On the mechanism of pharmacological regulation of neoinnervation in the subchondral bone by chondroitin sulfate at late stages of osteoarthritis

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BACKGROUND

Recent epidemiologic studies indicate that the global prevalence of osteoarthritis (OA) reached 7.6% in 2020, affecting 595 million people. The disease is more common in women, with a global age-standardized prevalence of 8058.9 per 100,000 among women and 5780.1 per 100,000 among men in 2020. Over the past 30 years, OA incidence has increased by 132.2% and is projected to rise by another 60% to 100% by 2050. In 2020, the global age-standardized rate of years lived with disability (YLDs) due to OA was 255.0 per 100,000, representing a 9.5% increase since 1990. After age 70, OA ranks as the seventh leading cause of disability worldwide. The growing prevalence of OA is partially attributed to elevated body mass index, accounting for approximately 20% of the increase in total OA cases [1]. More than half of new cases occur before age 55 and are classified as early-onset OA. This early onset incurs global economic costs exceeding US $106.87 billion, with indirect productivity losses approaching 60% [2].

Over the past three decades, significant advances have been made in understanding the molecular mechanisms of OA pathogenesis, including pain development and the role of neoinnervation in cartilage degradation. Pathological processes in OA that may cause pain and are associated with the sensitivity of tissues in a healthy joint to sudden pressure include synovitis, periosteal stretching over osteophytes, microfractures in the subchondral bone, venous hypertension due to impaired medullary blood flow in the bone, joint capsule stretching, muscle spasm, and damaged ligaments and menisci [3, 4]. Synovial innervation was first demonstrated in 1990 [5]; in OA-affected tissue, nerve fibers produce substance P and calcitonin gene–related peptide (CGRP), which sensitize nociceptive fibers and contribute to neurogenic inflammation by stimulating cytokine release from mast and stromal cells [6–8].

Studies on angiogenesis in OA have examined the role of the synovium in disease progression. Only a few have confirmed the presence of blood vessels and nerve fibers in the subchondral bone (SB) of osteoarthritic knees. However, these studies lack detailed descriptions of angiogenesis and nerve growth within SB or articular cartilage (AC). To date, the specific primary joint pathology causing OA pain remains unidentified, likely due to the strong correlation among various pathologic changes associated with OA and their relationship to pain [9–11].

A key breakthrough in the molecular mechanisms of OA pain was the identification of nerve growth factor (NGF) as a pivotal mediator. NGF promotes neuronal growth and neurite outgrowth [12, 13], sensitizes nociceptive fibers, and is considered a promising target for novel OA analgesics and a biomarker for evaluating current treatments [14–17].

The source of high NGF concentrations have been found in osteochondral channels, correlating with pain in advanced OA [18, 19]. NGF production appears significantly upregulated in SB by macrophages and osteoclasts in response to AC damage following joint destabilization, with levels corresponding to OA pain stages [19, 20].

Data have also emerged on other molecules involved in the development of pain sensitivity in OA: the C-C chemokine CCL2 (monocyte chemoattractant protein-1) [21], Piezo2 mechanosensitive ion channel component [22], Toll-like receptor signaling, granulocyte-macrophage colony-stimulating factor (GM-CSF), and other inflammatory cytokines [23].

However, the therapeutic arsenal for OA still lacks disease-modifying drugs with a structure-modifying effect or provide effective long-term symptom-modifying, particularly analgesic, effects.

Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate OA pain by inhibiting prostaglandin E2 synthesis, reducing nerve sensitization, and decreasing local inflammation. However, NSAIDs as a class lack evidence of true anti-inflammatory effects in OA, as they do not reduce synovial inflammatory cell infiltration. Similar findings were obtained following intra-articular and oral administration of glucocorticoids in OA: a temporary analgesic response was demonstrated with intra-articular injection of long-acting glucocorticoids, but no direct correlation with synovitis or vascularization was observed [24, 25]. In the case of NSAIDs and glucocorticoids, accelerated degradation of AC in OA was shown, accompanied by suppression of the normal anabolic response of damaged AC [26–30].

Currently, several approaches to pharmacological structural modification of OA have been proposed, including sprifermin, a truncated analog of FGF18, as well as methods for pharmacological pain management in OA through NGF neutralization [31].

Considering the aforementioned molecules involved in the mechanisms of pain sensitivity and AC degradation in OA, chondroitin sulfate (CS), a key component of the extracellular matrix of AC and the most commonly used molecule for baseline OA therapy with proven symptom- and structure-modifying effects [32–34], demonstrates multiple mechanisms of action [35–36]. Given its influence on angiogenic processes in the synovial membrane in OA and the associated remodeling processes in SB, CS is a promising molecule with activity against neoinnervation and related SB remodeling in patients with decompensated OA and indications for total joint replacement [37, 38]. Evaluating the effects of CS on neoinnervation is of great importance, as intensification of this pathological process is associated with reduced efficacy of total joint replacement (TJR), driven by uncontrolled postoperative pain, inflammation, progression of OA in the contralateral joint due to increased load in the early postoperative period and during rehabilitation [39].

This study aimed to analyze the mechanism of pharmacological regulation of chondroitin sulfate (CS) on neoinnervation in subchondral bone (SB) at advanced stages of osteoarthritis (OA) based on a retrospective analysis of results from a previously conducted phase—an open-label, prospective, controlled, randomized trial evaluating the efficacy of highly purified CS in parenteral form in patients with Kellgren–Lawrence grade 3 knee OA and grade 2 joint functional insufficiency.

METHODS

Study Design

This retrospective analysis evaluated data from a previous open-label, prospective, randomized controlled trial involving total knee replacement (TKR) in 67 patients (24 men and 43 women, aged 41 to 73 years).

Eligibility Criteria

Inclusion criteria:

• Age 40 to 75 years;
• Radiographically confirmed grade 3 knee OA based on Kellgren–Lawrence grading, consistent with the 2010 EULAR (European Alliance of Associations for Rheumatology) classification and diagnostic criteria for knee OA;
• Grade 2 functional joint insufficiency;
• Decompensated OA (screening score of 25) [40];
• No prior joint diseases before the onset of knee OA;
• Pain intensity ≥ 40 mm at rest and ≥ 55 mm during walking on the visual analog scale (VAS);
• Lequesne Functional Index > 8 and < 13 points;
• No treatment with SYSADOA agents for at least 60 days before enrollment;
• Signed informed consent for participation in the clinical trial;

Exclusion criteria:

• New-onset joint pain within the past 3 weeks;
• Pain during walking < 40 mm on the VAS;
• Grade 1–2 OA based on Kellgren–Lawrence grading;
• History of surgical joint interventions;
• Autoimmune diseases, oncological diseases, or hematologic disorders;
• Extensive post-traumatic scars adherent to subchondral bone in the knee;
• Signs of acute thrombophlebitis;
• Psychiatric disorders;
• Moderate to severe cognitive impairment;
• Parkinson disease;
• Exacerbation of cardiovascular disease;
• High or very high cardiovascular risk;
• Chronic kidney disease with estimated glomerular filtration rate < 50 mL/min;
• Decompensated diabetes mellitus or thyroid disorders;
• Hepatic failure;
• Senile asthenia;
• Hyperhydration;
• Dyspeptic complaints;
• Exacerbation of gastric or duodenal ulcer within the past year;
• Chronic erosive gastritis;
• COVID-19 within the past 6 months;
• Treatment with oral CS and/or glucosamine, diacerein, or unsaponifiable avocado/soy compounds;
• Hypersensitivity to chondroitin sulfate or NSAIDs;
• Participation in another clinical trial involving SYSADOA, NSAIDs, diacerein, or unsaponifiable avocado/soy compounds within 60 days before enrollment;
• Administrative restrictions precluding trial participation.

Study Setting

The clinical study was conducted at Bashkir State Medical University (Ufa, Russia), the Bashkir Research Institute of Traumatology and Orthopedics (Ufa, Russia), and the Novomedicina Medical Center (Rostov-on-Don, Russia).

Study Duration

The retrospective analysis was conducted over a 12-month period.

Medical Intervention

Based on preoperative therapy, patients were divided into two groups: the control group (CG, n = 35) to receive only NSAIDs (celecoxib, diclofenac, meloxicam) at standard daily doses, and the main group (MG, n = 32) to receive NSAIDs plus an intramuscular course of parenteral chondroitin sulfate (Chondroguard^®) every other day for two months prior to TKR. The first three injections were administered at 100 mg/day; from the fourth injection, the dose was increased to 200 mg/day if well tolerated (total: 25 injections) [41]. The average clinical duration of knee OA was 10 ± 3 years, with disease onset at 52 ± 5 years.

Standard anteroposterior and lateral knee radiography was performed [42]. TKR was performed based on radiographic analysis data using the C. Ranawat method: the procedure was planned considering the angle of deviation between the anatomical and mechanical axes of the femur (3–9°) [43]. Semi-constrained fixation systems without preservation of the cruciate ligaments were used. A parapatellar approach to the joint was performed, along with soft tissue release, opening of the femoral canal, resection of the femoral (with internal navigation) and tibial (with external navigation) epiphyses, and cement fixation of the prosthesis components. In the presence of osteophytes, marginal modeling resection of the patella was conducted. For morphological analysis, biopsy samples of SB and AC from the femur and tibia were obtained. For histological examination, biopsy samples were fixed in 10% neutral formalin and embedded in paraffin. Sections of 4–5 µm thickness were prepared using a microtome and stained with hematoxylin and eosin. Cartilage structure was examined using a 3DHISTECH Pannoramic 250 Flash digital microscope (Carl Zeiss, Germany) at ×125 and ×250 magnification. Quantitative morphologic analysis was performed using ImageJ 1.46 software (https://imagej.nih.gov/ij/). Calculations were performed in accordance with stereometric analysis recommendations. Synovitis was evaluated using the General Synovitis Score (GSS) [44].

To assess the severity of OA, the semi-quantitative histochemical cartilage assessment scale by HMankin (1971), modified by Kraus et al. [45, 46], was used, which evaluates cartilage surface structure (0–8 points), proteoglycan content via toluidine blue staining (0–6 points), chondrocyte density and clustering (0–3 points), integrity of the osteochondral junction (0–1 point), and the presence of osteophytes. Additionally, the OARSI (Osteoarthritis Research Society International) cartilage histopathology assessment scale (2006) [47] was applied. The dynamics of innervation characteristics in joint tissues of patients were evaluated based on analysis of biopsy samples of SB and AC from the femur and tibia, obtained during TKR surgery.

The following laboratory parameters were analyzed in blood samples from the cubital vein, collected from patients in both groups under fasting conditions as part of an open-label, prospective, controlled, randomized study using enzyme-linked immunosorbent assay (ELISA) at visits 0, 1, and 2: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), nerve growth factor beta (beta-NGF), calcitonin gene-related peptide (CGRP), and blood potassium and calcium concentrations at baseline (visit 0), at hospital discharge (visit 1), and 3 months post-TKR (visit 2).

Statistical Analysis

Statistical processing was performed using Statistica 10.0 (StatSoft, USA) and XLSTAT version 2019.3.2 (Addinsoft, USA). Stratified random sampling was applied based on age, body mass, height, sex, average number of comorbidities, Charlson comorbidity index, VAS pain score, functional insufficiency as measured by KOOS and Lequesne indices, knee pain exacerbation duration, and radiographic Kellgren–Lawrence OA grade. Distribution normality was assessed using the Kolmogorov–Smirnov test. Data are presented as median and interquartile range: Me (Q1; Q3). Between-group differences were analyzed using the Mann–Whitney U test. A p value < 0.05 was considered statistically significant.

Ethics Approval

The study protocol was approved by the local ethics committees of Bashkir State Medical University and Novomedicina Medical Center (Rostov-on-Don), Protocol No. 1/02 dated February 1, 2022.

RESULTS

Clinical and anamnestic characteristics of patients, including pain intensity assessment using VAS, KOOS, WOMAC index, joint functional insufficiency per the Lequesne Index, and WOMAC scale, as well as pronounced structural-functional transformation of AC with a significant increase in scores on the Mankin and OARSI scales in the control group (CG) and a significant reduction in Mankin and OARSI scores following parenteral administration of CS two months prior to TKR in the main group (MG), along with a detailed description of the histoarchitectonics of hyaline cartilage of the femoral and tibial bones obtained at the time of TKR, are presented in earlier works [38, 48]. In the CG, significant areas of destruction in the superficial and deep zones, deformed osteons in the intermediate zone, and areas with dystrophic changes at the bone-cartilage interface and in the deep cartilage zone were observed. In the MG, signs of adaptive remodeling with regenerates and columnar structures actively synthesizing glycosaminoglycans were noted. Macroscopic evaluation of the synovial membrane in CG patients revealed grade 1 inflammation with pronounced hypervascularization and proliferation of hypertrophic and hyperemic villi, and high-level synovitis (7 points on the Global Synovitis Score [GSS]), while in MG patients, a reactive synovial membrane (grade 0.5) with villi of normal morphology, absence of vascular network fixation due to loss of transparency, and low-level synovitis (3 points on the GSS) were observed, as reported in earlier works [38, 48].

During histological evaluation of hyaline cartilage in CG patients with OA, a significant number of capillary loops in the cartilage tissue from the SB side and nerve endings within hyaline cartilage were additionally identified (Fig. 1).

 

Fig. 1. Neoangiogenesis and neoinnervation in the articular cartilage of patients in the control group.

Note (here and in Fig. 2): Hematoxylin and eosin staining; ×125.

 

Additional morphological assessment of the AC of the femoral and tibial bones in MG patients revealed, alongside signs of adaptive remodeling, an absence of neoangiogenesis from the SB side and neoinnervation within hyaline cartilage (Fig. 2).

 

Fig. 2. Adaptive remodeling elements and a uniform subchondral bone line (a), chondrocytes oriented in columns (4 to 8 cells per lacuna; isogenous groups in the deep zone) (b). No capillary loops or nerve endings detected in the cartilage of patients in the main group; ×125 magnification.

 

At baseline (visit 0), there were no significant between-group differences in any lab parameters (beta-NGF, CGRP, VEGF, hsCRP, IL-6, potassium, calcium) (Table 1). At visit 1 (discharge), MG exhibited significantly greater reductions in all biomarkers (see Table 1). At 3 months post-TKR (visit 2), biomarker levels continued to decrease in MG compared to CG (Table 1).

 

Table 1. Comparative analysis of blood biomarkers in control and main groups before and after surgery (Me [Q1; Q3]).

Visit	Control group	Main group	p (Mann–Whitney U test)
beta-NGF (pg/mL)
0	85,5 (84,25; 86,25)	86,5 (84,75; 88,25)	0,51**
1	80,5 (78,75; 83) p=0,23*	62 (59,5; 64) p=0,03*	0,03**
2	83,5 (82,75; 84,5) p=0,49*	76 (73,5; 78,5) p=0,03*	0,03**
CGRP (pg/mL)
0	151 (146,5; 156)	148 (143;155,5)	0,89**
1	132 (129; 137) p=0,06*	69 (57,5; 77,5) p=0,03*	0,03**
2	137 (131,5; 140,5) p=0,06*	74 (64,5; 81) p=0,03*	0,03**
VEGF (pg/mL)
0	85,5 (84,25; 86,25)	86,5 (84,75; 88,25)	0,51**
1	80,5 (78,75; 83) p=0,06*	62 (59,5; 64) p=0,03*	0,03**
2	44,5 (43; 45,75) p=0,03*	34,5 (33,5; 35,75) p=0,03*	0,03**
hsCRP (μg/mL)
0	7,6 (7,0; 7,7)	7,6 (7,0; 7,6)	0,80**
1	5,1 (4,6; 5,2) p=0,01*	3,4 (3,3; 3,9) p=0,01*	0,01**
2	4,8 (4,6; 5,5) p=0,01*	3,4 (3,3; 3,5) p=0,01*	0,01**
IL-6 (pg/mL)
0	85 (84; 86)	85 (84; 86)	0,97
1	77 (76; 80) p=0,03*	69 (68; 70) p=0,01*	0,01
2	77 (74; 81) p=0,03*	65 (64; 68) p=0,01*	0,01
Potassium (mmol/L)
0	3,8 (3,7; 3,97)	3,85 (3,77; 3,95)	0,97
1	3,9 (3,85; 3,92) p=0,99*	3,55 (3,47; 3,62) p=0,06*	0,05
2	3,8 (3,77; 3,82) p=0,99*	3,45 (3,37; 3,53) p=0,03*	0,03
Calcium (mmol/L)
0	2,39 (2,37; 2,42)	2,39 (2,35; 2,42)	0,89
1	2,37 (2,36; 2,39) p=0,66*	2,31 (2,29; 2,34) p=0,14*	0,05
2	2,4 (2,38; 2,42) p=0,91*	2,28 (2,25; 2,32) p=0,09*	0,03

Note: * within-group differences vs Visit 0, ** statistical significance vs corresponding value in control group. β-NGF, nerve growth factor beta; CGRP, calcitonin gene-related peptide; VEGF, vascular endothelial growth factor; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin 6.

 

The obtained blood laboratory testing results enabled the characterization of the OA knee joint endophenotype, which facilitates early diagnosis of associated neoangiogenesis and neoinnervation processes, as well as a detailed understanding of the mechanisms underlying the disease-modifying effect of CS (Chondroguard^®). This effect is based on the drug’s ability to block the formation of new blood vessels from the SB and nerve endings within hyaline cartilage.

DISCUSSION

The observed patterns in changes to clinical pain and joint function assessment parameters, macroscopic evaluation of the synovial membrane, semiquantitative histological assessment and histoarchitectonics of AC, morphological characteristics of the synovial membrane, and alterations in laboratory biomarkers—key players in the pathogenesis of pain and structural changes in AC and the synovial membrane in patients with grade 3 radiographic OA of the knee joint and grade 3 joint functional impairment in the CG and MG before and during TKR—confirmed that neoinnervation, alongside uncontrolled angiogenesis, is a critical event in SB remodeling in OA.

A significant reduction in blood IL-6 concentration during surgery in patients with knee OA who received CS prior to TKR, with further decreases at hospital discharge and 3 months post-surgery, was associated with reduced pain intensity and a significant decrease in blood CRP levels in MG patients, consistent with findings from international studies [49, 50].

The significant reduction in blood IL-6 concentration at hospital discharge and 3 months post-surgery in patients with knee OA who received CS prior to TKR, combined with evidence of restricted neoangiogenesis and neoinnervation in the synovial membrane and SB in the MG, was accompanied by a simultaneous reduction in the expression of the dominant pro-angiogenic vascular endothelial growth factor (VEGF), associated with neoangiogenesis [51], and decreased production in blood and, likely, in SB of nerve fiber growth factors—beta-NGF [52] and CGRP. This reflects an effect of CS (Chondroguard^®) in limiting neoinnervation in SB, linked to its previously reported anti-angiogenic effects [53].

The significant reduction in beta-NGF concentration in blood and, concomitantly, in SB with CS (Chondroguard^®) administration likely disrupts the molecular pain model in OA described by Vincent et al. (2024) [31]. CS appears to block the two-stage process—neoinnervation of joint tissues, including the osteochondral junction, and sensitization of the nociceptive response at the joint and dorsal root ganglion levels—through key molecules (NGF, CCL2, and Piezo2), thereby limiting central sensitization. It is known that beta-NGF receptors (TrkA and p75) are expressed on various non-neuronal cell types and may thus exert additional effects on joint mesenchymal tissues. For example, p75 is expressed on mesenchymal stem cells in synovial fluid and osteoblasts, while chondrocytes express both TrkA and p75 [54]. Limiting beta-NGF synthesis in damaged basal AC and/or SB with CS reduces the intensity of neoinnervation and alters the activation threshold of adjacent neurons [55, 56]. Likely, reduced beta-NGF expression in AC and/or SB decreases CGRP expression and the presence of CGRP-positive and NaV1.8-positive neuronal fibers in SB below damaged AC areas [57–59]. This process is accompanied by reduced secretion of netrin-1 by SB osteoclasts, limiting neuronal growth and axonal conduction through SB [60].

Promising molecules whose activity warrants evaluation with CS administration include CCL2, levels of which may decrease in dorsal root ganglia concurrently with reduced macrophage infiltration [21], Piezo2 mechanosensitive ion channel component, which modulates pain sensitivity in OA and influences NGF-mediated responses [22], and mediators of neuroimmune inflammation—such as Toll-like receptor signaling, GM –CSF, and other inflammatory cytokines [23]. Several other molecules involved in nociceptor sensitization in OA are poorly understood. Fig. 3 illustrates key intermolecular interactions of nerve growth factor β.

 

Fig. 3. Molecular interactions of beta nerve growth factor (based on STRING v12.0 bioinformatic analysis).

Note. NGF, nerve growth factor beta; NGFR, nerve growth factor beta receptor, NTRK2, BDNF/NT-3 growth factors receptor; NTRK1, high-affinity nerve growth factor receptor; NTRK3, NT-3 growth factor receptor; SORT1, sortilin; GFRA1, GDNF family receptor alpha-1; SORCS2, VPS10 domain-containing receptor SorCS2; GDNF, glial cell line-derived neurotrophic factor; NTF4, neurotrophin-4; TRPA1, transient receptor potential cation channel, subfamily a, member 1.

 

The significant reduction in blood calcium and potassium levels in patients with knee OA who received CS prior to TKR, with further decreases at hospital discharge and 3 months post-surgery, may be linked to CS-mediated regulation of neoinnervation and antinociceptive events in AC and SB [61].

Consequently, the new data obtained in this study support recommending the use of Chondroguard^® in an effective regimen, per medical instructions, for 2 months prior to TKR to limit the synthesis of key mediators of neoinnervation and pathological SB remodeling in the contralateral lower limb under increased postoperative load, as well as in the operated joint to prevent postoperative complications, including reduced TKR efficacy due to uncontrolled pain.

Study Limitations

This retrospective analysis included a relatively small sample size, limiting generalizability. Large-scale, multicenter studies are needed to validate these findings.

CONCLUSION

Thus, our study findings suggest that the beneficial effect of parenteral chondroitin sulfate (Chondroguard^®) on clinical, morphological, and laboratory markers of OA progression may be attributed to its impact on the process of neoinnervation, representing a novel direction for therapeutic targeting of OA. A limitation of the study in real-world clinical practice is the insufficient amount of data obtained, necessitating further research to elucidate the mechanism underlying the effect of Chondroguard^® on blocking neoinnervation in OA, incorporating tools such as data value analysis.

ADDITIONAL INFO

Author contribution. All authors have approved the final version before publication and have also agreed to be responsible for all aspects of the work, ensuring that issues relating to the accuracy and integrity of any part of it are properly addressed and resolved.

Funding sources. No funding.

Disclosure of interests. The article was published with the support of PharmFirm Sotex CJSC. The article expresses the authors’ position, which may differ from the position of PharmFirm Sotex CJSC.

Ethics approval. The programme is approved by the local ethical committees of the Bashkir State Medical University of the Ministry of Health of Russia (Ufa) and ‘Medical Centre “Novomedicine” LLC (Rostov-on-Don), protocol No. 1/02 of 01.02.2022.

Statement of originality. In creating this work, fragments of my own text, published earlier ([doi: 10.14412/1996-7012-2022-6-55-63], distributed under the CC-BY 4.0 license) were used.

Data availability statement. Access to the data obtained in this study is closed due to confidentiality (the presence in the database of information on the basis of which the study participants can be identified and the lack of their consent to the dissemination of this information).

Provenance and peer-review. This article was submitted to the journal on an unsolicited basis and reviewed in accordance with the fast-track procedure. Two external reviewers and the scientific editor of the publication participated in the review.

About the authors

Timur B. Minasov

Bashkir State Medical University; LLC Medical Center “Novomeditsina”

Email: M004@ya.ru
ORCID iD: 0000-0003-1916-3830
SPIN-code: 7865-6011

MD

Russian Federation, Ufa; 74 Socialisticheskaya str., 344002 Rostov-on-Don, Rostov-on-Don region

Irina V. Sarvilina

LLC Medical Center “Novomeditsina”

Author for correspondence.
Email: isarvilina@mail.ru
ORCID iD: 0000-0002-5933-5732
SPIN-code: 7308-6756

MD

Russian Federation, 74 Socialisticheskaya str., 344002 Rostov-on-Don, Rostov-on-Don region

Olga A. Gromova

Federal Research Center “Informatics and Management”

Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-7663-710X
SPIN-code: 6317-9833

MD

Russian Federation, Moscow

Anton G. Nazarenko

Priorov National Medical Research Center for Traumatology and Orthopedics

Email: NazarenkoAG@cito.priorov.ru
ORCID iD: 0000-0003-1314-2887
SPIN-code: 1402-5186

MD, Dr. Sci. (Medicine), professor RAS

Russian Federation, Moscow

Nikolay V. Zagorodniy

Priorov National Medical Research Center for Traumatology and Orthopedics; Peoples’ Friendship University of Russia named after Patrice Lumumba

Email: zagorodniy@sustav.ru
ORCID iD: 0000-0002-6736-9772
SPIN-code: 6889-8166

MD, Dr. Sci. (Medicine), professor

Russian Federation, Moscow; Moscow

References

Supplementary files