Characterization of a preclinical model of chronic ischemic wound

Abstract

Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting.

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

“…We chose to force skin ischemia by adopting a fullthickness bipedicle-flap approach that we have recently described in swine (4). The goal was to generate an ischemic piece of skin tissue that would survive for at least 2 weeks.…”

“…Animal wound healing models are important biological tools to understand basic processes of tissue repair and to develop and validate strategies for clinical treatment. Recently we have reported a preclinical largeanimal model of ischemic wounds using a bipedicle flap approach (4). Although such a model is of high translational significance, enabling examination of clinically relevant problems, such models do not lend themselves to detailed scrutiny of molecular mechanisms because of limited availability of genetically modified animals, antibodies, and other molecular reagents.…”

Computational Approach To Characterize Causative Factors and Molecular Indicators of Chronic Wound Inflammation

“…In addition, reliable molecular indicators for the early detection of chronic inflammation have not been identified because of a lack of relevant data for human subjects. Chronic inflammatory pathologies have many manifestations, such as abnormal apoptotic neutrophil loading in diabetic ulcers (12) and increased presence of classically activated macrophages in chronic ischemic wounds (13). Yet, the most conspicuous and often-reported feature of many chronic (or delayed) inflammatory scenarios is the persistent presence of elevated levels of pro-inflammatory cytokines, such as TNF-a, IL1b, and IL-6 (12,(14)(15)(16)(17).…”

“…Animal model studies of chronic inflammation in wounds and diseases, such as obesity and atherosclerosis, have elucidated gene-and protein-level differences between normal and chronic inflammatory responses (12,13). Yet, it has not been firmly established whether the expression of the same genes is altered in humans during disease, questioning the validity of such indicators.…”

Elevated vacuum suspension preserves residual-limb skin health in people with lower-limb amputation: Randomized clinical trial

“…Lower-limb tissue oxygen saturation maps were generated using an OxyVu-2 Hyperspectral Camera (HyperMed; Burlington, Massachusetts) [19]. The hyperspectral camera was calibrated prior to each subject visit using a CheckPad and fiduciary marker provided.…”