wIRA-Related Research and Medical Applications: Cornerstones and Further Reading of Interest

Abstract

This chapter intends to fuel the readers’ discussion on wIRA applications, inspires further research and draws the readers’ attention to (a) some highlights of therapies that have delivered proven beneficial effects, (b) interesting basic research, and (c) the extensive breadth of wIRA applications that have been studied in an increasingly active area of research, as well as the clinical trials in different fields of medicine. Nevertheless, basic research on the nature and possible implementations of wIRA must be considered and continued. Of course, given the large amount of information in this area, it has only been possible to highlight some that might be of particular interest, and which might address often raised questions.

This chapter intends to fuel the readers’ discussion on wIRA applications, inspires further research and draws the readers’ attention to (a) some highlights of therapies that have delivered proven beneficial effects, (b) interesting basic research, and (c) the extensive breadth of wIRA applications that have been studied in an increasingly active area of research, as well as the clinical trials in different fields of medicine. Nevertheless, basic research on the nature and possible implementations of wIRA must considered and be continued. Of course, given the large amount of information in this area, it has only been possible to highlight some of them that might be of particular interest, and which might address often raised questions.

Two essential items concerning water-filtered IR should be stressed. First, this kind of irradiation is the natural energy transfer of the sun using 60–80% of its radiation energy. Sun energy is the base of the development/evolution of multicellular organisms on earth, and thus is the life conserving energy. In most parts of the earth, solar infrared (IR) radiation reaches the surface after passing through a humid atmosphere as water-filtered infrared (exceptions are arid zones like deserts). wIRA of the radiators described and nearly exclusively used in the aforementioned studies, almost 100% emulates the sun’s radiation on the earth. It can therefore be considered as an “artificial sun radiator” which is strictly limited to IR (without any UV), particularly on IR-A, which has deep-reaching, transcutaneous impacts without critically over-heating the skin surface. In other words, the wIRA radiator (syn.: wIRA-irradiator) almost perfectly imitates the solar IR reaching the Earth’s surface.

wIRA should not be seen as an alternative therapeutic approach in medicine rather as an effective adjuvant-based therapeutic measure.

References	Essence
1. Basics
− Vaupel, et al. Strahlenther Onkol. 1991; 167: 353  − Vaupel, et al. Strahlenther Onkol.1992; 168: 633  − Vaupel, Krüger. Stuttgart: Hippokrates Verlag, 1st ed. ISBN 3–37,773-1076-x	− First descriptions of water-filtered infrared-A (wIRA) irradiation as a novel technique to therapeutically heat superficial tumors (preclinical studies)  − Comprehensive review of wIRA applications: Basics and preclinical applications
− Kelleher et al. Int J Hyperthermia. 1995; 11: 241 https://doi.org/10.3109/02656739509022460  − Seegenschmiedt et al. Strahlenther Oncol. 1996; 172  − Vaupel, Krüger, Stuttgart: Hippokrates Verlag, 2nd ed; 1995 ISBN 3–7773–1196-0	− First description of changes in therapeutically relevant parameters of the tumor microenvironment upon wIRA  − First retrospective analysis of combined wIRA and radiotherapy of superficial cancers in the clinical setting  − Comprehensive review of wIRA applications: Basics, pre-clinical and clinical applications
− Kelleher et al. Int J Hyperthermia 1999; 15: 467 https://doi.org/10.1080/026567399285468  − Kelleher et al. Br J Cancer. 2003; 89: 405–2333 https://doi.org/10.1038/sj.bjc.6601036 https://doi.org/10.1038/sj.bjc.6601457	− First descriptions of enhanced efficacy of photodynamic therapy (PDT) in combination with wIRA irradiation
− Piazena et al. Int J Hyperthermia 2019; 36: 938 https://doi.org/10.1080/02656736.2019.1655594	− The formation of thermal fields within the skin and subcutis upon wIRA irradiation of piglets was studied in terms of the thermotherapy of superficial cancers and local infections of thermosensible microbial pathogens. Findings confirmed the high relevance of wIRA-hyperthermia based therapies to humans
− Piazena et al. Int J Hyperthermia 2020; 37: 887 https://doi.org/10.1080/02656736.2020.1792562	− An experimental study by the European Society for Hyperthermic Oncology (ESHO) which reports the criteria for superficial hyperthermia to be comparable with those reported for the in vivo setting in the abdominal wall and also in patients with recurrent breast cancer. The potential of wIRA heating for adequate treatment of cancers that have spread to the skin and subcutis were therefore confirmed for the clinical setting
− Multhoff et al., Chap. 10 (this book)	− This is the first article to comprehensively consider the immunobiological consequences of tissue warming by wIRA in tumors. The chapter covers the interdependencies of tumor physiology, immunology, and hyperthermia (HT) and describes the “cooperation” between the presence and development of protective anti-tumor immunity and HT
− Biena et al. Pharmaceutics. 2021; 13: 1147	− This extensive review highlights hyperthermia as being an essential part of the current, most promising combination therapies for cancer (chemotherapy, radiotherapy, PDT, surgery, immunotherapy in various combinations)
− van Rhoon et al. Adv Drug Deliv Rev. 2020;163–164;145–156 https://doi.org/10.1016/j.addr.2020.03.006	− This chapter provides an in-depth discussion of hyperthermia as a chemosensitiser of tumors and its capacity to enhance the efficacy of chemotherapy. It also considers the tumor temperatures that are required for optimal thermochemotherapy
− Karu TI. Int Union Biochem Mol Biol Life 2010; 62: 607 https://doi.org/10.1002/iub.359	− This review discusses the current knowledge in photobiology and medicine relating to the influence of monochromatic, quasi-monochromatic, and broad-band radiation of red-to-near infrared (IR-A), as part of the solar spectrum, on mammalian cells and human skin. The role of cytochrome c oxidase as a photoacceptor and photosignal transducer, and its photosensitivity are highlighted and considers ATP as a critical signaling molecule.
− Hartel et al. Br J Surg. 2006; 93: 952 https://doi.org/10.1002/bjs.5429	− Reports on the first randomized clinical trial showing that wIRA improves surgical wound healing and lowers postoperative pain
2. Oncology/Radiation Biology
− Notter et al. Int J Hyperthermia 2017; 33: 227 https://doi.org/10.1080/02656736.2016.1235731  − Notter et al. Cancers. 2020; 12: 606 https://doi.org/10.3390/cancers12030606  − Notter et al. Cancers. 2021; 13: 3911 https://doi.org/10.3390/cancers12030606	− Delivery of the first highly promising results reporting on thermography-controlled wIRA combined with hypofractionated re-irradiation of large recurrent breast cancers  − Using this combined modality, this study which evaluated the therapeutic outcome in 200 patients reports high overall clinical response rates and low toxicity  − This chapter proposes that combined wIRA-hyperthermia (wIRA-HT) and re-irradiation (re-RT) should be considered for (a) adjuvant treatment of radiation-associated angiosarcoma of the breast (RAASB) after surgery of local recurrence and (b) for definitive treatment of non-resectable RAAS
− Heselich et al. Photochem Photobiol. 2012; 88: 135 https://doi.org/10.1111/j,1751-1097,2011.01031.x	− Reports that combining nonthermal NIR with clinically/biologically relevant X-ray doses leads to genomic instability, elevated risks of mitotic catastrophes, increased ROS generation, and an impaired repair of DNA double-strand break, all of which suggest that this combined approach may increase the efficacy of radiotherapy
− König et al. Photochem. Photobiol B. 2018; 178: 115 https://doi.org/10.1111/j,1751-1097,2011.01031.x	− Reports that exposure to NIR modulates cellular responses to X-rays in human full thickness skin models and indicates that exposure to NIR prior to treatment can reduce the required effective X-ray dosages
− Zschaeck et al. Oral Oncol. 2021; 116: 105240 https://doi.org/10.1016/j.oraloncology.2021.105240	− Shows that fever-range whole body hyperthermia (WHB) improves tumor oxygenation in vivo and can therefore increase the radiosensitivity to subsequent irradiations of head and neck squamous cell carcinomas without an excess of toxicity
3. Nanomedicine
− Hainfeld et al. Nanomedicine. 2014; 10: 1609 https://doi.org/10.1016/j.nano.2014.05.006.	− Gold nanoparticles are known to enhance the efficacy of X-rays, resulting in tumor heating and ablation, as well as the absorbance of wIRA. Studying this dual property in a highly radio-resistant subcutaneous squamous cell carcinoma in mice revealed that the dose required to control 50% of the tumors could be reduced by a factor of >3.7
4. Psychiatry
− Janssen et al. JAMA Psychiatr. 2016; 73: 789 https://doi.org/10.1001/jamapsychiatry2016.1031	− Major depressive disorders were treated in a randomized clinical trial which included sham-treated controls. A single session of WBH using wiRA resulted a significant antidepressant effect within 1 week of treatment which persisted for 6 weeks after treatment. Based on these findings, this therapeutic concept is currently being followed at three universities in Germany and Switzerland (see Chap. 12 in this book)
5. Wound healing
− Hartel et al. Ann Surg. 2013; 258: 887 https://doi.org/10.1097/SLA.0000000000000235	− A prospective randomized study showing that preoperative wIRA reduces wound infections and postoperative pain
− Schumann et al. Br J Dermatol. 2011; 165: 541 https://doi.org/10.1111/j.1365-2133.2011.10410.x	− Patients with chronic venous stasis lower leg ulcers were treated with compression therapy, debridement, adhesive wound dressing, and 30 min wIRA irradiation or VIS (as control). Several essential symptoms significantly improved in the wIRA group
− Mercer et al. Ger Med Sci. 2008; 21: 6 PMID: 19675738	− wIRA irradiation of patients with chronic venous ulcers of the lower leg resulted in complete or nearly complete healing in most cases, a general reduction of pain and need for analgesics
− Tanaka et al. Australasian J Dermatol. 2018; 59: e87 https://doi.org/10.1111/ajd.12604	− Reports an upregulated expression of La ribonucleoprotein domain family member 6 and collagen type I gene following wIRA at 10 J/cm2 in a 3-dimensional model of human epidermal tissue using DNA microarray and real-time PCR, thereby demonstrating the ability of NIR irradiation to stimulate type I collagen production
− von Felbert et al. GMS Krankenhaushyg Interdiszip. 2008; 5: 2 PMID: 20204086; PMCDC2831243	− This randomized controlled study demonstrates that wIRA irradiation of patients with chronic venous ulcers of lower legs accelerated the healing process (18 vs. 42 days until complete wound closure; residual ulcer area: 0.4 cm2 vs. 28 cm2) and reduced the requirement of analgesics
6. Dermatology
− Fuchs et al. Ger Med Sci. 2004; 2 PMID: 19675691	− Treatment of verrucae vulgares, a significant problem in immunosuppressed patients, using PDT (5-ALA as photosensitizer) and wIRA delivered strong positive effects in this first prospective randomized controlled blinded study of recalcitrant warts. The findings suggest that other HPV-related neoplasia such as oral verrucous hyperplasia or cervical intraepithelial dysplasia should be explored as possible indications for this treatment modality
− von Felbert. Dermatology. 2011; 222: 347 https://doi.org/10.1159/000329024	− A series of patients with cutaneous scleroderma lesions, a chronic inflammatory disease leading to skin sclerosis, dysmorphism, contractures and movement restrictions were treated with wIRA. This approach led to a marked improvement which persisted during a long-term follow-up in 7 of 10 patients
− Knels et al. Photochem Photobiol. 2016; 92: 475 https://doi.org/10.1159/000329024	− An in vitro assay studied the therapeutic benefits of wIRA for wound healing in chronic diabetic skin lesions. For this, the effects of wIRA on 3 T3 fibroblast cultures with and without Glyoxal (causing a diabetic metabolic state) were examined. wIRA-reduced apoptotic cell numbers and more mitochondria showed a well-polarized MMP. This study underlines the immediate positive effects of wIRA, particularly on mitochondria
− Gebbers N, et al. Ger Med Sci. 2007; 14: 5 PMID: 19675716	− Infrared-induced skin damage, as communicated by some authors, has led to widespread confusion. This chapter documents that wIRA does not cause cellular degeneration of human skin, even at high irradiances. These high irradiances neither induce cell death or an MMP-1 mRNA overexpression (both of which are readily induced by UV-A irradiation)
7. Neonatology
− Singer et al. Z Geburtshilfe Neonatol. 2000; 204: 85 https://doi.org/10.1055/s-2000-10202	− This chapter reports on the advantages of wIRA over conventional infrared irradiation in neonatology using comparative physical means of irradiances in several clinically applied IR sources. Clinical observations on the protective effect of wIRA in incubator nursing and primary care of preterm neonates were evident
8. Infectiology
− Borel et al. Int J Hyperthermia. 2020; 37: 373 https://doi.org/10.1080/02656736.2020.1751312	− The emergence of antibiotic-resistant bacteria urgently requires the development of alternative, non-chemical treatments. This chapter presents recent research on reducing the infectious burden of thermosensitive bacteria such as mycobacterium ulcerans and chlamydia trachomatis using wIRA. M. Ulcerans causes chronic necrotizing skin disease (Buruli ulcer) and C. trachomatis infection of the ocular conjunctiva results in blinding trachoma. Both infections belong to the neglected tropical diseases and exhibit similar geographical distributions. Results of previous in vitro and in vivo studies have revealed wIRA to be a promising therapeutic tool against these bacteria  − wIRA irradiation of other bacterial species such as mycobacterium tuberculosis, Leishmania, Shigella, listeria monoytogenes, dermatophytes, Propionibacterium acnes, and helicobacter pylori should therefore also be tested
− Marti et al. PLos One. 2014; 9: e10223 https://doi.org/10.1371/journal.pone.0102239	− This seminal in vitro study showed, for the first time, that wIRA- irradiation inhibits acute chlamydial infection
− Inic-Kanada et al. J Photochem Photobiol B. 2020; 209: 111953 https://doi.org/10.1016/j.jphotobiol.2020.111953	− This in vivo study evaluated the influence of wIRA (2100 W/m2) in single or double treatments on the infectivity and bacterial load of chlamydia caviae and its ocular pathology in Guinea pigs. A marked decrease of infectivity was found, particularly in the double treated eyes. Importantly, no irradiation-related pathologies were microscopically detected in the follow-up period
− Oleg et al. Med Laser Appl. 2006; 21: 251 https://doi.org/10.1016/j.mla.2006.07.002	− This chapter comprehensively discusses the potential and problems of photodynamic therapy (PDT) against intracellular pathogens. Success depends on selecting the optimal approach for parasite killing while inflicting little or no host tissue damage: Short photosensitizer incubation time (1–5 min), low concentration of photosensitizer (0.1–1 μM), irradiance not exceeding 50 mW/cm2, a relatively low fluence (<5–10 J/cm2), and more than 3 PDT treatments
− Gelfand et al. FASEB J. 2019; 33: 3074 https://doi.org/10.1096/fj.201801095R	− This pilot trial tested a “near IR laser vaccine” adjuvant approach for safety, tolerability, and cutaneous immune cell trafficking. As the epidermis contains a large population of antigen-presenting cells (Langerhans cells, MHC class II), it is conceivable that wIRA could stimulate this population and promote an immunologically relevant trafficking of antigen to the regional lymph nodes
9. Ophthalmology
− Rahn et al. J Photochem Photobiol B. 2016; 165: 340 https://doi.org/10.1016/j.jphotobiol.2016.11.001	− This study reports that wIRA reduces chlamydial infectivity in vitro without causing ex vivo eye damage in pig and mouse models
− Nelidova et al. Science. 2020: 368:1108 https://doi.org/10.1126/science.aaz5887	− This study reports on enabling NIR sensitivity in a blind human retina by restoring light sensitivity using tunable NIR sensors. This approach may supplement or restore visual function in patients with regional retinal degeneration. Mammalian or snake transient receptor potential (TRP) channels were expressed in light-insensitive retinal cones in a mouse model of retinal degeneration, and NIR-induced sensitivity was induced using gold nanorods bound to temperature-sensitive TRP channels. NIR stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons and enabled mice to perform a learned light-driven behavior. Responses to different wavelengths were tuned by nanorods of different lengths and to different radiant powers using engineered channels with different temperature thresholds. TRP channels were targeted to human retinas, which allowed the postmortem activation of different cell types by NIR
10. Rheumatology
− Schuester et al. Phys Med Rehab Kuror. 2021 https://doi.org/10.1055/a-1349-1482	− Treatment of patients with gonarthrosis, the world’s most common joint disease, with wIRA in a prospective double blind controlled study resulted in a statistically proven efficacy with marked pain reduction and an improved life quality
− Xu et al. Orthop Surg Res. 2019; 14: 313 https://doi.org/10.1186/s13018-019-1322-7	− Patients with sacroiliitis and ankylosing spondylitis (AS) were treated with wIRA in a randomized controlled trial using a cross-over design. Treatment markedly decreased AS activity index (BASDAI), pain, morning stiffness, and CRP levels during treatment paralleled pain reduction (p < 0.018). Levels of serum VEGF were not affected
− Klemm et al. Int J Hyperthermia. 2020; 37: 965 https://doi.org/10.1080/02656736.2020.1804079	− Patients with axial spondyloarthritis were treated using serially applied, localized wIRA. The study group rapidly noted a reduction of pain and the consumption of NSAID after completion of the trial. Possible changes in TNF-α levels are discussed