Why Diabetic Foot Ulcers Are Difficult to Heal
Diabetic foot ulcers are serious wounds that can develop in people with diabetes. These ulcers often form because diabetes can affect circulation, nerve function, immune response, and the body’s natural ability to repair tissue.
For many patients, diabetic foot ulcers are difficult to heal and may remain open for weeks or months. When wounds become chronic, they can increase the risk of infection, hospitalization, and more serious complications.
Standard treatment usually includes wound cleaning, debridement, infection control, pressure offloading, dressings, and improving blood flow when needed. These steps are important, but some wounds still do not heal fully. Because of this, researchers are studying regenerative approaches that may help support the body’s healing environment.
A Cell-Free Approach Using hUC-MSC Derivatives
Human umbilical cord mesenchymal stromal cells, or hUC-MSCs, are studied in regenerative medicine because they release signals that may influence inflammation, blood vessel growth, immune activity, and tissue repair.
In this study, researchers did not use whole stem cells directly. Instead, they studied hUC-MSC derivatives, often shortened to hUC-MSCD. These derivatives include the beneficial substances released by umbilical cord MSCs, such as conditioned media, extracellular vesicles, and exosomes.
This type of approach is sometimes described as cell-free because it focuses on the signals released by the cells rather than using the living cells themselves.
For chronic wounds, hUC-MSC derivatives may be helpful because they may support several important parts of healing, including:
- Reducing excessive inflammation
- Supporting new blood vessel formation
- Encouraging skin cell movement and repair
- Helping rebuild the wound’s structural matrix
- Creating a more repair-supportive wound environment
Inside the Phase I/II Clinical Trial
This phase I/II clinical trial evaluated the safety and potential effectiveness of hUC-MSC derivatives in patients with chronic diabetic foot ulcers that had not responded well to standard care.
The study included 10 adults with type 2 diabetes and chronic diabetic foot ulcers. The ulcers were classified as Texas Grade II–III, meaning they were more advanced wounds that required careful treatment.
Participants received perilesional injections of allogeneic hUC-MSC derivatives. “Perilesional” means the injections were given around the edges of the wound, allowing the treatment to be delivered near the damaged tissue.
Patients received weekly injections for up to 10 treatment sessions. Researchers monitored the patients for safety, wound closure, healing time, and recurrence over a 24-month follow-up period.
What Researchers Observed
The results were encouraging for this early-stage study. The treatment was well tolerated, and the researchers reported no significant adverse events related to the therapy. This was important because safety was one of the main goals of the phase I/II trial.
The study also reported strong wound-healing results. All 10 patients achieved complete ulcer closure, with an average healing time of 4.2 weeks. The researchers also found that no ulcer recurrence was documented during the 24-month follow-up period.
In addition, the study reported no amputations, deaths, re-hospitalizations, or cardiovascular events during follow-up. While the number of patients was small, these results provide encouraging early evidence that hUC-MSC derivatives may be a promising area of study for chronic diabetic foot ulcers.
The Biology Behind the Healing Response
Chronic diabetic foot ulcers can become “stuck” in an inflammatory phase, making it harder for the wound to move into the later stages of repair. Healthy wound healing requires a coordinated process involving inflammation control, new blood vessel formation, skin cell migration, collagen production, and tissue remodeling.
The hUC-MSC derivatives used in this study contained a mixture of biologically active components released by umbilical cord MSCs. These included growth factors, cytokines, extracellular vesicles, and exosomes.
The researchers highlighted several important signaling molecules that may help explain the wound-healing effects:
- EGF, or epidermal growth factor, which can support skin cell growth and movement
- CXCL12/SDF-1, which is involved in blood vessel formation and cell recruitment
- TGF-β1, which plays a role in inflammation regulation, collagen production, and tissue remodeling
Together, these signals may help create a wound environment that is more supportive of repair. Instead of focusing on one single pathway, hUC-MSC derivatives may influence several healing processes at the same time.
Why These Findings Are Noteworthy
This study is meaningful because diabetic foot ulcers remain one of the most challenging complications of diabetes. Even with careful standard care, some wounds do not heal completely or may return after healing.
The study also highlights the growing interest in cell-free regenerative medicine. By using derivatives released by hUC-MSCs, researchers may be able to study the therapeutic signaling effects of MSCs without relying on direct stem cell transplantation.
This may offer practical advantages in the future, including easier storage, more standardized preparation, and a ready-to-use biologic product. For wound care, this could be especially important because chronic wounds often require consistent and targeted support over time.
What Still Needs to Be Studied
Although the results are promising, this was a small, open-label study with only 10 patients. Because there was no placebo or comparison group, the findings should be interpreted as early clinical evidence rather than final proof of effectiveness.
The researchers noted that larger randomized, double-blind, placebo-controlled trials are needed to confirm the results. Future studies should also help determine ideal dosing, treatment frequency, long-term safety, and which types of diabetic foot ulcers may respond best.
Additional research may also help clarify how much each part of the hUC-MSC derivative mixture, including conditioned media, extracellular vesicles, and exosomes, contributes to wound healing.
Takeaway
This phase I/II study provides encouraging early evidence that human umbilical cord MSC derivatives may support healing in chronic diabetic foot ulcers. In this small clinical trial, perilesional injections were well tolerated and were associated with complete wound closure in all participants, with no documented recurrence during 24 months of follow-up.
While larger controlled studies are still needed, the findings highlight the potential of hUC-MSC derivatives as a cell-free regenerative approach for chronic wound healing. By supporting inflammation balance, blood vessel formation, skin repair, and tissue remodeling, this research points to a promising direction for future diabetic foot ulcer care.
Source
Jafar H, Almousa R, Alhawari H, Shahin D, Al Soudi M, Abusharieh E, Aboalhaija NH, Awidi A. Human umbilical cord mesenchymal stromal cells derivatives in treating diabetic foot ulcers: a phase I/II safety and efficacy trial. Stem Cell Research & Therapy. 2025 Nov 24;16(1):657. doi: 10.1186/s13287-025-04736-1. PMID: 41287013; PMCID: PMC12642072. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12642072/
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