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ABSTRACT Purpose: To evaluate exogenous hyaluronic acid (HA) derived from bacterial fermentation through enteral and parenteral routes in ischemic skin flaps induced in rats, using clinical and histological exams; and interleukins (IL) as tissue inflammatory biomarkers. Methods: Sixty-four male adults Wistar rats with ischemic skin flaps on the dorsum were randomized into four groups, based on the treatment protocol: subcutaneous administration of saline solution (0.9%) (GI); oral administration of distilled water (GII); subcutaneous administration of HA (0.3%) (GIII); and oral administration of HA (1%) (GIV). Flaps of all groups were comparable regarding clinical and macroscopic evaluation, histological examination, pro-inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) and anti-inflammatory cytokine IL-10. Results: A lower percentage of necrosis was identified in flaps treated with subcutaneous administration of HA (0.3%). The pro- and anti-inflammatory cytokines, epidermis thickness, blood vessels, and inflammatory cells showed statistically significant inter-group and intra-group differences (p < 0.05). Conclusions: High molecular HA (1,400 ~ 2,000 kDa) administrated by subcutaneous or oral route exhibited beneficial effects in ischemic skin flaps of rats. However, subcutaneous administration of HA (0.3%) showed better results in terms of the percentage of necrosis and epithelialization. Purpose (HA exams IL (IL biomarkers Methods Sixtyfour Sixty protocol 0.9% 09 0 9 (0.9% GI (GI) GII (GII) 0.3% 03 3 (0.3% GIII (GIII) 1% 1 (1% GIV. GIV . (GIV) evaluation examination proinflammatory pro IL1β, IL1β ILβ 1β, 1β β (IL-1β IL6, IL6 6, 6 IL-6 factorα factor α factor-α antiinflammatory anti IL10. IL10 10. 10 IL-10 Results 0.3%. thickness vessels intergroup inter group intragroup intra p 0.05. 005 0.05 05 0.05) Conclusions 1,400 1400 400 (1,40 2000 2 000 2,00 kDa However epithelialization 0.9 (0.9 (GI (GII 0.3 (0.3 (GIII (1 (GIV IL- IL1 IL-1 00 0.0 1,40 140 40 (1,4 200 2,0 0. (0. ( 1,4 14 4 (1, 20 2, (0 1,