According to a report from the World Health Organization, an estimated 422 million adults were living with DM in 2016 [22]. In the United States, 9.3% of the population has diabetes [23]. In China, 11.6% of adults are diabetic, making China’s prevalence rate of DM the highest in the world [24]. The prevalence of diabetes is increasing rapidly; the prevalence among adults was high at 14.3% in the United States [25]. DFU is a major complication of DM, occurring in 15% of those with diabetes and preceding 84% of all diabetes-related lower leg amputations [4]. In the United States, DFUs represent a substantial cost burden among Medicare beneficiaries with diabetes, suggesting a 1-year cost of US$9–13 billion, in addition to the costs associated with the disease itself [26].

We present here the results of a systematic review and meta-analysis of RCTs complete with figures and a table (all original work from our team) where autologous stem cell treatment was administered to patients with DFUs. Our analysis suggests that stem cell treatment is safe and significantly helps diabetic ulcer healing, without any increased risk of treatment-related adverse events. To our knowledge, our study is the first meta-analysis evaluating the use of autologous stem cells as an effective treatment strategy for DFUs. The stem cell treatment was not associated with any increased risk of adverse events.

The prevalence of leg ulcers in the general population is 0.12%, but this rises to 1.2% in the population over 70 years of age. Two-thirds of pressure ulcers occur in patients who are over 70 years of age [27, 28]. Older adults with diabetes have significantly higher rates of major lower extremity amputation [29]. Considering the increasingly worsening general conditions and higher risks of traditional therapy, some older diabetic patients have a more immediate need for receiving stem cell treatment. However, advancing age negatively impacts stem cell function, and such age-related alterations may be detrimental for successful stem cell therapy [30, 31]. Duscher et al. [32] found that age-related changes in the mesenchymal stem cell population dynamics result in an impaired therapeutic potential of the aged progenitor cell. For older DFU patients, the efficacy of autologous stem cell transplantation is a clinical topic deserving attention. Our subgroup analysis suggests that stem cell treatment can effectively improve ulcer healing in diabetic patients < 70 years of age, as well as those ≥ 70 years of age. There are several possible reasons for this. First, biological functions of stem cells derived from an aged donor may be inferior to those derived from a younger donor, but both can enhance wound healing, especially in the hostile diabetic wound environment where many complicated factors may offset the difference in cells derived from aged and young donors. Second, only two research studies were included in our RCT subgroup of patients ≥ 70 years of age, where the mean ages were 70.9 years and 71.1 years. Given that both studies had a mean age close to the age endpoint of 70 years, this may have interfered with the accuracy of the RCT study results. Jiang et al. evaluated the effects of autologous stem cells on lower extremity ulcers and found autologous stem cell-based therapy was associated with better healing of lower extremity ulcers [33]; however, this study focused on patients with lower extremity ulcers that included diabetic patients and the non-diabetic population. Considering diabetes foot ulcers have specificity and distinctive risk factors, DFU patients should be seen as an independent observational target. Sun et al. conducted a meta-analysis concluding that applying autologous stem cell transplantation for curing limb ischemia does not show any obvious improvement in the limb ischemia, but that it can dramatically reduce the rate of amputation [34]. This meta-analysis has two shortages: one is that this study only assessed limb ischemia and did not discuss DFU; another is that this is an early study, published in 2015, where all the enrolled articles were published before 2012. As new studies on stem cells have been published more recently, the meta-analysis should be updated to give physicians more up-to-date information and conclusions. To our knowledge, our study is the first meta-analysis on the associations of diabetic foot ulcer treatment with autologous stem cells.

Ulcer size may have a negative effect on the healing of DFUs [1, 15]. The results of Skardal et al. [35] suggest that stem cells could be an effective treatment for large-scale wounds. In our analysis of the ulcer size subgroup, stem cell therapy had similar beneficial effects on the healing of both large and small ulcers (≥ 5 cm2 or < 5 cm2). This suggests that stem cell therapy may reduce the size of larger ulcers as well. Large diabetic cutaneous lesions typically have a poor blood supply, more serious tissue necrosis, inflammation, and bacterial contamination. The significant advantages of the application of regenerative therapies based on stem cells would be apt for this type of unfavorable environment [36]. As well as wound size, the wound depth, infection, and ischemia are also critical factors influencing wound healing [37]. Due to the limitations in article content, these parameters were not analyzed in our study.

The current study has several limitations. First, stem cell sources, the number of delivered cells, and the routes of cell administration differed among the studies. Due to these significant heterogeneities, optimized procedure protocols were not determined. Second, only the funnel plot was used to qualitatively assess publication bias, with no further examination by other methods such as Egger’s regression. Third, the claim about the older subgroup is not fully justified since the selected studies were performed on patients aged 63, 65, 67, 69, and 71 years. There is no remarkable difference between these ages. Looking forwards, we need to include more studies conducted on patients with a wider age range. Fourth, the RCTs were small in scale and size, and evidence from larger samples and more rigorous RCTs are required.