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Articular Cartilage Repair

Articular Cartilage Repair This review traces the genealogy of the field of articular cartilage repair from its earliest attempts to its present day vast proliferation of research advances. Prior to the 1980s there was only sporadic efforts to regenerate articular cartilage as it was considered to be incapable of regeneration based on historical dogma. The first flurry of reports documented the use of various cell types ultimately leading to the first successful demonstration of autologous chondrocyte transplantation which was later translated to clinical use and has resulted in the revised axiom that cartilage regeneration is possible. The current field of cartilage repair is multifaceted and some of the 1980s’ vintage concepts have been revisited with state of the art technology now available. The future of the field is now poised to undertake the repair of whole cartilage surfaces beyond focal defects and an appreciation for integrated whole joint health to restore cartilage homeostasis. Keywords chondrocytes, cells, articular cartilage, tissue, osteoarthritis, diagnosis Introduction Cartilage Repair: The Pre-Autologous Chondrocyte Transplantation Era Lesions in articular cartilage are difficult to treat and cause considerable musculoskeletal morbidity, with significant The well-referenced 1743 quote from the British anatomist economic and social implications. It is generally well Hunter in which he states “Cartilage injury is a troublesome accepted that such lesions eventually result in osteoarthri- thing and once injured is seldom repaired” was the general tis (OA). OA has a significant impact on human health, axiom for thinking about cartilage repair for the next particularly in populations who are at higher risk for carti- 200 years. Despite such negativity, there were pioneers lage trauma over the course of their lifetimes. These such as William Green, MD, who performed seminal include patients who have sustained sports injuries, have experiments investigating the reparative potential of autolo- biomechanical aberrations, or repetitive micro trauma to gus and homologous chondrocyte transplantation in the their joints. Although cartilage has a relatively simple 1970s. He used decalcified bone as a type of scaffold for structure compared with other tissues, cartilaginous inju- cell transplantation. He was also the first to use the rabbit as ries can be extremely unforgiving. The limited blood a model to study cartilage repair. Although his success was supply in cartilage is thought to be responsible for the hampered by the technology of the times, his work was a inadequate repair post-injury. A substantial fraction cornerstone for the future of cartilage repair as well as a (˜12%) of the overall burden of OA arises secondary to pioneer in what was to become the field of tissue joint trauma, where the risk of posttraumatic OA (PTOA) 1,2 ranges from 20% to 50%. Currently, 9% of the U.S. Department of Orthopaedic Surgery, Feinstein Institute for Medical population aged 30 years and older has OA of the hip or Research, North Shore–LIJ Health Systems, Manhasset, NY, USA knee, costing an estimated $28.6 billion dollars with Corresponding Author: >400,000 primary knee replacements currently being per- Daniel A. Grande, Department of Orthopaedic Surgery, Feinstein formed each year in the United States alone. Thus, meth- Institute for Medical Research, North Shore–LIJ Health Systems, ods for successful cartilage repair still remain a largely 350 Community Drive, Manhasset, NY 11030, USA. unmet clinical need. Email: [email protected] 282 Cartilage 4(4) engineering. Later, his colleagues George Bentley and to other previous surgical procedures. The results demon- Robert Greer experimented with epihyseal and articular strated nearly complete regeneration of the cartilage defects chondrocyte allografts in rabbits. with a tissue that was blindly classified as hyaline cartilage. By the early 1980s, the concept of healing cartilage with The fate of the transplanted cells was followed by autoradi- predominantly hyaline tissue was still largely considered a ography but only a small fraction, 10% to 15% of the cells myth. Popular procedures at the time included Pirdie drill- could be localized within the defect. The mechanism of car- ing and abrasion arthroplasty, which resulted in largely tilage regeneration was postulated to be either the result of fibrous to fibrocartilaginous tissue. Based on the combined the transplanted cells, however, the radiolabel was serially works of Green, Bentley, and Sokoloff, a multidisciplinary diluted to be nondetectable, or that the cells induced an group of orthopedic researchers at the Hospital for Joint endogenous repair response. Further recent studies with Diseases in New York City, hypothesized that hyaline car- better cell tracking methodology have determined that these tilage repair could be achieved by a cell-based approach to cells do persist and function in establishing new hyaline the problem. This began a collaboration to try and develop cartilage. a new method for achieving the goal of hyaline cartilage In spite of initial skepticism, Lars Peterson, MD, then repair. The clinical motivation for pursuing this project conducted the first human clinical trials using the exact were patients who had sustained cartilage injury but were same protocols developed for the preclinical studies back in still deemed too young for total joint arthroplasty and which his native Sweden. resulted in pain and disability for young active individuals. The ACI technique has been proven to be a successful The concept of a cell-based strategy was explored and treatment modality for treatment of cartilage lesions and determined to be a viable option. After several experiments which has resulted in long-term clinical success without the it was concluded that articular chondrocytes exhibited sev- need for total joint arthroplasty. The use of periosteum as a eral intrinsic properties of the tissue that were deemed key covering membrane has been the principal source of mor- to repair. bidity because of its capability of being stimulated to First, they were already programmed to synthesize type undergo hyperplasia when removed from its anatomical II collagen and aggrecan. The clinical strategy was devel- location. Significant research has subsequently been per- oped to first obtain a biopsy of cartilage, which would then formed to find alternative nonreactive membranes to replace be used to isolate free chondrocytes and expanded in culture periosteum as a cover. Further investigation has character- followed by a second transplant procedure. Based on earlier ized the importance of maintaining the chondrocyte phe- work by Benya and Shaffer, it was hypothesized that chon- notype and applying principles of big pharma to the drocyte phenotype was plastic and a limited culture time in performance of cells. Certifying that chondrocytes are monolayer 2-dimensional culture could then be reestab- expressing a gene profile consistent with a hyaline pheno- lished by return to a 3-dimensional environment. Optimizing type demonstrated superior structural repair in a prospec- cell delivery and a technique for maintaining the chondro- tive randomized clinical trial comparing ACI versus cytes within a defect was problematic as suitable biomate- microfracture. rial membranes were scarce at that time. The decision to use periosteum was based on its anatomical proximity to the Where We Are Now surgical site as well as its historical use in many orthopedic applications such as interpositional arthroplasty procedures. The 1980s-1090s period was a productive time for cartilage The first results of rabbit experiments were decidedly supe- research. Several concepts developed during this period laid rior then expectations and the realization that a new chapter the foundation for technologies in current use today. The in orthopedic research had been opened. The first report of use of immature, neonatal chondrocytes for cartilage repair the technique were presented at the annual meeting of the was based on the higher metabolic rates of these cells com- Orthopaedic Research Society in 1985 by Lars Peterson, pared to those of adult. These were shown to be capable of MD, and were promptly met with skepticism as the promis- excellent repair in an avian model by Itay et al. Although ing results were in conflict with current thinking as well as not developed further at that time the use of young cartilage more than 200 years of dogma. This was followed up by has recently been adapted by Zimmer (Warsaw, IN) as their 2 seminal publications, 1 in the Journal of Orthopedic product DeNovo-NT and has been used clinically in the Research in 1989 received significant attention. The other United States to treat more than 3,000 patients. The product published in the Anatomical Record as part of the first consists of minimally manipulated cartilage tissue har- author’s (DAG) thesis. The procedure is now known as vested young donors that is placed within a cartilage defect autologous chondrocyte implantation (ACI). and held in place by fibrin glue. The mechanism of action is The first reports studied chondral defects made in the unclear but it is likely that the cells within the transplanted patella of rabbits and did not violate the subchondral plate tissue are able to migrate out and contribute to the repair thus avoiding bleeding and the repair mechanism intrinsic tissue observed. Grande et al. 283 The archetypes of plug-type scaffolds for arthroscopic tissue. In MACI, a scaffold cut to the shape and size of the delivery were initially fabricated of carbon fiber by Dunlop defect is seeded with autologous chondrocytes and secured 26,27 Corp in Birmingham, United Kingdom, and investigated in in the defect using a fibrin glue. New techniques involv- clinical trials by McMinn, Coutts, and Amiel studied carti- ing tissue engineering use cells in combination with scaf- lage repair using the bioabsorbable scaffold material poly- folds to regenerate a cartilage plug in vitro for implantation l -lactic acid with the addition of perichondrial derived into the joint. 14 29 chondrocytes. The descendants of this research include Procedures such as platelet-rich plasma and bone mar- the currently available True-Fit plug (Smith & Nephew, row aspirate concentrate use a patient’s autologous blood Andover, MA) along with other similar collagen based or bone marrow in a perioperative setting to deliver stem plugs like the Chondromimetic product (formerly Tigenix) cells locally in cartilage defects. Other biological-based and being developed by Kensey-Nash (Exton, PA). treatments such as Orthokine or interleukin receptor antag- 15 31 Work done by Kandel et al, growing chondrocytes on a onist have also been isolated from each patient’s blood suspended membrane culture system, thus allowing nutrient and delivered locally into the joint. These technologies are diffusion in 2 planes resulted in reformation of cartilage tis- highly cost-effective relative to cell-based repair strategies sue with enhanced matrix deposition and multiple cell lay- and are readily available for adaption to clinical setting. ers in thickness. The membrane could then be used as a However, clinical studies and independent trials have delivery system to transplant the neocartilage construct. yielded largely mixed outcomes and will likely remain so This innovative approach is the basis for matrix-assisted until well-designed prospective randomized clinical trials chondrocyte implantation (MACI), currently in clinical tri- are conducted and demonstrate efficacy. als in the European Union. The prototype for a tissue engineered strategy was devel- Cartilage Repair: Where We Are oped by using vicryl suture (polylactic glycolide) formed Headed and the Future of Cartilage into a rudimentary nonwoven scaffold and seeded with Repair chondrocytes. This study demonstrated that chondrocytes could gener- The field of tissue engineering has largely been supplanted ate cartilage tissue de novo as the scaffold degraded leaving by the emergence of regenerative medicine. Regenerative only the cells and their synthesized extracellular matrix. medicine is defined as the “process of replacing or regener- The field of tissue engineering has seen a prolific amount of ating human cells, tissues, or organs to restore or establish activity with respect to cell types explored (chondrocytes, normal function.” It was first coined by William Haseltine, stem cells; marrow, muscle, adipose, synovial, embryonic, the founder of Human Genome Sciences and cartilage induced pluripotent stem cells) and scaffold fabrication. repair is highly attractive for implementing regenerative While the putative mechanisms for joint degeneration strategies. from cartilage defects leading to PTOA occur at the molec- ular, cellular, and tissue level, current treatments for PTOA 17-19 are primarily surgical. Several procedures are in wide The Need for Early Intervention in Cartilage use today such as microfracture, osteochondral autograft Repair transfer system, mosaicplasty, and ACI, and MACI have been devised to relieve pain, restore function, and delay or There is a new paradigm emerging suggesting the need to 17-19,22,23 halt the progression of focal cartilaginous defects. treat the whole joint as an organ system and not just the Each of these methods has its own characteristic advantages cartilage defect. The early phase of inflammation post joint 8,22-25 and limitations. Microfracture involves the piercing of trauma triggers a cascade of catabolic changes in cartilage, the subchondral bone to allow marrow and its host stem synovial tissue, and underlying bone. Whereas acute inflam- cells to colonize the wound bed, promoting cartilage forma- mation can be part of the normal healing process, chronic tion that is more fibrous than hyaline in quality. inflammation in PTOA is associated with a positive feed- Osteochondral allografting involves the transfer of bone– back cycle that augments the destructive and degenerative cartilage units from “healthy” regions to damaged regions pathways mediated by matrix-degrading enzymes, primar- and rapidly restores load-bearing capacity and cartilage ily matrix metalloproteinases (MMPs). The use of an MMP structure; however, limitations arise because of donor site inhibitor as an early intervention shortly after the incidence morbidity, lack of healthy donor tissue, and insufficient of injury is attractive because it may be deployed outside of integration. ACI (injection of chondrocytes in suspension a surgical unit, where oral administration may be preferred. under a periosteal flap) has shown promise in small defects Specifically inhibiting MMPs, target the pathophysiologic in non- and low load-bearing sites; however, it employs enzymes responsible for extracellular matrix breakdown, adult human chondrocytes from potentially OA cartilage, without inhibiting the other mediators of normal inflamma- which possess a limited capacity to form a hyaline rich tory responses, associated with physiological healing. MMP 284 Cartilage 4(4) inhibition can reduce or potentially delay the onset of that can biologically expedite recovery and improve the PTOA, thus decreasing the need for more invasive proce- quality of structural repair is a promising strategy as there dure such as total joint replacement. Moreover, MMP inter- are few surgical techniques that result in superior and dura- ventions early in the acute post-traumatic period can ble clinical outcomes in young active patients. significantly improve the therapeutic outcomes of treat- ments administered later during surgical repair, by reducing Acknowledgments and Funding the severity of the disease. MMP inhibition is also expected The author(s) received no financial support for the research, to reduce the production of fibrous cartilage (inferior qual- authorship, and/or publication of this article. ity “scar-like” tissue) in favor of improved production of hyaline (type II collagen rich) cartilage with mechanical Declaration of Conflicting Interests properties significantly improved over existing repair tech- The author(s) declared no potential conflicts of interest with niques. Studies using an equine model that delivered both respect to the research, authorship, and/or publication of this interleukin-1 receptor antagonist protein and insulin-like article. growth factor-1 demonstrated significant improvement in cartilage repair as a result of interleukin-1 inhibition. Ethical Approval This study was approved by our institutional review board. Successful Large Defect Resurfacing References Recent investigations have demonstrated proof of principle achievement of the ability to resurface large defect surfaces 1. Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. and in some cases whole joint surfaces by “in situ tissue Posttraumatic osteoarthritis: a first estimate of incidence, preva- lence, and burden of disease. J Orthop Trauma. 2006;20(10): engineering.” This approach seeks to recruit the endogenous 739-44. stem populations from both the bone marrow and synovial 2. Dirschl DR, Marsh JL, Buckwalter JA, Gelberman R, Olson SA, compartments via chemoattraction to an implanted scaffold Brown TD, et al. Articular fractures. J Am Acad Orthop Surg. impregnated with a homing factor such as transforming 2004;12(6):416-23. 33 34 growth factor-β3. Other approaches have demonstrated 3. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections success using 3-dimensional composite woven polycapro- of primary and revision hip and knee arthroplasty in the lactone scaffolds vacuum infiltrated with gel containing United States from 2005 to 2030. J Bone Joint Surg Am. cells. Such innovative designs are able to bear the high shear 2007;89(4):780-5. forces and loads encountered in a typical joint. The future 4. Green WT Jr. Articular cartilage repair: behavior of rabbit is now set for the age of biological whole joint resurfacing. chondrocytes during tissue culture and subsequent grafting. Clin Orthop Relat Res. 1977;(124):237-50. 5. Bentley G, Greer RB 3rd. Homotransplantation of isolated Summary epiphyseal and articular cartilage chondrocytes into joint sur- faces of rabbits. Nature. 1971;230(5293):385-8. The history of cartilage repair undergone significant evolu- 6. Sokoloff L. Edward A. Dunlop lecture. Cell biology and the tion over the past 40 years. Discoveries made more than 30 repair of articular cartilage. J Rheumatol. 1974;1(1):9-16. years ago are seeing rebirth as newer technologies have 7. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reex- been developed to overcome some the problems associated press the differentiated collagen phenotype when cultured in with the era in which they were first proposed. Effective agarose gels. Cell. 1982;30(1):215-24. and comprehensive treatment of all phases of injury is 8. Grande DA, Pitman MI, Peterson L, Menche D, Klein M. The essential to address the initial structural joint injury as well repair of experimentally produced defects in rabbit articular as the inflammatory and destructive processes that follow cartilage by autologous chondrocyte transplantation. J Orthop and can result in more diffuse joint pathology. Acute, sub- Res. 1989;7(2):208-18. 9. Grande DA, Singh IJ, Pugh J. The healing of experimentally acute, and chronic surgical resurfacing of larger or multifo- produced lesions in articular cartilage following chondrocyte cal symptomatic hyaline tissue traumatic defects and transplantation. Anat Rec. 1987;218(2):142-8. associated osteochondral defects is essential. Although cur- 10. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, rent marrow stimulation (microfracture) and autogenous Peterson L. Treatment of deep cartilage defects in the knee osteochondral transplantation techniques have been avail- with autologous chondrocyte transplantation. N Engl J Med. able, these methods have had less effective application in 1994;331(14):889-95. treating larger sizes defects (>2 cm ). Use of volume stable 11. Dell’Accio F, Vanlauwe J, Bellemans J, Neys J, De Bari C, scaffolds coated to chemotactically enhance mesenchymal Luyten FP. Expanded phenotypically stable chondrocytes per- stem cell recruitment to the repair construct is an attractive sist in the repair tissue and contribute to cartilage matrix for- option. The concurrent use of biochemical catabolic inhibi- mation and structural integration in a goat model of autologous tors that can reduce degradative inflammatory mechanisms chondrocyte implantation. J Orthop Res. 2003;21(1):123-31. Grande et al. 285 12. Van Assche D, Staes F, Van Caspel D, Vanlauwe J, Bellemans J, equine articular defects—results at 12 and 18 months. Saris DB, et al. Autologous chondrocyte implantation versus Osteoarthritis Cartilage. 2008;16:667-79. microfracture for knee cartilage injury: a prospective random- 25. Frisbie DD, Lu Y, Kawcak CE, DiCarlo EF, Binette F, ized trial, with 2-year follow-up. Knee Surg Sports Traumatol McIlwraith CW. In vivo evaluation of autologous cartilage Arthrosc. 2010;18(4):486-95. fragment-loaded scaffold implanted into equine articular 13. Itay S, Abramovici A, Nevo Z. Use of cultured embryonal defects and compared with autologous chondrocyte implanta- chick epiphyseal chondrocytes as grafts for defects in chick tion. Am J Sports Med. 2009;37(Suppl 1):71S-80S. articular cartilage. Clin Orthop Relat Res. 1987;(220):284-303. 26. Bentley G, Biant LC, Carrington RW, Akmal M, Goldberg A, 14. Chu CR, Coutts RD, Yokshioka M, Harwood FL, Monosov AZ, Williams AM, et al. A prospective, randomised comparison Amiel D. Articular cartilage repair using allogeneic peri- of autologous chondrocyte implantation versus mosaicplasty chondrocyte seeded biodegradable porous polylactic acid for osteochondral defects in the knee. J Bone Joint Surg Br. (PLA): a tissue-engineering study. J Biomed Mater Res. 2003;85(2):223-30. 2004;29(9):1147-54. 27. Saris DB, Vanlauwe J, Victor J, Haspl M, Bohnsack M, 15. Kandel RA, Chen H, Clark J, Renlund R. Transplantation Fortems Y, et al. Characterized chondrocyte implantation of cartilagenous tissue generated in vitro into articular joint results in better structural repair when treating symptomatic defects. Artif Cells Blood Substit Immobil Biotechnol. cartilage defects of the knee in a randomized controlled trial 1995;23(5):565-77. versus microfracture. Am J Sports Med. 2008;36(2):235-46. 16. Cima LG, Vacanti JP, Vacanti C, Ingber D, Mooney 28. Jeong CG and Hollister SJ. A comparison of the influence D, Langer R. Tissue engineering by cell transplantation of material on in vitro cartilage tissue engineering with PCL, using degradable polymer substrates. J Biomech Eng. PGS, and POC 3D scaffold architecture seeded with chondro- 1991;113(2):143-51. cytes. Biomaterials. 2010;31(15):4304-12. 17. Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema 29. Boswell SG, Cole BJ, Sundman EA, Karas V, Fortier LA. TR, Olson SA, et al. Post-traumatic osteoarthritis: improved Platelet-rich plasma: a milieu of bioactive factors. J Arthrosc understanding and opportunities for early intervention. J Relat Surg. 2012;28(3):429-39. Orthop Res. 2011;29(6):802-9. 30. Fortier LA, Potter HG, Rickey EJ, Schnabel LV, Foo LF, 18. Furman BD, Olson SA, Guilak F. The development of post- Chong LR, et al. Concentrated bone marrow aspirate improves traumatic arthritis after articular fracture. J Orthop Trauma. full-thickness cartilage repair compared with microfracture in 2006;20(10):719-25. the equine model. J Bone Joint Surg Am. 2010;92(10):1927-37. 19. Daher RJ, Chahine NO, Greenberg AS, Sgaglione NA, 31. Hraha TH, Doremus KM, McIlwraith CW, Frisbie DD. Grande DA. New methods to diagnose and treat cartilage Autologous conditioned serum: the comparative cytokine degeneration. Nat Rev Rheumatol. 2009;5(11):599-607. profiles of two commercial methods (IRAP and IRAP II) 20. Evans PJ, Miniaci A, Hurtig MB. Manual punch versus power har- using equine blood. Equine Vet J. 2011;43(5):516-21. vesting of osteochondral grafts. Arthroscopy. 2004;20(3):306-10. 32. Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIlwraith 21. Mithoefer K, Williams RJ 3rd, Warren RF, Potter HG, Spock CW. IL-1RA/IGF-1 gene therapy modulates repair of micro- CR, Jones EC, et al. The microfracture technique for the treat- fractured chondral defects. Clin Orthop Relat Res. 2007;462: ment of articular cartilage lesions in the knee. A prospective 221-8. cohort study. J Bone Joint Surg Am. 2005;87(9):1911-20. 33. Lee CH, Cook JL, Mendelson A, Moioli EK, Yao H, 22. Hangody L, Feczkó P, Bartha L, Bodó G, Kish G. Mosaicplasty Mao JJ. Regeneration of the articular surface of the rab- for the treatment of articular defects of the knee and ankle. bit synovial joint by cellhoming: a proof of concept study. Clin Orthop Relat Res. 2001;(391 Suppl):S328-36. Lancet. 2010;376(9739):440-8. 23. Knutsen G, Drogset JO, Engebretsen L, Grøntvedt T, Isaksen 34. Moutos FT, Freed LE, Guilak F. A biomimetic three-dimensional V, Ludvigsen TC, et al. A randomized trial comparing autolo- woven composite scaffold for functional tissue engineering of gous chondrocyte implantation with microfracture. Findings cartilage. Nat Mater. 2007;6:162-7. at five years. J Bone Joint Surg Am. 2007;89(10):2105-12. 35. Ng KW, Lima EG, Bian L, O’Conor CJ, Jayabalan PS, Stoker 24. Frisbie DD, Bowman SM, Calhoun HA, DiCarlo EF, AM, et al. Passaged adult chondrocytes can form engineered Kawcak CE, McIlwraith CW. Evaluation of autologous cartilage with functional mechanical properties: a canine chondrocyte concentration via a collagen membrane in model. Tissue Eng. 2010;16(3):1041-51. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cartilage Pubmed Central

Articular Cartilage Repair

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Pubmed Central
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Abstract

This review traces the genealogy of the field of articular cartilage repair from its earliest attempts to its present day vast proliferation of research advances. Prior to the 1980s there was only sporadic efforts to regenerate articular cartilage as it was considered to be incapable of regeneration based on historical dogma. The first flurry of reports documented the use of various cell types ultimately leading to the first successful demonstration of autologous chondrocyte transplantation which was later translated to clinical use and has resulted in the revised axiom that cartilage regeneration is possible. The current field of cartilage repair is multifaceted and some of the 1980s’ vintage concepts have been revisited with state of the art technology now available. The future of the field is now poised to undertake the repair of whole cartilage surfaces beyond focal defects and an appreciation for integrated whole joint health to restore cartilage homeostasis. Keywords chondrocytes, cells, articular cartilage, tissue, osteoarthritis, diagnosis Introduction Cartilage Repair: The Pre-Autologous Chondrocyte Transplantation Era Lesions in articular cartilage are difficult to treat and cause considerable musculoskeletal morbidity, with significant The well-referenced 1743 quote from the British anatomist economic and social implications. It is generally well Hunter in which he states “Cartilage injury is a troublesome accepted that such lesions eventually result in osteoarthri- thing and once injured is seldom repaired” was the general tis (OA). OA has a significant impact on human health, axiom for thinking about cartilage repair for the next particularly in populations who are at higher risk for carti- 200 years. Despite such negativity, there were pioneers lage trauma over the course of their lifetimes. These such as William Green, MD, who performed seminal include patients who have sustained sports injuries, have experiments investigating the reparative potential of autolo- biomechanical aberrations, or repetitive micro trauma to gus and homologous chondrocyte transplantation in the their joints. Although cartilage has a relatively simple 1970s. He used decalcified bone as a type of scaffold for structure compared with other tissues, cartilaginous inju- cell transplantation. He was also the first to use the rabbit as ries can be extremely unforgiving. The limited blood a model to study cartilage repair. Although his success was supply in cartilage is thought to be responsible for the hampered by the technology of the times, his work was a inadequate repair post-injury. A substantial fraction cornerstone for the future of cartilage repair as well as a (˜12%) of the overall burden of OA arises secondary to pioneer in what was to become the field of tissue joint trauma, where the risk of posttraumatic OA (PTOA) 1,2 ranges from 20% to 50%. Currently, 9% of the U.S. Department of Orthopaedic Surgery, Feinstein Institute for Medical population aged 30 years and older has OA of the hip or Research, North Shore–LIJ Health Systems, Manhasset, NY, USA knee, costing an estimated $28.6 billion dollars with Corresponding Author: >400,000 primary knee replacements currently being per- Daniel A. Grande, Department of Orthopaedic Surgery, Feinstein formed each year in the United States alone. Thus, meth- Institute for Medical Research, North Shore–LIJ Health Systems, ods for successful cartilage repair still remain a largely 350 Community Drive, Manhasset, NY 11030, USA. unmet clinical need. Email: [email protected] 282 Cartilage 4(4) engineering. Later, his colleagues George Bentley and to other previous surgical procedures. The results demon- Robert Greer experimented with epihyseal and articular strated nearly complete regeneration of the cartilage defects chondrocyte allografts in rabbits. with a tissue that was blindly classified as hyaline cartilage. By the early 1980s, the concept of healing cartilage with The fate of the transplanted cells was followed by autoradi- predominantly hyaline tissue was still largely considered a ography but only a small fraction, 10% to 15% of the cells myth. Popular procedures at the time included Pirdie drill- could be localized within the defect. The mechanism of car- ing and abrasion arthroplasty, which resulted in largely tilage regeneration was postulated to be either the result of fibrous to fibrocartilaginous tissue. Based on the combined the transplanted cells, however, the radiolabel was serially works of Green, Bentley, and Sokoloff, a multidisciplinary diluted to be nondetectable, or that the cells induced an group of orthopedic researchers at the Hospital for Joint endogenous repair response. Further recent studies with Diseases in New York City, hypothesized that hyaline car- better cell tracking methodology have determined that these tilage repair could be achieved by a cell-based approach to cells do persist and function in establishing new hyaline the problem. This began a collaboration to try and develop cartilage. a new method for achieving the goal of hyaline cartilage In spite of initial skepticism, Lars Peterson, MD, then repair. The clinical motivation for pursuing this project conducted the first human clinical trials using the exact were patients who had sustained cartilage injury but were same protocols developed for the preclinical studies back in still deemed too young for total joint arthroplasty and which his native Sweden. resulted in pain and disability for young active individuals. The ACI technique has been proven to be a successful The concept of a cell-based strategy was explored and treatment modality for treatment of cartilage lesions and determined to be a viable option. After several experiments which has resulted in long-term clinical success without the it was concluded that articular chondrocytes exhibited sev- need for total joint arthroplasty. The use of periosteum as a eral intrinsic properties of the tissue that were deemed key covering membrane has been the principal source of mor- to repair. bidity because of its capability of being stimulated to First, they were already programmed to synthesize type undergo hyperplasia when removed from its anatomical II collagen and aggrecan. The clinical strategy was devel- location. Significant research has subsequently been per- oped to first obtain a biopsy of cartilage, which would then formed to find alternative nonreactive membranes to replace be used to isolate free chondrocytes and expanded in culture periosteum as a cover. Further investigation has character- followed by a second transplant procedure. Based on earlier ized the importance of maintaining the chondrocyte phe- work by Benya and Shaffer, it was hypothesized that chon- notype and applying principles of big pharma to the drocyte phenotype was plastic and a limited culture time in performance of cells. Certifying that chondrocytes are monolayer 2-dimensional culture could then be reestab- expressing a gene profile consistent with a hyaline pheno- lished by return to a 3-dimensional environment. Optimizing type demonstrated superior structural repair in a prospec- cell delivery and a technique for maintaining the chondro- tive randomized clinical trial comparing ACI versus cytes within a defect was problematic as suitable biomate- microfracture. rial membranes were scarce at that time. The decision to use periosteum was based on its anatomical proximity to the Where We Are Now surgical site as well as its historical use in many orthopedic applications such as interpositional arthroplasty procedures. The 1980s-1090s period was a productive time for cartilage The first results of rabbit experiments were decidedly supe- research. Several concepts developed during this period laid rior then expectations and the realization that a new chapter the foundation for technologies in current use today. The in orthopedic research had been opened. The first report of use of immature, neonatal chondrocytes for cartilage repair the technique were presented at the annual meeting of the was based on the higher metabolic rates of these cells com- Orthopaedic Research Society in 1985 by Lars Peterson, pared to those of adult. These were shown to be capable of MD, and were promptly met with skepticism as the promis- excellent repair in an avian model by Itay et al. Although ing results were in conflict with current thinking as well as not developed further at that time the use of young cartilage more than 200 years of dogma. This was followed up by has recently been adapted by Zimmer (Warsaw, IN) as their 2 seminal publications, 1 in the Journal of Orthopedic product DeNovo-NT and has been used clinically in the Research in 1989 received significant attention. The other United States to treat more than 3,000 patients. The product published in the Anatomical Record as part of the first consists of minimally manipulated cartilage tissue har- author’s (DAG) thesis. The procedure is now known as vested young donors that is placed within a cartilage defect autologous chondrocyte implantation (ACI). and held in place by fibrin glue. The mechanism of action is The first reports studied chondral defects made in the unclear but it is likely that the cells within the transplanted patella of rabbits and did not violate the subchondral plate tissue are able to migrate out and contribute to the repair thus avoiding bleeding and the repair mechanism intrinsic tissue observed. Grande et al. 283 The archetypes of plug-type scaffolds for arthroscopic tissue. In MACI, a scaffold cut to the shape and size of the delivery were initially fabricated of carbon fiber by Dunlop defect is seeded with autologous chondrocytes and secured 26,27 Corp in Birmingham, United Kingdom, and investigated in in the defect using a fibrin glue. New techniques involv- clinical trials by McMinn, Coutts, and Amiel studied carti- ing tissue engineering use cells in combination with scaf- lage repair using the bioabsorbable scaffold material poly- folds to regenerate a cartilage plug in vitro for implantation l -lactic acid with the addition of perichondrial derived into the joint. 14 29 chondrocytes. The descendants of this research include Procedures such as platelet-rich plasma and bone mar- the currently available True-Fit plug (Smith & Nephew, row aspirate concentrate use a patient’s autologous blood Andover, MA) along with other similar collagen based or bone marrow in a perioperative setting to deliver stem plugs like the Chondromimetic product (formerly Tigenix) cells locally in cartilage defects. Other biological-based and being developed by Kensey-Nash (Exton, PA). treatments such as Orthokine or interleukin receptor antag- 15 31 Work done by Kandel et al, growing chondrocytes on a onist have also been isolated from each patient’s blood suspended membrane culture system, thus allowing nutrient and delivered locally into the joint. These technologies are diffusion in 2 planes resulted in reformation of cartilage tis- highly cost-effective relative to cell-based repair strategies sue with enhanced matrix deposition and multiple cell lay- and are readily available for adaption to clinical setting. ers in thickness. The membrane could then be used as a However, clinical studies and independent trials have delivery system to transplant the neocartilage construct. yielded largely mixed outcomes and will likely remain so This innovative approach is the basis for matrix-assisted until well-designed prospective randomized clinical trials chondrocyte implantation (MACI), currently in clinical tri- are conducted and demonstrate efficacy. als in the European Union. The prototype for a tissue engineered strategy was devel- Cartilage Repair: Where We Are oped by using vicryl suture (polylactic glycolide) formed Headed and the Future of Cartilage into a rudimentary nonwoven scaffold and seeded with Repair chondrocytes. This study demonstrated that chondrocytes could gener- The field of tissue engineering has largely been supplanted ate cartilage tissue de novo as the scaffold degraded leaving by the emergence of regenerative medicine. Regenerative only the cells and their synthesized extracellular matrix. medicine is defined as the “process of replacing or regener- The field of tissue engineering has seen a prolific amount of ating human cells, tissues, or organs to restore or establish activity with respect to cell types explored (chondrocytes, normal function.” It was first coined by William Haseltine, stem cells; marrow, muscle, adipose, synovial, embryonic, the founder of Human Genome Sciences and cartilage induced pluripotent stem cells) and scaffold fabrication. repair is highly attractive for implementing regenerative While the putative mechanisms for joint degeneration strategies. from cartilage defects leading to PTOA occur at the molec- ular, cellular, and tissue level, current treatments for PTOA 17-19 are primarily surgical. Several procedures are in wide The Need for Early Intervention in Cartilage use today such as microfracture, osteochondral autograft Repair transfer system, mosaicplasty, and ACI, and MACI have been devised to relieve pain, restore function, and delay or There is a new paradigm emerging suggesting the need to 17-19,22,23 halt the progression of focal cartilaginous defects. treat the whole joint as an organ system and not just the Each of these methods has its own characteristic advantages cartilage defect. The early phase of inflammation post joint 8,22-25 and limitations. Microfracture involves the piercing of trauma triggers a cascade of catabolic changes in cartilage, the subchondral bone to allow marrow and its host stem synovial tissue, and underlying bone. Whereas acute inflam- cells to colonize the wound bed, promoting cartilage forma- mation can be part of the normal healing process, chronic tion that is more fibrous than hyaline in quality. inflammation in PTOA is associated with a positive feed- Osteochondral allografting involves the transfer of bone– back cycle that augments the destructive and degenerative cartilage units from “healthy” regions to damaged regions pathways mediated by matrix-degrading enzymes, primar- and rapidly restores load-bearing capacity and cartilage ily matrix metalloproteinases (MMPs). The use of an MMP structure; however, limitations arise because of donor site inhibitor as an early intervention shortly after the incidence morbidity, lack of healthy donor tissue, and insufficient of injury is attractive because it may be deployed outside of integration. ACI (injection of chondrocytes in suspension a surgical unit, where oral administration may be preferred. under a periosteal flap) has shown promise in small defects Specifically inhibiting MMPs, target the pathophysiologic in non- and low load-bearing sites; however, it employs enzymes responsible for extracellular matrix breakdown, adult human chondrocytes from potentially OA cartilage, without inhibiting the other mediators of normal inflamma- which possess a limited capacity to form a hyaline rich tory responses, associated with physiological healing. MMP 284 Cartilage 4(4) inhibition can reduce or potentially delay the onset of that can biologically expedite recovery and improve the PTOA, thus decreasing the need for more invasive proce- quality of structural repair is a promising strategy as there dure such as total joint replacement. Moreover, MMP inter- are few surgical techniques that result in superior and dura- ventions early in the acute post-traumatic period can ble clinical outcomes in young active patients. significantly improve the therapeutic outcomes of treat- ments administered later during surgical repair, by reducing Acknowledgments and Funding the severity of the disease. MMP inhibition is also expected The author(s) received no financial support for the research, to reduce the production of fibrous cartilage (inferior qual- authorship, and/or publication of this article. ity “scar-like” tissue) in favor of improved production of hyaline (type II collagen rich) cartilage with mechanical Declaration of Conflicting Interests properties significantly improved over existing repair tech- The author(s) declared no potential conflicts of interest with niques. Studies using an equine model that delivered both respect to the research, authorship, and/or publication of this interleukin-1 receptor antagonist protein and insulin-like article. growth factor-1 demonstrated significant improvement in cartilage repair as a result of interleukin-1 inhibition. Ethical Approval This study was approved by our institutional review board. Successful Large Defect Resurfacing References Recent investigations have demonstrated proof of principle achievement of the ability to resurface large defect surfaces 1. Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. and in some cases whole joint surfaces by “in situ tissue Posttraumatic osteoarthritis: a first estimate of incidence, preva- lence, and burden of disease. J Orthop Trauma. 2006;20(10): engineering.” This approach seeks to recruit the endogenous 739-44. stem populations from both the bone marrow and synovial 2. 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Cartilage – Pubmed Central

Published: Oct 1, 2013

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