Topical gel-based biomaterials for the treatment of diabetic foot ulcers

Abstract

Diabetic foot ulcers (DFUs) are a devastating ailment for many diabetic patients with increasing prevalence and morbidity. The complex pathophysiology of DFU wound environments has made finding effective treatments difficult. Standard wound care treatments have limited efficacy in healing these types of chronic wounds. Topical biomaterial gels have been developed to implement novel treatment approaches to improve therapeutic effects and are advantageous due to their ease of application, tunability, and ability to improve therapeutic release characteristics. Here, we provide an updated, comprehensive review of novel topical biomaterial gels developed for treating chronic DFUs. This review will examine preclinical data for topical gel treatments in diabetic animal models and clinical applications, focusing on gels with protein/peptides, drug, cellular, herbal/antioxidant, and nano/microparticle approaches. STATEMENT OF SIGNIFICANCE: By 2050, 1 in 3 Americans will develop diabetes, and up to 34% of diabetic patients will develop a diabetic foot ulcer (DFU) in their lifetime. Current treatments for DFUs include debridement, infection control, maintaining a moist wound environment, and pressure offloading. Despite these interventions, a large number of DFUs fail to heal and are associated with a cost that exceeds $31 billion annually. Topical biomaterials have been developed to help target specific impairments associated with DFU with the goal to improve healing. A summary of these approaches is needed to help better understand the current state of the research. This review summarizes recent research and advances in topical biomaterials treatments for DFUs.

Keywords: Topical; biomaterials; diabetic; foot ulcers; gels; wound healing.

Figure 1.. Topical gel application to Diabetic Foot Ulcers.

Topical gels provide simple application of treatments to the DFU. Image created with Biorender.com.

Figure 2.. Acute vs. diabetic wound healing.

Acute wounds maintain a balance of hemostasis, inflammation characterized by neutrophil, macrophage engulfment of foreign material and neutrophil clearance by macrophages, proliferation of fibroblasts and myofibroblasts for ECM deposition, and tissue remodeling with keratinocyte migration and maturation of collagen. Diabetic wounds, however, have vascular impairment that delays hemostasis. Inflammation and proliferation stages are characterized by reduced leukocyte recruitment, reduced macrophage clearance of neutrophils causing neutrophil accumulation, increased ROS, increased proinflammatory cytokines, and increased MMP degradation of ECM materials such as collagen. Tissue remodeling and re-epithelialization is not completed, and the wound site remains open. Image created with Biorender.com.

Figure 3.. Topical gel treatment approaches in animal and clinical applications.

The peptide Substance P Gel promoted near full wound closure in diabetic rats[155]. The drug Valsartan® in gel form promotes accelerated wound closure in diabetic pigs.[163] A zwitterionic gel with CNP-miR146a demonstrated significantly improved wound healing in a diabetic mouse model.[190] In a clinical trial, a chitosan gel promoted full wound closure in DFU patients after 30 days (top) and 90 days (bottom).[96] Gel treatment diagrams created with Biorender.com. Wound closure images edited and obtained with permission from Elsevier Publishing.