In addition, new methods or modifications of current ones are continually introduced. The application of these new methods is experimental medicine and should occur under study conditions until valid information on risks and benefits can be demonstrated.

Because cartilage defects have a very limited, age-dependent, self-healing capacity, a surgical approach is required in adults with symptomatic International Cartilage Repair Society grade 3 or 4 defects in the knee joint.

The MFX technique of J. Richard Steadman, MD, is well-proven and is the most used cartilage repair technique worldwide. The arguments in favor of MFX are it is a minimally invasive method, limited cost and ability to be combined with other arthroscopic procedures, such as ligament and meniscus repair. MFX promotes the formation of fibrous tissue with a histologic range from primitive scar tissue to a mix of fibrous and hyaline cartilage under local biochemical and biomechanical factors.

Analysis of more than 3,000 patients with 17 years of follow-up indicates initially there is clinical improvement in 47% to 90% of patients after MFX, but after 18 months to 36 months, the function and pain deteriorates. Reported medium-term revision rates are up to 31%. Drawbacks of the technique are the inferior mechanical tissue properties and formation of intralesional osteophytes.

A return to the pre-injury level of sport after MFX can be expected in 45% to 67% of athletes within 8 months to 17 months of surgery. When onset of symptoms occurred less than 12 months before surgery, MFX is associated with a significantly higher 67% return to sports vs. 14% for those with symptom durations that exceed 12 months. This technique is still considered in young (under 40 years) and active patients with small isolated defects (<2.5 cm^²), low body mass index and a short duration of preoperative symptoms.

MFX studies show a wide range of outcomes, which can perhaps be explained by large differences in the patient populations. The literature indicates MFX does not solve the problem of cartilage regeneration in the medium term. Currently, it is still unclear whether bone marrow cells in the joint form bone (intralesional osteophytes) rather than high quality cartilage. Therefore, better control of bone marrow cell maturation is necessary.

• References:
• Mithoefer K. Am J Sports Med. 2009;doi:10.1177/0363546508328414.
• Steinwachs MR. Scientific evidence base for cartilage injury and repair in the athlete. Cartilage. 2012;3(Supp 1):11S-17S.

Matthias R. Steinwachs, MD, is at the Center of Orthobiology and Cartilage Repair at Schulthess Klinik in Zurich.
Disclosure: Steinwachs has no relevant financial disclosures.

Evidence supports autograft transplantation

In the last 2 decades, there have been many new developments in the surgical treatment of full-thickness chondral and osteochondral defects. Successful surgical treatment of affected weight bearing articular cartilage surfaces represents a real challenge, but we now have an increasing amount of experimental data and clinical findings to identify more effective treatment modalities.

The intention with earlier cartilage repair techniques, like Pridie drilling or abrasion arthroplasty, was to substitute for the missing gliding surface with fibrocartilage. This offered only limited improvement because of the moderate biomechanical characteristics of the fibrous repair tissue so it therefore remained a research goal to provide hyaline cartilage or hyaline-like cartilage to cover defects.

More recently, extended experimental research was done to better understand the microstructure of hyaline cartilage, collect information about limited regenerative capacity and investigate chondrocyte behavior. These efforts led to clinical use of osteochondral autograft transplantation and chondrocyte implantation methods. It seems these two approaches have the most extended clinical experience and longest follow-up of all modern cartilage repair alternatives. However, the merits of transplantation and regeneration are still debated. It is not a question of whether cell therapies represent the future, however, since transplantation remains an option that yields durable tissue immediately and shortens the rehabilitation time.

We introduced the mosaicplasty technique in humans 21 years ago. Since then, we have performed continuous clinical evaluation, biomechanical studies and new experimental studies of the technique. Initial dog, horse, goat and sheep experiments and implantations provided more information about graft integration, donor site healing and cartilage remodeling and, as mosaicplasty became popular for treating dog and horse pathologies, we also collected information about the technique from veterinary practices.

Certain limitations of this transplantation technique led to new research directions. For example, we realized empty donor sites may cause excessive bleeding and painful hemarthrosis. To eliminate this problem, we carried out animal trials to find an ideal biodegradable material for donor site filling and realized the material should block excessive bleeding at the donor site and serve as a scaffold for local healing. We subsequently investigated some modern biodegradable materials and their capability to aid the repair process and then extended our efforts hoping to identify substances suited for weight bearing cartilage defect repair. Animal trials and research conducted at many centers have led to newly developed biodegradable implants for small osteochondral defects of weight bearing cartilage.

For extensive defects, autologous osteochondral allograft transfer is an acceptable option. It has a long history of use in cadaveric knee joint transplantation done in 1908. Use of cryopreserved grafts was attempted early on, but was limited by its fibrous transformation of the gliding surface. More recently the transplantation of fresh 1-week-old allografts provided better results and we have since performed these implantations within 24 hours of graft harvest and observed better chondrocyte survival. This may lead to extended indications for “ultra-fresh” osteochondral transfer.

In conclusion, we have several evidence-based cartilage repair techniques for a variety of indications. All of them have limitations, such as compromised repair tissue, graft degradation, incorporation problems, donor site morbidity, extended rehabilitation, and financial and technical issues. Well-determined evidence-based therapeutic algorithms based on optimal indications are needed for optimal long-term cartilage repair results.

László Hangody, MD, PhD, DSc, is Clinical Professor at Semmelweis University and Uzsoki Hospital and Director of Traumatology at the Traumatology Center at Péterfy Sándor Hospital in Budapest.
Disclosure: Hangody receives royalty payments from Smith & Nephew for mosaicplasty instrumentation and from Zimmer for Chondrofix Osteochondral Allograft.