Kris Motmans PhD
Intellectual Property Management and Corporate
Communications
Tigenix
Belgium
Frank P Luyten
MD PhD
Professor and Chairman
Division of Rheumatology
University Hospitals
Leuven, Belgium
E: [email protected]
Traditionally, the repair of damaged musculoskeletal tissues (mainly synovial joints, cartilage and bone), whether resulting from injury or degenerative conditions, takes place most often through a surgical intervention that involves implanting mechanical devices, such as prostheses, plates and screws, to ultimately restore function. Despite a tremendous evolution in orthopaedic surgery, the use of mechanical implants poses limitations to the surgeon and to the patient. The limited lifespan of the devices is a significant financial burden to healthcare budgets. The increasing number of older people and changes in lifestyle throughout the world imply that this burden on patients and society will increase dramatically.
The field of orthobiologics combines recent advances in biotechnology with material sciences, tissue biology and orthopaedic surgery to promote the body’s natural capacity to regenerate and repair musculoskeletal tissue. The modern study of orthobiology originated when Urist et al discovered in the 1960s that a factor in demineralised bone – later identified as bone morphogenic protein (BMP) – was able to induce ectopic bone formation.(1) Since then several other growth factors were isolated and a plethora of orthobiologic materials have become available. Products considered “orthobiologic” include combinations of bone and soft tissue substitutes, autologous or allograft bone/tissue, tissue-engineered implants, growth and differentiation factors, and biological matrices.
Orthobiologics promises to dramatically transform the clinical focus of orthopaedics from traditional metal implants, plates and screws to biologically based devices and medicinal products for hard and soft tissue regeneration. This new generation of products is expected to expand treatment options, improve quality of life for patients and reduce healthcare costs.
Biological treatments of joint surface defects
Joint disorders are the most common musculoskeletal disorder and are increasing in clinical relevance in a more active ageing population. Curl et al reported evidence from a review of a large database of knee arthroscopies showing a 63% incidence of chondral lesions.(2) Articular cartilage damage can have immediate dramatic consequences on the knee function and the long-term degenerative effects appear to be even more detrimental to the joint.(3) If left untreated, articular cartilage lesions may lead to chronic joint degeneration and eventually end-stage osteoarthritis (OA). It is known that patients who suffered a cartilage injury earlier in life are diagnosed with OA on average 10 years earlier than patients who have not suffered cartilage damage.(4) OA is one of the leading causes of disability at older age, affecting more than 10% of the Western population. The impact of this debilitating disease on society is demonstrated by a study published by the US Arthritis Foundation quoting the cost to the US economy of arthritic diseases as being more than €66.92 billion per year.
In view of the tremendous cost of OA to society and the disabling effects for the individual patient, the ultimate goal is prevention. Waiting until there is an established disease before starting treatment is not the effective strategy – early treatment has a much better chance to stop or reverse the process and restore joint homeostasis. It is therefore crucial to treat cartilage defects early and properly. Tissue regeneration resulting in the structural restoration of damaged joint surfaces at an early stage is expected to prevent the development of OA. Different solutions and therapies are currently available for the local treatment of joint surface defects that range from small-scale arthroscopic debridement, bone-marrow stimulation techniques and osteochondral grafting (grafting articular cartilage and underlying bone), to radical surgery involving total joint replacement by implanting prostheses.
Alternatives to prosthesis
However, the life span of joint prosthesis is limited. With an ageing population eager to continue an active lifestyle, there is an increased need for long-lasting biological regeneration procedures aimed at resurfacing articular cartilage defects in the joint. The critical element to guarantee long-term structural, functional and clinical restoration of the joint defect is to create repair tissue that matches the functions of the original hyaline cartilage as closely as possible. It was demonstrated by Peterson et al that there is a positive correlation between the hyaline content of the repair tissue and the clinical outcome.(5)
Bone-marrow stimulation techniques, such as microfracture, are based on the arthroscopic perforation of the subchondral bone plate, which releases blood and associated marrow cells that lead to the formation of a plug at the site of the defect. This results in fibrous tissue repair.(6) Despite the fact that bone marrow stimulation techniques can be performed arthroscopically, which is technically easy to perform with little associated morbidity, the technique is limited because it results in the formation of fibrous or fibrocartilage repair tissue. This fibrous tissue does not reach the full functional spectrum of articular cartilage – including the biomechanical elasticity of healthy (hyaline) cartilage of the joint – and degrades over time, which might explain the only short- to medium-term clinical efficacy.(7,8)
Contrary to marrow stimulation techniques, transplanting osteochondral autografts provides the possibility of resurfacing a joint defect with native hyaline cartilage. In this procedure, small osteochondral plugs are harvested from limited weight-bearing areas of the knee and then inserted side by side into the defect. Although a number of studies have reported good medium-term results, several issues remain – restoring the precise surface anatomy is technically very demanding. Height mismatch, cleft formation and lack of peripheral integration with the surrounding cartilage may lead to less optimal results. Moreover, the treatment of larger lesions is limited by the number of grafts that can be harvested.
Autologous chondrocyte implantation
While initial therapies aimed at repairing or replacing damaged tissue, more recent therapeutic approaches seek the regeneration of the original articular cartilage in vivo by implanting ex-vivo expanded cartilage cells, a technique known as autologous chondrocyte implantation (ACI). It consists of a two-step procedure where a small cartilage biopsy is taken from the patient’s joint with arthroscopy. The chondrocytes are released from the cartilage tissue and selectively expanded. Approximately four to five weeks later, the cells are then reimplanted into the patient in a second, mostly open knee procedure. Brittberg et al were the first to publish promising results from this technique.(9)
Although there is a strong scientific rationale behind ACI for achieving long-term articular cartilage regeneration, a number of critical elements still need to be addressed in order to progress this procedure to a consistent, well-defined and regulated cartilage cell product.(5,9,10) One element would be the quality of the cells that produce the new articular cartilage in vivo. It became clear that simply expanding the cells leads to de-differentiation and loss of their proper function – the potential to form stable hyaline cartilage – which often leads to unpredictable treatment outcomes.
Therefore potency assays need to be established for assessing the chondrogenic potential, as well as quality control criteria for the expanded cartilage cells before implantation. Dell’Accio et al have established a genetic marker profile associated with the stable chondrocyte phenotype.(11,12) Phenotype profiling during ex-vivo cell expansion will definitely contribute to a more consistent formation of stable hyaline cartilage in vivo, leading to better clinical outcome. Another important element in treating symptomatic cartilage defects is making the ACI procedure more surgeon-friendly by using a scaffold for a cell delivery vehicle that provides a (temporary) 3D support to facilitate cell migration, attachment and stability. Scaffolds are more suitable for arthroscopic application, which would reduce the need for the more invasive open-knee surgery in ACI procedures.
In Europe, the use of collagen-based and hyaluronic acid-based scaffolds seeded with ex-vivo expanded chondrocytes has been introduced.(13,14) Combinations with biological response modifiers will also play an important role in the next generation of cartilage regeneration products. Novel insights in cartilage biology and the pathophysiology of cartilage degradation has led to a better understanding of the molecular processes underlying the catabolic and anabolic processes that lead to homeostasis in a healthy joint. Several bioactive factors have been reported that might either strengthen the phenotype of the implanted chondrocytes or act as inhibitors of the degenerative process.(15)
Some issues remain to be solved on the regulatory front. Despite the wealth of clinical experience in orthobiologic treatments of joint defects, none of the available biological treatment methods stands out as optimal. Few have been compared in clinical trials with a correct methodology, and evidence-based outcomes are limited. Today, it is clear that regulatory agencies will only allow new therapies when these have proven to be safe and effective in prospective, randomised and controlled studies. The evidence-based medical approach offers a systematic way of interpreting study results based on a hierarchy of clinical evidence. It should assist physicians in making decisions in daily practice.
Conclusion
The field of orthobiology is rapidly evolving and there is a shift in joint resurfacing strategies – from repairing and replacing damaged joints to regenerating tissue. In spite of the availability of several joint resurfacing techniques, there is still lack of well-designed clinical trial data and a high unmet medical need. This new domain of regenerative medicine will hopefully bring new therapies to market that will provide long-term solutions and prevent patients from developing OA.
Orthobiologic treatments have also come into the regulatory authorities’ field of vision, giving an impetus to an evidence-based medicine approach for assessing the efficacy and effectiveness of new and existing therapies.
The future of orthobiology in joint surface repair lies in a multidisciplinary approach that involves clinicians, molecular and cell biologists, chemists and material scientists. This would lead to the development of combination products validated by evidence-based medical scrutiny. Proper evaluation of these novel approaches will require the development of new tools and methodologies to assess tissue repair and functional outcomes. Successful clinical trials in this field are needed to move it forward.
Acknowledgement: The authors thank Gil Beyen, Luc Dochez and Heico Breek for their feedback.
References
- Urist MR, Silverman BF, Buring K, et al. The bone induction principle. Clin Orthop Relat Res 1967;53:243-83.
- Curl WW, Krome J, Gordon ES, et al. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthroscopy 1997;13:456-60.
- Buckwalter JA. Articular cartilage injuries. Clin Orthop Relat Res 2002;402:21-37.
- Gelber AC,Hochberg MC, Mead LA, et al. Joint injury in young adults and the risk for subsequent knee and hip osteoarthritis. Ann Intern Med 2000;133:321-28.
- Peterson L, Minas T, Brittberg M, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res 2000;374:212-34.
- Frisbie DD, Oxford JT, Southwood L, et al. Early events in cartilage repair after subchondral bone microfacture. Clin Orthop Relat Res 2003;407:215-27.
- Nehrer S, Spector M, Minas T. Histologic analysis of tissue after failed cartilage repair procedures. Clin Orthop Relat Res 1999;365:149-62.
- Brown WE, Potter HG, Marx RG, et al. Magnetic resonance imaging appearance of cartilage repair in the knee. Clin Orthop Relat Res 2004;422:214-23.
- Brittberg M, Lindahl A, Nilsson A. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-95.
- Knutsen G,Engebretsen L, Ludvigsen TC, et al. Autologous chondrocyte implantation compared with microfracture in the knee: a randomized trial. J Bone Joint Surg Am 2004;86:455-65.
- De Bari C, Dell’Accio F, Luyten FP. Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum 2001;44:85-95.
- Dell’Accio F, De Bari C, Luyten F. Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. Arthritis Rheum 2001;44:1608-19.
- Warren SM,Sylvester K, Chen CM, et al. New directions in bioabsorbable technology. Orthopedics 2002;25:s1201-10.
- Hollander AP, Dickinson SC, Sims TJ, et al. Maturation of tissue engineered cartilage implanted in injured and osteoarthritic human knees. Tissue Eng 2006;12:1-12.
- Hickey DG, Frenkel SR, Di Cesare PF. Clinical applications of growth factors for articular cartilage repair. Am J Orthop 2003;32:70-6.
