Articular Cartilage Repair
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This document discusses various methods for rebuilding articular cartilage, including anti-inflammatory medications, injections of corticosteroids and hyaluronic acid, and surgical procedures like microfracture and mosaicplasty. It also covers the use of growth factors, scaffolds, and mechanical loading to stimulate and support cartilage regeneration. Effective scaffold designs are biocompatible, limit immune responses, induce cell maturation, provide structural support, and allow controlled delivery of stimulatory molecules.
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Articular Cartilage Repair
- 1. Rebuilding from the ground up.
- 2. Anti-inflammatory Medication or Systemic Steroids Injections Corticosteroids Hyaluronic Acid Surgery (major types) Bone Marrow Stimulation (e.g. Microfracture) Mosaicplasty Surgery combined with tissue engineering (e.g. Autologous Chondrocyte Implantation (ACI))
- 3. Growth Factors The transforming growth factor beta (TGF-β) superfamily, specifically the BMPs, CDMPs, OPs, and GDFs, have a dramatic effect on the development of bone and cartilage tissue. These growth factors help produce an extracellular matrix that can withstand extreme loading conditions in the body. Mechanical Loading Load-bearing tissue, such as articular cartilage, will atrophy in the absence of mechanical forces
- 4. Design Criteria Types Advantages • Biocompatibility • Natural • deliver the repair materials to the site of injury • Limit immune reaction responses • Fibrin • Induce maturation and • Agarose and Alginate • remain in place long enough to differentiation of cellular effect repair • Collagen structures that they are to • Chitosan • provide an even distribution of support • Hyaluronan implanted cells • Biodegrade into non-harmful substances • provide an instructive three • Synthetic dimensional environment for • Polylactic Acid (PLA) seeded and colonising cells • Structural integrity & • Polyglycolic acid (PGA) stability • allow for the controlled local • PLA-PGA Copolymer delivery of polypeptide or chemical molecules that • Durability stimulate repair • the ability of the scaffold to be retained at the implantation site
- 6. 1. Frenkel, S, & Di Cesare, P. (2004) ‘Scaffolds for Articular Cartilage Repair’ Annals of Biomedical Engineering, Vol. 32, No. 1, pp. 26–34. 2. Steinert, A et al. (2007) ‘Major biological obstacles for persistent cell-based regeneration of articular cartilage’, Arthritis Research & Therapy, Vol. 9, No. 3, pp. 213-228. 3. Bhosale, A, & Richardson, J. (2008) ‘Articular cartilage: structure, injuries and review of management’, British Medical Bulletin, No. 87, pp. 77-95. 4. Darling, E, & Athanasiou, K. (2003) ‘Biomechanical Strategies for Articular Cartilage Regeneration’, Annals of Biomedical Engineering, Vol. 31, No. 9, pp. 1114–1124. 5. Marcacci, M et al (2005) ‘Articular cartilage engineering with Hyalograft C: 3-year clinical results’, Clinical orthopaedics and related research, No. 435, pp. 96–105. 6. Khan, I et al (2008) ‘Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review’, European cells and materials, Vol. 16, pp. 26-39 7. Ma, C (2008) ‘Cartilage Injury and repair: Current treatment of cartilage injuries’, Google Knol, [Online] Accessed on September 1 2008, Available from: http://knol.google.com/k/c-benjamin-ma/cartilage-injury-and- repair/uOR7Q0inq/hpms2a# 8. Pavesio A, et al. (2003) ‘Hyaluronan-based scaffolds (Hyalograft C) in the treatment of knee cartilage defects: preliminary clinical findings.’, Novartis Found Symp, No. 249, pp. 203—17
Notas do Editor
- Cartilage is abundant throughout the body and has varying roles depending on its composition and location. Articular cartilage (AC) is an important type which supports the diathrodial joints of the body and allows free-flowing movement. AC has extraordinary mechanical properties and lasting durability even though it is only a few millimetres thick. Its unique structure and composition provides joints with a surface that combines low friction with high lubrication, shock absorption, and wear resistance while bearing large repetitive loads throughout a person’s lifetime. Healthy cartilage has a great capacity to maintain itself, however damaged cartilage has a limited capability for repair. As such, today, I shall be chiefly focusing on tissue engineering and the integration of new cartilaginous tissue with the host cells.External cartilage repair is important as unlike other tissues which are present in a vascular environment, AC is an avascular structure. This avascular nature limits cartilages to only a small pool of potential reparative cells and humoral factors thus hindering the intrinsic healing capabilities of AC (Frenkel & Di Cesare, 2004). AC tissue also has a low cell to matrix ratio, a by-product of this avascular structure, meaning that local chondrocytes have very little ability to repair damage AC (Frenkel & Di Cesare, 2004). Rather, chondrocytes tend to function in a maintenance role.
- Treatment for AC damage uses a wide spectrum of methodologies, treating the symptoms and assisting in the repair of cartilaginous tissue alike. Anti-inflammatory medications and injections, and systemic steroids are methods by which the symptoms of AC are treated. They are used to suppress and decrease inflammation and accordingly decrease pain (Ma, 2008). The most common medications are ibuprofen, motrin, naproxyn, methylprednisolone and corticosteroid injections. Treatment via injections can also involve artificial joint fluids such as Hyaluronic acid, which act as lubricants similar to human synovial fluid (Marcacci et al, 2005). While these treatments are effective in treating the symptoms of AC damage in the short term the underlying condition remains and consequently these symptoms will continue to arise and most get worse with age. To date no pharmacological agents have been able to promote the healing of AC either in vitro or in vivo (Steinert et al, 2007). Thus, some form of surgery is typically the only viable option to repair AC to a meaningful level. Some of the major surgery categories and techniques are (Bhosale & Richardson, 2008);- Bone Marrow Stimulation- MosaicplastySurgery combined with tissue engineeringThe core efforts for AC repair are targeted at filling of the AC defect with a tissue that possesses the same mechanical properties of hyaline cartilage and the consolidation of this tissue with the AC. Tissue engineering is one methodology combating two of the major biological obstacles for regenerating and repairing AC, tissue development and subsequent integration in vivo.
- Tissue engineering is a rapidly developing field covering a large continuum of tissues and other supporting biomaterials. Tissue engineering in AC repair has three key objectives; to create a tissue that will have similar properties to the native cells, to delivery engineered tissues and cells to the site of damage, and initiate the mobilization of the native cells. Tissue development is the probably the most important objective as it the first limiting factor in successful AC repair. The figure provides a general summary of tissue development from the beginning to evaluation of the resulting AC repair in vivo (Darling & Athanasiou, 2003). Scientific research has found that the two chief factors in the optimum development of AC are exposure to mechanical loading and the presence of growth factors (Darling & Athanasiou, 2003). Growth factors for example initiate the production of an extracellular matrix with high load bearing capabilities. Mechanical loading is analogous with other bodily stimuli such as electrical impulses which stimulate neuronal growth. Consequently, some mechanical stimulation is required to promote chondrogenesis, but within a limit so as not to cause more damage to either the native or repair tissues (Darling & Athanasiou, 2003). Currently, researchers are attempting to find techniques and routines which will result in the optimum AC tissue.The second objective is to deliver the engineered tissues and cells to the site of damage. This is achieved by integrating the cells into a scaffold, and thereby creating a high density cell-seeded scaffold for implantation.
- As outline previous, scaffolds are increasingly becoming more significant in the overall AC repair solution. Scaffolds provide an essential supportive matrix in which cells, growth factors and other essential components can reside. In order to be used in the repair solution scaffold materials must fulfil specific requirements in regards to predominately biocompatibility, durability and structural stability. These materials can either be natural or synthetic both of which have shown variability in their support capabilities. The most common natural materials are hyaluronan and collagen based matrices that simulate the natural regrowth of AC. Hyaluronic acid based scaffolds, such as Hyalograft C have been used clinically in AC repair for some time with over 3600 patients as of 2005 (Marcacci et al, 2005). One clinical study found that that 96.7% of the repaired tissue was hyaline cartilage which is important as it possess the desired biomechanical properties, unlike fibro-cartilage which is the usual by-product of intrinsic repair (Pavesio et al, 2003).Polyglycolic, polylactic acid and copolymer variations are synthetic scaffolds. In general, synthetic materials are very promising, avoiding at the same time the immune reaction problems of the natural materials (Frenkel & Di Cesare, 2004). Good short term results have been found in pigs, rabbits and goats, but limited positive findings in large animals (Frenkel & Di Cesare, 2004). To date the repair tissue in the long term at gross-inspection has had biomechanical properties inferior to those of normal AC (Frenkel & Di Cesare, 2004). This is because scaffolds are only one integral component in assisting the successful integration of new cartilage tissue.
- Integration is one of the major biological obstacles for the repair of AC to its original functional state. This is especially evident in the long term whereby, the new tissue begins to degenerate due to factors such as; inferior biomechanical properties, immune system responses and so on (Khan et al, 2008). The nature of the injury itself presents different challenges for the tissue to overcome, whether it be a chondral or osteochondral defect. Simply, chondral defects will typically require the effective integration of cartilage with cartilage, whilst osteochondral defects will also require integration of the cartilage with the bone (Steinert, A et al). The origin of the cells used to repopulate the defect, chondrocyte dedifferentiation, chondrocyte cell death and the nature of the collagenous and proteoglycan networks that constitute the extracellular matrix are all factors which have been cited as hindering cartilage to cartilage integration in vivo (Khan et al, 2008).This figure provides a summary of the factors known to influence either directly or indirectly the level of lateral integrative AC repair (Khan et al, 2008). Although the affect of each factor on integration varies, a better understanding of each factor is important if AC repair strategies are to be improved. These enhanced strategies will ultimately result in better outcomes for patients.
- In summary, while the integration of new cartilage tissue is an important phase in AC repair, it is the integration of some of the above mentioned technologies and strategies which will allow us to rebuild functional, biomechanical adequate AC tissue. An integrated strategy that will account for, if not only all known factors, at the very least the foundations on which successful AC repair so heavily relies upon.REFERENCES1.Frenkel, S, & Di Cesare, P. (2004) ‘Scaffolds for Articular Cartilage Repair’ Annals of Biomedical Engineering, Vol. 32, No. 1, pp. 26–34.2. Steinert, A et al. (2007) ‘Major biological obstacles for persistent cell-based regeneration of articular cartilage’, Arthritis Research & Therapy, Vol. 9, No. 3, pp. 213-228.3. Bhosale, A, & Richardson, J. (2008) ‘Articular cartilage: structure, injuries and review of management’, British Medical Bulletin, No. 87, pp. 77-95.4 Darling, E, & Athanasiou, K. (2003) ‘Biomechanical Strategies for Articular Cartilage Regeneration’, Annals of Biomedical Engineering, Vol. 31, No. 9, pp. 1114–1124.5. Marcacci, M et al (2005) ‘Articular cartilage engineering with Hyalograft C: 3-year clinical results’, Clinical orthopaedics and related research, No. 435, pp. 96–105.6. Khan, I et al (2008) ‘Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review’, European cells and materials, Vol. 16, pp. 26-39 7. Ma, C (2008) ‘Cartilage Injury and repair: Current treatment of cartilage injuries’, Google Knol, [Online] Accessed on September 1 2008, Available from: http://knol.google.com/k/c-benjamin-ma/cartilage-injury-and-repair/uOR7Q0inq/hpms2a#8. Pavesio A, et al. (2003) ‘Hyaluronan-based scaffolds (Hyalograft C) in the treatment of knee cartilage defects: preliminary clinical findings.’, Novartis Found Symp, No. 249, pp. 203—17