Molecular mechanisms of skin wound healing in non-diabetic and diabetic mice in excision and pressure experimental wounds

Abstract

Experimental models for chronic skin lesions are excision and pressure ulcer, defined as “open” and “closed” lesions, respectively, only the latter characterized by tissue hypoxia. Moreover, systemic diseases, such as diabetes mellitus, affect wound repair. Thus, models for testing new therapies should be carefully selected according to the expected targets. In this study, we present an extensive and comparative histological, immunohistochemical, and molecular characterization of these two lesions in diabetic (db/db) and non-diabetic (C57BL/6 J) mice. In db/db mice, we found significant reduction in PGP9.5-IR innervation, reduction of capillary network, and reduced expression of NGF receptors. We found an increase in VEGF receptor Kdr expression, and the PI3K-Akt signaling pathway at the core of the altered molecular network. Db/db mice with pressure ulcers showed an impairment in the molecular regulation of hypoxia-related genes (Hif1a, Flt1, and Kdr), while extracellular matrix encoding genes (Itgb3, Timp1, Fn1, Col4a1) were upregulated by hyperglycemia and lesions. Overall, the molecular analysis suggests that db/db mice have a longer inflammatory phase of the wound repair process, delaying the progression toward the proliferation and remodeling phases.

Accelerated infected wound healing by probiotic-based living microneedles with long-acting antibacterial effect

“…S. aureus is the most common pathogenic species in chronic wounds [ 50 , 51 ]. It has been reported that a full-thickness skin excision wound on a rodent, for example mouse, is very clinically relevant [ 52 , 53 ]. Therefore, to further assess the antibacterial effect and therapeutic efficacy of the designed MN patches in promoting wound healing, we established a full-thickness skin wound model (diameter: 1 cm) with S. aureus infection on the backs of mice.…”

Poly(l-lactic acid) Scaffold Releasing an α4β1 Integrin Agonist Promotes Nonfibrotic Skin Wound Healing in Diabetic Mice

“…PLLA loaded with 15% GM18 (PLLA15GM18) was chosen, based on the results of the GM18 release tests and from previous in vitro studies on mesenchymal stem cells . This experiment was conducted in the pressure ulcer model in diabetic mice, as already established and characterized in our lab. , Photos of representative ulcers from the three experimental groups at 14 days from the first medication are shown in Figure A. The repaired area was measured as % value on day 14 compared to day 3 (when surgical curettage and the first medication were performed) and expressed as “residual wound area”.…”

“…For this in vivo study, we used a model of skin wound currently used by researchers to mimic chronic, nonhealing wounds, consisting of a pressure ulcer in db/db mice, a widely used mouse model of type 2 diabetes mellitus . These mice develop progressive sensory loss, electrophysiological impairments, and skin innervation loss: the skin repair process is also much slower in db/db than in control mice, making this mouse model highly appropriate for testing pro-healing compounds.…”

“…A fold of skin was raised and placed between two magnetic disks (anisotropic ferrite, 12 mm diameter and 5.0 mm thickness, with an average weight of 2.4 g and 1000 G magnetic force; Algamagnetic, Italy) to create a bridge of skin approximately 1 cm thick . Based on the results of our previous experiments, , we opted for three ischemia–reperfusion (I/R) cycles, with a single I/R cycle involving the application of the magnets for 12 h, followed by a rest period of 12 h without magnets. Following the third application of the magnets, the wounds were covered with a Tegaderm dressing (Tegaderm Roll, 3M).…”

Engineered multi-functional, pro-angiogenic collagen-based scaffolds loaded with endothelial cells promote large deep burn wound healing

“…We accomplished this by studying not only vascularization but also collagen deposition. We used Day 14 and Day 35 to represent time points within the proliferation and remodeling phases, respectively (Baldassarro et al, 2022). In a previous study, DS-SILY was shown to decrease collagen degradation by inhibiting MMP, thus, reducing dermal scarring (Stuart et al, 2011).…”