Anyone involved in diabetic foot care is well acquainted with the experience of facing a wound that simply refuses to heal. This is not merely a clinical metaphor: it is an accurate description of what occurs at the molecular level when a diabetic ulcer ceases to follow the physiological trajectory of tissue repair and instead stabilizes in a state of persistent inflammation, refractory to any attempt at closure. Epidemiological estimates indicate that the lifetime risk of developing a diabetic foot ulcer is approximately 25% among individuals with diabetes, and a substantial proportion of these cases ultimately progress to amputation. The associated five-year mortality has, in some reports, been compared in severity to that of certain malignancies. Within this context, silk fibroin has progressively emerged as one of the most promising biomaterial platforms, not simply for promoting "wound healing" in general, but specifically for targeting the mechanisms that keep diabetic ulcers locked in the inflammatory phase.
Why diabetic wounds fail to follow the normal healing process
Physiological skin repair proceeds through a sequence of overlapping stages: hemostasis, inflammation, proliferation, and remodeling. In patients with diabetes, this process almost invariably stalls during the transition from the inflammatory to the proliferative phase. Chronic hyperglycemia disrupts the function of neutrophils and macrophages, driving the latter to remain trapped in a pro-inflammatory M1 phenotype instead of switching to the pro-reparative M2 phenotype that normally predominates after the first few days. The result is a wound microenvironment saturated with inflammatory cytokines such as TNF-α and IL-1β, accompanied by persistently elevated levels of matrix metalloproteinases, particularly MMP-9. These enzymes degrade not only damaged tissue but also the newly formed extracellular matrix and the growth factors required for cell proliferation. This pathological environment is further compounded by peripheral neuropathy, which eliminates protective pain sensation and promotes repetitive microtrauma; vascular disease, which limits the delivery of oxygen and nutrients essential for tissue regeneration; and a markedly increased susceptibility to bacterial colonization and biofilm formation. In many chronic ulcers, biofilm represents a more important driver of impaired healing than the metabolic disturbance itself. Consequently, any biomaterial intended as a realistic therapeutic solution for diabetic wounds must address several challenges simultaneously: modulating inflammation, protecting and supporting the extracellular matrix, maintaining a controlled moist environment, and, in most cases, actively reducing the microbial burden.
The properties of fibroin that directly target these pathological mechanisms
This is where fibroin comes into play with a set of properties that appears ideally suited to the specific requirements of diabetic wounds. Its β-sheet structure, which is responsible for the protein's mechanical strength and structural stability, enables fibroin-based dressings to maintain their integrity even in a highly exudative, protease-rich wound environment. This is far from a trivial advantage, considering how rapidly other protein-based matrices—such as non-crosslinked collagen—are degraded by the matrix metalloproteinases that are overexpressed in chronic ulcers. By contrast, fibroin possesses an intrinsic resistance to enzymatic degradation, allowing it to function as a durable temporary scaffold that supports cell migration long enough for the healing process to resume.
Another important characteristic is its tunable exudate absorption capacity, which can be adjusted by modifying the porosity of the matrix. This makes it possible to regulate the hydration level at the wound–dressing interface, maintaining it within the range considered optimal for keratinocyte migration while avoiding both excessive moisture, which leads to maceration, and dehydration, which impairs re-epithelialization.
From an immunomodulatory perspective, several preclinical studies have shown that fibroin promotes the phenotypic switch of macrophages toward the M2 reparative profile, thereby directly facilitating the transition from inflammation to proliferation that fails to occur spontaneously in diabetic wounds. This is not a secondary effect but rather one of the most significant therapeutic mechanisms attributed to fibroin in the treatment of chronic lesions.
Direct support for fibroblasts, keratinocytes, and angiogenesis
Beyond creating a favorable healing environment, fibroin also interacts directly with the cellular populations responsible for wound closure. The RGD-like sequences present within its protein structure, although less abundant than those found in collagen, provide sufficient adhesion sites to promote the attachment and migration of fibroblasts and keratinocytes across the scaffold surface. This is an essential requirement in wounds where the native extracellular matrix has already been extensively degraded by proteolytic enzymes.
At the same time, fibroin serves as an excellent functional reservoir for growth factors. Its molecular architecture can be exploited for the loading and controlled release of molecules such as VEGF, EGF, PDGF, and bFGF—the very growth factors whose bioavailability is often markedly reduced within the diabetic wound microenvironment because of accelerated enzymatic degradation. Encapsulating these molecules within a fibroin matrix protects them from proteolysis and prolongs their local activity, an advantage that is particularly important for the angiogenic component of tissue repair.
Insufficient neovascularization is one of the major barriers to diabetic ulcer healing, and several experimental studies using VEGF-functionalized fibroin scaffolds have demonstrated significantly greater microvascular density than dressings lacking controlled growth factor delivery. This enhanced vascularization translates directly into improved oxygenation of the tissue surrounding the wound, thereby supporting more effective regeneration.
Antibacterial functionalization as an essential component
When designing advanced dressings for diabetic foot ulcers, antimicrobial activity cannot be regarded as an optional feature. Bacterial colonization—and especially biofilm formation—is one of the principal causes of wound chronicity, often exerting a greater influence on impaired healing than hyperglycemia alone.
Fibroin is particularly well suited to antibacterial functionalization strategies because its porous structure and tunable crystallinity enable the efficient incorporation of antimicrobial agents with controllable release kinetics. Silver nanoparticles remain the most extensively investigated approach. In preclinical models, fibroin–silver scaffolds have demonstrated effective activity against common diabetic foot pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while maintaining limited cytotoxicity toward host cells when silver concentrations are appropriately optimized.
Alongside silver-based systems, alternative strategies are increasingly being explored, including antimicrobial peptides incorporated into the fibroin matrix, naturally derived bioactive compounds such as polyphenolic extracts, and surface modification approaches designed to prevent initial bacterial adhesion rather than acting only after biofilm formation has occurred.
A particularly attractive aspect of fibroin-based dressings is that many of these antimicrobial strategies can be combined within the same device with the controlled release of growth factors described above. This has led to the development of multifunctional systems capable of simultaneously controlling infection and promoting tissue regeneration—two therapeutic objectives that have traditionally been addressed separately by conventional wound dressings.
From films to hydrogels
The remarkable processing versatility of fibroin makes it possible to translate these biological properties into a wide range of material formats, each designed for a specific stage of wound healing or a particular type of lesion.
Fibroin membranes and films, produced by casting or electrospinning, provide an effective physical barrier against external contamination while maintaining selective gas permeability that supports oxygen exchange without dehydrating the wound bed. Electrospun nanofibers, in particular, more closely mimic the topography of the native extracellular matrix than compact films, providing a substantially larger surface area for cell adhesion.
Porous fibroin sponges, typically produced by freeze-drying, are especially suitable for deep or cavitary ulcers, where a material capable of filling the tissue defect while simultaneously absorbing large amounts of exudate is required.
Fibroin hydrogels, generated through controlled gelation of the β-sheet structure, are perhaps the most promising format for superficial, highly exudative ulcers. They combine an optimal moist environment with excellent conformability, allowing the material to adapt to the irregular surfaces that characterize many diabetic foot lesions. In addition, hydrogels provide a particularly efficient vehicle for the controlled delivery of therapeutic agents dissolved within the aqueous phase.
Finally, the possibility of combining fibroin with sericin—the other major protein found in raw silk—should not be overlooked. Sericin contributes complementary hygroscopic and antioxidant properties, and composite fibroin–sericin formulations are attracting increasing interest as advanced wound dressings for the management of chronic wounds.
Comparison with the current standard of care
To properly assess the potential of fibroin, it is useful to compare it with the approaches most commonly employed in the clinical management of diabetic foot ulcers. These include collagen- and hyaluronic acid-based dressings, negative pressure wound therapy (NPWT), and bioengineered dermal substitutes derived from allogeneic or xenogeneic matrices.
Compared with pure collagen dressings, fibroin offers the important advantage of greater resistance to proteolytic degradation, a particularly relevant feature in chronic wounds where matrix metalloproteinase activity is pathologically elevated. Unlike animal-derived dermal substitutes, properly purified fibroin—following the removal of residual sericin—generally exhibits a more favorable immunogenicity profile. In addition, its production has the potential to be more cost-effective on an industrial scale owing to the widespread availability of silk as a raw material.
This does not imply that fibroin should be viewed as a universal replacement for existing therapies. Rather, it should be considered a complementary biomaterial platform that is particularly well suited to cases in which persistent inflammation and a high risk of infection constitute the principal barriers to healing. In such settings, the possibility of functionalizing a single fibroin scaffold with multiple bioactive agents simultaneously represents a significant advantage over less versatile materials with more limited chemical modification capabilities.
