No abstract

Diabetes mellitus is one of the most challenging epidemics facing the world today, with over 300 million patients affected worldwide. A significant complication associated with diabetes is hyperglycemia, which impairs wound healing. The rise in the diabetic patient population in recent years has precipitated an increase in the incidence and prevalence of chronic diabetic wounds, most commonly the diabetic foot ulcer. Although foot ulcers are difficult to treat due to their complicated pathology, outcomes have improved with the development of increasingly sophisticated biomaterials that accelerate healing. In this review, we describe recently developed biomaterials that elicit healing through cell-material interactions and/or the sustained delivery of drugs. These tunable therapeutic systems increase angiogenesis, collagen deposition, cell proliferation, and growth factors concentrations, while decreasing inflammation and enzymatic degradation of the extracellular matrix. As the field of biomaterials for wound healing continues to mature, we expect to witness a broader range of clinical options that will speed healing times and improve patient quality of life.

No abstract

Diabetes mellitus is a mounting concern in the United States, as are the mortality and morbidity that result from its complications. Of particular concern, diabetes patients frequently suffer from impaired wound healing and resultant nonhealing diabetic foot ulcers. These ulcers overproduce tumor necrosis factor α (TNFα), which reduces wound bed cell migration and proliferation while encouraging apoptosis. Herein, we describe the use of siRNA‐loaded lipid nanoparticles (LNPs) as a potential wound treatment to combat an overzealous immune response and facilitate wound closure. LNPs were formulated with an ionizable, degradable lipidoid and siRNA specific for TNFα. Topical application of nanoparticles reduced TNFα mRNA expression in the wound by 40–55% in diabetic and nondiabetic mice. In diabetic mice, this TNFα knockdown accelerated wound healing compared to untreated controls. Together, these results serve as proof‐of‐concept that RNA interference therapy using LNPs can reduce the severity and duration of chronic diabetic wounds.

Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.