Although research on the use of stem cells in orthopaedic surgery is still in its infancy, there are promising early results in cartilage repair, treating nonunions and osteoarthritis Significant work remains, however, before they can be used routinely in patients. “The use of stem cells in orthopaedics is quite a recent technique,” Alberto Gobbi, MD, presiden Orthopaedic Arthroscopic Surgery International, in Milan, Italy, told Orthopaedics Today Europe. “The application of mesenchymal stem cells (MSCs) in regenerative medicine is quite new.” However, the use of these cells in orthopaedic surgery is increasing rapidly, according to Gobbi. “We know that we can help the healingof bone [and that] we can help the healing of tendons and of cartilage”
with stem cells, he said. “Mesenchymal stem cells have had a big impact on orthopaedic surgery over a short period of time,” said Ramon Cugat, MD, PhD, who is president of the medical council for the Catalan Soccer Delegation’s Health Insurance Company under the Spanish Soccer Federation. “This impact continues to grow on a daily basis. “The big difference between treating with cells and traditional treatments is that cells focus on regeneration,” said Cugat, an Orthopaedics Today Europe Editorial Board member. “Until now, orthopaedic surgery has focused on restoring the anatomy and recovering function. Now it is time to work with biology.”

Cell-based treatments work with biology by inducing regeneration; they restore the tissue with its original properties. With repair, the tissue is restored without conserving its original architecture and function, Cugat said. With all of this promise comes great excitement; however, orthopaedic surgeons must remember the field is still growing and data are lacking, these experts noted. “It is a developing field, which I think is associated with a lot ofhope and expectation, but I do not think we have much in the way of solid data yet to talk about its clinical contributions at this point,” Thomas A. Einhorn, MD, professor and chairman of the department of orthopaedic surgery at Boston University, in Boston, said. “Lots of animal studies have been done — many of them with very positive and very encouraging results — but to my knowledge, there has not been much in the peer-reviewed literature on really good clinical studies,” Einhorn said.

Correct terminology needed

In this article, specialists discussed the latest stem cell research. They all agreed that any discussion of this topic must start with the correct terms. “One thing that I think needs to be pointed out is that particularly in the field of orthopaedics, the term ‘stem cell’ is used rather loosely,” Einhorn said. “To a molecular biologist, a stem cell is a cell that has the ability to renew itself.”

There are several stem cell types:

• embryonic stem cells, which differentiate into any cell type;
• peripotent cells, which can also differentiate into any cell type except for extra-embryonic tissue;
• induced pluripotent stem cells, which come from patients and are manipulated in the laboratory to become pluripotent cells; and
• multipotent progenitor cells, which can differentiate into limited tissue types.

“I think most of the cells that we talk about and refer to as ‘stem cells’ in orthopaedics are probably progenitor cells,” Einhorn said. “There has already been some genetic commitment to a particular lineage. To be more accurate, we probably need to talk about osteoprogenitor cells or skeletal progenitor cells or mesenchymal stem cells, which at least qualifies the stem cell as being part of the mesenchymal family.”

Functional potential of MSCs

Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes and are probably the most commonly used cells in orthopaedics, according to Einhorn. But there is more to MSCs than being able to differentiate into new cells, according to Wa’el Kafienah, PhD, senior lecturer in stem cell biology at the University of Bristol, in Bristol, United Kingdom. These cells can offer layers of function, including enhancing the body’s own repair mechanisms and immunosuppressive ability, dampening the immune response to minimize the rejection of transplanted cells or tissues, Kafienah told Orthopaedics Today Europe.

Repair of cartilage damage with MSCs

Overall, researchers have obtained good results with MSCs, Cugat said. “Clinically, the experience is still small,” he said. “In orthopaedics, there is more experience in the treatment of chondral defects. A large percentage of the population worldwide suffers from osteoarthritis in one or more of their joints.” April 2013 | Healio.com/Orthopaedics | 11 “The aim of researchers in regenerative medicine is to repair organs or tissues that are damaged by aging, disease or trauma, such that function is restored or improved,” Gobbi said. “The use of bone marrow derived multipotent MSCs represents a valuable treatment option, especially for the treatment of the degenerative diseases of cartilage,” he said. Gobbi and colleagues started using bone marrow aspirate concentrate (BMAC) for cartilage repair in 2006. They found that combining BMAC with a scaffold to treat full-thickness cartilage defects achieved good results. “Therefore, we started treating big defects [in] patients who were referred to total knee replacement (TKR),” Gobbi said. “We started
talking about biological arthroplasty.”

Tissue regrowth studied

The results were encouraging and yielded regrown tissue that was similar to normal hyaline cartilage, he said. In a prospective study, Gobbi and colleagues followed 25 patients who were operated on for grade IV knee cartilage lesions for a minimum period of 3 years. All patients underwent a mini-arthrotomy and concomitant transplantation of a BMAC covered with a collagen matrix. The average lesion the patients had was sized 8.6 cm2. The researchers observed significant improvement in the knee visual analog scale, the objective and subjective portions of the International Knee Documentation Committee (IKDC) scale, the Knee Injury and Osteoarthritis Outcome Scale (KOOS) and the Lysholm scale. The preoperative IKDC subjective score was 41 points and postoperatively it was 82 points, Gobbi said. The preoperative KOOS score was 66 points, which increased to 89 points postoperatively. Furthermore, there were no adverse reactions or serious postoperative complications, he said. Mesenchymal stem cells are an option for many patients with cartilage defects, regardless of age, according to Gobbi. 12 | April 2013 | Healio.com/Orthopaedics “This is a good therapy for patients who are in the gray zone,” he said. “They are not young, [but] they are not so old as to be treated with TKR.” The patients suited for this kind of MSC therapy range in age from 45 years to 55 years, and they are active. Their cartilage has degenerated, and they have a lesion, Gobbi noted. “They don’t want to go to TKR,” Gobbi said. “We can probably give this patient maybe 15 years or 20 more years before going on to TKR, with a huge difference in terms of cost to society, rehabilitation, etc. These people can go back — not to competitive sport, but to a normal life,” he said. Clinically, MSC treatment yields cartilage repair results that are quite similar to the standard therapy, autologous chondrocyte implantation (ACI), according to Francesca Vannini, MD, PhD, of the Rizzoli Orthopaedic Institute in Bologna. However, this procedure is simpler than ACI. “The mesenchymal cells are more convenient because the procedure can be performed in one step,” Vannini said. And, she said it costs less because MSCs do not require a laboratory phase or a second procedure. In the literature, Nejdanik and colleagues studied 72 patients matched according to age and lesion size and their results demonstrated that bone marrow-derived stem cells were as effective as ACI for cartilage repair. Those researchers found in their 2010 study that the one-step stem cell-based procedure reduced health care costs and minimized donor-site morbidity.

Osteochondral lesions

A one-step repair that used MSCs to treat talar osteochondral lesions also demonstrated effectiveness. In a study published last year, Giannini and colleagues performed a single-step arthroscopic procedure using bone marrow-derived cells in 49 patients, who achieved good clinical results that persisted over time. There are some key elements that ensure optimal outcomes with April 2013 | Healio.com/Orthopaedics | 13 MSC procedures. Precise indications are critical, according to Gobbi. For example, the surgeon must correct any malalignment before or during surgery. The technique is not well suited for patients who are obese or who have diabetes. In addition, patients must understand that the rehabilitation is long and demanding with strict nonweight bearing for at least 45 days. Gobbi said they cannot return to sports activities for 9 months to 12 months. “It is not like [getting] a TKR, and then after one month, you go bicycling,” he said.

MSCs to treat hip AVN

There is evidence that MSCs can treat hip avascular necrosis (AVN). The MSCs help cover the dead bone with live bone. The goal is to produce enough bone to maintain the strength and integrity of the femoral head, preventing its collapse, Einhorn said. Einhorn learned this surgical technique from Philippe Hernigou, MD, who has more than 10 years of experience with the procedure. After returning home from visiting with Hernigou, Einhorn modified the technique a bit and developed instrumentation that helped make the procedure easier to carry out. Over the years, Hernigou has achieved good results, Einhorn said. “I am just now seeing my results,” he said. One-year results from his prospective case series show that 80% of patients still have intact femoral heads. Further, that group of patients demonstrated 74% improvement in various pain and function scales. “In other words, there is a 1 out of 5 chance that the operation is going to fail,” Einhorn said. “If you are in the lucky group of 4 out of 5 [who don’t fail], you can anticipate up to 75% improvement in your pain and function.” Einhorn’s patients have encountered few complications. “I had one or two patients who had persistent drainage for a few days,” he said. “It was just a little bother that went way in a few days.” He has seen no deep infections, but has seen one major complication. A patient who travelled to Einhorn’s office for treatment broke her hip as she raced through the airport on her return trip home. Einhorn looks forward to presenting 2-year data on his first 50 patients with AVN treated with MSCs. “Then I can make more robust statements about how well I think the procedure worked,” he added.

Unanswered questions

Investigators must resolve some key issues, such as lingering questions about the cells’ efficacy, Einhorn said. “I am sure it depends on the setting,” Einhorn told Orthopaedics Today Europe. “In other words, they may work to heal certain nonunions but not others. They may be effective in the treatment of AVN, but not osteoarthritis.” What’s more, researchers must find a way to ensure cell potency, Kafienah said. The other issue is cost, Kafienah noted. “Especially when you talk about 2-step procedures that involve taking the cells from the patient, expanding them in a clean lab and then returning them to the patient — that is very costly,” he said. “It can cost $10,000 to $20,000” per case. However, “cost would not be a problem as long as we can identify a potent approach,” Kafienah said. “If MSCs are potent, people will be happy to use them, even if they are costly, because the assumption is that if they work, there will be no further need for care, treatment or drugs.” Long-term follow-up studies are needed first to figure out what happens to these cells post-implantation, Kafienah said. Finally, researchers must determine the optimal method for delivering these cells, Einhorn said. Still, the future looks fairly bright for using MSCs in orthopaedic surgery. “As our experience and understanding [of stem cells] grows, the indications will increase,” Cugat said. Surgeons will likely rely more on these types of non-drug and non-implant approaches to orthopaedic care because they all know that “regeneration is better than repair,” Cugat said. – by Colleen Owens

What is the best current delivery method to ensure that mesenchymal stem cells get to the intended target?

Scaffold-free tissue-engineered construct ideal

The key issues for success in stem cell therapy are the safety and cost-effectiveness, in addition to biological activities (proliferation and differentiation) of the delivered cells. In this regard, I believe a scaffoldfree tissue engineered construct (TEC) is one of the best methods to locally deliver mesenchymal stem cells (MSCs). The TEC contains MSCs at high density within a 3-D collagen rich matrix that is synthesized by the cells. No animal or chemical materials are used. Therefore, in terms of safety and cost effectiveness, the TEC has advantages over MSCs in “scaffolds” because there is no need to use extrinsic biomaterials. On the other hand, the TEC is rich in adhesion molecules such as fibronectin and has adhesive property to various tissues and, therefore, a simple implantation procedure is available with a short duration without any reinforcement needed for fixation. Finally, the TEC has strong multi-differentiation capacity, including the ability to differentiate into bone, cartilage and adipose tissue. Based on such biological properties, the feasibility of the TEC for tissue repair has been demonstrated in various musculoskeletal tissues, such as cartilage, as noted in studies by Ando and Shimomura and colleagues, the meniscus, as Moriguchi and colleagues showed, the growth plate, based on work that Yoshida and colleagues did, and the intervertebral disc, which Moriguchi presented results of at the Orthopaedic Research Society Annual Meeting this year. The TEC can be a promising bioimplant for the future of regenerative medicine using stem cells in musculoskeletal tissues.

3-D scaffold is the best choice

The high regenerative potential and the capacity of differentiation of bone marrow mononuclear cells makes them suitable for multiple indications in orthopaedic pathology, especially where injured osseous or chondral tissue is not healing well or shows the healing potential. These cells can be both harvested and implanted in a single-step technique. The best way to deliver these cells into the lesion site is with the help of a 3-D scaffold, which can be loaded with the stem cells and directly implanted. There are different biomaterials for this. We currently use a disposable kit for the whole procedure, which includes aspiration of the cells from the iliac crest, and their concentration and implantation (IOR-G1; Novagenit Srl, Mezzolombardo, TN, Italy). The biomaterial included in this kit is a collagen membrane, which is particularly useful because it drives the differentiation of the stem cells into osteoblasts and chondrocytes. When an osteochondral defect is treated with stem cells it is possible to use an arthroscopic technique with specifically designed instrumentation to deliver them, with the advantages of this being less surgical trauma and a faster postoperative recovery.

Many highlights, many registrations

The 14th Congress of the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) takes place this year in Istanbul, from June 5 to 8. A city of growing prominence, with a magnificent history and rapidly developing economy, is the ideal location for a congress dedicated to a particularly dynamic field. Appropriately for such a setting, the program offers impressive highlights. The 14th Congress of the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) takes place this year in Istanbul, from June 5 to 8. It is the most important scientific event for orthopaedists and trauma surgeons at the European level. In putting together the program, EFORT had much to choose from. More than 4,000 abstracts were submitted, with approximately half of these passing the selection process. Six hundred papers will be presented in lectures and oral presentations, the rest to be presented and discussed in poster sessions. The subjects to be dealt with at this year’s congress go beyond the field of orthopaedics and touch on collaboration with other specialties. “One of the scientific focal points this year is the subject of hemophilia in relation to orthopaedic surgical and traumatological issues,” says the Chairman of the EFORT Scientific Committee, Prof Dr Enric Caceres (Hospital Universitari Vall d`Hebron, Barcelona). Prof Caceres says another highlight of the Congress, an issue encountered often in daily practice, will be the important area of treatment of infected fractures. “Infection and the question of how to avoid it is of great significance for every orthopaedic surgeon, regardless of his or her specific specialization,” says EFORT President Prof Dr Pierre Hoffmeyer (Hôpitaux Universitaires de Genève). Prof Hoffmeyer also draws attention to lectures on the latest developments in hip and knee replacement: “The courses in which we deal with these subjects are practically booked out.” A number of lectures will also be given by renowned international experts on injuries to the spine. Prof Hoffmeyer says a focus on pediatrics is also planned, dealing with the treatment of femur fractures and malignant bone tumours in children.

Evidence-based medicine in orthopaedics

Another area of special emphasis will be evidence-based medicine in orthopaedics. This is of great interest in that the approach used in other specialties, in which clinical conclusions are derived primarily from randomized controlled drug studies, cannot be applied directly to orthopaedics. One of the sessions will deal with metatarsalgia. Another session will focus on the standard treatment of spinal metastases. In the course of the conference, sessions will also be held to help those preparing for the EBOT Examination, set by the European Board of Orthopaedics and Traumatology. In general, much attention will be paid to the subject of further education and advanced training. Prof Hoffmeyer: “We know that participants particularly appreciate presentations in the form of courses and so have put special emphasis on this aspect of the Congress. Sessions involving discussions on especially difficult cases also belong in this area.” With the newly introduced “Interactive Experts Exchange” sessions, participants are also given the opportunity to exchange experiences with renowned experts. Plenary sessions will also take up areas that are less often addressed. For instance, spinal surgery specialist Prof Dr Jean Dubousset will offer his reflections on balance and posture and their impact on his view of the treatment of various orthopaedic diseases. As guest societies, this year the Latin American SLAOT (Federation of Latin American Societies) and the Brazilian SBOT (Brazilian Society of Traumatology and Orthopaedics), holding their own sessions, will augment the EFORT Congress. The location on the border between Europe and Asia is also reflected. “We have seen in recent years a steadily growing interest from Asian colleagues in our congress with 600 participants from Japan, China and other east Asian countries in 2010,” says Prof Caceres. “This year there will be significantly more.” The distinguished Japanese spinal surgeon and pioneer of numerous surgical techniques, Prof Katsuro Tomita from Kanazawa University, will deliver a lecture in one of the plenary sessions. Generally, the EFORT Congress is expected to be wellattended. “The house will be rather full,” says Prof Hoffmeyer. “Compared to last year, we already had twice as many confirmed registrations by mid- February. And from experience, many colleagues register only at the last moment. So I think we may be on the way to a new record in attendance.”