- Clinical trials with the highest standard of scientific quality will help to understand new developments in the field of cartilage repair. Critical analysis according to EBM criteria will help to qualify those treatment options.
3.2.1 - Long-Term Results
Several surgical strategies have been investigated to address cartilage lesions, ranging from classic microfracturing to the most recent cell-based therapies or cell-free approaches based on “smart” biomimetic scaffolds. Treatments such as mosaicplasty, autologous or allogeneic osteochondral transplantation, autologous chondrocyte implantation, matrix-assisted autologous chondrocyte transplantation (MACT), and osteochondral scaffolds can all be considered as possible treatments for cartilage pathology. However, each technique has advantages and limits. Therefore, surgeons should evaluate every option before deciding how to proceed. In particular, while most new approaches seem to hold promise, it is important to understand their real potential by focusing on the long-term results.
Expensive high-tech procedures are often available only in highly specialized centers and are not an option for many orthopedic surgeons. Therefore, besides the fashionable and ambitious regenerative treatments, it is important to start by evaluating also the less expensive and easily available treatments to address the damaged osteochondral unit. Among these, mosaicplasty and single-plug autologous osteochondral transplantation are viable solutions. These approaches present some analogies in terms of treatment rationale and technical aspects. Both procedures consist of harvesting autologous osteochondral grafts from a healthy region of the knee to be placed in the defect site. Looking at the long-term results of single-plug autologous osteochondral transplantation, we documented in a series of 15 patients studied at minimum 16 years’ follow-up a significant improvement and only 3 failures, although the absolute scores reached were only moderately satisfactory .
Mosaicplasty is a less invasive approach, which can be performed also arthroscopically, with the possibility of harvesting multiple small cylinder-shaped autografts from different articular sites. This technique is less invasive and contribute to less donor site morbidity, which in theory should allow for the treatment of larger lesions. Still, while showing overall good clinical results, our analysis of 26 patients followed up to 12 years of follow-up, the radiographic evaluation showed significantly poorer Kellgren-Lawrence scores and a reduction of the joint line in the treated compartments, and knees with 3-4 plugs presented a significantly higher joint degeneration level with respect to those implanted with 1-2 plugs . The comparison of mosaicplasty and MACT showed in both cases a clinical improvement, however, for larger lesions MACT presented better subjective and objective outcomes, as well as less failures, which should be considered when choosing the most suitable treatment for patients affected by knee cartilage lesions .
MACT showed actually really good results over time. A long-term evaluation of 113 patients documented a long-lasting improvement that was stable over time and resulted in a limited number of failures and reinterventions for up to 15 years of follow-up. However, not all patients benefited in the same way, and several factors were identified as having a prognostic value . Arthroscopic bone grafting followed by MACT for unfixable knee osteochondritis dissecans (OCD) can offer a promising and stable clinical outcome over time especially in lesions smaller than 4 cm2, with a low failure rate, but persistent subchondral alterations were documented at long-term MRI evaluation, suggesting the limits of this approach to regenerate the osteochondral unit in patients affected by knee OCD [5,6]. More challenging are the patello-femoral lesions, which provide overall lower results than condyle lesions, even though the improvement achieved was relatively stable at long-term. The clinical results of hyaluronan-based MACT treatment of chondral lesions of the patellofemoral joint did not worsen over time in our series, with an overall low rate of failure at long-term follow-up . Still, these overall findings may be misleading. In fact, while commonly studied together in the group of patello-femoral lesions, patient characteristics differ between patellar and trochlear cartilage defects. Moreover, the results obtained are significantly different, with a markedly good outcome in cases with trochlear lesions and less satisfactory results for patients affected by cartilage lesions of the patella. Thus, patellar and trochlear defects should be considered separately when evaluating the outcome of cartilage treatments in this anatomic region .
MACT was also used as salvage procedures for young, active patients affected by chondral and osteochondral lesions in osteoarthritic knees. This led to a limited improvement, with the majority of patients experiencing failure at long-term follow-up, for a total surgical and clinical failure rate of 59% at 15 years. Although a minor subpopulation experienced favorable and stable improvement, the use of MACT for such a challenging indication remains questionable until responding patients can be profiled .
For degenerative lesions, as well as for large OCDs, treatments should also aim at addressing the damaged subchondral bone. A cell-free biomimetic osteochondral scaffold has been developed to this purpose. The 10-year follow-up evaluation showed that the clinical improvement was significant and stable over time both in terms of subjective and objective outcomes, including activity level, with overall good results. On the other hand, the regenerative potential of this scaffold is limited, as demonstrated by the signal alterations persisting over time on MRI scans . Thus, while the clinical improvement is still relevant and stable over time, efforts are being placed to further improve the biological potential of this osteochondral scaffold. An ongoing Eu project is investigating both chemical and biological strategies to enhance the subchondral bone regenerative potential, with promising results in the animal model .
The partial results obtained by these new treatments aiming at addressing challenging lesions of the articular surface are also explainable by an unfavorable joint environment, which should be addressed as well. This is a rapidly growing field, where increasing efforts have been invested to develop orthobiologics to positively modulate the articular homeostasis. Among these, platelet-rich plasma (PRP) is the most used and documented. A meta-analysis of 34 RCTs showed that the effect of platelet concentrates goes beyond its mere placebo effect, and PRP injections provide better results than other injectable options. This benefit increases over time, being not significant at earlier follow-ups but becoming clinically significant after 6 to 12 months . However, although substantial, the improvement remains partial and supported by low level of evidence. Among the controversial aspects, the long-term results of such injections remain poorly documented. Few reports beyond 2 years follow-up report an overall declining outcome [13,14]. Moreover, results are even less successful when addressing the more demanding middle-aged sport-active patients with knee osteoarthritis, which showed only a limited return to sport . Thus, while a recent systematic review  documented that platelet-rich plasma injections induce disease-modifying effects in the treatment of osteoarthritis in animal models, results in human are still modest, and further research efforts are needed to optimize the potential of platelet concentrates, as well as to identify the ideal candidates that could benefit more by these emerging orthobiologic approaches.
1) Filardo G, Kon E, Di Matteo B, Di Martino A, Marcacci M. Single-plug autologous osteochondral transplantation: results at minimum 16 years' follow-up. Orthopedics. 2014 Sep;37(9):e761-7. doi: 10.3928/01477447-20140825-51.
2) Filardo G, Kon E, Perdisa F, Tetta C, Di Martino A, Marcacci M. Arthroscopic mosaicplasty: long-term outcome and joint degeneration progression. Knee. 2015 Jan;22(1):36-40. doi: 10.1016/j.knee.2014.10.001.
3) Zaffagnini S, Boffa A, Andriolo L, Reale D, Busacca M, Di Martino A, Filardo G. Mosaicplasty versus Matrix-Assisted Autologous Chondrocyte Transplantation for Knee Cartilage Defects: A Long-Term Clinical and Imaging Evaluation. Appl Sci. 2020 Jul 3; 10(13), 4615; doi.org/10.3390/app10134615.
4) Andriolo L, Reale D, Di Martino A, De Filippis R, Sessa A, Zaffagnini S, Filardo G. Long-term Results of Arthroscopic Matrix-Assisted Autologous Chondrocyte Transplantation: A Prospective Follow-up at 15 Years. Am J Sports Med. 2020 Oct;48(12):2994-3001. doi: 10.1177/0363546520949849.
5) Andriolo L, Di Martino A, Altamura SA, Boffa A, Poggi A, Busacca M, Zaffagnini S, Filardo G. Matrix-assisted chondrocyte transplantation with bone grafting for knee osteochondritis dissecans: stable results at 12 years. Knee Surg Sports Traumatol Arthrosc. 2021 Jun;29(6):1830-1840. doi: 10.1007/s00167-020-06230-y.
6) Roffi A, Andriolo L, Di Martino A, Balboni F, Papio T, Zaffagnini S, Filardo G. Long-term Results of Matrix-assisted Autologous Chondrocyte Transplantation Combined With Autologous Bone Grafting for the Treatment of Juvenile Osteochondritis Dissecans. J Pediatr Orthop. 2020 Feb;40(2):e115-e121.
7) Kon E, Filardo G, Gobbi A, Berruto M, Andriolo L, Ferrua P, Crespiatico I, Marcacci M. Long-term Results After Hyaluronan-based MACT for the Treatment of Cartilage Lesions of the Patellofemoral Joint. Am J Sports Med. 2016 Mar;44(3):602-8. doi: 10.1177/0363546515620194.
8) Filardo G, Kon E, Andriolo L, Di Martino A, Zaffagnini S, Marcacci M. Treatment of "patellofemoral" cartilage lesions with matrix-assisted autologous chondrocyte transplantation: a comparison of patellar and trochlear lesions. Am J Sports Med. 2014 Mar;42(3):626-34. doi: 10.1177/0363546513510884.
9) Andriolo L, Reale D, Di Martino A, Zaffagnini S, Vannini F, Ferruzzi A, Filardo G. High Rate of Failure After Matrix-Assisted Autologous Chondrocyte Transplantation in Osteoarthritic Knees at 15 Years of Follow-up. Am J Sports Med. 2019 Jul;47(9):2116-2122. doi: 10.1177/0363546519855029.
10) Di Martino A, Perdisa F, Filardo G, Busacca M, Kon E, Marcacci M, Zaffagnini S. Cell-Free Biomimetic Osteochondral Scaffold for the Treatment of Knee Lesions: Clinical and Imaging Results at 10-Year Follow-up. Am J Sports Med. 2021 Aug;49(10):2645-2650. doi: 10.1177/03635465211029292.
11) EuroNanoMed III Project: this project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 723770. Funding was also provided by the following funding organisations (Science Foundation of Ireland, Ireland, Grant Number SFI/16/ENM-ERA/3458, Ministero della Salute (IMH), Italy, Stated Education Development Agency SEDA/VIAA, Latvia, Technology Foundation (STW), The Netherlands).
12) Filardo G, Previtali D, Napoli F, Candrian C, Zaffagnini S, Grassi A. PRP Injections for the Treatment of Knee Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials. Cartilage. 2020 Jun 19:1947603520931170
13) Kon E, Engebretsen L, Verdonk P, Nehrer S, Filardo G. Autologous Protein Solution Injections for the Treatment of Knee Osteoarthritis: 3-Year Results. Am J Sports Med. 2020 Sep;48(11):2703-2710. doi: 10.1177/0363546520944891.
14) Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-Rich Plasma Versus Hyaluronic Acid Injections for the Treatment of Knee Osteoarthritis: Results at 5 Years of a Double-Blind, Randomized Controlled Trial. Am J Sports Med. 2019 Feb;47(2):347-354. doi: 10.1177/0363546518814532.
15) Altamura SA, Di Martino A, Andriolo L, Boffa A, Zaffagnini S, Cenacchi A, Zagarella MS, Filardo G. Platelet-Rich Plasma for Sport-Active Patients with Knee Osteoarthritis: Limited Return to Sport. Biomed Res Int. 2020 Jan 31;2020:8243865. doi: 10.1155/2020/8243865.
16) Boffa A, Salerno M, Merli G, De Girolamo L, Laver L, Magalon J, Sánchez M, Tischer T, Filardo G. Platelet-rich plasma injections induce disease-modifying effects in the treatment of osteoarthritis in animal models. Knee Surg Sports Traumatol Arthrosc. 2021 Aug 2. doi: 10.1007/s00167-021-06659-9.
3.2.3 - MSCs: Where is the Evidence?
Injury of the knee articular cartilage and osteochondral unit is a significant cause of functional limitation in which the goal of treatment is preservation of the native knee joint. There are a variety of cell-based cartilage and osteochondral unit repair methods that may be used to treat different injuries, given the limited potential for cartilage injury to heal without intervention. Restoration of hyaline-like cartilage is the ultimate goal in treatment of osteochondral unit as it offers an improved durability of repaired tissue and preferable wear characteristics. Over the years many cell-based therapies have been developed to address the need for the long-term viability of repaired tissue. Some of the techniques use mesenchymal stem cells (MSCs) as a core ingredient for tissue repair.
Microfracture, a bone marrow stimulation technique using MSCs, when used wisely and with caution in selected patients has shown good clinical results at short-term follow up. Nonetheless, deterioration of the clinical outcome may be expected after 2 -3 years post-treatment, and degenerative changes are present at long-term follow-up, with a higher rate in older patients with extensive and multiple lesions [1, 2]. Autologous Matrix-Induced Chondrogenesis (AMIC) has emerged as a modification of the microfracture technique by addition of a collagen scaffold. However both of these techniques raise a concern of the damage of the subchondral bone and the formation of microcysts, that may quicken the deterioration of the cartilage and compromise the articular surface for future procedures [3, 4]. Autologous chondrocyte implantation (ACI) consists of a two-step procedure; first, a sample of healthy cartilage is harvested from a non-weight bearing site, followed by an in vitro cell expansion. The second step is the implantation of the chondrocyte suspension into the cartilage defect. Compared to bone marrow stimulating techniques such as microfracture, ACI technique has appeared to be superior over time due to longer-lasting effects, without the concerns of destruction of the subchondral bone [5,6]. However, while techniques using autologous chondrocytes have demonstrated durable cartilage repair, these methods require the patient to undergo two surgical procedures due to the need for chondrocyte culture.
Hyaluronic acid-based scaffold with bone marrow aspirate concentrate (HA-BMAC) was developed 30 years ago, it allowed the treatment of larger cartilage defects in a one-step surgery with biologic tissue such as mesenchymal stem cells, chondrocytes, or platelet-rich plasma. This technique has provided long-term results and has proven its superiority to microfracture due to lasting effect over ten years compared to the 2-3 years with microfracture technique . Moreover, it can be used even in cases of multiple compartment injury, extensive lesions, or in older patients [7-10]. This procedure provides a good source of chondrocytes, whether directly or through differentiation of multipotent precursor cells, capable of producing hyaline-like cartilage, with minimal formation of fibrocartilage tissue .
Lately more attention was brought to the osteochondral unit and especially the role of subchondral bone in maintaining homeostasis of the joint . Bone marrow lesions (BMLs) are the focal changes in the subchondral bone and can be identified by magnetic resonance imaging (MRI). A technique using MSCs to treat BMLs, the Osteo-Core-Plasty (Marrow Cellution™) is a minimally invasive subchondral bone augmentation that offers both biologic and structural components to optimize the osteochondral environment for regeneration. This technique may also by applied in treatment of insufficiency fractures, subchondral cysts, and avascular necrosis [11, 12].
MSCs are also found in other sources than bone marrow, one of which is fat tissue. Adipose derived Mesenchymal Stem Cells (ADMSCs) are quickly becoming a viable source of MSC, not only because they are easy to harvest but also have a high concentration of progenitor cells. Primary outcomes of the use of microfragmented adipose tissue (MFAT) injection in elderly patients with knee osteoarthritis (OA) have shown good clinical results compared with the pre-treatment state and could be an alternative treatment for elderly patients 60 years or older [13, 14].
Summarizing, over 30 years of using MSCs have shown good and very good clinical outcomes in treatment of osteochondral unit lesions and OA.
1. Gobbi A, Karnatzikos G, Kumar A. Long-term results after microfracture treatment for full-thickness knee chondral lesions in athletes. Knee Surg Sports Traumatol Arthrosc. 2014 Sep;22(9):1986–96.
2. Gobbi A, Whyte GP. One-Stage Cartilage Repair Using a Hyaluronic Acid-Based Scaffold With Activated Bone Marrow-Derived Mesenchymal Stem Cells Compared With Microfracture: Five-Year Follow-up. Am J Sports Med. 2016 Nov;44(11):2846–54.
3. Frank RM, Cotter EJ, Nassar I, Cole B. Failure of Bone Marrow Stimulation Techniques. Sports Med Arthrosc Rev. 2017 Mar;25(1):2–9.
4. Gobbi A, Alvarez R, Irlandini E, Dallo I. Current Concepts in Subchondral Bone Pathology. In: Gobbi A, Lane JG, Longo UG, Dallo I, editors. Joint Function Preservation: A Focus on the Osteochondral Unit [Internet]. Cham: Springer International Publishing; 2022
5. Gobbi A, Lane JG, Dallo I. Editorial Commentary: Cartilage Restoration-What Is Currently Available? Arthroscopy. 2020 Jun;36(6):1625–8.
6. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994 Oct 6;331(14):889–95.
7. Gobbi A, Karnatzikos G, Sankineani SR. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med. 2014 Mar;42(3):648–57.
8. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-Step Cartilage Repair with Bone Marrow Aspirate Concentrated Cells and Collagen Matrix in Full-Thickness Knee Cartilage Lesions: Results at 2-Year Follow-up. Cartilage. 2011 Jul;2(3):286–99.
9. Gobbi A, Scotti C, Karnatzikos G, Mudhigere A, Castro M, Peretti GM. One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years. Knee Surg Sports Traumatol Arthrosc. 2017 Aug;25(8):2494–501.
10. Gobbi A, Whyte GP. Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate. Am J Sports Med. 2019 Jun;47(7):1621–8.
11. Szwedowski D, Dallo I, Irlandini E, Gobbi A. Osteo-core Plasty: A Minimally Invasive Approach for Subchondral Bone Marrow Lesions of the Knee. Arthrosc Tech. 2020 Nov;9(11):e1773–7
12. Gobbi A, Dallo I. Osteo-Core-Plasty technique for the treatment of a proximal tibial subchondral cystic lesion. 2021;
13. Dallo I, Morales M, Gobbi A. Platelets and Adipose Stroma Combined for the Treatment of the Arthritic Knee. Arthroscopy Techniques. 2021 Oct 6;10.
14. Gobbi A, Dallo I, Rogers C, Striano RD, Mautner K, Bowers R, et al. Two-year clinical outcomes of autologous microfragmented adipose tissue in elderly patients with knee osteoarthritis: a multi-centric, international study. Int Orthop. 2021 May;45(5):1179–88.
3.2.4 - Guidelines for Cartilage Repair (Recorded Presentation)
There is a noteworthy difference between the breadth and depth of data on cartilage repair techniques and their clinical use. Despite more than three decades of accumulated supporting information, most cartilage repair options are still rarely encountered outside the specialized community.
One reason for this are the problems associated with navigating the data to chose an appropriate treatment for the patient at hand. In order to facilitate this process, individual data points are being assembled to evidence, as seen in the prior talks in the session. This evidence can be thought of as the “map to cartilage repair”
However, true to this analogy, a map alone is of little use if one does not know the present position, the destination, headings et cetera. Adding such extra information, such as cost-effectiveness, access and availability, timing, interest of other stakeholders, to the baseline evidence allows creating clinical guidelines.
Before discussing guidelines in cartilage repair, both the need for and the process of formulating and supporting clinical guidelines are worthwhile critical appraisal. Not all guidelines are created equal and not all guidelines are being employed within the scope of the intended use. A general understanding of guideline development processes, including pitfalls and shortcomings, is a valuable tool for present day clinicians.
Guidelines for cartilage repair have been brought forward by scientific societies, public bodies, and insurance companies. These guidelines arrive at a general consensus that cartilage repair, particularly autologous chondrocyte implantation ACI over mosaicplasty and/or microfracture, is an effective and cost-effective treatment option for a defined population. Shortcomings exist: Treatment effectiveness outside of this narrowly defined population is not commented on. Estimates on cost and utility are presented, but obviously highly dependent on geographic location. The dissemination of guidelines is incomplete. The extent to which these guidelines influence health care policy remains unknown.
In summary, guideslines are valuable tools for clinical decision making and to direct clinicians in choosing cartilage repair options. However, their applicability is limited to the scope of the studied populations and dependent on quality and consistency of the primary data. Deduction and extrapolations beyond this scope are not warranted, but research in uncharted new techniques is.