Effects of Photobiomodulation Therapy on the Expression of Hypoxic Inducible Factor,Vascular Endothelial Growth Factor,and Its Specific Receptor: A Randomized Control Trial in Patients with Diabetic Foot Ulcer
Restricted accessResearch articleFirst published online April, 2024
Effects of Photobiomodulation Therapy on the Expression of Hypoxic Inducible Factor,Vascular Endothelial Growth Factor,and Its Specific Receptor: A Randomized Control Trial in Patients with Diabetic Foot Ulcer
Impaired angiogenesis is a significant factor contributing to delayed healing in diabetic foot ulcers (DFUs) due to inadequate oxygenation.
Objective:
This study aimed to investigate the impact of photobiomodulation (PBM) using a Ga-As laser on the release of serum hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2, and nitric oxide (NO) in diabetic patients with DFUs.
Materials and methods:
In this double-blind RCT, a total of 30 patients with grade II DFUs were enrolled. The patients were randomly divided into two groups: the PBM (n = 15) and the placebo (n = 15). In the PBM group, a Ga-As laser (904 nm, 2 J/cm2, 90 W) was given for 3 days/week for 4 weeks (11 sessions). In the placebo group, the power was turned off. Both groups received similar standard wound care. Before and after interventions, the levels of serum HIF-1α, VEGF, NO, and sVEGFR-2 were measured. In addition, the percentage decrease in the wound surface area (%DWSA) was measured.
Results:
Following the intervention, the results revealed that the PBM group had significantly lower levels of VEGF than the placebo group (p = 0.005). The %DWSA was significantly higher in the PBM group compared to the placebo group (p = 0.003). Moreover, VEGF showed a significant negative correlation with %DWSA (p < 0.001).
Conclusions:
The observed decrease in serum levels of VEGF and an increase in %DWSA, compared to the placebo group, suggests that PBM effectively improves angiogenesis. Furthermore, the significant correlation found between VEGF levels and %DWSA emphasizes the importance of evaluating wound surface in patients as a dependable indicator of enhanced wound angiogenesis.
RodriguesM, KosaricN, BonhamCA, et al.Wound healing: A cellular perspective. Physiol Rev, 2019; 99(1):665–706; doi: 10.1152/PHYSREV.00067.2017.
3.
ShahA, Amini-NikS. The role of phytochemicals in the inflammatory phase of wound healing. Int J Mol Sci, 2017; 18(5); doi: 10.3390/IJMS18051068.
4.
WilkinsonHN, HardmanMJ. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol, 2020;10(9):200223; doi: 10.1098/rsob.200223.
5.
ZubairM, AhmadJ. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord, 2019; 20(2); doi: 10.1007/S11154-019-09492-1.
6.
ZhengS-Y, WanX-X, KambeyPA, et al.Therapeutic role of growth factors in treating diabetic wound. World J Diabetes, 2023; 14(4):364–395; doi: 10.4239/WJD.V14.I4.364.
7.
FengJ, ZhangY, XingD. Low-power laser irradiation (LPLI) promotes VEGF expression and vascular endothelial cell proliferation through the activation of ERK/Sp1 pathway. Cell Signal, 2012; 24(6):1116–1125; doi: 10.1016/J.CELLSIG.2012.01.013.
8.
RochaAM, VieiraBJ, De AndradeLCF, et al.Effects of low-level laser therapy on the progress of wound healing in humans: The contribution of in vitro and in vivo experimental studies. J Vasc Bras, 2007; 6(3):257–265; doi: 10.1590/S1677-54492007000300009.
9.
BaoP, KodraA, Tomic-CanicM, et al.The role of vascular endothelial growth factor in wound healing. J Surg Res, 2009; 153(2):347–358; doi: 10.1016/J.JSS.2008.04.023.
10.
CorralCJ, SiddiquiA, WuL, et al.Vascular endothelial growth factor is more important than basic fibroblastic growth factor during ischemic wound healing. Arch Surg, 1999; 134(2):200–205; doi: 10.1001/ARCHSURG.134.2.200.
11.
Gomez-VillamandosRJ, ValenzuelaJMS, CalatravaIR, et al.He-Ne laser therapy by fibroendoscopy in the mucosa of the equine upper airway. Lasers Surg Med, 1995; 16(2):184–188; doi: 10.1002/LSM.1900160208.
12.
JohnsonKE, WilgusTA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care, 2014; 3(10):647–661; doi: 10.1089/WOUND.2013.0517.
13.
DulakJ, JózkowiczA, Dembinska-KiecA, et al.Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 2000; 20(3):659–666; doi: 10.1161/01.ATV.20.3.659.
14.
TubyI, MaltzL, OronU. Modulations of VEGF and iNOS in the rat heart by low level laser therapy are associated with cardioprotection and enhanced angiogenesis. Lasers Surg Med, 2006; 38(7):682–688; doi: 10.1002/LSM.20377.
15.
SpampinatoSF, CarusoGI, De PasqualeR, et al.The treatment of impaired wound healing in diabetes: Looking among old drugs. Pharmaceuticals (Basel), 2020; 13(4); doi: 10.3390/PH13040060.
16.
HoureldN. Healing effects of photobiomodulation on diabetic wounds. Appl Sci, 2019; 9(23):5114; doi: 10.3390/app9235114.
17.
ZhangG, YiL, WangC, et al.Photobiomodulation promotes angiogenesis in wound healing through stimulating the nuclear translocation of VEGFR2 and STAT3. J Photochem Photobiol B Biol, 2022; 237:112573; doi: 10.1016/J.JPHOTOBIOL.2022.112573.
18.
Lenifa PriyadharshiniMJ, PremalathaS, NaziyagulnaazAS. Effect of low level therapy of diabetic foot ulcers. Ann Rom Soc Cell Biol, 2021; 25:3643–3663.
19.
LiuH, Ya-QingX, Cai-FengY, et al.Diabetic foot wound ulcer management by laser therapy: A meta-analysis. Int Wound J, 2023; 20(10):4208–4216; doi: 10.1111/iwj.14320.
20.
RuhAC, FrigoL, XistoMF, et al.Laser photobiomodulation in pressure ulcer healing of human diabetic patients: Gene expression analysis of inflammatory biochemical markers. Lasers Med Sci, 2018; 33(1):165–171; doi: 10.1007/s10103-017-2384-6.
21.
OtterçoAN, AndradeAL, BrassolattiP, et al.Photobiomodulation mechanisms in the kinetics of the wound healing process in rats. J Photochem Photobiol B, 2018; 183:22–29; doi: 10.1016/J.JPHOTOBIOL.2018.04.010.
22.
AmaroliA, RaveraS, BaldiniF, et al.Photobiomodulation with 808-nm diode laser light promotes wound healing of human endothelial cells through increased reactive oxygen species production stimulating mitochondrial oxidative phosphorylation. Lasers Med Sci, 2019; 34(3):495–504; doi: 10.1007/S10103-018-2623-5.
23.
NtelekiB, AbrahamseH, HoureldNN. Conventional podiatric intervention and phototherapy in the treatment of diabetic ulcers. Semin Vasc Surg, 2015; 28(3–4):172–183; doi: 10.1053/J.SEMVASCSURG.2016.02.001.
24.
MathurRK, SahuK, SarafS, et al.Low-level laser therapy as an adjunct to conventional therapy in the treatment of diabetic foot ulcers. Lasers Med Sci, 2017; 32(2):275–282; doi: 10.1007/S10103-016-2109-2.
25.
KavianiA, DjavidGE, Ataie-FashtamiL, et al.A randomized clinical trial on the effect of low-level laser therapy on chronic diabetic foot wound healing: A preliminary report. Photomed Laser Surg, 2011; 29(2):109–114; doi: 10.1089/PHO.2009.2680.
26.
ChenQ, YangJ, YinH, et al.Optimization of photo-biomodulation therapy for wound healing of diabetic foot ulcers in vitro and in vivo. Biomed Opt Express, 2022; 13(4):2450; doi: 10.1364/BOE.451135.
27.
ZeinR, SeltingW, HamblinMR. Review of light parameters and photobiomodulation efficacy: Dive into complexity. J Biomed Opt, 2018; 23(12):1–17; doi: 10.1117/1.JBO.23.12.120901.
28.
HashmiJ T, HuangY-Y, SharmaSK, et al.Effect of pulsing in low-level light therapy. Lasers Surg Med, 2010; 42(6): 450–466; doi: 10.1002/lsm.20950.
29.
Hoseini-SanatiM, TorkamanG, HedayatiM, et al.Effect of Ga-As (904nm) and He-Ne (632.8 nm) laser on injury potential of skin full-thickness wound. J Photochem Photobiol B, 2011; 103(2):180–185; doi: 10.1016/J.JPHOTOBIOL.2011.03.003.30.
30.
ThangarajahH, VialIN, GroganRH, et al.HIF-1alpha dysfunction in diabetes. Cell Cycle, 2010; 9(1):75–79; doi: 10.4161/CC.9.1.10371.
31.
HsiehYL, ChouLW, ChangPL, et al.Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: Possible involvements in hypoxia-inducible factor 1α (HIF-1α). J Comp Neurol, 2012; 520(13):2903–2916; doi: 10.1002/CNE.23072.
32.
ChouE, SuzumaI, WayKJ, et al.Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: A possible explanation for impaired collateral formation in cardiac tissue. Circulation, 2002; 105(3):373–379; doi: 10.1161/HC0302.102143.
33.
HuangS-J, LeeS-Y, TengY-H et al. Photobiomodulation therapy to promote angiogenesis in diabetic mice with hindlimb ischemia. Photobiomodul Photomed Laser Surg, 2021; 39(7):453–462; doi: 10.1089/photob.2020.4896.
34.
SobankoJF, AlsterTS. Efficacy of low-level laser therapy for chronic cutaneous ulceration in humans: A review and discussion. Dermatol Surg, 2008; 34(8):991–1000; doi: 10.1111/J.1524-4725.2008.34197.X.
35.
WangCJ, KoJY, KuoYR, et al.Molecular changes in diabetic foot ulcers. Diabetes Res Clin Pract, 2011; 94(1):105–110; doi: 10.1016/J.DIABRES.2011.06.016.
36.
NambaT, KoikeH, MurakamiK, et al.Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. Circulation, 2003; 108(18):2250–2257; doi: 10.1161/01.CIR.0000093190.53478.78.
37.
ZhangF, LeiMP, OswaldTM, et al.The effect of vascular endothelial growth factor on the healing of ischaemic skin wounds. Br J Plast Surg, 2003; 56(4):334–341; doi: 10.1016/s0007-1226(03)00175-9.
38.
ManickamV, TiwariA, JungJJ, et al.Regulation of vascular endothelial growth factor receptor 2 trafficking and angiogenesis by Golgi localized t-SNARE syntaxin 6. Blood, 2011; 117(4):1425–1435; doi: 10.1182/BLOOD-2010-06-291690.
39.
EmingSA, LauerG, ColeM, et al.Increased levels of the soluble variant of the vascular endothelial growth factor receptor VEGFR-1 are associated with a poor prognosis in wound healing. J Invest Dermatol, 2004; 123(4):799–802; doi: 10.1111/J.0022-202X.2004.23310.X.
40.
TousoulisD, KampoliA-M, Tentolouris Nikolaos PapageorgiouC, et al.The role of nitric oxide on endothelial function. Curr Vasc Pharmacol, 2012; 10(1):4–18; doi: 10.2174/157016112798829760.
41.
ChenCH, HungHS, HsuSH. Low-energy laser irradiation increases endothelial cell proliferation, migration, and eNOS gene expression possibly via PI3K signal pathway. Lasers Surg Med, 2008; 40(1):46–54; doi: 10.1002/LSM.20589.
42.
MoriyamaY, NguyenJ, AkensM, et al.In vivo effects of low level laser therapy on inducible nitric oxide synthase. Lasers Surg Med, 2009; 41(3):227–231; doi: 10.1002/LSM.20745.
