biomedicines Article Far-Infrared Therapy Accelerates Diabetic Wound Healing via Recruitment of Tissue Angiogenesis in a Full-Thickness Wound Healing Model in Rats Rong-Fu Chen 1 , Keng-Fan Liu 1 , Su-Shin Lee 1,2 , Shu-Hung Huang 1,2 , Yi-Chia Wu 1,2 , Yun-Nan Lin 1 , Chun-Ting Wang 1 and Yur-Ren Kuo 1,2,3,4,5, *   Citation: Chen, R.-F.; Liu, K.-F.; Lee, S.-S.; Huang, S.-H.; Wu, Y.-C.; Lin, Y.-N.; Wang, C.-T.; Kuo, Y.-R. Far-Infrared Therapy Accelerates Diabetic Wound Healing via Recruitment of Tissue Angiogenesis in a Full-Thickness Wound Healing Model in Rats. Biomedicines 2021, 9, 1922. https://doi.org/10.3390/ biomedicines9121922 Academic Editors: Barbara De Angelis, Pietro Gentile, Luigi Toma and Rica Tanaka Received: 13 October 2021 Accepted: 13 December 2021 Published: 15 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Surgery, Division of Plastic Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; dr.chenrf@gmail.com (R.-F.C.); cell77821@gmail.com (K.-F.L.); k831702000@gmail.com (S.-S.L.); huangsh63@gmail.com (S.-H.H.); yichiawu1124@gmail.com (Y.-C.W.); yunnan1123@gmail.com (Y.-N.L.); chuntingb20120@gmail.com (C.-T.W.) 2 Regenerative Medicine and Cell Therapy Research Center, Department of Biotechnology, Faculty of Medicine, College of Medicine, College of Life Science, Kaohsiung Medical University, Kaohsiung 80756, Taiwan 3 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan 4 Orthopaedic Research Center, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan 5 Academic Clinical Programme for Musculoskeletal Sciences, Duke-NUS Graduate Medical School, Singapore 169857, Singapore * Correspondence: kuoyrren@gmail.com; Tel.: +886-7-3121101 (ext. 7675); Fax: +886-7-7311482 Abstract: Far-infrared ray (FIR) therapy has been applied in the tissue regeneration field. Studies have revealed that FIR could enhance wound healing. However, the biological effects of FIR on diabetic wounds remain unclear. Our study aims to investigate whether FIR could accelerate diabetic wound healing and analyze the biomechanisms. A dorsal skin defect (area, 6 × 5 cm 2 ) in a streptozotocin (STZ)-induced diabetes rodent model was designed. Thirty-two male Wistar rats were divided into 4 groups (n = 8 each subgroup). Group 1 consisted of sham, non-diabetic control; group 2, diabetic control without treatment; group 3, diabetic rats received 20 min FIR (FIR-20, 20 min per session, triplicate/weekly for 4 weeks) and group 4, diabetic rats received 40 min FIR (FIR-40, 40 min per session, triplicate in one week for 4 weeks). The wound healing was assessed clinically. Skin blood flow was measured by laser Doppler. The vascular endothelial growth factor (VEGF), 8-hydroxy- 2-deoxyguanosine (8-OHdG), eNOS, and Ki-67, were analyzed with immunohistochemical (IHC) staining. Laser Doppler flowmetry analysis of the blood flow of wounding area revealed the blood flow was higher in diabetic rats who received 40 min FIR (FIR-40) as compared to that in FIR-20 group. The wounding area was significantly reduced in the FIR-40 group than in the diabetic control groups. Histological findings of peri-wounding tissue revealed a significant increase in the neo-vessels in the FIR-treated groups as compared to the controls. IHC staining of periwounding biopsy tissue showed significant increases in angiogenesis expressions (VEGF, eNOS, and EGF), cell proliferation (Ki-67), and suppressed inflammatory response and oxygen radicles (CD45, 8-OHdG) expressions in the FIR-treated groups as compared to that in controls. Treatment with the optimal dosage of FIR significantly facilitated diabetic wound healing and associated with suppressed pro-inflammatory response and increased neovascularization and tissue regeneration. Keywords: far infrared; diabetic wound healing; angiogenesis 1. Introduction Chronic wounds occur commonly and reduce the quality of life of those affected, posing a relevant clinical and socioeconomic burden. The healing of a skin wound is a complex multistep process that involves the integration of activities of a variety of tissue and cell types [1]. Diabetic foot ulcers are a major complication of diabetes mellitus and Biomedicines 2021, 9, 1922. https://doi.org/10.3390/biomedicines9121922 https://www.mdpi.com/journal/biomedicines