Description

Globally, it is estimated that every 20 seconds, a lower limb is lost due to diabetic foot ulcers (DFUs). This devastating complication threatens not only physical health but also profoundly affects psychological well-being, often leading to depression. Patients frequently experience prolonged hospitalizations, recurrent infections, costly interventions, and lasting functional limitations, all of which severely diminish quality of life. Each year, approximately 18.6 million people are affected by DFUs, and about half of these patients develop wound infections. Among those who experience infections, up to 20% will require amputation, and of those, up to 70% may die within five years. The burden extends beyond the individual: DFUs impose a significant economic strain on healthcare systems and families alike. As the global diabetes population grows, from 589 million in 2024 to an estimated 853 million in 2050, the number of individuals at risk for DFUs will continue to rise.

Diabetic foot ulcers are one of the most severe and debilitating complications of diabetes. Epidemiological studies indicate that approximately one-third of people with diabetes will develop DFUs in their lifetime. These ulcers arise from a complex interplay of factors, including peripheral neuropathy, vasculopathy, and chronic metabolic stress associated with long-standing hyperglycemia. Together, these factors impair skin integrity, reduce protective sensation, predispose the foot to deformities, and establish a chronic inflammatory state that hinders normal wound repair.

To tackle DFUs effectively, our project, AGEs ROBBER, adopts a dual approach: treatment, focusing on existing wounds, and prevention, targeting at-risk patients before ulcers develop. Our ultimate goal is to redefine the global standard for DFU management, transforming it from a cycle of delayed treatment and amputation into a future centered on early intervention, tissue regeneration, and sustained well-being. Through this dual-pillar strategy, we aim to provide effective healing for today’s patients while simultaneously offering protection for tomorrow’s high-risk populations.

Unfortunately, current therapies for DFUs largely fail to address the biochemical root causes of impaired healing. Antibacterial dressings can reduce infection risk but do not resolve persistent inflammation. Absorbent dressings help control exudate but offer minimal regenerative support. Growth factor or collagen-based products may accelerate healing, but they often degrade rapidly in the harsh wound environment, leaving wounds inflamed and slow to heal. Moreover, most treatments are inconvenient, require frequent changes, and fail to integrate multiple therapeutic functions, limiting their overall efficacy.

Through our research, we identified Advanced Glycation End-products (AGEs) as a central culprit behind impaired healing in diabetes. AGEs are harmful molecules formed when sugars attach to proteins through the Maillard reaction.

In diabetic patients, prolonged hyperglycemia accelerates this process, leading to excessive accumulation of AGEs in tissues and blood vessels. These molecules bind to a receptor called RAGE on cell surfaces, triggering inflammatory cascades, particularly through NF-κB, a transcription factor that activates pro-inflammatory genes. The resulting chronic cycle of inflammation, oxidative stress, and tissue damage creates a toxic wound microenvironment that significantly slows, or even halts, healing.

The body does possess a natural defense: soluble RAGE (sRAGE), which acts as a “decoy receptor” to neutralize AGEs and prevent excessive RAGE activation. However, in DFU patients, endogenous sRAGE levels are insufficient to counteract the overwhelming AGE accumulation. This insight led to a critical question: what if we could deliver a concentrated dose of sRAGE directly into the wound, precisely where it is needed most?

To address the biochemical and structural challenges of DFUs, we developed a novel hydrogel patch that delivers engineered sRAGE directly to the wound site. This patch is designed to block AGE-RAGE interactions, thereby reducing chronic inflammation. Its composition combines collagen and chitosan: collagen provides a scaffold that promotes tissue regeneration, while chitosan absorbs exudate and lowers the risk of infection. The hydrogel incorporates a modular system, using Npu DnaE split intein technology to couple sRAGE with a cellulose-binding domain (CBD), ensuring the therapeutic protein remains stable on the patch and can be replaced or upgraded as needed. This multifunctional design simultaneously addresses inflammation, tissue repair, and infection control, providing an integrated solution for complex diabetic wounds.

While treatment is critical, proactive prevention is equally essential. Many diabetic patients suffer from neuropathy and poor circulation, meaning minor injuries often go unnoticed until they develop into severe ulcers. Our project includes a non-invasive foot-imaging device that enables regular monitoring, allowing both patients and clinicians to detect micro-injuries early. By equipping patients with real-time information, the device empowers them to take timely preventive actions, reducing the likelihood of ulcers progressing to advanced stages.

Beyond technical interventions, public health engagement is a cornerstone of our project. By collaborating with clinicians, patients, and community organizations, we promote awareness of DFU symptoms, the importance of foot care, and practical preventive practices. Encouraging a culture of proactive self-care can help reduce both the incidence and severity of DFUs worldwide.

Through this integrated approach, combining therapeutic innovation with preventive technology and public health engagement, we aim to offer DFU patients not just improved healing outcomes, but a brighter, healthier future.