Sex and gender determinants following spinal fusion surgery: A systematic review of clinical data

Introduction

In the last decade, sex/gender differences attracted considerable interest in several specialties, including cardiothoracic and trauma surgery (1). These differences are key issues for a personalized treatment. The National Institutes of Health (NIH) promotes investigators to design their studies in a way that allows the participants to self-identify their sex or gender (2). By sex, we mean the biological character of male and female as opposed to gender, which reflects societal roles and expectations (2). Although, sex and gender are two different concepts, in medicine they are often linked, and, in the review, they were used as synonyms. Within orthopedic surgery, a patient's sex/gender is thought to influence outcomes after total joint arthroplasty (manly in total knee arthroplasty), after rotator cuff repair, and after anterior shoulder surgical stabilization (3). Sex-based differences in spinal disease incidence have been previously described in several studies, such as lumbar degenerative disc disease (4), lumbar radiculopathy (5), and cauda equina syndrome (6). Nevertheless, Taylor et al. (7) highlighted that male patients generally receive more recommendations than female ones for spine surgery despite similar underlying disorders (7). The impact of male or female sex/gender on clinical outcomes in spinal fusion surgery is less well defined. This is in part because most of the studies do not consider patient sex when examining demographic trends in outcomes, reporting “sex-adjusted” statistics, or using sex-matched groups. Despite this, some data demonstrated individual differences in the postoperative outcomes between male and female patients after spinal fusion surgery. In detail, several clinical trials found a better global and functional outcome after lumbar spine fusion for males than for females. A retrospective study by Gehrchen et al. (8) reported that the female gender is an independent risk factor for nonoptimal outcomes after lumbar fusion; a randomized controlled trial (9) observed that the female gender was also associated with worse postoperative results (10). However, a prospective clinical study on 4,780 patients in the Swedish National Spine Register with lumbar degenerative disc disease and chronic low back pain showed that female patients had worse pain and function preoperatively but improved more than males after surgery (11). These conflicting results are due to the fact that several of the studies are limited to small samples size, which has insufficient power to reach accurate conclusions. Regarding complications, there are several hypothetical reasons for male and female differences after spinal surgery. Differences in anthropomorphic parameters, body mass index, and comorbidity may contribute to differences in complications and mortality risks between females and males after spine surgery (12–14). Additionally, specific differences in tobacco and alcohol use/abuse as well as in unhealthy lifestyles (malnutrition, unhealthy diet, drug abuse, etc.) might also increase the odds of postoperative death or the development of specific complications, such as surgical site infection (SSI) (15).

The number of studies suggesting that sex/gender may affect patient outcomes after a spinal fusion procedure begets the need for a comprehensive examination of these data. Thus, we performed a systematic review of the literature to better understand sex/gender-based differences in spinal fusion surgery outcomes. These aspects are of key interest for both physician and patient thus, to be informed about predictive gender and sex-related differences. This information could also have a prognostic value, playing a critical role in the decision-making process.

Methods

Eligibility criteria

The PICOS model (Population, Intervention, Comparison, Outcomes, Study design) was used to design this study: (1) studies that considered female and male patients (Population) submitted to, (2) spinal fusion surgery (Interventions), (3) with a comparison between them (female and male) (Comparisons), (4) that reported postoperative clinical and/or functional outcomes of spinal fusion surgery (Outcomes), in (5) randomized, retrospective, prospective and case series studies (Study design). Studies from May 2000 to May 2022 were included in this review if they met the PICOS criteria. We excluded studies that evaluated (1) surgeries other than the spine, (2) patients undergoing spine surgery with other severe pathological conditions (genetic and rare diseases, diffuse metastases, advanced neurodegenerative disorders), and (3) articles with incomplete outcomes or data. Additionally, we excluded reviews, case reports, letters, comments to editors, in vivo and in vitro studies, pilot studies, meta-analyses, editorials, protocols and recommendations, guidelines, and articles not written in English.

Search strategies

Our literature review involved a systematic search conducted in May 2022. We performed our review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (16). The search was carried out on three databases: PubMed, Scopus, and Web of Science Core Collection. The following combination of terms was used (spinal fusion OR spinal arthrodesis OR vertebral fusion OR vertebral arthrodesis) AND (gender differences OR sex differences OR gender-specific OR sex-specific), and for each of these terms, free words, and controlled vocabulary specific to each bibliographic database were combined using the operator “OR.” The combination of free-vocabulary and/or Medical Subject Headings (MeSH) terms for the identification of studies in PubMed, Scopus, and Web of Science Core Collection were reported in Supplementary Table S1.

Selection process

After submitting the articles to a public reference manager (Mendeley Desktop 1.19.8) to eliminate duplicates, possible relevant articles were screened using the title and abstract by three reviewers (FS, DC, and MT). Studies that did not meet the inclusion criteria were excluded from review and any disagreement was resolved through discussion until a consensus was reached, or with the involvement of a fourth reviewer (MF). Subsequently, the remaining studies were included in the final stage of data extraction.

Data collection process and synthesis methods

The data extraction and synthesis process started with cataloging the studies' details. To increase validity and avoid omitting potentially findings for the synthesis, three authors (MT, VB, and CG) extracted and performed tables taking into consideration: the study design, female and male patients' number and age, type of surgery (indication and operation types), presence of comorbidities, complications, main objectives related to sex/gender, follow-up, assessment measures, pre-and postoperative quantitative measures, complications, and outcomes/endpoints (specific sex/gender differences).

Assessment of methodological quality

The methodological quality of the selected studies was independently assessed by two reviewers (DC and FS), using the Cochrane risk-of-bias tool RoB for randomized trials and the Cochrane risk of bias ROBINS-I for nonrandomized studies of interventions (17). The tool for randomized trials included five domains, which assessed the possible sources of bias: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. For each domain were assigned one of three levels: low risk of bias, some concerns, or high risk of bias until an overall bias risk judgment is reached. The tool for nonrandomized trials included seven domains, which assessed the possible sources of bias: bias due to confounding, bias in the selection of participants into the study, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in the measurement of the outcome, and bias in the selection of the reported result. For each domain were assigned one of three levels: low risk of bias, moderate risk of bias, or high risk of bias until an overall bias risk judgment is reached. In case of disagreement, the reviewers attempted to reach a consensus by discussion; if this failed, a third reviewer (MF) was consulted to make the final decision.

Results

Study selection and characteristics

The initial literature search retrieved 1,885 studies. Of those, 798 studies were identified using PubMed, 435 using Scopus, and 652 were found in the Web of Science Core Collection. Articles were screened for title and abstract and 100 articles were selected. Subsequently, these articles were submitted to a public reference manager to eliminate duplicates. The resulting 77 complete articles were then reviewed to establish whether the publications met the inclusion criteria, and 47 studies were considered eligible for this review. Search strategy and study inclusion and exclusion criteria are detailed in Figure 1. Of these articles, 33 were retrospective studies, 12 were prospective studies, 1 was a case series, and another 1 was a randomized clinical trial (RCT).

FIGURE 1

Figure 1. Systematic review flow diagram. The PRISMA flow diagram for the systematic review detailing the database searches, the number of abstracts screened, and the full texts retrieved.

Assessment of methodological quality

In our quality assessment, the randomized trial is judged to raise some concerns, but not to be at high risk of bias for any domain. The risk of bias was mainly about the randomization process and measurement of the outcome. The 70% of the nonrandomized studies were rated at low risk of bias for all domains, 21% were rated at moderate risk of bias, and 9% were rated at critical risk of bias. Methodological weaknesses that led to moderate or weak quality scores often included bias due to confounding, missing data, deviations from intended interventions, and bias in the measurement of the outcome. Risks of bias assessments for each randomized and nonrandomized study were reported in Supplementary Tables S2 and S3.

Studies general information, objectives, and cohort characteristics

Descriptive characteristics of each study are presented in Tables 1 and 2. The included studies involved a total of 1,158,555 patients. The overall percentages of female and male patients were 51.31% and 48.69%, respectively. Apart from five studies evaluating adolescent patients, the others consider patients operated at a mean age of 55.55 ± 7.38 years. Most studies (n = 23) examined the association between sex/gender and clinical outcomes in relation to a general clinical assessment and/or to specific scores. Eighteen studies also evaluated the association between sex/gender and postoperative complications, such as intensive care unit (ICU) admission, superficial and deep SSI, postoperative fractures, cardiac events, heterotopic ossifications, instrumentation failure and reoperation rate, length of stay (LOS), or specific risk factors (opioid use, smoking, obesity). Furthermore, one study examined sex/gender differences in relation to recombinant human bone morphogenetic protein-2 (rhBMP2) use during spinal fusion surgery.

TABLE 1

Table 1. Studies general information.

TABLE 2

Table 2. Clinical assessment and outcomes.

Examining sex/gender differences was the primary objective in 25 (52.1%) studies while the remaining evaluated the influence of several predictors and risk factors (age, smoking history, number, and location of fusion segments, plate-to-disc distances, excessive disc space distraction, kyphotic malalignment), also including sex/gender as a secondary aim.

Comorbidities were assessed in 63.8% of the studies (n = 30). In two of these studies, no comorbidities were present. In the remaining 28 studies, different comorbidities were present that include diabetes (in 50% of included studies), cardiac diseases (25%) and/or hypertension (17.8%), blending disorders (14.2%), pulmonary diseases (10.7%), obesity and overweight (10.7%), osteoporosis (7.1%), dyslipidemia (7.1%), renal diseases (7.1%), osteoarthritis (7.1%), depression (7.1%), and others less common comorbidity, i.e., liver diseases, brain attack, vascular diseases, asthma, and anxiety. In 12/27 studies where comorbidities were present and described gender-related differences in comorbidities distribution were also reported. The major comorbidity reported in females was obesity while in males were diabetes, cardiovascular morbidities (prevalently atrial fibrillation and hypertension), and bleeding disorders.

Qualitative and quantitative measures used for patient assessment were detailed in Table 1. The Visual Analogue Scale (VAS) score for back or leg pain was used, alone or in association with other measurements, by 21.2% of the studies, the Oswestry Disability Index (ODI) by 25.5% of studies, x-ray, to evaluate pre-and postoperative sized main curves, sagittal Cobb angle, kyphosis, by 27.6% and specific patient-reported outcomes measures and standardized measure of health-related quality of life (HRQoL) by 42.5% of studies. Other less common measures used include the numeric rating scale (NRS) scores for low back pain (NRS-BP), leg pain (NRS-LP), Japanese Orthopedic Association (JOA) scale, magnetic resonance imaging (MRI), computed tomography (CT), and laboratory values. Except for one study that evaluated sex/gender differences at discharge, all other studies performed clinical assessments from 30-day of follow-up up to 10 years.

Types of spine surgery and pathological conditions

Patients were diagnosed with different spine diseases, mainly degenerative pathological conditions such as disc herniation, stenosis, spondylolysis, radiculopathy, spondylolisthesis, myelopathy (55.3%), spinal deformities as adult scoliosis or kyphosis (12.7%), adolescent idiopathic scoliosis (10.6%), degenerative and deformity conditions together (14.8%), and traumatic pathologies such as fractures (6.3%). In detail, 235,140 patients (26 studies) were treated for degenerative diseases using anterior or posterior approaches (Table 1). Of these, 17 studies were retrospective and analyzed 188,278 patients, 8 were prospective and included 46,862 patients, and 1 study was an RCT with 72 patients. A total of five studies (four retrospective and one prospective) analyzed 1,769 adolescent patients' treated for idiopathic scoliosis (AIS) using a posterior approach. Concerning adult deformities, a total of 4,714 patients were evaluated in two prospective studies and 5,752 patients in four retrospective studies, using anterior or posterior approaches. Studies that analyzed degenerative and deformity conditions together (six retrospective studies and one prospective) evaluated 910,835 patients. Finally, 315 patients (three studies) were treated for traumatic sacral or thoracolumbar fractures after posterior instrumented fusion. Of these, two studies were retrospective with 271 patients, and one study was a case series with 44 patients.

Procedures associated with spinal fusion surgery included minor, major, and complex surgeries, such as posterior lumbar interbody fusion (PLIF), hemilaminectomy, decompression, anterior cervical discectomy and fusion (ACDF), transforaminal lumbar interbody fusion (TLIF), discectomy, anterior lumbar interbody fusion (ALIF) and laminectomy (Table 1). Because the types of spine fusion surgery were not standardized across the 47 studies, it was difficult to quantify the prevalence of any single type of procedure among the studies. However, most interventions were implemented for lumbar spine procedures, through techniques such as PLIF and TLIF, followed by cervical procedures such as ACDF.

Sex/gender differences in outcomes after spinal fusion surgery

In this review, 76.6% (n = 36) of studies reported sex/gender-related differences in postoperative clinical outcomes and/or complications, while the remaining studies described comparable results between males and females (Table 2). Of these 36 studies where sex/gender differences were present, n = 21 (58.3%) were on degenerative diseases, prevalently of the lumbar spine, 13.9% were on spine deformities (1 on AIS and 4 on adult deformities), 8.4% on spine fractures, and 19.4% considered degenerative conditions and deformities together (Table 1).

Degenerative spine diseases

More than half of studies on degenerative spine diseases on the lumbar spine reported worse female experiences after spinal fusion surgery (63.8%). Kay et al. showed that the female gender was associated with an increased risk of postoperative ICU admission in patients undergoing lumbar spine surgery (35). Furthermore, Maragkos et al. also reported that female patients were 2.55 times more likely than male ones to develop adjacent segment disease requiring reoperation (44). In detail, within 30 days of follow-up female gender resulted in an independent risk factor significantly associated with a LOS longer than 3 days, occurrence of complications, including wound complications, urinary tract infection (UTI), and nonhome discharge; while the adverse outcomes associated with males were renal complication and myocardial infarction (20, 43). At the same follow-up female gender also resulted in an increased risk of readmission for pain or neurological symptoms (55). At a longer follow-up, 1 year, it was analyzed the influence that gender plays on HRQoL, disability, and the correlation between these two in patients undergoing spinal fusion for chronic low back pain (60). Results showed that male patients had higher disability scores at the preoperative evaluation but improved more than females in all domains of disability postoperatively. HRQoL improved similarly in both genders. The ODI score showed a strong or moderate correlation with six of the domains of the Short Form Health Survey 36 (SF-36) in males, but with only three domains in females (60). At the same follow-up, it was also shown that gender differences influence the satisfaction rate of lumbar spinal stenosis surgery in elderly patients (≥65 years) with female patients that had less satisfactory results than male ones (57). After 2 years of follow-up, it was shown that the female gender was also associated with prolonged opioid use (19). Several studies reported different results. Parrish et al. reported that females experienced significantly more improvement in postoperative Patient-Reported Outcome Measurement Information System-Physical Function (PROMIS-PF) score than males at the 3-month time point (51). Chan et al. reported that at 1 year of follow-up, the female gender resulted also associated with more satisfaction than males (58.4% vs. 38.5%) (26). These results were further confirmed by Triebel et al. where it was shown that females had a high rate of improvement from baseline to follow-up (2 years) in leg pain, back pain, HRQoL, and disability, in comparison to males, but it was also reported that females improve more slowly in leg pain, back pain, and disability (11). At longer follow-up (up to 4.5 years), Park et al. showed that the male gender was a risk factor for reoperation (49, 50).

In cervical degenerative diseases at 1 year of follow-up a higher percentage of improvement was detected in male patients than in females (27). This result was also confirmed at 10 years of follow-up, where it was demonstrated a higher neck- and arm-related pain intensity, more disability, and worse psychosocial status in females than in males (32). Specifically, the male gender was a predictor of clinically relevant improvement in neck-specific disability (32). Differently, Nunley et al. (46) showed that males were ∼3 times more likely to develop heterotopic ossification than females as well as they were at greater risk of any adverse event (23). Alomari et al. (21) described an increased risk for UTI in females and myocardial infarction in males. Two studies also evaluated the correlation between gender, spinal fusion surgery, and smoking. A higher proportion of male smokers who underwent posterior cervical decompression and fusion (PCDF) compared to female smokers (9.93% vs. 5.98%) was detected (28). In addition, a significant difference in the early fusion process among current smokers, former smokers, and nonsmokers was detected for male patients, but no significant differences were founded at 1-year of follow-up. For female patients, statistical differences were found in both the early fusion process and the 1-year fusion rate (62).

The only study on sex/gender differences considering thoracic spine surgery was by Ogihara et al. using a multivariate analysis that showed that male gender was significantly correlated with a higher incidence of deep SSI, although it was not a significant factor in univariate analysis (48).

Spine deformities

Of the 36 studies where sex/gender differences were evaluated, n = 4 were on adult spinal deformities. Two studies reported that female sex/gender was associated with increased postoperative morbidity compared to males; after 30 days from spinal surgery, it was observed an increased postoperative transfusion rate and complications, in particular, UTI and LOS longer than 5 days, in female patients (29, 39). Conversely, one study reported that male patients were at a greater risk for bleeding compared to females (24). Differently, from the above-mentioned studies, Schmitt et al. evaluated at 2 years of follow-up the fusion rates using relatively low-dose rhBMP-2 for the treatment of adult spinal deformity surgery, showing that gender was associated with fusion status, with 79.8% of females with a good spinal fusion compared to 60.4% of males (56).

Only one study on AIS detected gender-related differences, showing that male patients, with severe thoracic lordosis, were at a higher risk of bleeding than females (18).

Degenerative conditions and deformities

Seven studies reported sex/gender-related differences considering patients treated for degenerative conditions and deformities together. In detail, at 30 days of follow-up, Heyer et al. (33) reported postoperative differences in complications between males and females. Females were at increased risk for superficial SSI, UTI, transfusions, and longer LOS while males were at increased risk of pneumonia and reintubation (33, 41). At the same experimental time, it was also shown that the male gender was associated with an increased risk of cardiac events (36). At a longer experimental time, 1-year follow-up, it was shown that the male gender represented a risk factor for deep SSI (47).

In a study on the mortality rates after spinal fusion surgery and on factors associated with its occurrence over a 10-year follow-up, it was shown that the male gender was a risk factor significantly associated with increased mortality rates (53). In addition to complications and risk factors related to gender, Gulbrandsen et al. (30) indicated that females reported slightly more pain and worse function than males at the time of surgery. Finally, Sharma et al. also showed that in spine surgeries gender interacted with obesity at 1 year of follow-up: obese males with at higher odds of improvement when compared to nonobese males; among females, obesity did not affect the odds of improvement (58).

Spine fractures

Of the 35 studies where sex/gender differences were present, n = 3 were on spine fractures after spinal fusion surgery. One study was on sacral fractures (54), and two studies were on thoracolumbar burst fractures (34, 42). Salzmann et al. observed, at a 6-month follow-up, that female gender (76.2%), advanced age (mean, 66.4 years), and obesity were risk factors for post-op sacral fractures (54). Differently, Jang et al. showed that the male gender was a risk factor for recollapse of thoracolumbar burst fractures (34). At 1-year follow-up, Maior et al. reported that male patients have better outcomes than females after thoracolumbar burst fractures; an increased score in each item of the SF-36 in male than female patients was also observed (42).

Discussion

From an epidemiological perspective, it would be critical to understand how sex/gender differences can affect clinical outcomes after spinal fusion surgery. This aspect becomes more critical from a surgical point of view since the identification of specific sex/gender differences would offer personalized approaches for patients undergoing spinal fusion procedures. Thus, the focus of this review was to analyze clinical studies aimed at evaluating sex/gender differences following spinal fusion surgery.

Our review showed that most of the analyzed studies (76.6%) report sex/gender-related differences in postoperative clinical status, outcomes, and/or complications, while the remaining described equivalent results. Furthermore, in 38.3% of the studies where comorbidities were described gender-related differences in their distribution were reported. In the female sex, obesity was the most prevalent comorbidity while in the male sex the prevalently dominant comorbidities were diabetes, cardiovascular morbidities (prevalently atrial fibrillation and hypertension), and bleeding disorders. These differences are of critical importance and could represent potential risk factors related to gender differences (both pre-op and post-op) to be analyzed in future studies, in which it will be mandatory to analyze a larger homogeneous cohort of patients, considering specific and individual spine diseases and surgical approaches. In fact, it is important to highlight that there is significant heterogeneity across the analyzed studies in terms of pathological spine diseases (degenerative, deformity, fracture), type of the spinal level treated (cervical, thoracic, lumbar, sacral), number of levels treated, and surgical approaches. In addition, it is important to underline that none of the analyzed studies evaluated specific physiological changes related to postmenopausal status in female patients submitted to spinal fusion procedures. It is known that the direct negative effects of estrogen-deficiency on bone as well as the indirect effects of altered immune status in postmenopausal women contribute to low bone mass and bone microarchitecture destruction. These bone alterations may represent a negative prognostic factor for the success of spinal fusion surgery.

In this review, most of the studies where sex/gender-related differences were present were on the patient treated for lumbar degenerative diseases (disc degeneration, disc herniation, and spondylolisthesis). Of those more than half reported a worse postoperative outcome in terms of pain, disability, HRQoL, and complications in female patients, while the remaining reported worse outcomes in terms of HRQoL and satisfaction in male patients. In studies examining pain, disability, and HRQoL differences between females and males, the complexity of evaluating these parameters which include many clinical signs and subjective outcomes must be considered. Undoubtedly, females treated for lumbar degenerative disease reported the worst postoperative scenario, but the perception and measurements of pain and disability have been debated and investigated: some studies concluded that females had lower perception thresholds and pain thresholds than males (64). This worst postoperative state in female patients is probably the reason for the prolonged postoperative opioid consumption associated with this gender (19). However, epidemiological studies have indicated that analgesic use may vary between males and females, suggesting that opioid use was higher in the female gender in general adult populations (65, 66). This systematic review found that females were also at increased risk of complications (UTI, readmission for pain or neurological symptoms, adjacent segment disease), and consequent longer LOS, following spinal fusion surgery for lumbar degenerative disease (20, 43, 44, 55). These postoperative complications may also have a link to the long-term opioid use detected in female patients. While for degenerative lumbar spine diseases a potential link between gender and clinical outcomes resulted more evident, for degenerative diseases of the cervical and thoracic spine this link is not so clear. This is probably due to the heterogenicity of the analyzed studies but also to the small number of studies found in this review. However, at 10-year to 13-year of follow-up, a prospective randomized study indicated that predictive factors of good outcome after ACDF included initial high neck-related pain intensity, nonsmoking status at the time of surgery, and male gender (32). On the contrary, other clinical studies indicated that males were more likely to develop clinically relevant heterotopic ossification than females as well as a greater risk of any adverse event, also severe (23). Similar contradictory results were also found after spinal deformity surgery, when degenerative diseases and deformities were considered and analyzed together and following spine fractures (sacral fractures and thoracolumbar burst fractures). Also, in these cases, the limited number of studies and the heterogeneity between studies remained critical factors that limit the interpretation of the results. For adult spinal deformities, a gender difference was founded by using relatively low-dose rhBMP-2 with the female gender demonstrating a better spinal fusion compared to of male one (56). In this study, there were substantial differences between the patient's series and those in the comparison groups. When degenerative diseases and deformities were considered and analyzed together it was also shown that gender interacted with obesity at 1 year of follow-up; obese males showed a higher odd of improvement when compared to nonobese males while among females, obesity did not affect the odds of improvement (58). Nevertheless, it should be noted that numerous studies present in the literature did not investigate and analyze spinal fusion outcomes dichotomizing by gender, thus it is difficult to establish a real conclusion and draw definitive results. As such, a true systematic review was not feasible. Furthermore, some limitations of this review warrant discussion. Most eligible studies in this review were retrospective and only one RCT on 47 analyzed studies was found and included. Additionally, many included studies had a small sample size and may be underpowered to identify significant clinical responses. Numerous studies, accounting for most patients, were prevalently published by groups in the United States; cultural discrepancies in patient-reported clinical assessment scores may differ geographically. The clinical assessment tools used to determine the postoperative outcomes are, prevalently, subjective patient-reported measures. Results were also difficult to interpret due to specific differences in spine diseases in the retrieved studies; for example, insufficient heterogenic data were retrieved for cervical and sacral degenerative diseases, spinal deformities, and traumatic spinal fractures. Furthermore, also searching for “spinal fusion” and “sex” or “gender” on the www.clinicaltrialg.gov website (accessed on 22 May 2022) no clinical trials had, as a primary or secondary outcome, the analysis of sex/gender differences.

Conclusions

The review highlighted those female patients treated for lumbar degenerative spine diseases probably require more clinical awareness during postoperative care. The understanding of how sex/gender differences can really affect clinical outcomes after spinal fusion surgeries have the potential to enhance clinical decision-making and care practices and may be crucially important in the context of providing patient personalized care, a critical field of contemporary medical practice.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author contributions

FS, DC, and MF contributed to the conceptualization of the study and to the writing—original draft preparation. FS, DC, MT, VB, and CG contributed to the methodology and data curation. FS, DC, AG, and MF contributed to the writing—review, and editing. AG and MF contributed to the supervision. MF contributed to the funding acquisition. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by grants from IRCCS Istituto Ortopedico Rizzoli (Ricerca Corrente), by 5X1000 2019 project entitled “Medicina rigenerativa e riparativa personalizzata per le patologie dei tessuti muscolo-scheletrici e la chirurgia ricostruttiva ortopedica” (PRWEB: 2021/730567).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fsurg.2022.983931/full#supplementary-material.

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