Tissue-engineered and cell-based therapies for cartilage defects

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Introduction

The treatment of knee cartilage injuries presents a challenging clinical problem due to the low regenerative capacity of cartilage tissue. Cartilage defects are found in approximately 12% of the population and are most often caused by traumatic or degenerative conditions, for which there is currently no etiological therapy [1]. In addition, cartilage destruction can be induced by certain medications with chondrotoxic effects, including fluoroquinolone antibiotics [2] as well as drugs for SARS-CoV-2 infection [3].

At present, the most common methods for treating articular cartilage degeneration include bone marrow stimulation via microfracture, osteochondral autograft transplantation, and autologous chondrocyte implantation (ACI). During microfracture, small perforations are drilled into the subchondral bone, creating microfractures within the bone without compromising its supporting function, thereby allowing bone marrow cells to migrate freely and stimulate cartilage regeneration. However, this technique results in the formation of fibrocartilage, which, compared to hyaline cartilage, exhibits inferior mechanical properties and is therefore less resistant to mechanical stress [4]. Historically, the next step in articular cartilage repair was osteochondral autograft transplantation, which involves harvesting tissue blocks from a non-weight-bearing joint surface with simultaneous implantation into the defect site [4]. Both microfracture and osteochondral autograft transplantation are invasive for the patient, yet have been widely used in clinical practice for a long time due to the relative simplicity of the procedures. Their main disadvantages are additional trauma during autograft harvesting and the limited availability of donor tissue. The description of surgical methods for cartilage injury is not limited to those mentioned above. Further discussion will focus on novel methods involving the implantation of various cell-containing therapeutic products, primarily chondrocytes.

One of the earliest types of such products or approaches for joint repair was ACI. In this technique, arthroscopically obtained cartilage biopsies serve as source material for in vitro cell isolation and expansion, followed by the production of cell-based preparations for personalized therapy. The further development of this approach led to subsequent generations of ACI, including matrix-induced autologous chondrocyte implantation (MACI) and the implantation of tissue-engineered products (TEPs)—three-dimensional, tissue-like structures based on chondrocytes [4].

In recent years, there has been a rapid increase in the number of registered clinical studies using various biotherapeutics for cartilage restoration following trauma and for the treatment of arthrosis and osteoarthritis. From 2000 to 2022, a total of 365 clinical studies were registered on ClinicalTrials.gov, with the number of trials increasing by 16.4% annually since 2006. Among completed clinical studies, autologous cellular components studied have included not only chondrocytes but also mesenchymal stem cells (MSCs) [4]. Over the past two years, the number of approved clinical studies has grown, including one successfully conducted in the Russian Federation [5]. Given the steady increase in the number of clinical studies and the ongoing development of new cell-based products, a comprehensive evaluation of completed studies and prospects for future developments is warranted.

Clinical Studies of Autologous Chondrocyte Implantation

Since Brittberg et al. first reported the clinical outcomes of ACI in 1994 [6], this technique has been recognized as a treatment option for large cartilage defects. The essence of the technique is that autologous chondrocytes are isolated from a biopsy of healthy cartilage obtained arthroscopically, cultured for 14–21 days, and then transplanted into the defective tissue area [7]. The use of autologous chondrocytes is being actively investigated, as the number of cases of joint injury and age-related cartilage degeneration is increasing due to population aging [8]. ACI is a standard procedure for the treatment of large cartilage defects of the knee [9] and is recommended by international medical associations on the basis of large-scale clinical studies. Long-term follow-up data on the use of autologous chondrocytes are now available, including data from patients who received treatment approximately 20 years ago. Prolonged follow-up of patients treated with ACI has demonstrated improvements in clinical outcomes; however, no reduction in the incidence of osteoarthritis has been identified. Moreover, numerous randomized studies have been published comparing ACI with other approaches, most often microfracture [10–12]. The results of these studies suggest that microfracture should be considered more as a complementary treatment, since it is used only for small tissue defects and leads to the formation of fibrocartilage rather than hyaline cartilage. Recently, studies have been published comparing the development status [13], clinical progress [14], and regulatory frameworks [15] for autologous chondrocyte-based products approved for clinical use [16] in different countries. Although these sources cover different generations of cell-based products for the treatment of articular cartilage in various locations, most research focuses on knee joint therapy.

In first-generation ACI, a cell suspension is introduced into the defect, which is then covered with a periosteal flap. This approach was used in studies of the autologous chondrocyte-based product ChondroCelect¹. However, certain limitations and drawbacks of this method have been identified and documented [17], including cell leakage from the implantation site, uneven distribution of implanted cells, and periosteal hypertrophy, all of which reduced the effectiveness of the procedure. To minimize periosteum-related adverse effects, a second-generation ACI technique was developed, in which a collagen membrane is used instead of a periosteal flap. However, the use of collagen scaffolds in combination with ChondroCelect has not been evaluated. An example of second-generation ACI is the transplantation of autologous chondrocytes on a Chondro-Gide membrane, made of porcine type I/III collagen. Such membranes can influence the phenotype of the cells used, potentially affecting the efficacy of the cell product. It should be noted that Chondro-Gide is more often used as a covering flap in microfracture procedures, and fixation of the membrane itself requires fibrin glue or sutures. Taking these considerations into account, it can be concluded that the indications for second-generation ACI are limited to small cartilage defects.

Clinical Studies of Matrix-Assisted Autologous Chondrocyte Implantation

Matrix-assisted autologous chondrocyte implantation (MACI), also referred to as third-generation ACI, was developed to minimize cell loss from the transplantation site. Cell–matrix interaction also supports the maintenance of the chondrocyte phenotype during in vitro culturing. Autologous chondrocytes are either cultured directly within the matrix or transferred onto a scaffold after achieving the required cell quantity in culture [18]. Currently, MACI is the only FDA (Food and Drug Administration, USA)-approved cell therapy option for patients with articular cartilage defects larger than 2 cm² for whom non-surgical treatments were ineffective [19]. The chondrocyte-seeded matrix is affixed to the cartilage defect using fibrin glue or bioresorbable sutures, without covering it with a collagen flap [20]. Owing to its simpler technique compared to earlier generations of cell-based products, MACI has gained popularity, and clinical studies have yielded promising results with positive clinical outcomes [7, 21].

Chondrocyte-based scaffold implants used in clinical practice have specific features. For example, the commercially available hydrogel NOVOCART® Inject plus (Tissue Engineering Technologies AG, Germany), approved in Europe, was compared for efficacy with the microfracture technique. The investigational product is a two-component injectable system: the first component consists of in vitro cultured and characterized autologous chondrocytes resuspended in a solution containing modified human albumin, isotonic sodium hyaluronate, human blood serum, and cell culture medium. The second component consists of the cross-linking agent α,ω-bis-thio-polyethylene glycol. Upon simultaneous injection of both components through a dual-chamber syringe system, in situ hydrogel formation is achieved. Manufacture of the cell product takes 24 ± 5 days [22]. During a two-year follow-up, hydrogel NOVOCART® Inject plus with cells demonstrated superior clinical outcomes compared with microfracture [23]. Another study showed high efficacy of chondrocyte transplantation in the NOVOCART® Inject plus gel compared with conventional cell transplantation without a carrier into the damaged cartilage [24, 25].

In the case of another product—Maci²—chondrocytes obtained from biopsy material were cultured in a monolayer for 4 weeks. The cells were then transferred onto a type I/III collagen matrix (ACI-Maix), cultured for several days, and subsequently transplanted into the defect site. Interestingly, ACI-Maix is classified as a medical device rather than an advanced therapy medicinal product, which exempts the manufacturer from conducting additional biocompatibility studies of the scaffold when the cell component is modified. In a clinical study evaluating Maci, full-thickness hip cartilage defects were treated in 13 patients. Clinical changes were assessed at 6 weeks and at 3, 6, and 12 months postoperatively. The study demonstrated increased patient activity levels, improved quality of life, and reduced pain during the follow-up period. Despite the success of these studies, Maci was withdrawn from the market due to the manufacturer’s bankruptcy [26].

Another notable product in this category is Chondrocytes-T-Ortho-ACI³, in which chondrocytes, after short-term cultivation, are transferred into collagen scaffolds and then further cultured for 5 weeks until transplantation. According to the latest published data, the product is undergoing additional safety studies as part of post-marketing surveillance; however, the final report has not yet been published.

One of the first approved products of the MACI type, Chondron, is obtained from autologous chondrocytes cultured for 4–6 weeks on a fibrin gel [27]. The use of a gel-based scaffold may not only eliminate the need for a second intervention to harvest periosteum and shorten the operative time, but also reduce the risk of chondrocyte loss from the membrane. In addition, the use of gel decreases the likelihood of detachment of the implanted construct from surrounding tissues due to the viscoelastic properties of the scaffold, without using suture material.

The next ACI third-generation product approved for clinical use is JACC⁴, manufactured using atelocollagen with periosteum or a collagen membrane. This product was made from autologous chondrocytes cultured within the scaffold for 4 weeks. The use of JACC has been included in the public medical insurance system of Japan. An alternative third-generation ACI product is CaReS, developed by the Austrian company Arthro Kinetics Biotechnology GmbH. In this product, chondrocytes are cultured for 2 weeks on a type I collagen matrix derived from rat tails, and then implanted into the cartilage defect using fibrin glue. The uniqueness of this technology lies in the three-dimensional cultivation of chondrocytes without the need for monolayer culture. This approach minimizes phenotypic changes of the cells toward fibroblasts. Moreover, compared with other commercially available scaffolds, CaReS demonstrates the highest level of aggrecan and type II collagen expression, as well as a physiological COL2/COL1 ratio, confirming its superior ability to maintain the chondrocyte phenotype [28]. Positive results for this product were obtained in clinical studies [29, 30], in which transplantation was performed 14 days after the cartilage biopsy procedure—a record time for such technologies. Prior to implantation, a drop of fibrin glue was applied to the pre-cleaned cartilage defect, followed by the investigational product and a second layer of fibrin glue for more secure fixation. After the glue had set, the wound was closed in layers. The mean score on the International Knee Documentation Committee (IKDC) scale significantly improved from 36.4 before surgery to 74.1 at 52 weeks after implantation (p < 0.001). MRI and arthroscopy revealed complete integration of the product with surrounding tissues in 6 of 7 patients [30].

The results of these clinical studies are encouraging, despite the use of xenogeneic materials for securing the transplanted product, which is associated with the risk of adverse reactions. In addition, a matrix requires further testing for biocompatibility with the cell product and host tissues. To mitigate potential reactions to xenogeneic scaffolds, the scientific community is developing products that use, as a matrix, components of the extracellular matrix (ECM) synthesized by the cells themselves in vitro. Such TEPs are referred to in the scientific sources as fourth-generation ACI or 3D cartilage-like structures based on chondrocytes.

Clinical Studies of 3D Cartilage-Like Structures Based on Chondrocytes

Perhaps the most well-known cell product in this category is Spherox⁵ (Co.don, Germany), which is produced by isolating autologous chondrocytes from a cartilage biopsy of a non-weight-bearing joint area, followed by monolayer cultivation of the autologous chondrocytes. The cells are then transferred to conditions that promote the formation of a three-dimensional spheroidal shape. No growth factors or xenogeneic compounds are used during cultivation. As a result, the final product consists of spherical structures, or chondrospheres, composed of chondrocytes and their own newly synthesized ECM in physiological saline. The transplanted spheroids adhere to the prepared defect surface through increased expression of adhesion molecules on the surface of the chondrocytes comprising the spheroid; de novo synthesize hyaline-like ECM components, and thereby integrate into the surrounding tissue, filling the defect without the need for xenogeneic material or fixation with a periosteal flap. Notably, in the Russian Federation, Generium successfully transferred the Spherox production technology, and clinical studies of this biomedical cell product were completed in 2023. This cell product has been registered in Russia under the trade name Easytence [5].

In Germany, a prospective, randomized, open-label, multicenter phase III clinical study (102 patients) was conducted to demonstrate the non-inferiority of Spherox implantation (n = 51) compared with microfracture (n = 50) in patients with knee articular cartilage defects. Patient outcomes were evaluated using a broad range of clinical scales: KOOS, the MOCART scoring system, the Bern score, the modified Lysholm scale, the International Cartilage Repair Society (ICRS) rating, and the IKDC examination form [31]. Preoperative cartilage defect sizes ranged from 0.5 to 4.0 cm². It is important to note that patients were evenly distributed between the treatment groups by this parameter.

The study confirmed the non-inferiority of the new treatment method compared to microfracture: sustained improvement in clinical outcomes was observed throughout the two-year follow-up period. Moreover, there were no differences in the incidence of such complications as graft hypertrophy, inadequate integration of transplanted cells into the surrounding tissue, or insufficient regeneration at the surgical site [32]. When comparing treatment effects across patient subgroups by sex, age, diagnosis, and defect location, no association was found between treatment efficacy and any of these parameters [33]. Histological analysis of biopsies from 16 patients (ACI, n = 9; microfracture, n = 7) demonstrated better tissue repair quality in those who underwent ACI. However, according to the patient-reported outcome measures used—except for the KOOS subscales—no statistically significant differences between the treatment methods were found.

Overall, the reported findings are consistent with earlier studies comparing autologous chondrocyte implantation and microfracture [34–36]. However, in longer-term follow-up, the advantage of fourth-generation ACI has been confirmed [37–39]. In addition to the clinical study described above, several non-randomized studies and a prospective, randomized, multicenter phase II clinical study have confirmed the efficacy and safety of treatment using spheroid technology, particularly for defects up to 10 cm² in size [40–42]. Nevertheless, data on the dose effect (the number of spheroids implanted per 1 cm² of defect) remain very limited [43].

Another autologous chondrocyte-based product containing newly synthesized ECM components is Cartilife⁶, for which chondrocytes are obtained from the patient’s costal cartilage. The isolated cells are cultured for 6–7 weeks to form spheroids, which are then transplanted into the defect site. In a clinical study of Cartilife, its efficacy was confirmed by MRI and the MOCART score, and was found to be no lower than that of microfracture, which was selected as the comparator method [44]. In this clinical study, the mean defect size in the experimental group was larger than in the microfracture group, and Cartilife demonstrated superior clinical efficacy at week 48 after surgery [44].

Autologous chondrocytes derived from nasal septal cartilage have also been used as a cell source [45]. This product was tested in two patients with osteoarthritis. A phase II clinical study is currently being conducted. Notably, the authors selected nasal chondrocytes as the cell source because, according to previous in vitro and in vivo experiments, cells from this location are more resistant to inflammatory factors [46].

Thus, it has been demonstrated that cells from the nasal septum and costal cartilage can serve as promising sources for the treatment of degenerative joint diseases when direct biopsy of articular cartilage is not feasible. It should be noted that the use of 3D chondrocyte-based constructs from alternative sources may be more effective than ACI or MACI, as the synthesis and secretion of ECM components begin before implantation into the body, which naturally accelerates the integration of the product into the surrounding tissues. However, despite the success of these studies, further investigation of this technology in a large homogeneous patient cohort is needed. Moreover, to demonstrate efficacy, the preferred comparator would be another ACI product, which would allow for the conduct of a blinded clinical study.

Clinical Studies of Cartilage Tissue Therapy Based on Mesenchymal Stem Cells and Differentiated Derivatives of Induced Pluripotent Stem Cells

Despite the proven clinical efficacy of autologous chondrocytes, many authors believe that the use of alternative cell types is also a promising direction (Fig. 1). Among the cellular sources used in the manufacture of TEPs for the treatment of grade III–IV knee cartilage defects according to the modified Outerbridge classification, the most common are listed in Table 1. It should be noted that products based on autologous chondrocytes from articular and costal cartilage have already undergone additional safety assessments as part of post-marketing surveillance.

 

Fig. 1. Chondrocyte sources for cell-based and tissue-engineered therapies of cartilage defects iPSC, induced pluripotent stem cell; MSC, mesenchymal stem cell. ИПСК — induced pluripotent stem cells, МСК — mesenchymal stem cells.

 

Table 1. Cellular sources used in the treatment of cartilage defects

Cell culture used in therapy	Cell source	Technology type	Product name	Year of registration	Pharmacovigilance activities	Study references
Autologous chondrocytes	Articular cartilage	MACI	MACI®	2016	5-year long-term safety and efficacy	См. сноску 2
		MACI	Chondrocytes-T-Ortho-ACI	2017	В настоящее время проходят дополнительные исследования безопасности в рамках пострегистрационного наблюдения	[26]
		MACI	Chondron	2001	4-year long-term safety and efficacy	См. сноску 3
		MACI	JACC	2012	7-year long-term safety and efficacy	[28]
		ACI	ChondroCelect	2009	5-year long-term safety and efficacy	[17]
		3D structure	Spherox	2017	5-year long-term safety and efficacy	См. сноску 5, [30, 39–42]
	Costal cartilage	3D structure	Cartilife	2019	6-year long-term safety and efficacy	[44]
	Nasal septum cartilage	3D structure	Cartilife	—	—	[45, 46]
MSCs	Adipose tissue	3D structure	3D bioprinted micronized adipose tissue (MAT)	—	—	[47]
	Synovial membrane	3D structure	—	—	—	[48]
	Bone marrow	Cells in gel	—	—	—	[52]
iPSCs	Dermal fibroblasts	3D structure	—	—	—	[61, 62]

 

A small pilot clinical study conducted in Egypt demonstrated the efficacy of a 3D-bioprinted graft composed of a mixture of MSCs from autologous lipoaspirate and allogeneic powder made from hyaline cartilage [47]. The described procedure is single-stage and more cost-effective than the aforementioned methods. One year after surgery, cartilage biopsies were taken from the implantation sites in five patients. Histological analysis showed de novo formation of hyaline cartilage. However, it was not specified in which patients repeat arthroscopy had been performed. The reported efficacy raises questions, as the patient sample was quite heterogeneous in age and in the severity of cartilage damage; therefore, further comparative studies with larger homogeneous patient samples and longer follow-up are needed.

The scientific publications also contain data on clinical studies of a tissue-engineered product based on autologous MSCs isolated from the knee synovial membrane [48]. The cells were characterized using flow cytometry and immunohistochemistry, after which spheroids were generated from the cells and their deposited matrix and subsequently cultured in a chondrogenic medium. Under these conditions, MSCs synthesized ECM components characteristic of hyaline cartilage. Moreover, the number of adhesion molecules on the cell surface increased, facilitating better integration of the cell construct into the defect area [49]. This MSC-based TEP has attracted the attention of the scientific community as a next-generation tool for cartilage repair. A pilot clinical study enrolled patients aged 20–60 years with isolated knee joint lesions not exceeding 5 cm² in size [50]. The study demonstrated the safety and efficacy of this therapeutic approach in five patients over a 5-year follow-up period [50]. The use of such a product for the repair of chondral defects in patients with traumatic articular cartilage injury could potentially reduce the incidence of complications such as osteoarthritis. Moreover, TEPs can be manufactured from MSCs obtained from other sources, such as adipose tissue, which is an accessible cell source. When using lipoaspirate, a sufficient number of MSCs can be obtained without entering the joint, thereby avoiding potential complications associated with arthroscopy and synovial membrane biopsy. The same research group also attempted to combine MSCs with an artificial bone block in a single TEP to produce a biphasic osteochondral implant. Such innovative technologies are currently at the preclinical stage.

In a rabbit study [51], the feasibility of using such biphasic constructs for the treatment of full-thickness osteochondral defects of the joint was demonstrated. In this experiment, animals received cartilage defects measuring 5 mm in diameter and 6 mm in depth, into which the test product was implanted. The rabbits were sacrificed 1, 2, and 6 months after the surgery. Notably, the implants with surrounding tissues were retrieved from the animal joints not only for histological examination but also for biomechanical testing, which confirmed the functional integrity of the implant.

In another study [52], TEPs derived from differentiated autologous MSCs incorporated into an atelocollagen gel were transplanted into damaged hip cartilage. Repeat arthroscopy demonstrated good integration of the product with the surrounding tissues. As many of the study participants were followed up for 8 years or longer, this allowed the long-term efficacy of the procedure to be demonstrated. Consequently, there is a trend towards the development of multi-component TEPs, in which cells are placed on a scaffold, thereby improving the mechanical properties of the implant.

In order to enhance the efficacy of MSCs for cartilage repair, the interaction between the cells and various substrates is being actively investigated. Type I or type II collagen can support MSC adhesion, proliferation, and chondrogenic differentiation [53, 54]. Matrices based on type II collagen have been shown to provide greater secretion of ECM components characteristic of hyaline cartilage compared with type I collagen [53]. However, chondrogenic stimulation of MSCs by this substrate was not confirmed at the gene expression level [55]. It should be noted that type II collagen is a potential arthritogenic agent [56] and has not gained widespread approval in orthopedics, with its use remaining limited [57]. In another study [58], autologous synovial membrane-derived MSCs were applied to a type I/III collagen membrane (Chondro-Gide), and the resulting product—matrix-induced implantation of autologous mesenchymal stem cells—was compared in terms of efficacy with MACI, rather than with microfracture. The results indicated comparable efficacy between these treatment methods; however, the follow-up period was only 2 years, which does not allow for an assessment of long-term therapeutic effects. In this case, further prospective, randomized, controlled, long-term studies supported by histological data are needed. Thus, the presence or absence of a substrate, as well as its composition, is an important component of tissue-engineered products, including those based on MSCs, and must be taken into account when designing a clinical study [59]. The application of MSCs is also limited by the finite number of cell culture passages, which may be overcome by the use of induced pluripotent stem cells (iPSCs) and their differentiated derivatives.

In recent years, the popularity of iPSCs has grown, with these cells being investigated for potential clinical applications in the treatment of neurodegenerative, ophthalmic, and other diseases [60]. Usually, iPSCs themselves are not used to create cell- or tissue-engineered products due to the high risk of teratoma formation; however, their differentiated derivatives are considered promising. Their unlimited capacity for proliferation and differentiation into the chondrocytic lineage makes it possible to overcome the limitations of biomaterial availability and slow culture growth. Despite the obvious advantages of using iPSC-derived chondrocyte-like cell constructs, researchers rarely proceed to preclinical studies of such products and almost never advance to clinical studies. The challenges of using iPSCs are primarily associated with the lack of a standardized, scalable protocol for cell differentiation. To date, relatively few experiments have been conducted worldwide to evaluate the safety and efficacy of iPSC-derived products for the treatment of cartilage defects [61–63]. Nevertheless, the relevance of such a minimally invasive and fully autologous approach continues to grow, and further research is needed.

Conclusion

All of the above studies highlight the clinical significance of procedures involving the transplantation of cell-based products, particularly those based on chondrocytes associated with the matrix and newly synthesized components of the ECM. The described TEPs have their own advantages and disadvantages; therefore, each of the proposed approaches to the treatment of cartilage injuries may serve as the method of choice under certain clinical conditions. The cited clinical studies confirm the relevance of applying novel treatment modalities, provide grounds for further consideration, and underscore the need for additional comparative studies. Primarily, the investigated products may be used to prevent complications arising from articular cartilage injuries. Considering the success of cell therapy for knee cartilage defects, it is equally important to adapt such technologies for the treatment of more severe conditions, such as osteoarthritis. Since osteoarthritis is often accompanied by inflammation, cell-based products should be modified by incorporating an anti-inflammatory component into the final formulation. The authors regard the use of differentiated derivatives of iPSCs as promising in cases where obtaining the required number of autologous chondrocytes is challenging. Despite the absence of a standardized protocol for obtaining iPSC derivatives, their use may serve as the method of choice in specific clinical situations. Furthermore, when planning new clinical studies, several factors should be taken into account, including patient inclusion and exclusion criteria, the clinical assessment scales used, and the choice of the comparator method. The authors consider the duration of patient follow-up and the completion of a course of medical rehabilitation to be important parameters in clinical studies, as the formation of cartilage tissue under timely loading of the operated joint directly affects the long-term outcomes of any cell-based therapy.

Additional information

Authors' contributions. P.A. Golubinskaya — literature review, collection and analysis of literary sources, editing of the article; A.S. Pikina — preparation and writing of the text of the article; E.S. Ruchko — literature search; O.S. Lebedeva — editing; A.V. Eremeev — final editing. All authors approved the manuscript (version for publication) and agreed to take responsibility for all aspects of the work, ensuring the proper consideration and resolution of any issues related to the accuracy and integrity of any part of the study.

Ethics approval. Not applicable.

Funding sources. This publication was carried out within the framework of the state task “Chondrosphere 2”, #124031500116-4 from 15.03.2024.

Disclosure of interests. The authors have no relationships, activities or interests for the last three years related with for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality. In the preparation of this work, the authors did not use any previously published information (text, illustrations, or data).

Data availability statement. The editorial policy regarding data sharing does not apply to this work, no new data was collected or created, and the work is descriptive in nature.

Generative AI. No generative artificial intelligence technologies were used in the preparation of this article.

Provenance and peer-review. This paper was submitted to the journal on an initiative basis and reviewed according to the usual procedure. Three members of the editorial board and the scientific editor of the publication participated in the review.

 

¹ European Medicines Agency. Science medicines health. ChondroCelect®. Accessed on: https://www.ema.europa.eu/en/medicines/human/EPAR/chondrocelect

² European Medicines Agency. Science medicines health. Maci. Accessed on: https://www.ema.europa.eu/en/medicines/human/EPAR/maci

³ Orthocell Ltd home page. Accessed on: https://www.orthocell.com.au/cartilage-regeneration

⁴ Pharmaceutical and medical device agency. Review reports: regenerative medical products for JACC®. Accessed on: https://www.pmda.go.jp/english/review-services/reviews/approved-information/0004.html

⁵ European Medicines Agency. Science medicines health. Spherox® Accessed on: https://www.ema.europa.eu/en/medicines/human/EPAR/spherox

⁶ Ministry of Food and Drug Safety. Approval review report for Cartilife®. Accessed on: https://nedrug.mfds.go.kr/pbp/CCBAC02/getItem?totalPages=1&limit=10&searchYn=true&page=1&title=%EC%B9%B4%ED%8B%B0%EB%9D%BC%EC%9D%B4%ED%94%84&jdgmnResultInfoSeq=20210000172

About the authors

Polina A. Golubinskaya

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Author for correspondence.
Email: polinapigeon@gmail.com
ORCID iD: 0000-0002-1765-9042
SPIN-code: 5299-9693

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow

Evgenii S. Ruchko

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency; Koltzov Institute of Developmental Biology Russian Academy of Science

Email: ruchkoevgeny@yandex.ru
ORCID iD: 0000-0002-1361-666X
SPIN-code: 7220-6031
Russian Federation, Moscow; Moscow

Arina S. Pikina

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: arina.pikina@yandex.ru
ORCID iD: 0000-0002-8967-2318
SPIN-code: 8654-7318
Russian Federation, Moscow

Olga S. Lebedeva

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: oslebedeva@rcpcm.org
ORCID iD: 0000-0003-0767-5265
SPIN-code: 4911-1830

Cand. Sci. (Biology)

Russian Federation, Moscow

Artem V. Eremeev

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency; Koltzov Institute of Developmental Biology Russian Academy of Science

Email: art-eremeev@yandex.ru
ORCID iD: 0000-0002-3428-7586
SPIN-code: 4825-5440

Cand. Sci. (Biology)

Russian Federation, Moscow; Moscow

References

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