Skip to main content
Download PDF
  • Systematic Review
  • Open access
  • Published:

Mesenchymal stem cells therapy for the treatment of non-union fractures: a systematic review and meta-analysis

BMC Musculoskeletal Disorders volume 26, Article number: 245 (2025) Cite this article

Abstract

Background

This meta-analysis aimed to pool the existing evidence to determine the clinical efficacy and safety of mesenchymal stem cells (MSC) in patients with non-unions.

Methods

A systematic search in PubMed and Scopus was performed until October 2024 to gather pertinent studies. The inclusion criteria included participants with non-unions, the intervention of MSC administration, a comparator of standard treatment (bone graft), and outcomes focused on healing rate, healing time, or side effects. The Jadad score Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in randomized and non-randomized studies, respectively. Moreover, GRADE criteria were used to assess the quality of evidence. Using a random effects model, odds ratios (OR) with 95% confidence intervals (CIs) were calculated for healing and complication rates, while standardized mean differences (SMD) with their 95% CIs were used to assess the impact of MSC therapy on bone union time.

Results

Twenty-one studies, with 866 patients, were included. The bone healing rates were 44% at 3 months, 73% at 6 months, 90% at 9 months, and 86% at 12 months, eventually reaching 91% after 12 months of follow-up. MSC therapy, with or without scaffolds, was linked to higher odds of bone healing rate at 3 and 6 months, compared to bone grafts as the standard care (OR = 1.69). The time to union following the treatment was 6.30 months (95%CI: 86-96%), with patients treated with MSC/Scaffold experiencing a shorter time compared to MSC alone (5.85 vs. 6.36 months). MSC therapy significantly decreased bone union time (SMD:-0.54 months, 95% CI: -0.75 to -0.33). The complication rate was 1% (MSC/Scaffold: 0%, MSC alone: 2%), with MSC alone or MSC/Scaffold showing a lower risk than the standard care (OR = 0.41, 95% CI: 0.22–0.78).

Conclusion

MSC is a potential adjunct therapy for patients with non-union fractures.

Clinical trial number

Not applicable.

Peer Review reports

Introduction

Non-union fractures frequently arise during the healing phase of fractures, affecting approximately 5–10% of all fractures. Managing these cases presents a remarkable challenge given the complexities involved in diagnosing, treating, and achieving favorable patient outcomes [1]. Non-unions are identified as the inability of a fractured bone to achieve bone union within 9 months of the initial injury, with no signs of healing observed for a consecutive period of 3 months [2]. Functional limitations, chronic pain, and an elevated risk of additional injuries associated with non-union fractures have detrimental effects on the physical and mental well-being of patients and result in substantial medical expenses [3,4,5]. Non-unions can be attributed to various factors, including advanced age, lack of compliance with rehabilitation protocols, malnutrition, diabetes, smoking, immunosuppression, alcoholism, and peripheral neuropathy [6]. In addition, patient-independent factors associated with the fracture site, such as compromised blood supply, the severity of the injury (large gap), surgical osteosynthesis, fracture stability, biomechanics, and infections could contribute to poor healing and increase the risk of non-unions [7, 8].

The economic burden associated with non-union fractures is substantial, leading to significant increases in healthcare costs and resource utilization. It has been reported that the mean total care cost for non-union patients was more than double that of patients without a non-union ($35,317 vs. $102,989) [9]. This financial strain not only impacts healthcare systems but also affects patients’ quality of life due to prolonged recovery times and potential loss of income from missed work [10], highlighting the critical need for effective management strategies for fracture non-unions.

The management of non-union fractures poses a significant challenge for orthopedic surgeons. One major issue is the complexity of the condition itself, as non-unions can arise from various factors, including biological deficiencies and mechanical instability, necessitating tailored treatment approaches for each case [11]. Additionally, the presence of complications such as broken implants from previous surgeries can complicate management strategies and require innovative solutions like combined surgical techniques [12]. The need for meticulous pre-operative planning and a multidisciplinary approach is critical, as improper management can lead to further complications and prolonged recovery times [11]. Furthermore, the high prevalence of non-union fractures, particularly among elderly and osteoporotic patients, adds to the burden on healthcare systems and emphasizes the importance of effective treatment modalities [13].

Currently, the gold standard approach for treating fracture non-unions involves ensuring sufficient stability of the affected area and utilizing autologous bone grafts [14]. Autografts, which involve using the patient’s own bone, have shown union rates ranging from 69 to 89% in various studies [15]. However, complications such as infection and the need for additional surgeries can affect these rates. The overall effectiveness of autografts is attributed to their ability to provide biological support and promote healing, making them a preferred option despite potential drawbacks like donor site morbidity and variability in individual healing responses [16].

Indeed, bone autografts not only serve to fill the gap in non-union cases but also have the potential to enhance the local biology of the fracture site [17]. However, autografts have limitations in their effectiveness. This is particularly evident in cases where there is a reduced availability of endogenous stem cells and their associated bioactive signals within the patient’s bone. These issues are especially prevalent in older individuals or those with certain comorbidities [18, 19].

Consequently, the autograft approach may often fail to promote optimal healing process of nonunions, particularly in cases where there is a reduced availability of endogenous stem cells and their associated bioactive signals within the patient’s own bone, especially in older individuals or those with certain comorbidities [20]. To address this challenge, in recent years, biological therapies, particularly mesenchymal stem cells (MSC), have emerged as a promising approach to improve bone healing and the clinical outcomes of non-union cases [21]. MSC, a type of multipotent stem cells found in various tissues (bone marrow, adipose tissue, placenta, umbilical cord blood), possess remarkable regenerative and immunomodulatory properties [22]. Bone marrow serves as a primary source of MSC [23]. While bone marrow can be utilized directly as Bone Marrow Aspirate Concentrate (BMAC) or processed in vitro to yield Bone Marrow-Derived Mesenchymal Stem Cells (BMSC), BMAC consists of a small proportion of progenitor cells (0.001–0.01%) compared to the more concentrated and purified cell population of expanded BMSC, which belong to the mesenchymal lineage and show promising effects in regenerative medicine and tissue engineering [8]. Their ability to differentiate into osteoblasts, secrete growth factors, and promote angiogenesis makes MSC an attractive candidate for augmenting bone healing processes [24, 25].

Evidence indicates that MSC treatments have a strong safety profile, with most adverse events being mild and manageable [26, 27]. Several studies have investigated the therapeutic potential of MSC in non-unions, demonstrating promising results [28, 29]. However, despite a growing body of literature on the use of MSC in non-unions, the effectiveness and safety of MSC for these patients remain a topic of debate, and the findings of the available studies have been inconclusive. While the study by Hernigou et al. [28] showed that MSC is associated with higher odds of bone healing compared to bone graft, other studies failed to find such an association [30, 31]. Also, the effects on time to bone union is different substantially across studies [32,33,34]. These differences in the results of studies could be due to the differences in the intervention protocol, sample size, duration of follow-up, and age of participants. Previous meta-analyses included a limited number of studies with small sample sizes and did not comprehensively perform subgroup analyses based on the potential covariates. Furthermore, the available meta-analyses mainly focused on short-term outcomes, neglecting long-term follow-up data that are crucial for assessing the durability of MSC therapy benefits. This meta-analysis aimed to assess the efficacy and safety of MSCs in treating non-union fractures while addressing these gaps by evaluating outcomes across different follow-up durations. Additionally, this study aimed to examine whether the effects are influenced by covariates, such as age, follow-up duration, and intervention protocol.

Methods

The meta-analysis was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Supplementary file 1) [35]. Since this review was conducted based on the previously published data, no ethical approval was required to perform the study.

Search strategy

A comprehensive systematic literature search was conducted in PubMed and Scopus from the inception of each database until October 2024 to obtain pertinent studies with the use of the following search strategy: (“Mesenchymal Stem Cells“[Majr] OR “Mesenchymal Stem Cell*“[Title/Abstract] OR “Mesenchymal Stromal Cell*“[Title/Abstract] OR “Mesenchymal Progenitor Cell*“[Title/Abstract] OR MSCs[Title/Abstract] OR “Bone Marrow Stromal Stem Cells“[Title/Abstract] OR “Bone Marrow Stromal Cell*“[Title/Abstract] OR “Wharton Jelly Cell*“[Title/Abstract] OR “Whartons Jelly Cell*“[Title/Abstract] AND (nonunion*[Title/Abstract] OR non-union*[Title/Abstract] OR “delayed union*“[Title/Abstract] OR “non union*“[Title/Abstract] OR bone graft*[Title/Abstract] OR (union*[Title/Abstract]). No language restriction was considered for the search. Two authors independently reviewed the title/abstract of identified studies to exclude irrelevant studies. In the case of any disagreements, they were resolved through a group discussion. The full texts of the potentially relevant studies were then obtained and assessed based on the eligibility criteria. Subsequently, the references list of the eligible studies underwent a manual screening to identify additional suitable studies.

Inclusion criteria

To enhance clarity regarding the selection of studies for inclusion in the proportional meta-analysis versus controlled studies, we employed a systematic approach based on predefined eligibility criteria. We established specific inclusion and exclusion criteria that prioritized studies based on their design, methodology, and relevance to the research question, ensuring that both randomized controlled trials (RCTs) and non-randomized studies were assessed for their quality and applicability. Each study underwent a two-phase screening process—initial title/abstract screening followed by full-text evaluation—conducted independently by multiple reviewers to minimize bias and ensure consistency in the selection process. Two independent reviewers (CC and FL) evaluated the eligibility of the studies, and any disagreements were addressed by consulting all the authors. During the group discussion, the two independent reviewers (CC and FL) presented their evaluations of the studies, highlighting the reasons for any disagreements regarding eligibility. The authors collectively reviewed the evidence and rationale provided by each reviewer, engaging in a constructive dialogue to clarify any misunderstandings. This collaborative approach allowed the authors to reach a consensus on the inclusion or exclusion of the studies based on established criteria. Based on the PICOS criteria, the inclusion criteria for this study included: Participants (patients with non-unions), intervention (MSC administration), Comparator (for RCTs, standard treatment (bone graft) was considered as the control, while no restriction for intervention comparison was implied for non-randomized studies), outcomes (healing rate, healing time, or side effects), and study type (clinical studies). The criteria specifically focused on human studies without any date or language limitation and required full-text studies. We included studies with a minimum follow-up period of 3 months to ensure that sufficient time was allowed for evaluating the effects of MSC therapy on bone healing outcomes. Case reports on single patients, reviews, republished studies, protocols, in vitro investigations, animal studies, and studies with irrelevant interventions were excluded. Furthermore, studies involving BMAC, which lacks concentrated MSC, were excluded due to the low MSC concentration and the presence of a blend of progenitor cells.

Data extraction and quality assessment

The following data were obtained from the included studies: first author, country, year of publication, types of studies, type of MSC, sample size, follow-up duration, time to union, healing rate at 3, 6, 9, 12, and over 12 months following the treatment, type of non-unions, type of fractures, and complications. The process of data extraction was carried out by two independent investigators (CC and FL) and discordances were resolved by a group discussion involving all authors. For randomized clinical trials, the Jadad score, with a range of possible scores of 0 to 5 was used for quality assessment. The Jadad score evaluates four main aspects of the study design, including randomization, blinding, withdrawals, and dropouts [36]. The Newcastle-Ottawa Scale (NOS) was used for assessing the quality of non-randomized studies. The NOS assesses study quality across three main domains, including selection, comparability, and outcome. The NOS uses a star system, with a maximum of nine stars awarded based on criteria met in the three domains, with scores equal to or greater than 7 considered high quality [37]. Moreover, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) [38] was used to assess the quality of evidence, categorizing evidence into four levels, including high, moderate, low, and very low, based on factors such as risk of bias, inconsistency, indirectness, and imprecision. The quality assessment was conducted by two independent investigators (CC and FL), and any discrepancies were resolved through a group discussion that included all authors.

Statistical analysis

In studies without a control group, we applied proportional meta-analysis to pool the data. The Effect Sizes (ES) with 95% confidence intervals (CIs) for healing rate (at 3, 6, 9, 12, and over 12 months post-treatment) and complication rate relative to the total number of patients in each study were pooled to estimate the overall effects. In controlled studies, we assessed treatment effects by examining the odds of bone healing and complications as dichotomized outcomes, compared to the standard care, utilizing the odds ratios (OR) and 95% CIs. Moreover, standardized mean differences (SMD) with their 95% CIs were used to examine the effect of MSC on time-to-bone union. Statistical heterogeneity was evaluated by employing the I2 statistic, considering it significant when I2 exceeded 50% and p < 0.10. In case of significant heterogeneity, a random effects model was used for the analyses, otherwise, a fixed effect model was applied. Subgroup analysis by type of intervention (combined therapy with MSC/scaffolds vs. MSC only) and age of participants (≥ 40 years vs. <40 years) was conducted to assess the sources of heterogeneity. Publication bias was measured using Egger’s test. All the analyses were conducted with STATA software (version 13).

Results

Characteristics of studies

Out of the initial search of 1024 studies, a total of 21 studies [28,29,30,31,32,33,34, 39,40,41,42,43,44,45,46,47,48,49,50,51,52], with a combined sample size of 866 patients, were included (Fig. 1). Of which, there were 8 randomized studies (MSC vs. bone autograft as the standard care) [28, 30,31,32, 40, 43, 50, 52] and 13 non-randomized studies (received MSC). In all studies, MSCs were injected into the fracture site. For trials with two arms, the intervention group received MSCs combined with autograft and the control group received only autograft, while in non-randomized studies, the intervention consisted of MSCs alone. All studies defined bone healing as bone union, using radiographic follow-ups. The sample size of the included studies ranged from 3 to 307 participants, with a mean age between 5.8 and 77 years. Out of the 21 studies, 6 studies [28, 29, 31, 32, 34, 52] included a scaffold when utilizing MSC. The follow-up duration varied from 3 months to 96 months. The majority of the investigated non-unions involved the tibia/fibula, femur, humerus, and ulna. Healing rate at 3, 6, 9, 12, and over 12 months was presented in 5 [30, 46, 47, 50, 52], 10 [28, 30, 32,33,34, 42, 46, 47, 49, 50], 4 [31, 34, 39, 50], 7 [30, 32,33,34, 42, 47, 49], and 10 [29, 30, 34, 40, 41, 43,44,45, 48, 51] publications, respectively. Moreover, time to bone union was reported in 11 articles [29,30,31, 33, 34, 40,41,42,43, 46, 49]. The characteristics of the eligible publications are presented in Table 1.

Fig. 1
figure 1

Flow diagram of the study

Full size image
Table 1 Characteristic of the included studies for the effect of mesenchymal stem cells therapy on non-unions
Full size table

Meta-analysis

Bone healing at 3 months

Overall, the pooled rate of bone healing was 44.0% (95% CI: 38.0 − 50.0%) after 3 months. Bone healing in patients receiving MSC/Scaffold was 80.0% (95% CI: 38.0 − 96.0%) followed by MSC alone with 44.0% (95% CI: 38.0 − 49.0%). There was no between-group heterogeneity (P = 0.12) (Fig. 2). Pooling effect sizes from 3 controlled studies [30, 50, 52] identified that intervention with MSC therapy, with or without scaffold support, is significantly associated with the increased odds of bone healing (OR = 1.69, 95% CI: 1.02–2.81), compared to the standard care (Fig. 3).

Fig. 2
figure 2

Meta-analysis for the effect of mesenchymal stem cells on bone healing rate at 3 months (A), 6 months (B), 9 months (C), 12 months (D), and over 12 months (E) post-treatment

Full size image
Fig. 3
figure 3

Meta-analysis for the odds of bone healing in patients receiving mesenchymal stem cells, compared to the standard care, at 3 months (A), 6 months (B), 9 months (C), 12 months (D), and over 12 months (E) post-treatment

Full size image

Bone healing at 6 months

Pooling all effect sizes demonstrated a 73.0% bone healing (95% CI: 68.0 − 78.0%) after 6 months. In patients receiving MSC/Scaffold, bone healing rate was 78.0% (95% CI: 67.0 − 87.0%), while in MSC alone subgroup, the healing rate was 71.0% (95% CI: 66.0 − 77.0%), with no significant between-group heterogeneity (P = 0.37) (Fig. 2). Combining effect sizes from 3 controlled studies [28, 30, 50] revealed that MSC therapy, with or without scaffold support, is significantly linked to higher odds of bone healing at 6 months (OR = 1.69, 95% CI: 1.13–2.53), compared to the standard care (Fig. 3).

Bone healing at 9 months

In the overall analysis, the rate of bone healing was 90.0% after 9 months (95% CI: 86.0 − 95.0%). In the MSC/Scaffold group, the healing rate was 87.0% (95% CI: 70.0 − 96.0%), while the MSC alone subgroup showed a healing rate of 90.0% (95% CI: 85.0 − 94.0%). No remarkable heterogeneity was found between the groups (P = 0.44) (Fig. 2). Meta-analysis of 2 controlled studies [31, 50] revealed no significant distinction in the risk of bone healing (OR = 1.04, 95% CI: 0.51–2.14), compared to the standard care (Fig. 3).

Bone healing at 12 months

The analysis indicated that the bone healing rate was 86.0% after 12 months (95% CI: 77.0 − 94.0%). Within the MSC/Scaffold group, the healing rate was 68.0% (95% CI: 28.0 − 98.0%), while the MSC alone subgroup exhibited a healing rate of 87.0% (95% CI: 78.0 − 94.0%). No between-group heterogeneity was found (P = 0.22) (Fig. 2). No significant difference in the odds of bone healing was observed (OR = 2.45, 95% CI: 0.92–6.50), compared to the standard care (Fig. 3).

Bone healing after over 12 months

Overall, the pooled rate of bone healing was 91.0% (95% CI: 86.0 − 96.0%) after more than 12 months of follow-ups. Bone healing in patients receiving MSC/Scaffold was 100% (95% CI: 84.0 − 100.0%) followed by MSC alone with 90.0% (95% CI: 84.0 − 94.0%). No between-group heterogeneity was detected (P = 0.25) (Fig. 2). When the results of controlled studies were pooled [30, 40], no significant difference in odds of bone healing (OR = 1.07, 95% CI: 0.23–5.11) was found compared to the standard care (Fig. 3).

Time to bone union

The mean time to bone union following the stem cell therapy was 6.30 months (95% CI: 6.15–6.45), with a significant heterogeneity (P = 0.001). Patients who were treated with MSC/Scaffold had a shorter union time in comparison to MSC alone (5.85 months, 95% CI: 5.39–6.31 vs. 6.36 months, 95% CI: 6.20–6.51) (Fig. 4-A). In contrast, in the group receiving only autograft (without MSCs), the mean time to bone union was 7.78 months (95% CI: 3.17–12.39) (Fig. S1). Pooled analysis from 5 controlled studies [30, 31, 40, 43, 50] showed that stem cell therapy significantly reduced bone union time by 0.54 months (effect size: − 0.54, 95% CI: -0.75 to − 0.33), with remarkable evidence of heterogeneity across the studies (P = 0.001). MSC/Scaffold demonstrated superiority over MSC alone in reducing union time (-0.60 months, 95% CI: -1.18 to– 0.02 vs. -0.53 months, 95% CI: -0.75 to– 0.30) (Fig. 4-B).

Fig. 4
figure 4

Meta-analysis for time to bone union in patients receiving mesenchymal stem cells (months) (A) and in patients receiving mesenchymal stem cells, compared to the standard care (mean difference in months) (B)

Full size image

Side effects

Of 21 included studies, 11 studies reported no complications following the treatment, while 10 studies reported some complications [28, 30, 43,44,45, 48,49,50,51,52]. The most common complication was infection. Other complications included minor wound problems, temporary sensory loss, pain, screw breakage, persisting fistula, hematoma, transient lateral high paresthesia, and refracture (Table 1). The overall complication rate following the treatment was 1.0% (95% CI: 0.0– 4.0%). The rate of complications was lower in patients reviving MSC/Scaffold in comparison to MSC alone (pooled estimate: 0.0%, 95% CI: 0.0 − 5.0% vs. 2.0%, 95% CI: 0.0 − 6.0%) (Fig. 5). In contrast, in the group receiving only autograft (without MSCs), the rate of complications was 8.0% (95% CI: 5– 12%) (Fig. S2). Meta-analysis of 7 controlled studies [28, 30, 31, 40, 43, 50, 52] revealed that treatment with MSC therapy, with or without scaffold support, is significantly associated with a lower risk of developing complications (OR = 0.41, 95% CI: 0.22–0.78), compared to the standard care (Fig. 6).

Fig. 5
figure 5

Meta-analysis for complications rate in patients receiving mesenchymal stem cells

Full size image
Fig. 6
figure 6

Meta-analysis for the odds of developing complications in patients receiving mesenchymal stem cells, compared to the standard care

Full size image

Subgroup analysis by age of patients

In older patients (age ≥ 40 years), compared to younger patients (age < 40 years), the bone healing rate was higher at 3 (55.0%, 95% CI: 48.0 − 62.0% vs. 16.0%, 95% CI: 8.0 − 26.0%) and 6 (79.0%, 95% CI: 74.0 − 83.0% vs. 49.0%, 95% CI: 38.0 − 61.0%) months post-treatment, while the rate of healing was comparable at 9 months (91.0%, 95% CI: 86.0 − 95.0% vs. 90.0%, 95% CI: 74.0 − 97.0%) and, in contrast, healing rate was lower for older people at 12 months (63.0%, 95% CI: 34.0 − 83.0% vs. 88.0%, 95% CI: 80.0 − 95.0%) and after over 12 months (86.0%, 95% CI: 77.0 − 93.0% vs. 96.0%, 95% CI: 90.0 − 99.0%) of follow-up. Older patients (age ≥ 40 years), compared to younger patients (age < 40 years), had a shorter time to union (4.13 months, 95% CI: 3.89–4.37 vs. 7.62, 95% CI: 7.43–7.81 months). Moreover, the rate of complications was lower in older patients (age ≥ 40 years), compared to younger patients (age < 40 years) (0%, 95% CI: 0 − 1% vs. 2%, 0% CI: 0%% − 6%).

Publication bias

No significant evidence of publication bias was observed for outcomes (Fig. 7).

Fig. 7
figure 7

Funnel plot for publication bias for studies on the effect of mesenchymal stem cells on bone healing rate at 3 months (A), 6 months (B), 9 months (C), 12 months (D), and over 12 months (E) as well as for time to bone union (F)

Full size image

Risk of bias and quality of evidence

Regarding the risk of bias, all eight randomized studies included in this meta-analysis were considered as high quality according to the Jadad score, with scores ranging from 3 to 5. In terms of blinding, 2 studies were conducted as open-label studies [28, 50], whereas the blinding status of the other studies remained uncertain. In comparison, the quality of the 13 non-randomized studies varied according to the Newcastle-Ottawa Scale (NOS), with nine studies rated as low quality and four as high quality, yielding scores between 4 and 9 (Table 1). Based on the GRADE criteria, the quality of evidence for the bone healing rate across various follow-up durations was moderate, while the quality for time to bone union was low (Table 2). For all outcomes, no serious risk of bias was observed in the inconsistency or indirectness domains. The quality of evidence for the bone healing rate was downgraded due to significant bias originating from imprecision, which resulted from a low number of studies, small sample sizes, and wide confidence intervals of the effects. Additionally, the quality of evidence for time to bone union was further downgraded due to significant inconsistency detected across the studies.

Table 2 Quality of evidence based on the GRADE scale for randomized clinical trials
Full size table

Discussion

The treatment of long bone non-unions is still a major clinical and socio-economical problem. Autologous bone grafts (ABGs) have long been regarded as the standard care for treating non-unions, particularly due to their effectiveness in promoting bone healing and regeneration [14]. This approach involves harvesting bone tissue from the patient, typically from sites such as the iliac crest, and transplanting it to the non-union site. ABGs are favored due to their unique properties, which include osteogenic, osteoinductive, and osteoconductive capabilities [53]. This means ABGs not only provide a scaffold for new bone growth but also contain living cells and growth factors that actively promote healing. Despite their effectiveness, ABGs have some limitations, including the availability of donor tissue and potential complications at the donor site [54].

This meta-analysis was conducted in response to the inconclusive findings from recent studies that assessed the clinical efficacy of MSC administration in patients with non-union fractures. The healing rates observed after MSC therapy, 44% at 3 months, 73% at 6 months, 90% at 9 months, and 91% after 12 months, indicate a progressive improvement in bone healing, which is clinically significant as it suggests that patients may experience quicker recovery and return to normal activities. The odds ratios (OR = 1.69) at both 3 and 6 months further emphasize the enhanced odds of successful healing compared to standard care, translating to improved patient outcomes and reduced risk of complications. However, the lack of significant differences in healing rates beyond 6 months, compared to standard care, suggests that while MSC therapy is beneficial in the short term, long-term outcomes may require additional interventions or monitoring to ensure sustained recovery. The short-term benefits of MSCs in bone healing rates, compared to allografts, can be attributed to their unique biological properties and the dynamic nature of the healing process. Initially, MSCs enhance osteogenesis and promote rapid tissue regeneration through their ability to differentiate into osteoblasts and chondrocytes, which are essential for forming the bone matrix and cartilage during early healing stages [55, 56]. Additionally, MSCs secrete various cytokines that modulate inflammation and promote angiogenesis, creating a favorable microenvironment for bone repair [57]. However, as healing progresses into the long term, the initial advantages provided by MSCs may diminish due to factors such as senescence of transplanted cells, altered local microenvironments, and potential competition with endogenous stem cells or other repair mechanisms that may not rely on MSCs [58]. Thus, while MSCs are highly effective in the early phases of bone healing, their long-term efficacy may be limited by these biological dynamics and the complexity of the bone remodeling process.

Patients receiving MSC/Scaffold generally exhibited higher healing rates, compared to those receiving MSC alone. Notably, the MSC/Scaffold group showed improved bone healing rates at 3, 6, and after more than 12 months, while the MSC alone subgroup demonstrated comparable or slightly higher rates at 9 and 12 months. These results suggested that MSC/Scaffold may have a more significant impact on bone healing, with both treatment groups showing substantial healing rates over time. The results also indicated that intervention with MSC/Scaffold, or MSC alone, significantly reduced overall bone union time, with MSC/Scaffold proving more effectiveness than MSC alone in reducing union time, showcasing a potential advantage of this combined therapy. Furthermore, we identified that MSC therapy, especially with scaffold support, may potentially lower the risk of developing complications in these patients.

Studies indicate that age significantly impacts bone healing rates and times, with older individuals experiencing delayed healing due to decreased function of MSCs and alterations in inflammatory responses [59]. Subgroup analysis based on the age of patients revealed interesting trends. The findings suggested that while older patients may have higher bone healing rates in the short term (6 months), they may exhibit a lower healing rate in the long term (after 12 months). Older patients also showed shorter time to unionand fewer complications. These findings suggest that age may play a significant role in bone healing outcomes and complication rates following MSC treatment for non-union bones. These observations propose that MSC may be more effective in promoting initial healing in older patients, but the long-term healing outcomes may be better in younger patients. Physiological differences due to age-related changes in bone metabolism, regenerative capacity, and healing processes may influence the initial response to treatment, leading to higher short-term healing rates in older patients [60]. Older patients may have fewer complications due to better management of comorbidities or a more controlled healing environment. The slower long-term healing in older patients could be attributed to age-related factors affecting the later stages of bone repair and remodeling [61, 62]. MSC obtained from older donors have demonstrated a decline in proliferative abilities, differentiation potential, and migratory capacity, which could affect the bone healing process [63]. Aging is associated with increased levels of inflammatory cytokines, which can disrupt the balance between bone formation and resorption [64]. This chronic low-grade inflammation may impair the regenerative capacity of MSCs and other bone cells, leading to a lower healing rate [65]. The interplay between MSCs and macrophages also shifts with age, affecting how well these cells can coordinate the healing process [66]. These findings highlight the need for tailored treatment strategies that consider age-related factors when utilizing MSC therapy for non-union fractures. Understanding these dynamics can guide clinicians in optimizing patient management and setting realistic expectations for recovery timelines. Given that older patients may have fewer complications but lower long-term healing rates, it may be beneficial to develop specific protocols that address these differences. For example, enhancing the regenerative environment for older patients through adjunct therapies or modifying MSC treatment approaches could improve long-term outcomes. These results highlight the complex interplay of age-related factors in bone healing in response to MSCs, emphasizing the necessity for further research to elucidate the underlying mechanisms involved.

The clinical trial study by Gómez-Barrena et al. evaluated the efficacy of autologous bone marrow-derived MSCs combined with bioceramics for healing long bone delayed unions and non-unions in 28 patients. Radiological consolidation rates improved significantly over time, reaching 92.8% at 12 months, with histopathological confirmation of bone formation. Non-smokers exhibited better consolidation outcomes compared to smokers, highlighting the influence of lifestyle factors on bone healing [47]. In another study, the long-term efficacy and safety of autologous human MSCs embedded in fibrin clots for treating upper limb non-unions were examined. Eight patients received ex vivo expanded MSCs with no evidence of tissue overgrowth or tumor formation, achieving successful clinical outcomes and restored limb function over an average follow-up of 76 months. The findings supported the use of this entirely autologous approach as a safe and effective treatment for bone non-unions [67]. The effect of MSC on non-unions has been investigated as a secondary outcome in two small meta-analyses [8, 68], both of which, in contrast to the present study, showed no significant association between MSC therapy and odds of bone healing, compared to the standard care. Previous meta-analyses [8, 68] included a small number of studies (3 and 8 studies), included case reports on single patients, combined the results of animal studies with human studies [8, 69], did not assess the complications comprehensively, and did not perform subgroup analysis based on the age of participants, which reduce the reliability of their findings and prone them to the risk of bias. The lack of significant association between adjunct therapy with MSC and risk bone healing in previous studies may be due to their small sample size and lack of statistical power to detect the associations.

Supporting our findings, there is evidence that using MSC in combination with a scaffold may have an advantage over MSCs alone to improve clinical outcomes of non-unions [8]. Appling bone scaffolds is crucial for enhancing the engraftment of implanted progenitor cells. These scaffolds provide a supportive framework that mimics the natural structure of bones, facilitating the integration of the implanted cells with the surrounding tissue [70]. By offering mechanical support, guiding cell growth, and promoting vascularization, bone scaffolds play a vital role in promoting cell attachment, proliferation, and differentiation [71]. This, in turn, improves the overall success of progenitor cell-based therapies in bone regeneration and repair [72]. The application of tissue-engineered scaffolds together with stem cell technologies, particularly MSCs, is believed to hold great potential for bone tissue engineering and regenerative medicine. These scaffolds, in combination with stem cells, are aimed at inducing bone regeneration through the synergistic integration of biomaterial scaffolds, bone progenitor cells, and bone-forming factors [73]. The clinical utilities of the present study include providing a promising treatment approach, reducing recovery time, improving union rates, offering potential non-surgical options, and inspiring further advancements in the field of MSC-based therapies for non-unions. The combination of MSCs and scaffolds improves the biological and mechanical environment necessary for effective bone healing. This synergy not only promotes osteogenesis but also improves the mechanical stability of the fracture, reducing strain and allowing for the gradual transition from soft to hard callus formation [74]. Compared to standard treatments like autografts, which often involve invasive surgical procedures with higher complication rates, the MSC-scaffold approach minimizes surgical intervention and associated risks while potentially improving patient outcomes through enhanced healing capabilities. This method emphasizes the importance of combining biological factors with mechanical stability to address non-union effectively.

The findings of this meta-analysis have some implications for health-care providers and policy makers. The demonstrated efficacy of MSC therapy in improving bone healing rates and reducing time to union suggests that healthcare authorities could consider integrating MSC treatments into clinical guidelines for managing non-union fractures. This could enhance treatment options available to patients, particularly those who do not respond well to standard treatments like bone grafting. Given the positive outcomes associated with MSC therapy, policymakers may need to evaluate funding and reimbursement frameworks for regenerative medicine. This includes establishing reimbursement protocols for MSC therapies, which could encourage wider adoption among clinicians and increase patient access to innovative treatments. The variability in MSC application (with or without scaffolds) and the observed differences in healing times highlight the need for standardized treatment protocols. Policymakers should advocate for multi-center trials that establish best practices for MSC administration, ensuring consistency in treatment approaches across different healthcare settings. To facilitate the adoption of MSC therapies, educational initiatives should be implemented to inform healthcare providers about the latest advancements in stem cell research and its applications in treating non-unions. This could enhance clinician confidence in utilizing these therapies effectively. Moreover, incorporating MSC therapy into treatment plans can shift care models towards more patient-centric approaches, where individualized treatment options are prioritized based on specific patient needs and responses to prior interventions.

The favorable effects of MSCs on non-union healing can be attributed to several biological mechanisms. MSCs possess the ability to differentiate into various cell types involved in the bone healing process, such as osteoblasts, chondrocytes, and endothelial cells; by differentiating into these cell types, MSCs contribute to the formation of new bone tissue, cartilage, and blood vessels, thereby promoting the healing process [24, 25]. MSCs release a variety of bioactive molecules, including growth factors, cytokines, and chemokines [75]. These molecules have immunomodulatory properties and can regulate the inflammatory response at the injury site [22]. By modulating inflammation, MSCs create an environment that is conducive to tissue regeneration and healing [76]. Additionally, MSCs possess paracrine effects, where they secrete extracellular vesicles containing various signaling molecules. These vesicles can stimulate nearby cells, promoting their proliferation, migration, and differentiation, which are all crucial steps in the healing process [77, 78]. MSCs have been also shown to enhance angiogenesis and the formation of new blood vessels. This is particularly important for non-unions, as the presence of a sufficient blood supply is crucial for the delivery of oxygen, nutrients, and cells necessary for efficient healing [79].

Regarding the safety of MSCs in nonunion cases, the majority of the included studies reported no complications. The overall complication rate was low at 1.0%, and treatment with MSCs combined with scaffolds showed a lower complication (0.0%) rate compared to MSCs alone (2.0%), with infection being the most common, highlighting the potential of this approach to improve patient outcomes while minimizing risks associated with traditional grafting techniques. In contrast, in the group receiving only autograft (without MSCs), the rate of complications was remarkably higher (8.0% vs. 1.0%). The lower complication rate observed with the combination of MSCs and scaffolds, compared to MSCs alone, can be explained by several factors related to scaffold properties and their interaction with MSCs. Scaffolds provide a three-dimensional structure that supports cell attachment, proliferation, and differentiation, which enhances the retention of MSCs at the injury site and promotes a more organized tissue regeneration process [80]. This structural support can help mitigate complications such as infection, which was the most common adverse event noted in MSC treatments alone [56]. In contrast, MSCs without scaffolding may disperse too quickly from the site or fail to integrate effectively into the healing tissue, leading to higher complication rates [81]. Additionally, meta-analysis indicated that MSC therapy is significantly associated with a reduced risk of complications compared to standard care. In line with our findings, evidence indicates that MSC treatments have a strong safety profile, with most adverse events being mild and manageable [26, 27].

This study represents the most comprehensive meta-analysis of prior studies on the clinical efficacy and safety of MSCs in non-union fractures. The strengths of this study include its comprehensive analyses based on various follow-ups, absence of publication bias, and subgroup analyses based on the intervention protocol and age of participants, allowing for a more reliable conclusion.

However, it is important to consider the limitations of this meta-analysis. The quality of evidence was low for time to bone union, primarily due to imprecision, because confidence intervals included null effect or appreciable harm or benefit, which resulted from the small sample size and significant inconsistency across studies. Thus, these results should be approached with caution and verified in future well-designed RCTs. Furthermore, we did not register the protocol for this study, which should be considered as a limitation. A significant heterogeneity was observed for some analyses. The stratified analysis revealed that the differences in study intervention (MSC alone vs. MSC /scaffolds), follow-up durations, and age of participants were sources of the observed heterogeneity. In addition, the majority of included articles were non-randomized studies, which can potentially introduce bias. It is important to acknowledge the risk of bias inherent in the included studies, particularly among the non-randomized studies, which may introduce systematic biases in the results. Additionally, the heterogeneity in study designs, including variations in interventions, follow-up durations, and participant characteristics, complicates the interpretation of pooled data may affect the generalizability of our findings. The included studies also did not provide detailed information on smoking, fracture type, and comorbidities, such as diabetes or cardiovascular conditions, which are known to influence healing outcomes and complications. As a result, we were unable to perform a subgroup analysis based on these confounding factors to assess their effects on heterogeneity. This lack of reporting highlights a significant gap in the literature, highlighting the need for future studies to standardize the reporting of environmental risk factors, comorbidities, and fracture classifications. The dosages of MSCs utilized in each study and the protocols for isolating and preparing MSCs varied among the studies. These differences could contribute to heterogeneity across the studies. However, this is a common limitation in meta-analyses involving MSCs, given that there is no standardized protocol for MSC preparation and administration across different studies. Accordingly, standardizing the protocols for isolating and administering MSCs could help reduce heterogeneity among the studies.

Identifying potential sources of heterogeneity, such as differences in MSC interventions, follow-up durations, and participant age, strengthens the analysis by allowing for a more nuanced understanding of treatment effects across diverse patient populations. This stratification can help identify specific factors that influence outcomes, thereby enhancing the robustness of the conclusions drawn from the meta-analysis. Furthermore, recognizing the predominance of non-randomized studies highlights the need for caution in interpreting results and underscores the importance of future randomized controlled trials to mitigate bias. Nevertheless, the presence of significant heterogeneity suggests that the results may not be universally applicable to all patients with non-union fractures. For instance, older patients with fewer comorbidities might respond differently to MSC therapy compared to younger patients or those with underlying health issues. Clinicians must consider MSC types, dosing, age, and follow-up duration when interpreting the findings and making treatment decisions.

In conclusion, this meta-analysis indicated the effectiveness of adjunct therapy with MSCs, either alone or as MSCs/scaffold, in accelerating fracture union time and enhancing fracture union rate in the healing process of bones, especially in older patients. Overall, the use of MSCs was safe; however, there was weak evidence suggesting a risk of post-treatment infections following MSCs therapy. Therefore, this study suggests that combining MSCs with surgical techniques in patients with non-unions can lead to positive clinical outcomes. Future research, particularly with a randomized clinical trial design, is needed to explore the optimal MSC types, dosing, and long-term follow-up protocols in these patients.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Fayaz HC, Giannoudis PV, Vrahas MS, Smith RM, Moran C, Pape HC, et al. The role of stem cells in fracture healing and nonunion. Int Orthop. 2011;35:1587–97.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Secretariat MA. Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Ont Health Technol Assess Ser. 2005;5(6):1.

    Google Scholar 

  3. Tay W-H, de Steiger R, Richardson M, Gruen R, Balogh ZJ. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury. 2014;45(10):1653–8.

    Article  PubMed  Google Scholar 

  4. Johnson L, Igoe E, Kleftouris G, Papachristos IV, Papakostidis C, Giannoudis PV. Physical health and psychological outcomes in adult patients with long-bone fracture non-unions: evidence today. J Clin Med. 2019;8(11):1998.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hak DJ, Fitzpatrick D, Bishop JA, Marsh JL, Tilp S, Schnettler R, et al. Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. Injury. 2014;45:S3–7.

    Article  PubMed  Google Scholar 

  6. Imam MA, Holton J, Ernstbrunner L, Pepke W, Grubhofer F, Narvani A, et al. A systematic review of the clinical applications and complications of bone marrow aspirate concentrate in management of bone defects and nonunions. Int Orthop. 2017;41(11):2213–20.

    Article  PubMed  Google Scholar 

  7. Holmes D. Non-union bone fracture: a quicker fix. Nature. 2017;550(7677):S193–S.

    Article  PubMed  CAS  Google Scholar 

  8. Palombella S, Lopa S, Gianola S, Zagra L, Moretti M, Lovati AB. Bone marrow-derived cell therapies to heal long-bone nonunions: a systematic review and meta-analysis—which is the best available treatment? Stem cells international. 2019;2019.

  9. Dunlop S, McCormack M, Zigler J, Neher R. PIT23 the cost burden OF NONUNION following long bone fracture in a commercially insured population in the United States. Value Health. 2019;22:S215.

    Article  Google Scholar 

  10. Flores MJ, Brown KE, O’Marr JM, Adejuyigbe B, Rodarte P, Gomez-Alvarado F, et al. The economic impact of infection and/or nonunion on long-bone shaft fractures: a systematic review. OTA Int. 2024;7(3):e337.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Stewart S. Fracture non-union: a review of clinical challenges and future research needs. Malaysian Orthop J. 2019;13(2):1.

    Article  CAS  Google Scholar 

  12. Khan MJ, Firoz MA, Anwer A, Agrawal P, Rashid M, Asif A. Management of Non-union Distal Femur fracture with augmentation nail-plate construct: a Case Report. J Orthop Case Rep. 2024;14(9):167.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schlundt C, Bucher CH, Tsitsilonis S, Schell H, Duda GN, Schmidt-Bleek K. Clinical and research approaches to treat non-union fracture. Curr Osteoporos Rep. 2018;16:155–68.

    Article  PubMed  Google Scholar 

  14. Sen M, Miclau T. Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? Injury. 2007;38(1):S75–80.

    Article  PubMed  Google Scholar 

  15. Ammori MB, Elvey M, Mahmoud SS, Nicholls AJ, Robinson S, Rowan C, et al. The outcome of bone graft surgery for nonunion of fractures of the scaphoid. J Hand Surg (European Volume). 2019;44(7):676–84.

    Article  Google Scholar 

  16. Lapcin O, Arıkan Y, Yavuz U, Akman YE, Çetinkaya E, Gür V, et al. Evaluation of outcomes in aseptic non-unions of the forearm bones in adults treated with LCP and autograft. Turkish J Trauma Emerg Surgery/Ulusal Travma ve Acil Cerrahi Dergisi. 2016;22(3).

  17. Smakaj A, De Mauro D, Rovere G, Pietramala S, Maccauro G, Parolini O, et al. Clinical application of adipose derived stem cells for the treatment of aseptic non-unions: current stage and future perspectives—systematic review. Int J Mol Sci. 2022;23(6).

  18. Betz RR. Limitations of autograft and allograft: new synthetic solutions. Orthopedics. 2002;25(5):S561–70.

    Article  PubMed  Google Scholar 

  19. Maceroli MA, Gage MJ, Wise BT, Connelly D, Ordonio K, Castillo RC, et al. Risk factors for failure of bone grafting of tibia nonunions and segmental bone defects: a new preoperative risk assessment score. J Orthop Trauma. 2017;31:S55–9.

    Article  PubMed  Google Scholar 

  20. Nauth A, Lee M, Gardner MJ, Brinker MR, Warner SJ, Tornetta P III, et al. Principles of nonunion management: state of the art. J Orthop Trauma. 2018;32:S52–7.

    Article  PubMed  Google Scholar 

  21. Toosi S, Behravan N, Behravan J. Nonunion fractures, mesenchymal stem cells and bone tissue engineering. J Biomedical Mater Res Part A. 2018;106(9):2552–62.

    Article  CAS  Google Scholar 

  22. Law S, Chaudhuri S. Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges. Am J stem Cells. 2013;2(1):22.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Kemp KC, Hows J, Donaldson C. Bone marrow-derived mesenchymal stem cells. Leuk Lymphoma. 2005;46(11):1531–44.

    Article  PubMed  Google Scholar 

  24. Fakhry M, Hamade E, Badran B, Buchet R, Magne D. Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J stem Cells. 2013;5(4):136.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M. Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science. 2005;308(5727):1472–7.

    Article  PubMed  CAS  Google Scholar 

  26. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safe ty of cell therapy with mesenchymal stromal cells (safecell): a systematic review and meta-analysis of clinical trials. PLoS ONE. 2012;7(10):e47559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS ONE. 2017;12(4):e0175449.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hernigou P, Guissou I, Homma Y, Poignard A, Chevallier N, Rouard H, et al. Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes. Int Orthop. 2015;39:1639–43.

    Article  PubMed  Google Scholar 

  29. Giannotti S, Bottai V, Ghilardi M, Dell’Osso G, Fazzi R, Trombi L, et al. Treatment of pseudoarthrosis of the upper limb using expanded mesenchymal stem cells: a pilot study. Eur Rev Med Pharmacol Sci. 2013;17(2):224–7.

    PubMed  CAS  Google Scholar 

  30. Dallari D, Rani N, Sabbioni G, Mazzotta A, Cenacchi A, Savarino L. Radiological assessment of the PRF/BMSC efficacy in the treatment of aseptic nonunions: a retrospective study on 90 subjects. Injury. 2016;47(11):2544–50.

    Article  PubMed  CAS  Google Scholar 

  31. Wang X, Chu W, Zhuang Y, Shi D, Tao H, Jin C, et al. Bone mesenchymal stem cell-enriched β-Tricalcium phosphate scaffold processed by the screen-enrich-combine circulating system promotes regeneration of diaphyseal bone non-union. Cell Transplant. 2019;28(2):212–23.

    Article  PubMed  Google Scholar 

  32. Ismail HD, Phedy P, Kholinne E, Djaja YP, Kusnadi Y, Merlina M, et al. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: a translational study. Bone Joint Res. 2016;5(7):287–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Labibzadeh N, Emadedin M, Fazeli R, Mohseni F, Hosseini SE, Moghadasali R, et al. Mesenchymal stromal cells implantation in combination with platelet lysate product is safe for reconstruction of human long bone nonunion. Cell J (Yakhteh). 2016;18(3):302.

    Google Scholar 

  34. Wittig O, Romano E, González C, Diaz-Solano D, Marquez ME, Tovar P, et al. A method of treatment for nonunion after fractures using mesenchymal stromal cells loaded on collagen microspheres and incorporated into platelet-rich plasma clots. Int Orthop. 2016;40:1033–8.

    Article  PubMed  Google Scholar 

  35. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372.

  36. Clark HD, Wells GA, Huët C, McAlister FA, Salmi LR, Fergusson D, et al. Assessing the quality of randomized trials: reliability of the Jadad scale. Control Clin Trials. 1999;20(5):448–52.

    Article  PubMed  CAS  Google Scholar 

  37. Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute. 2011;2(1):1–12.

  38. Mustafa RA, Santesso N, Brozek J, Akl EA, Walter SD, Norman G, et al. The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses. J Clin Epidemiol. 2013;66(7):736–42. e5.

    Article  PubMed  Google Scholar 

  39. Centeno C, Schultz J, Cheever M, Freeman M, Robinson B, Faulkner S. A case series of percutaneous treatment of non-union fractures with autologous, culture expanded, bone marrow derived, mesenchymal stem cells and platelet lysate. J Bioengineer Biomedical Sci S. 2011;2:2.

    Google Scholar 

  40. Thua THL, Bui DP, Nguyen DT, Pham DN, Le QB, Nguyen PH, et al. Autologous bone marrow stem cells combined with allograft cancellous bone in treatment of nonunion. Biomedical Res Therapy. 2015;2:1–9.

    Article  Google Scholar 

  41. Flouzat-Lachaniette CH, Heyberger C, Bouthors C, Roubineau F, Chevallier N, Rouard H, et al. Osteogenic progenitors in bone marrow aspirates have clinical potential for tibial non-unions healing in diabetic patients. Int Orthop. 2016;40:1375–9.

    Article  PubMed  Google Scholar 

  42. Emadedin M, Labibzadeh N, Fazeli R, Mohseni F, Hosseini SE, Moghadasali R, et al. Percutaneous autologous bone marrow-derived mesenchymal stromal cell implantation is safe for reconstruction of human lower limb long bone atrophic nonunion. Cell J (Yakhteh). 2017;19(1):159.

    Google Scholar 

  43. Zhang H, Xue F, Xiao HJ. Ilizarov method in combination with autologous mesenchymal stem cells from iliac crest shows improved outcome in tibial non-union. Saudi J Biol Sci. 2018;25(4):819–25.

    Article  PubMed  CAS  Google Scholar 

  44. Bhattacharjee A, Kuiper JH, Roberts S, Harrison PE, Cassar-Pullicino VN, Tins B, et al. Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow‐derived mesenchymal stromal cells. J Orthop Research®. 2019;37(6):1303–9.

    Article  CAS  Google Scholar 

  45. Dilogo IH, Phedy P, Kholinne E, Djaja YP, Fiolin J, Kusnadi Y, et al. Autologous mesenchymal stem cell implantation, hydroxyapatite, bone morphogenetic protein-2, and internal fixation for treating critical-sized defects: a translational study. Int Orthop. 2019;43:1509–19.

    Article  PubMed  Google Scholar 

  46. Toro G, Lepore F, Calabrò G, Toro G, Rossini M, Vasso M, et al. Humeral shaft non-union in the elderly: results with cortical graft plus stem cells. Injury. 2019;50:S75–9.

    Article  PubMed  Google Scholar 

  47. Gómez-Barrena E, Padilla-Eguiluz N, Rosset P, Gebhard F, Hernigou P, Baldini N, et al. Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions. Injury. 2020;51:S63–73.

    Article  PubMed  Google Scholar 

  48. Dilogo IH, Rahmatika D, Pawitan JA, Liem IK, Kurniawati T, Kispa T, et al. Allogeneic umbilical cord-derived mesenchymal stem cells for treating critical-sized bone defects: a translational study. Eur J Orthop Surg Traumatol. 2021;31:265–73.

    Article  PubMed  Google Scholar 

  49. Van Vugt T, Geurts J, Blokhuis T. Treatment of infected tibial non-unions using a BMAC and S53P4 BAG combination for reconstruction of segmental bone defects: a clinical case series. Injury. 2021;52:S67–71.

    Article  PubMed  Google Scholar 

  50. Hernigou P, Housset V, Dubory A, Rouard H, Auregan JC. Early injection of autologous bone marrow concentrates decreases infection risk and improves healing of acute severe open tibial fractures. Injury. 2022;53:S26–33.

    Article  PubMed  Google Scholar 

  51. Kurniawan A, Ivansyah MD, Dilogo IH, Hutami WD. Umbilical cord mesenchymal stem cells combined with secretome for treating congenital pseudarthrosis of the Tibia: a case series. Eur J Orthop Surg Traumatol. 2023;33(7):2881–8.

    Article  PubMed  Google Scholar 

  52. Toosi S, Naderi-Meshkin H, Moradi A, Daliri M, Moghimi V, Majd H-M, et al. Scaphoid bone nonunions: clinical and functional outcomes of collagen/PGA scaffolds and cell-based therapy. ACS Biomaterials Sci Eng. 2023;9(4):1928–39.

    Article  CAS  Google Scholar 

  53. Marsh J. Principles of bone grafting: non-union, delayed union. Surg (Oxford). 2003;21(9):213–6.

    Article  Google Scholar 

  54. Schmidt AH. Autologous bone graft: is it still the gold standard? Injury. 2021;52:S18–22.

    Article  PubMed  Google Scholar 

  55. Oryan A, Kamali A, Moshiri A, Baghaban Eslaminejad M. Role of mesenchymal stem cells in bone regenerative medicine: what is the evidence? Cells Tissues Organs. 2017;204(2):59–83.

    Article  PubMed  CAS  Google Scholar 

  56. Knight MN, Hankenson KD. Mesenchymal stem cells in bone regeneration. Adv Wound care. 2013;2(6):306–16.

    Article  Google Scholar 

  57. Zhang Y, Fan M, Zhang Y. Revolutionizing bone defect healing: the power of mesenchymal stem cells as seeds. Front Bioeng Biotechnol. 2024;12:1421674.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Fu J, Wang Y, Jiang Y, Du J, Xu J, Liu Y. Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis. Stem Cell Res Ther. 2021;12:1–15.

    Article  Google Scholar 

  59. Wagner DR, Karnik S, Gunderson ZJ, Nielsen JJ, Fennimore A, Promer HJ, et al. Dysfunctional stem and progenitor cells impair fracture healing with age. World J stem Cells. 2019;11(6):281.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gonzalez-Garza MT, Cruz-Vega DE. Regenerative capacity of autologous stem cell transplantation in elderly: a report of biomedical outcomes. Regen Med. 2017;12(2):169–78.

    Article  PubMed  CAS  Google Scholar 

  61. Hirata H, Zhang N, Ueno M, Barati D, Kushioka J, Shen H, et al. Ageing attenuates bone healing by mesenchymal stem cells in a microribbon hydrogel with a murine long bone critical-size defect model. Immun Ageing. 2022;19(1):14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Foulke BA, Kendal AR, Murray DW, Pandit H. Fracture healing in the elderly: a review. Maturitas. 2016;92:49–55.

    Article  PubMed  Google Scholar 

  63. Thurairajah K, Briggs GD, Balogh ZJ. Stem cell therapy for fracture non-union: the current evidence from human studies. J Orthop Surg. 2021;29(3):23094990211036545.

    Article  Google Scholar 

  64. Mi B, Xiong Y, Knoedler S, Alfertshofer M, Panayi AC, Wang H, et al. Ageing-related bone and immunity changes: insights into the complex interplay between the skeleton and the immune system. Bone Res. 2024;12(1):42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Mancinelli L, Intini G. Age-associated declining of the regeneration potential of skeletal stem/progenitor cells. Front Physiol. 2023;14:1087254.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther. 2016;7:1–7.

    Article  Google Scholar 

  67. Giannotti S, Trombi L, Bottai V, Ghilardi M, D’Alessandro D, Danti S, et al. Use of autologous human mesenchymal stromal cell/fibrin clot constructs in upper limb non-unions: long-term assessment. PLoS ONE. 2013;8(8):e73893.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Kaspiris A, Hadjimichael AC, Vasiliadis ES, Papachristou DJ, Giannoudis PV, Panagiotopoulos EC. Therapeutic efficacy and safety of osteoinductive factors and cellular therapies for long bone fractures and non-unions: a meta-analysis and systematic review. J Clin Med. 2022;11(13):3901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Qu Z, Guo S, Fang G, Cui Z, Liu Y. AKT pathway affects bone regeneration in nonunion treated with umbilical cord-derived mesenchymal stem cells. Cell Biochem Biophys. 2015;71(3):1543–51.

    Article  PubMed  CAS  Google Scholar 

  70. Venkataiah VS, Yahata Y, Kitagawa A, Inagaki M, Kakiuchi Y, Nakano M, et al. Clinical applications of cell-scaffold constructs for bone regeneration therapy. Cells. 2021;10(10):2687.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Hosseinkhani M, Mehrabani D, Karimfar MH, Bakhtiyari S, Manafi A, Shirazi R. Tissue engineered scaffolds in regenerative medicine. World J Plast Surg. 2014;3(1):3.

    PubMed  PubMed Central  Google Scholar 

  72. Xia B, Deng Y, Lv Y, Chen G. Stem cell recruitment based on scaffold features for bone tissue engineering. Biomaterials Sci. 2021;9(4):1189–203.

    Article  CAS  Google Scholar 

  73. Zhang Y, Wu D, Zhao X, Pakvasa M, Tucker AB, Luo H, et al. Stem cell-friendly scaffold biomaterials: applications for bone tissue engineering and regenerative medicine. Front Bioeng Biotechnol. 2020;8:598607.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Khatkar H, See A. Stem cell therapy in the management of fracture non-union–evaluating cellular mechanisms and clinical progress. Cureus. 2021;13(3).

  75. Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Therapy. 2022;7(1):92.

    Article  Google Scholar 

  76. Medhat D, Rodríguez CI, Infante A. Immunomodulatory effects of MSCs in bone healing. Int J Mol Sci. 2019;20(21):5467.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Chang C, Yan J, Yao Z, Zhang C, Li X, Mao HQ. Effects of mesenchymal stem cell-derived paracrine signals and their delivery strategies. Adv Healthc Mater. 2021;10(7):2001689.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Kusuma GD, Carthew J, Lim R, Frith JE. Effect of the microenvironment on mesenchymal stem cell paracrine signaling: opportunities to engineer the therapeutic effect. Stem Cells Dev. 2017;26(9):617–31.

    Article  PubMed  CAS  Google Scholar 

  79. Tao H, Han Z, Han ZC, Li Z. Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem cells international. 2016;2016.

  80. Stamnitz S, Klimczak A. Mesenchymal stem cells, bioactive factors, and scaffolds in bone repair: from research perspectives to clinical practice. Cells. 2021;10(8):1925.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Brown MG, Brady DJ, Healy KM, Henry KA, Ogunsola AS, Ma X. Stem cells and Acellular preparations in Bone Regeneration/Fracture Healing: current therapies and future directions. Cells. 2024;13(12):1045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

None.

Funding

No Funding.

Author information

Authors and Affiliations

  1. Department of Joint Surgery, Central Hospital Affiliated to Shandong First Medical University, NO. 105, Jiefang Road, Jinan, 250013, China

    Cunbao Cui, Feng Lin & Xinguang Zhang

  2. Department of Thoracic Surgery, Central Hospital Affiliated to Shandong First Medical University, NO. 105, Jiefang Road, Jinan, 250013, China

    Liang Xia

Authors
  1. Cunbao Cui
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Feng Lin
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Liang Xia
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Xinguang Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Study design: Cunbao Cui and Feng Lin. Search strategy, study selection and data extraction: Feng Lin, Liang Xia, and Xinguang Zhang. Literature assessment: Liang Xia and Xinguang Zhang. Manuscript preparation: Cunbao Cui, Feng Lin, and Liang Xia. Data curation and writing-original draft preparation: Feng Lin, Liang Xia, and Xinguang Zhang. Supervision: Xinguang Zhang. Edition and rewriting the manuscript: Xinguang Zhang and Liang Xia.

Corresponding author

Correspondence to Xinguang Zhang.

Ethics declarations

Ethical approval

Not applicable.

Human ethics and consent to participate

Not applicable.

Consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file 1

Supplementary figures

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, C., Lin, F., Xia, L. et al. Mesenchymal stem cells therapy for the treatment of non-union fractures: a systematic review and meta-analysis. BMC Musculoskelet Disord 26, 245 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08365-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08365-w

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

Contact us