Introduction

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.

Content

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 [1].

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 [2]. 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 [3].

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 [4]. 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 [7]. 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 [8].

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 [9].

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 [10]. 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 [11].

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 [12]. 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 [15]. Thus, while a recent systematic review [16] 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.

References

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.

Introduction

Conservative strategies to treat osteoarthritis (OA) have modest efficacy, with short-lasting clinical results, and are not able to arrest the disease process. Research efforts have been made to develop new minimally invasive disease-modifying procedures. Among these, orthobiologics are gaining increasing interest due to the availability of several new products with promising biologic potential. These approaches exploit the high concentrations of growth factors, cytokines, and bioactive molecules of blood derivatives, as well as the presence of mesenchymal stromal cells (MSCs) in tissue derived concentrates like bone marrow aspirate concentrates (BMAC), aiming at improving symptoms, a satisfactory joint function, and possibly slowing down OA progression [1,2].

Content

Platelet Rich Plasma (PRP) is increasingly applied due to its safety, low costs, and simple preparation technique to obtain its biologically active content. PRP seems to promote a positive joint environment, favoring the restoration of a homeostatic balance in OA joints. A recent systematic review on animal studies evaluated intra-articular PRP injections as treatment for OA joints [3]. Forty-four articles were included, for a total of 1251 animals. PRP injections showed clinical effects in 80% and disease-modifying effects in 68% of the studies, attenuating cartilage damage progression and reducing synovial inflammation, coupled with changes in biomarker levels. Intra-articular PRP injections showed disease-modifying effects in most preclinical studies, both at the cartilage and synovial level. These findings in animal OA models can play a crucial role in understanding mechanism of action and structural effects of this biological approach. Nevertheless, the overall low quality of the published studies warrants further preclinical studies to confirm the positive findings, as well as high-level human trials to demonstrate if these results translate into disease-modifying effects when PRP is used in the clinical practice to treat OA. Disease-modifying effects are still controversial in humans, while several data are available on the clinical effects of PRP.

Despite the presence of different platelet concentrates, clinical evidence supported the safety and effectiveness of intra-articular PRP injections for the treatment of knee OA, with better clinical results compared to saline, corticosteroids, and hyaluronic acid injections at 6 and 12 months of follow-up. Some studies also suggest that PRP benefits can be perceived by patients beyond 24 months and can delay the need for total knee arthroplasty [4,5]. Recently, some researchers also supported the effectiveness of subchondral PRP injections, reporting positive results in reducing pain and improving functional status, although more studies are needed in this direction.

BMAC is a combination of biologically active proteins and cells obtained through a mini-invasive and technically easy procedure. Clinical studies investigating the use of BMAC to address OA evaluated mainly the knee injective treatment, reporting promising results in terms of safety and effectiveness for symptom management. Nevertheless, evidence is much lower for BMAC than for PRP. The few available comparative studies do not show BMAC superiority over the other intra-articular options like PRP and the Stromal Vascular Fraction (SVF), and the benefits versus the placebo saline injections remain to be proven as well [6]. A new application of BMAC has been recently suggested to further exploit its potential by targeting the subchondral bone. This strategy demonstrated promising clinical results, especially in patients with knee OA and subchondral bone alterations [7].

Due to the higher costs and invasive nature, more data are needed to justify BMAC treatment and subchondral bone injections, while PRP appears to be a suitable option to provide short-term benefit in patients affected by knee OA. Further high-level studies are needed to better clarify potential and limitations of these biological approaches, identifying the most suitable products and formulations, as well ideal patient candidate, for the management of joints affected by OA.

References

1) Filardo G, Kon E, Longo UG, Madry H, Marchettini P, Marmotti A, Van Assche D, Zanon G, Peretti GM. Non-surgical treatments for the management of early osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2016 Jun;24(6):1775-85. doi: 10.1007/s00167-016-4089-y.

2) Mariani E, Roffi A, Cattini L, Pulsatelli L, Assirelli E, Krishnakumar GS, Cenacchi A, Kon E, Filardo G. Release kinetic of pro- and anti-inflammatory biomolecules from platelet-rich plasma and functional study on osteoarthritis synovial fibroblasts. Cytotherapy. 2020 Jul;22(7):344-353. doi: 10.1016/j.jcyt.2020.02.006.

3) 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

4) 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

5) 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.

6) Kon E, Boffa A, Andriolo L, Di Martino A, Di Matteo B, Magarelli N, Marcacci M, Onorato F, Trenti N, Zaffagnini S, Filardo G. Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study. Knee Surg Sports Traumatol Arthrosc. 2021 Mar 27. doi: 10.1007/s00167-021-06530-x.

7) Cavallo C, Boffa A, Andriolo L, Silva S, Grigolo B, Zaffagnini S, Filardo G. Bone marrow concentrate injections for the treatment of osteoarthritis: evidence from preclinical findings to the clinical application. Int Orthop. 2021 Feb;45(2):525-538. doi: 10.1007/s00264-020-04703-w.