Jianzhou Tian1†
Guanghui Yao
Saisheng Zhang- 1Department of Burn and Plastic Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- 2Reproductive Medicine Center, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- 3Hubei Clinical Research Center for Reproductive Medicine, Shiyan, Hubei, China
- 4Shiyan Key Laboratory of Reproduction and Genetics (Renmin Hospital, Hubei University of Medicine), Shiyan, Hubei, China
- 5Biomedical Engineering College, Hubei University of Medicine, Shiyan, China
- 6Department of Ophthalmology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
Objective: This study aimed to evaluate the efficacy and safety of different growth factors (GFs) in the treatment of diabetic foot ulcers (DFUs) through a network meta-analysis.
Methods: A systematic search was conducted in PubMed, Embase, The Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) comparing GFs with standard of care (SOC) or comparing different GFs for the treatment of DFU. Two independent reviewers screened the studies, extracted data, and assessed the quality of the included literature according to predefined inclusion and exclusion criteria. A network meta-analysis was performed using R software. Relative risk (RR) was used as the effect measure for dichotomous outcomes, and mean difference (MD) was used for continuous outcomes.
Results: A total of 51 RCTs, involving 3,401 patients with DFUs and six different types of GFs, were included. The network meta-analysis revealed that, compared with SOC, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and platelet-rich plasma (PRP) significantly improved the healing rate. EGF and PRP also significantly reduced healing time, while PDGF significantly reduced ulcer area. Moreover, PRP was associated with a significant reduction in the incidence of adverse events (AEs) and amputation rates. In terms of ranking: For healing rate, the top three GFs were EGF, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor (G-CSF). For healing time, EGF, PRP, and fibroblast growth factor (FGF) ranked the highest. For ulcer area reduction, PDGF, EGF, and PRP were the top-ranking interventions. Regarding AEs, PRP, PDGF, and FGF showed the most favorable safety profiles. For amputation rate, PRP, G-CSF, and PDGF were ranked the highest.
Conclusion: Almost all GFs outperformed SOC in terms of healing rate, healing time, and ulcer area reduction. Compared to SOC, EGF, PDGF, and PRP significantly improved healing rates; EGF and PRP significantly reduced healing time; and PDGF significantly decreased ulcer area. Among them, EGF may be the most effective GF. Except for VEGF, which significantly increased AEs, other GFs did not show a significant increase in AEs compared to SOC. PRP had the lowest amputation rate and incidence of AEs.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251035765
Introduction
Diabetic foot ulcer (DFU) is a common and serious complication in patients with diabetes, characterized by a high recurrence rate and associated with increased amputation and mortality rates (1). Currently, approximately 18.6 million people worldwide are affected by DFU (2). With the continuous rise in diabetes prevalence, the incidence of DFU has also shown a significant increase, placing a heavy economic burden on patients, their families, and society (3). Wound healing is frequently compromised in patients with DFUs, and their clinical condition can easily worsen (4). Common standard of care (SOC) treatments such as debridement, dressing changes, pressure relief, and blood glucose control have limited efficacy (5). Therefore, there is an urgent need for new treatment options.
Growth factors (GFs) play a crucial role in the wound healing process. Platelet-derived growth factor (PDGF), platelet-rich plasma (PRP), epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor (G-CSF) are among the most extensively studied GFs in the treatment of DFU. PDGF facilitates cell recruitment and tissue repair and has been approved by the Food and Drug Administration (FDA); PRP, rich in multiple GFs, accelerates wound healing and is increasingly used in clinical practice; EGF promotes keratinocyte proliferation and migration, enhancing wound healing; FGF supports granulation tissue formation and collagen synthesis, though its application remains limited; VEGF improves local perfusion through angiogenesis but is less commonly used clinically; and G-CSF enhances immune function, although related research is relatively limited (6). Several direct meta-analyses have shown that GFs can significantly improve DFU healing compared to standard treatment (7–9). However, the International Working Group on the Diabetic Foot believes that the existing evidence is insufficient to support the use of GFs in the treatment of DFU (10). Since current studies mainly focus on comparing the efficacy of a single GF with SOC, there is a lack of evidence on the differences in efficacy and safety between different GFs for treating DFU. Two previous network meta-analyses have both suggested that EGF is the most effective GF for healing DFU (11, 12). However, the outcome measures reported in these studies were limited to healing rate, without addressing other important outcomes such as healing time, ulcer area reduction, and the incidence of adverse events (AEs). Additionally, clinical research on GF treatment for DFU is continuously being updated (6). Therefore, an updated network meta-analysis is needed to evaluate the efficacy and safety of different GFs in the treatment of DFU, with the aim of providing more evidence-based medical support for DFU treatment.
Methods
This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (13). The study has been registered in PROSPERO with the registration number CRD420251035765.
Literature search strategy
PubMed, Embase, The Cochrane Library, and Web of Science were searched to identify randomized controlled trials (RCTs) comparing GFs with SOC, or comparing different GFs for the treatment of DFU. The search was conducted from the inception of each database to 12 January 2025. A combination of subject terms and free-text terms was used for the search. Detailed search strategies for each database are provided in Supplementary file S1.
Inclusion criteria
(1) The study participants were patients with DFU. (2) The study design was an RCT. (3) The study included two or more comparison groups. (4) The interventions included one group receiving SOC and the other group(s) receiving GF treatment, or different groups receiving different types of GFs. (5) The study reported at least one of the following outcome measures: healing rate, healing time, ulcer area reduction, amputation rate, or AEs. AEs included events such as infection, allergic reactions, and pain.
Exclusion criteria
The following types of studies were excluded: (1) studies from which valid data could not be extracted and for which attempts to contact the authors were unsuccessful; (2) conference abstracts and letters; (3) publications derived from the same study population; (4) single-arm studies, case reports, retrospective studies, and other non-randomized designs; and (5) studies published in languages other than English.
Study selection, data extraction, and quality assessment
(1) Two researchers independently screened the literature, extracted relevant data, and assessed the methodological quality of the included studies based on pre-defined inclusion and exclusion criteria. The results were cross-checked between the two reviewers. Any discrepancies that could not be resolved through discussion were adjudicated by a third reviewer. (2) Extracted data included the following: basic study information such as first author, year of publication, and study location; patient-related information such as interventions, the number of male and female patients in each group, age, duration of ulcers, and ulcer area; and outcome-related data including healing rate, healing time, ulcer area reduction, amputation rate, and incidence of AEs. If a study involved different doses of the same GF, data from the group receiving the highest dose were used. Relevant elements for risk of bias assessment were also extracted. (3) The risk of bias of the included RCTs was assessed using the Risk of Bias 2.0 (RoB 2.0) tool (14).
Statistical analysis
A network meta-analysis was performed using the Gemtc package in R (15). Network evidence diagrams were generated for each outcome measure. A Bayesian statistical approach was employed to conduct indirect comparisons of the efficacy and safety of different GFs in the treatment of DFU. For healing rate and incidence of AEs, relative risk (RR) was used as the effect measure; for healing time and ulcer area reduction, mean difference (MD) was used. When the interventions related to the outcome indicators do not form a closed loop, the assumption of consistency is satisfied. If the interventions form a closed loop, a node-splitting method is used to assess consistency; a p-value greater than 0.05 suggests an acceptable level of consistency between direct and indirect evidence. A Bayesian Markov Chain Monte Carlo (MCMC) random-effects model was used for the analysis (16). Model parameters were set as follows: four chains, 50,000 iterations, and 20,000 burn-ins. Effect sizes and their 95% credible intervals (CIs) were calculated for each outcome across the interventions. The efficacy and safety of different treatments were compared, and the surface under the cumulative ranking curve (SUCRA) was used to rank the treatments in terms of efficacy and safety (17). Sensitivity analysis was performed by excluding studies with a high risk of bias.
Results
Results of literature search
A total of 6,740 relevant studies were identified through a systematic search of the databases. After rigorous screening, 51 studies (18–68) were found to meet the inclusion criteria. The detailed process and results of study selection are illustrated in Figure 1.
Figure 1. Literature screening process and results.
Basic characteristics of included studies
A total of 51 RCTs, involving 3,401 patients with DFU, were included. These studies examined seven different interventions, namely, EGF, VEGF, G-CSF, FGF, PDGF, PRP, and SOC. Detailed characteristics of the included studies are presented in Table 1.
Table 1. The characteristics of included studies on the treatment of diabetic foot ulcers.
Quality assessment
The risk of bias assessment showed that 1 study was judged to have a low risk of bias, 46 studies were judged to have some concerns, and 4 studies were judged to have a high risk of bias. Overall, the methodological quality of the included studies was relatively low. Detailed results of the risk of bias assessment are presented in Supplementary Figure S1.
Network evidence diagrams
Figures 2A–E present the network evidence diagrams for healing rate, healing time, ulcer area reduction, incidence of AEs, and amputation rate, respectively. In these diagrams, each node represents an intervention. The lines connecting the nodes indicate the presence of direct comparison evidence, and the thickness of the lines is proportional to the number of studies included in the comparison. In the network plots of healing rate and healing time, closed loops were formed among the interventions (consistency assessed using the node-splitting method, p > 0.05), while no closed loops were observed for the remaining outcome indicators, suggesting acceptable consistency across the studies.
Figure 2. Network evidence plots for (A) healing rate, (B) healing time, (C) ulcer area reduction, (D) incidence of adverse events, and (E) amputation rate. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.
Healing rate
Compared to SOC, EGF (RR = 1.55, 95% CI = 1.26–1.96), PDGF (RR = 1.29, 95% CI = 1.06–1.60), and PRP (RR = 1.24, 95% CI = 1.07–1.50) significantly improved the healing rate, with statistically significant differences. Among comparisons of different GFs for healing rate, only EGF showed a statistically significant difference when compared to FGF (RR = 2.0, 95% CI = 1.16–3.59). The league table comparing the healing rates of various treatments is shown in Figure 3.
Figure 3. League table of pairwise comparisons for healing rates among different treatment interventions. Each cell presents the relative risk (RR) and 95% confidence interval (CI) for the treatment listed in the column compared with the treatment listed in the row. If the RR is greater than 1 and the difference is statistically significant, the treatment in the column is superior to the treatment in the row. Statistically significant results (p < 0.05) are highlighted in bold red font. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.
Healing time
Compared to SOC, EGF (MD = −24.94, 95% CI = −40.76 to −9.38) and PRP (MD = −16.92, 95% CI = −26.15 to −7.09) significantly reduced healing time, with statistically significant differences. No statistically significant differences were found in the comparisons of healing time among different GFs. The league table comparing healing times across various treatments is shown in Supplementary Figure S2.
Reduction in ulcer area
Compared to SOC, PDGF (MD = −9.91, 95% CI = −17.79 to −2.04) significantly reduced ulcer area, with a statistically significant difference. No statistically significant differences were observed in the comparisons of ulcer area reduction among different GFs. The league table comparing the reduction in ulcer area across various treatments is shown in Supplementary Figure S3.
AEs
Compared to SOC, PRP (RR = 0.27, 95% CI = 0.09–0.79) significantly reduced the incidence of AEs. VEGF was associated with a significantly increased incidence of AEs compared to EGF, FGF, PDGF, PRP, and SOC, with all differences being statistically significant. No statistically significant differences were observed in other treatment comparisons. The league table comparing the incidence of AEs across various treatments is shown in Supplementary Figure S4.
Amputation rate
Compared to SOC, PRP (RR = 0.17, 95% CI = 0.01–0.61) significantly reduced the amputation rate, with a statistically significant difference. No statistically significant differences were observed in the comparisons of amputation rates among different GFs. The league table comparing amputation rates across various treatments is shown in Supplementary Figure S5.
SUCRA
Network meta-analysis enables the ranking of interventions through the calculation of SUCRA, which ranges from 0 to 100%. A higher SUCRA value corresponds to a better ranking position, indicating that the intervention not only demonstrates superior efficacy but also has better safety.
Detailed SUCRA values for healing rate, healing time, ulcer area reduction, incidence of AEs, and amputation rate are shown in Table 2. Figures 4A–E present the cumulative ranking probability plots for healing rate, healing time, ulcer area reduction, incidence of AEs, and amputation rate, respectively. EGF ranks first in healing rate and healing time, second to PDGF in ulcer area reduction, and PRP ranks first in amputation rate and incidence of AEs. Therefore, in terms of healing rate, all GFs except FGF ranked higher than SOC, with EGF, PDGF, and PRP showing significantly better outcomes than SOC. Regarding healing time, all GFs ranked higher than SOC, with EGF and PRP demonstrating statistically significant improvements. For ulcer area reduction, all GFs outperformed SOC, with PDGF showing a significant advantage. Among the GFs, EGF appears to be the most effective. Compared to SOC, only VEGF was associated with a significant increase in AEs, while other GFs did not show a significant difference. PRP was associated with the lowest incidence of AEs and the lowest amputation rate.
Table 2. SUCRA values and ranks of efficacy outcomes for different interventions in diabetic foot ulcer treatment.
Figure 4. Cumulative ranking curves (SUCRA plots) for (A) healing rate, (B) healing time, (C) ulcer area reduction, (D) incidence of adverse events, and (E) amputation rate. The surface under the cumulative ranking curve (SUCRA) indicates the relative ranking probability of each treatment, with higher SUCRA values representing better performance for positive outcomes and lower risk for negative outcomes. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.
Sensitivity analysis
After excluding high-risk studies, the healing rate was reassessed. The results showed no significant difference from the findings before excluding the high-risk studies, and the rankings remained unchanged. This indicates that the results of the primary outcome measures in this study are reliable.
Discussion
The wound healing in patients with DFU is influenced by factors such as vascular abnormalities, neuropathy, and inflammation stasis, which obstruct the healing process (69). Additionally, the levels of GFs in the wound are low, further exacerbating the difficulty of healing (70). GFs play specific roles in regulating the healing process, and their positive effects on diabetic wound treatment have been well established (71). As a novel therapeutic approach, GFs are considered an effective means for treating DFU, although consensus has not yet been reached (6). Current studies mainly focus on comparing the efficacy of a single GF with SOC, leading to a lack of evidence regarding the head-to-head comparison of different GFs in terms of their effectiveness and safety in treating DFU. Therefore, the aim of our study is to evaluate the efficacy and safety of different GFs in treating DFU, providing more evidence-based medicine for the treatment of DFU.
To the best of our knowledge, this study is the first to comprehensively assess the efficacy and safety of different GFs in the treatment of DFU. Two previous network meta-analyses (11, 12) only reported healing rate as an outcome. To determine both efficacy and safety, we further evaluated healing time, ulcer area reduction, AEs, and amputation rate. The results of our primary outcome measures are consistent with those of the above-mentioned network meta-analyses, both showing that, compared to SOC, EGF, PDGF, and PRP significantly improved the healing rate of DFU. Among these, EGF may be the most effective GF for healing rate. Our study suggested that almost all GFs demonstrated superior performance to SOC in terms of healing rate, healing time, and ulcer area reduction, with EGF emerging as the most potentially effective GF. Except for VEGF, which significantly increased AEs, other GFs did not show a significant increase in AEs. PRP was associated with the lowest incidence of AEs and the lowest amputation rate. After excluding high-risk studies, we re-evaluated the healing rate and found no significant changes in the results, with the ranking of interventions remaining consistent, indicating that the primary outcome was robust and reliable. However, because of the limited number of studies reporting secondary outcomes, sensitivity analyses could not be performed, which restricts further validation of these results.
In terms of healing rate and healing time, EGF shows the greatest consistency across multiple RCTs (24, 29, 32, 38, 39, 44, 50, 51, 54, 56, 57), with its efficacy significantly outperforming SOC. EGF promotes the proliferation and migration of keratinocytes, enhances collagen synthesis, and accelerates the epithelialization process (72, 73). Compared to FGF, EGF has a significant advantage in healing rate, which may be related to the lower levels of EGF in diabetic foot tissue (74). The supplementation of exogenous EGF directly promotes wound healing and accelerates tissue repair by inhibiting non-enzymatic glycosylation through a feedback mechanism (49). On the other hand, FGF, as a competitive antagonist of advanced glycation end products, typically requires higher concentrations to improve wound healing and its effects appear more slowly, leading to a longer treatment cycle (75–77). Additionally, it is noteworthy that in our network meta-analysis, FGF’s healing rate ranking was lower than SOC. In the relevant RCT, FGF did not significantly improve the healing rate of DFU compared to SOC (19). Since the number of RCTs involving FGF is limited, this result still needs to be further verified through more multi-center, high-quality, and long-term follow-up RCTs.
PDGF significantly outperforms SOC in ulcer area reduction. During the wound healing process, PDGF plays a key role by promoting the proliferation and migration of inflammatory cells, aiding in debridement, and stimulating the formation of granulation tissue (78–80). Additionally, PDGF promotes angiogenesis and the differentiation of myofibroblasts, which accelerates the healing of diabetic wounds (81). Clinical trials have shown that PDGF significantly increases the healing speed of diabetic wounds and greatly enhances the probability of complete healing (7, 82–84).
PRP significantly outperforms SOC in terms of incidence of AEs and amputation rate. As an autologous treatment, PRP effectively avoids immune rejection and allergic reactions, reduces the risk of infection, and, owing to its excellent biocompatibility, typically does not cause severe side effects (85). In reducing the amputation rate, PRP accelerates wound healing, improves local blood supply, regulates inflammatory responses, and controls infections, successfully preventing the deterioration of DFU, reducing the occurrence of complications, and significantly lowering the amputation risk, thereby improving treatment outcomes and prognosis (86).
Despite the variety of GFs, the products currently entering clinical trials remain relatively limited (87). This study provides more evidence-based medical evidence for the treatment of DFU and further validates the application prospects of GFs in this field. Future research should focus on the impact of different doses of GFs on treatment outcomes and compare the efficacy and cost-effectiveness of different GFs. Additionally, the combined use of different GFs or GFs with other treatment modalities (such as stem cell transplantation and anti-inflammatory drugs) may offer more promising treatment options for DFU (69, 88). Therefore, conducting more clinical trials to evaluate the efficacy and feasibility of these combination therapies is crucial.
Our study also has certain limitations: (1) Network meta-analysis can be affected by confounding factors and cannot fully replace clinical trials that directly compare treatments. Therefore, the conclusions of this study still require further confirmation through direct comparisons of different GFs. (2) The included studies had varying patient ages, wound duration, and drug dosages, and because of the limited number of studies included, we were unable to perform in-depth subgroup analyses. Owing to the varying quality of the studies included, we were unable to conduct subgroup analyses based on the type of ulcer (neuropathic, vascular, or mixed) or the severity of the ulcers in patients with DFU. The reporting time for outcome measures in the included studies was inconsistent, and thus, we were unable to conduct analyses based on specific time points. These factors may compromise the accuracy of the results. For instance, patients in different age groups may respond differently to GF therapy, and the type and severity of ulcers can significantly influence treatment outcomes. Furthermore, variations in GF dosage may lead to differences in therapeutic efficacy. Consequently, the absence of subgroup analyses may obscure treatment effect differences across specific patient subgroups, thereby limiting a comprehensive evaluation of the intervention’s overall effectiveness. (3) Although SOC in the included studies was based on guideline recommendations, the specific types varied, which may have influenced the efficacy evaluation of different GFs.
In summary, almost all GFs outperformed SOC in terms of healing rate, healing time, and ulcer area reduction, with EGF appearing to be the most efficacious GF. Except for VEGF, which significantly increased the incidence of AEs, other GFs did not show significant effects on AEs, suggesting a favorable safety profile. Among them, PRP was associated with the lowest incidence of AEs and the lowest amputation rate. After excluding high-risk studies, the changes in healing rate were not significant, and the ranking of interventions remained consistent, supporting the robustness of the results. However, the limited availability of data for secondary outcomes restricted the ability to fully assess their reliability. Because of the limitations of the current study, the conclusions still require validation through a large number of high-quality RCTs that directly compare different GFs with SOC or compare different GFs in the treatment of DFU.
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
JT: Methodology, Data curation, Software, Writing – original draft, Writing – review & editing. GY: Methodology, Data curation, Writing – original draft, Writing – review & editing. TT: Methodology, Data curation, Writing – original draft, Writing – review & editing. XL: Methodology, Writing – original draft, Writing – review & editing. SL: Methodology, Writing – original draft, Writing – review & editing. CW: Methodology, Writing – original draft, Writing – review & editing. SZ: Conceptualization, Project administration, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
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.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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/fendo.2025.1614597/full#supplementary-material
References
1. Armstrong DG, Tan TW, Boulton A, and Bus SA. Diabetic foot ulcers: A review. JAMA. (2023) 330:62–75. doi: 10.1001/jama.2023.10578
2. Zhang Y, Lazzarini PA, McPhail SM, van Netten JJ, Armstrong DG, and Pacella RE. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016. Diabetes Care. (2020) 43:964–74. doi: 10.2337/dc19-1614
3. Ong KL, Stafford LK, McLaughlin SA, Boyko EJ, Vollset SE, Smith AE, et al. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. Lancet. (2023) 402:203–34. doi: 10.1016/S0140-6736(23)01301-6
4. Burgess JL, Wyant WA, Abdo AB, Kirsner RS, and Jozic I. Diabetic wound-healing science. Medicina (Kaunas). (2021) 57(10):1072. doi: 10.3390/medicina57101072
5. OuYang H, Yang J, Wan H, Huang J, and Yin Y. Effects of different treatment measures on the efficacy of diabetic foot ulcers: A network meta-analysis. Front Endocrinol (Lausanne). (2024) 15:1452192. doi: 10.3389/fendo.2024.1452192
6. Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, et al. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes. (2023) 14:364–95. doi: 10.4239/wjd.v14.i4.364
7. Zhao XH, Gu HF, Xu ZR, Zhang Q, Lv XY, Zheng XJ, et al. Efficacy of topical recombinant human platelet-derived growth factor for treatment of diabetic lower-extremity ulcers: Systematic review and meta-analysis. Metabolism. (2014) 63:1304–13. doi: 10.1016/j.metabol.2014.06.005
8. Yang Q, Zhang Y, Yin H, and Lu Y. Topical recombinant human epidermal growth factor for diabetic foot ulcers: A Meta-Analysis of randomized controlled clinical trials. Ann Vasc Surg. (2020) 62:442–51. doi: 10.1016/j.avsg.2019.05.041
9. Su YN, Li J, Feng DH, Lu RR, Dong GX, and Zhao DY. Efficacy and safety of autologous platelet-rich plasma for diabetic foot ulcers: A systematic review and meta-analysis. J Wound Care. (2023) 32:773–86. doi: 10.12968/jowc.2023.32.12.773
10. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Fitridge R, Game F, et al. Practical guidelines on the prevention and management of diabetes-related foot disease (IWGDF 2023 update). Diabetes Metab Res Rev. (2024) 40:e3657. doi: 10.1002/dmrr.3657
11. Sridharan K and Sivaramakrishnan G. Growth factors for diabetic foot ulcers: Mixed treatment comparison analysis of randomized clinical trials. Br J Clin Pharmacol. (2018) 84:434–44. doi: 10.1111/bcp.13470
12. Thanigaimani S, Jin H, Ahmad U, Anbalagan R, and Golledge J. Comparative efficacy of growth factor therapy in healing diabetes-related foot ulcers: A network meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. (2023) 39:e3670. doi: 10.1002/dmrr.3670
13. Moher D, Liberati A, Tetzlaff J, and Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ. (2009) 339:b2535. doi: 10.1136/bmj.b2535
14. Sterne J, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. (2019) 366:l4898. doi: 10.1136/bmj.l4898
15. Shim SR, Kim SJ, Lee J, and Rücker G. Network meta-analysis: Application and practice using R software. Epidemiol Health. (2019) 41:e2019013. doi: 10.4178/epih.e20190132
16. Agostinho NB, MaChado KS, and Werhli AV. Inference of regulatory networks with a convergence improved MCMC sampler. BMC Bioinf. (2015) 16:306. doi: 10.1186/s12859-015-0734-6
17. Watt J and Del GC. Network meta-analysis. Methods Mol Biol. (2022) 2345:187–201. doi: 10.1007/978-1-0716-1566-9_12
18. Steed DL, Goslen JB, Holloway GA, Malone JM, Bunt TJ, and Webster MW. Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabetes Care. (1992) 15:1598–604. doi: 10.2337/diacare.15.11.1598
19. Richard JL, Parer-Richard C, Daures JP, Clouet S, Vannereau D, Bringer J, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study. Diabetes Care. (1995) 18:64–9. doi: 10.2337/diacare.18.1.64
20. Wieman TJ. Clinical efficacy of becaplermin (rhPDGF-BB) gel. Becaplermin Gel Studies Group. Am J Surg. (1998) 176:74S–9S. doi: 10.1016/s0002-9610(98)00185-8
21. Wieman TJ, Smiell JM, and Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care. (1998) 21:822–7. doi: 10.2337/diacare.21.5.822
22. Yönem A, Cakir B, Güler S, Azal OO, and Corakçi A. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Diabetes Obes Metab. (2001) 3:332–7. doi: 10.1046/j.1463-1326.2001.00142.x
23. de Lalla F, Pellizzer G, Strazzabosco M, Martini Z, Du Jardin G, Lora L, et al. Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Antimicrob Agents Chemother. (2001) 45:1094–8. doi: 10.1128/AAC.45.4.1094-1098.2001
24. Tsang MW, Wong WK, Hung CS, Lai KM, Tang W, Cheung EY, et al. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care. (2003) 26:1856–61. doi: 10.2337/diacare.26.6.1856
25. Kästenbauer T, Hörnlein B, Sokol G, and Irsigler K. Evaluation of granulocyte-colony stimulating factor (Filgrastim) in infected diabetic foot ulcers. Diabetologia. (2003) 46:27–30. doi: 10.1007/s00125-002-0998-z
26. Saldalamacchia G, Lapice E, Cuomo V, De Feo E, D’Agostino E, Rivellese AA, et al. A controlled study of the use of autologous platelet gel for the treatment of diabetic foot ulcers. Nutr Metab Cardiovasc Dis. (2004) 14:395–6. doi: 10.1016/s0939-4753(04)80029-2
27. Huang P, Li S, Han M, Xiao Z, Yang R, and Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. (2005) 28:2155–60. doi: 10.2337/diacare.28.9.2155
28. Robson M, Payne W, Garner W, Biundo J, and Ouyang SP. Integrating the results of phase IV (Postmarketing) clinical trial with four previous trials reinforces the position that regranex (Becaplermin) gel 0.01% is an EffectiveAdjunct to the treatment of diabetic foot ulcers. ournal Appl Res. (2005) 5(1):35–45.
29. Afshari M, Larijani B, Fadayee M, Ghahary A, Pajouhi M, Bastanhagh M, et al. Efficacy of topical epidermal growth factor in healing diabetic foot ulcers. Therapy. (2005) 2:759–65. doi: 10.1586/14750708.2.5.759
30. Driver VR, Hanft J, Fylling CP, and Beriou JM. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. (2006) 52:68–70, 72, 74.
31. Hanft JR, Pollak RA, Barbul A, van Gils C, Kwon PS, Gray SM, et al. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. J Wound Care. (2008) 17:30–2,34-7. doi: 10.12968/jowc.2008.17.1.27917
32. Fernández-Montequín JI, Valenzuela-Silva CM, Díaz OG, Savigne W, Sancho-Soutelo N, Rivero-Fernández F, et al. Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers: Multicenter, randomised, placebo-controlled, double-blind study. Int Wound J. (2009) 6:432–43. doi: 10.1111/j.1742-481X.2009.00641.x
33. Bhansali A, Venkatesh S, Dutta P, Dhillon MS, Das S, and Agrawal A. Which is the better option: Recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized contact cast? Diabetes Res Clin Pract. (2009) 83:e13–6. doi: 10.1016/j.diabres.2008.10.005
34. Agrawal R, Jhajharia A, Mohta N, Dogra R, Chaudhari V, and Nayak KC. Use of a platelet-derived growth factor gel in chronic diabetic foot ulcers. Diabetic Foot J. (2009) 12:80–8.
35. Landsman A, Agnew P, Parish L, Joseph R, and Galiano RD. Diabetic foot ulcers treated with becaplermin and TheraGauze, a moisture-controlling smart dressing: A randomized, multicenter, prospective analysis. J Am Podiatr Med Assoc. (2010) 100:155–60. doi: 10.7547/1000155
36. Jaiswal SS, Gambhir RP, Agrawal A, and Harish S. Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers. Indian J Surg. (2010) 72:27–31. doi: 10.1007/s12262-010-0005-8
37. Khandelwal S, Chaudhary P, Poddar DD, Saxena N, Singh RA, and Biswal UC. Comparative study of different treatment options of grade III and IV diabetic foot ulcers to reduce the incidence of amputations. Clin Pract. (2013) 3:e9. doi: 10.4081/cp.2013.e9
38. Singla S, Garg R, Kumar A, and Gill C. Efficacy of topical application of beta urogastrone (recombinant human epidermal growth factor) in Wagner’s Grade 1 and 2 diabetic foot ulcers: Comparative analysis of 50 patients. J Nat Sci Biol Med. (2014) 5:273–7. doi: 10.4103/0976-9668.136160
39. Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, Fabian-Victoriano MR, Kresch-Tronik NS, et al. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: A randomized double-blinded controlled trial. Wound Repair Regen. (2014) 22:497–503. doi: 10.1111/wrr.12187
40. Ma C, Hernandez MA, Kirkpatrick VE, Liang LJ, Nouvong AL, and Gordon II. Topical platelet-derived growth factor vs placebo therapy of diabetic foot ulcers offloaded with windowed casts: A randomized, controlled trial. Wounds. (2015) 27:83–91.
41. Li L, Chen D, Wang C, Yuan N, Wang Y, He L, et al. Autologous platelet-rich gel for treatment of diabetic chronic refractory cutaneous ulcers: A prospective, randomized clinical trial. Wound Repair Regen. (2015) 23:495–505. doi: 10.1111/wrr.12294
42. Liu G, Deng X, Sun Y, Wang M, Gao J, and Gou J. Effect of autologous platelet-rich gel on the treatment of diabetic foot ulcer. J Xi’ an Jiao tong Univ (Medical Sciences). (2016) 37:264–7. doi: 10.7652/jdyxb201602024
43. Karimi R, Afshar M, Salimian M, Sharif A, and Hidariyan M. The effect of platelet rich plasma dressing on healing diabetic foot ulcers. Nurs Midwifery Stud. (2016) 5(3):e30314. doi: 10.17795/nmsjournal30314.
44. Antony SR. Efficacy of recombinant epidermal growth factor in the healing process of diabetic ulcer. J Evol Med Dental Sci. (2016) 5(31):1642–8. doi: 10.14260/jemds/2016/387
45. Samuel A, Mahajan A, Mam M, and Prakash J. Platelet derived growth factor in diabetic lower extremity ulcer: A randomized, double blind, placebo controlled study in Indian condition. Int J Pharm Sci Res. (2016) 7:3887–92. doi: 10.13040/IJPSR.0975-8232.7(9).3887-92
46. Ahmed M, Reffat SA, Hassan A, and Eskander F. Platelet-Rich plasma for the treatment of clean diabetic foot ulcers. Ann Vasc Surg. (2017) 38:206–11. doi: 10.1016/j.avsg.2016.04.023
47. Yang L, Gao L, Lv Y, and Wang J. Autologous platelet-rich gel for lower-extremity ischemic ulcers in patients with type 2 diabetes. Int J Clin Exp Med. (2017) 10:13796–801.
48. Singh SP, Kumar V, Pandey A, Pandey P, Gupta V, and Verma R. Role of platelet-rich plasma in healing diabetic foot ulcers: A prospective study. J Wound Care. (2018) 27:550–6. doi: 10.12968/jowc.2018.27.9.550
49. Xu J, Min D, Guo G, Liao X, and Fu Z. Experimental study of epidermal growth factor and acidic fibroblast growth factor in the treatment of diabetic foot wounds. Exp Ther Med. (2018) 15:5365–70. doi: 10.3892/etm.2018.6131
50. Park KH, Han SH, Hong JP, Han SK, Lee DH, Kim BS, et al. Topical epidermal growth factor spray for the treatment of chronic diabetic foot ulcers: A phase III multicenter, double-blind, randomized, placebo-controlled trial. Diabetes Res Clin Pract. (2018) 142:335–44. doi: 10.1016/j.diabres.2018.06.002
51. David TD. The role of epidermal growth factor cream in healing of diabetic foot ulcer- comparative analytical study in south India. Int J Health Sci Res. (2018) 6:1–6. Available online at: https://www.ijhsr.org/IJHSR_Vol.8_Issue.6_June2018/IJHSR_Abstract.01.html (Accessed April 02, 2025).
52. Rainys D, Cepas A, Dambrauskaite K, Nedzelskiene I, and Rimdeika R. Effectiveness of autologous platelet-rich plasma gel in the treatment of hard-to-heal leg ulcers: A randomised control trial. J Wound Care. (2019) 28:658–67. doi: 10.12968/jowc.2019.28.10.658
53. Gude W, Hagan D, Abood F, and Clausen P. Aurix gel is an effective intervention for chronic diabetic foot ulcers: A pragmatic randomized controlled trial. Adv Skin Wound Care. (2019) 32:416–26. doi: 10.1097/01.ASW.0000577140.19174.9e
54. Viswanathan V, Juttada U, and Babu M. Efficacy of recombinant human epidermal growth factor (Regen-D 150) in healing diabetic foot ulcers: A Hospital-Based randomized controlled trial. Int J Low Extrem Wounds. (2020) 19:158–64. doi: 10.1177/1534734619892791
55. Elsaid A, El-Said M, Emile S, Youssef M, Khafagy W, and Elshobaky A. Randomized controlled trial on autologous Platelet-Rich plasma versus saline dressing in treatment of non-healing diabetic foot ulcers. World J Surg. (2020) 44:1294–301. doi: 10.1007/s00268-019-05316-0
56. Xie J, Fang Y, Zhao Y, Cao D, and Lv Y. Autologous Platelet-Rich gel for the treatment of diabetic sinus tract wounds: A clinical study. J Surg Res. (2020) 247:271–9. doi: 10.1016/j.jss.2019.09.069
57. Oliveira BC, de Oliveira B, Deutsch G, Pessanha FS, and de Castilho SR. Effectiveness of a synthetic human recombinant epidermal growth factor in diabetic patients wound healing: Pilot, double-blind, randomized clinical controlled trial. Wound Repair Regen. (2021) 29:920–6. doi: 10.1111/wrr.12969
58. Malekpour AN, Shafiee A, Mirmohseni A, and Besharat S. Evaluation of the efficacy of platelet-rich plasma on healing of clean diabetic foot ulcers: A randomized clinical trial in Tehran, Iran. Diabetes Metab Syndr. (2021) 15:621–6. doi: 10.1016/j.dsx.2021.03.005
59. Habeeb T. Platelet-Rich plasma (PRP) Bio-Stimulant gel dressing in treating chronic non- healing leg and foot ulcers; Cost and effectiveness. Randomized controlled clinical trial. Surg Chron. (2021) 25(3)210–6.
60. Gupta A, Channaveera C, Sethi S, Ranga S, and Anand V. Efficacy of intralesional Platelet-Rich plasma in diabetic foot ulcer. J Am Podiatr Med Assoc. (2021) 111(3). doi: 10.7547/19-149
61. Hossam EM, Alserr A, Antonopoulos CN, Zaki A, and Eldaly W. Autologous platelet rich plasma promotes the healing of Non-Ischemic diabetic foot ulcers. A randomized controlled trial. Ann Vasc Surg. (2022) 82:165–71. doi: 10.1016/j.avsg.2021.10.061
62. Mandadap S. Convectional Dressing versus Platelet Rich Plasma in the Management of Diabetic Foot Ulcers - a Prospective Comparative Study. Int J Pharm Clin Res. (2022) 11:325–30. Available online at: https://ijpcr.com/volume14issue11/ (Accessed April 02, 2025).
63. Zhao P, Zhou G, Jiang J, Li H, and Xiang X. Platelet-rich plasma (PRP) in the treatment of diabetic foot ulcers and its regulation of autophagy. Int J Low Extrem Wounds. (2023), 2143394665. doi: 10.1177/15347346221144937
64. Satapathy A, Jena SR, Das AK, George JJ, and Panda A. Efficacy of autologous platelet rich plasma in treatment of diabetic foot ulcers- a prospective study. J Cardiovasc Dis Res. (2023) 14:1203–12. doi: 10.31838/jcdr.2023.14.04.146
65. Kamineni R and Tupkar G. Efficacy of platelet rich plasma dressing versus normal saline dressing in the management of diabetic foot ulcers. Int J Pharm Clin Res. (2023) 15:237–42.
66. Abhirami C, Vignesh KA, and Sivasubramanian V. Assessing the effect of platelet rich plasma(prp) among patients with chronic diabetic foot ulcers attending dermatology opd from a private medical institute in kancheepuram district, tamilnadu. Eur J Mol Clin Med. (2023) 10:2630–43.
67. Mohammadi TA and Tajik M. Comparing the standard surgical dressing with dehydrated amnion and platelet-derived growth factor dressings in the healing rate of diabetic foot ulcer: A randomized clinical trial. Diabetes Res Clin Pract. (2022) 185:109775. doi: 10.1016/j.diabres.2022.109775
68. Gowsick S, Balaji D, Arul, Unnikrishnan ES, and Manish R. Comparison of the efficacy of autologous Platelet-Rich plasma and saline dressing in healing of diabetic foot ulcer- a randomised control study. J Clin Diagn Res. (2023) 17:C17–22. doi: 10.7860/JCDR/2023/60861.17987
69. Mohsin F, Javaid S, Tariq M, and Mustafa M. Molecular immunological mechanisms of impaired wound healing in diabetic foot ulcers (DFU), current therapeutic strategies and future directions. Int Immunopharmacol. (2024) 139:112713. doi: 10.1016/j.intimp.2024.112713
70. Zubair M and Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord. (2019) 20:207–17. doi: 10.1007/s11154-019-09492-1
71. Legrand J and Martino MM. Growth factor and cytokine delivery systems for wound healing. Cold Spring Harb Perspect Biol. (2022) 14(8):a041234. doi: 10.1101/cshperspect.a041234
72. Berry-Kilgour C, Cabral J, and Wise L. Advancements in the delivery of growth factors and cytokines for the treatment of cutaneous wound indications. Adv Wound Care (New Rochelle). (2021) 10:596–622. doi: 10.1089/wound.2020.1183
73. Shin SH, Koh YG, Lee WG, Seok J, and Park KY. The use of epidermal growth factor in dermatological practice. Int Wound J. (2023) 20:2414–23. doi: 10.1111/iwj.14075
74. Qi M, Zhou Q, Zeng W, Wu L, Zhao S, Chen W, et al. Growth factors in the pathogenesis of diabetic foot ulcers. Front Biosci (Landmark Ed). (2018) 23:310–7. doi: 10.2741/4593
75. Pepper MS, Ferrara N, Orci L, and Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. (1992) 189:824–31. doi: 10.1016/0006-291x(92)92277-5
76. Chen RR and Mooney DJ. Polymeric growth factor delivery strategies for tissue engineering. Pharm Res. (2003) 20:1103–12. doi: 10.1023/a:1025034925152
77. Zhu XH, Wang CH, and Tong YW. In vitro characterization of hepatocyte growth factor release from PHBV/PLGA microsphere scaffold. J BioMed Mater Res a. (2009) 89:411–23. doi: 10.1002/jbm.a.31978
78. Heldin CH and Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. (1999) 79:1283–316. doi: 10.1152/physrev.1999.79.4.1283
79. Pontén A, Folestad EB, Pietras K, and Eriksson U. Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ Res. (2005) 97:1036–45. doi: 10.1161/01.RES.0000190590.31545.d4
80. Folestad E, Kunath A, and Wågsäter D. PDGF-C and PDGF-D signaling in vascular diseases and animal models. Mol Aspects Med. (2018) 62:1–11. doi: 10.1016/j.mam.2018.01.005
81. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. (2014) 31:722–33. doi: 10.1016/j.devcel.2014.11.012
82. Tokatlian T, Cam C, and Segura T. Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model. Adv Healthc Mater. (2015) 4:1084–91. doi: 10.1002/adhm.201400783
83. Chereddy KK, Lopes A, Koussoroplis S, Payen V, Moia C, Zhu H, et al. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine-Uk. (2015) 11:1975–84. doi: 10.1016/j.nano.2015.07.006
84. Almquist BD, Castleberry SA, Sun JB, Lu AY, and Hammond PT. Combination growth factor therapy via electrostatically assembled wound dressings improves diabetic ulcer healing in vivo. Adv Healthc Mater. (2015) 4:2090–9. doi: 10.1002/adhm.201500403
85. Smith J and Rai V. Platelet-Rich plasma in diabetic foot ulcer healing: Contemplating the facts. Int J Mol Sci. (2024) 25(23):12864. doi: 10.3390/ijms252312864
86. Oneto P and Etulain J. PRP in wound healing applications. Platelets. (2021) 32:189–99. doi: 10.1080/09537104.2020.1849605
87. Ganesan O and Orgill DP. An overview of recent clinical trials for diabetic foot ulcer therapies. J Clin Med. (2024) 13(24):7655. doi: 10.3390/jcm13247655
Keywords: diabetic foot ulcer, growth factors, standard of care, randomized controlled trial, network meta-analysis
Citation: Tian J, Yao G, Tian T, Li X, Li S, Wu C and Zhang S (2025) Comparison of the efficacy and safety of different growth factors in the treatment of diabetic foot ulcers: an updated network meta-analysis. Front. Endocrinol. 16:1614597. doi: 10.3389/fendo.2025.1614597
Received: 19 April 2025; Accepted: 06 June 2025;
Published: 25 June 2025.
Edited by:
Vinod Kumar Yata, Malla Reddy University, IndiaReviewed by:
Anjaneyulu Musini, Jawaharlal Nehru Technological University, Hyderabad, IndiaAnanda Kumar Chettupalli, Galgotias University, India
Copyright © 2025 Tian, Yao, Tian, Li, Li, Wu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Saisheng Zhang, MjI3ODkwNjdAcXEuY29t
†These authors have contributed equally to this work