Molecular Mechanisms and Therapeutic Strategies in Diabetic Foot Ulcer Healing

Diabetic foot ulcers arise from a convergence of chronic hyperglycaemia, peripheral neuropathy and vascular insufficiency, leading to persistent inflammation, impaired angiogenesis and defective tissue remodelling. At the molecular level, accumulation of advanced glycation end-products and excessive reactive oxygen species disrupt endothelial integrity and prolong the inflammatory phase by skewing macrophage polarisation toward a pro-inflammatory M1 phenotype. Fibroblast dysfunction, altered extracellular matrix deposition and dysregulated growth factor signalling further retard granulation tissue formation. Emerging therapeutic strategies aim to restore balance by scavenging oxidative stress, modulating epigenetic regulators such as microRNAs, and delivering targeted growth factors or cells. Biomaterial scaffolds, nanocarriers and platelet-rich plasma formulations enhance local delivery of reparative signals, while single-cell transcriptomics and machine-learning-guided target identification promise personalised approaches. Integrating insights into immune cell dynamics, vascular regeneration and extracellular matrix interactions is critical to developing multifaceted interventions that can accelerate healing, reduce amputation rates and improve quality of life for people with diabetes.

Research from Nature Portfolio

High-resolution single-cell transcriptomic profiling of diabetic foot tissue has delineated distinct fibroblast subpopulations overexpressing metalloproteinases and hypoxia-responsive genes, and revealed that a greater ratio of M1 to M2 macrophages characterises healing wounds. Spatial transcriptomics further localised reparative fibroblasts to the wound bed, suggesting precise cellular targets for intervention. In a preclinical diabetic mouse model, a combination of selenium nanoparticles and platelet-rich plasma synergistically reduced oxidative damage, enhanced angiogenesis and accelerated closure of full-thickness wounds, demonstrating the translational potential of nano-enabled antioxidant and growth-factor therapies.

Molecular Mechanisms and Therapeutic Strategies in Diabetic Foot Ulcer Healing publication trend

The graph below shows the total number of articles in molecular mechanisms and therapeutic strategies in diabetic foot ulcer healing across all publications each year (not limited to Nature Index journals).

Technical terms

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, essential for nutrient delivery and tissue repair.

Macrophage polarisation: Functional states of macrophages, with M1 promoting inflammation and M2 supporting resolution and repair.

Extracellular matrix (ECM): Network of proteins and glycoproteins that provides structural support and regulates cellular behaviour.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that at high levels cause cellular damage.

microRNA (miRNA): Small non-coding RNA molecules that regulate gene expression post-transcriptionally, influencing inflammation and angiogenesis.

References

1. Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAS, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction. Cardiovascular Diabetology (2023).
2. SDC4 protein action and related key genes in nonhealing diabetic foot ulcers based on bioinformatics analysis and machine learning. International Journal of Biological Macromolecules (2024).
3. Single cell transcriptomic landscape of diabetic foot ulcers. Nature Communications (2022).
4. Assessment of wound healing activity in diabetic mice treated with a novel therapeutic combination of selenium nanoparticles and platelets rich plasma. Scientific Reports (2024).