Citation: Chirumbolo, S.; Valdenassi, L.; Tirelli, U.; Ricevuti, G.; Pandolfi, S.; Vaiano, F.; Galoforo, A.; Loprete, F.; Simonetti, V.; Chierchia, M.; et al. The Oxygen–Ozone Adjunct Medical Treatment According to the Protocols from the Italian Scientific Society of Oxygen–Ozone Therapy: How Ozone Applications in the Blood Can Influence Clinical Therapy Success via the Modulation of Cell Biology and Immunity. Biology 2023, 12, 1512. https://doi.org/10.3390/ biology12121512 Academic Editor: Seung-Yong Seong Received: 30 October 2023 Revised: 27 November 2023 Accepted: 6 December 2023 Published: 11 December 2023 Copyright: © 2023 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/). biology Article The Oxygen–Ozone Adjunct Medical Treatment According to the Protocols from the Italian Scientific Society of Oxygen–Ozone Therapy: How Ozone Applications in the Blood Can Influence Clinical Therapy Success via the Modulation of Cell Biology and Immunity Salvatore Chirumbolo 1, * , Luigi Valdenassi 2 , Umberto Tirelli 3 , Giovanni Ricevuti 4 , Sergio Pandolfi 2 , Francesco Vaiano 2 , Antonio Galoforo 2 , Fortunato Loprete 2 , Vincenzo Simonetti 2 , Marianna Chierchia 2 , Debora Bellardi 5 , Tommaso Richelmi 2 and Marianno Franzini 2 1 Department of Engineering for Innovation Medicine, University of Verona, 37134 Verona, Italy 2 Italian Scientific Society of Oxygen–Ozone Therapy (SIOOT), High Master School of Oxygen-Ozone Therapy, University of Pavia, 27100 Pavia, Italy; luigi.valdenassi@unipv.it (L.V.); sergiopandolfis2@gmail.com (S.P.); vaiano.francesco@gmail.com (F.V.); antonio@galoforo.it (A.G.); dottf.loprete@gmail.com (F.L.); simonetti.vinc@gmail.com (V.S.); mariannachierchia@virgilio.it (M.C.); dottrichelmitommaso@gmail.com or info@ossigenoozono.it (T.R.); marianno.franzini@gmail.com (M.F.) 3 Tirelli Medical Group, 33170 Pordenone, Italy; utirelli@tirellimedical.it 4 Department of Drug Science, University of Pavia, 27100 Pavia, Italy; giovanni.ricevuti@unipv.it 5 Magenta Clinical Service, 16125 Genoa, Italy; debora.bellardi@gmail.com * Correspondence: salvatore.chirumbolo@univr.it; Tel.: +39-04-5802-7645 Simple Summary: In this article, we show the effect of ozonated blood, i.e., ozone used via major autohemotherapy, on fighting antibiotic resistance in post-surgical infected wounds and via minor autohemotherapy (ozonated blood) for the adjunct treatment of knee osteoarthrosis. Ozone exhibited the ability to reduce bacterial inflammation and bacterial sepsis, pain, discomfort and musculoskeletal disability in the studies presented herein. Abstract: Background. Ozone is an allotrope of oxygen whose use in medicine has rapidly grown in recent years. Ozonated blood allows for the use of ozone in a safe modality, as plasma and blood cells are endowed with an antioxidant system able to quench ozone’s pro-oxidant property and to elicit the Nrf2/Kwap1/ARE pathway. Methods. We present two clinical studies, a case-series (six patients) observational study adopting ozone as a major autohemotherapy and topical ozone to address infected post-surgical wounds with multi-drug resistant bacteria and an observational study (250 patients) using ozonated blood for treating knee osteoarthritis. Results. Ozonated blood via major autohemotherapy reduced the extent of infections in wounds, reduced the inflammatory biomarkers by more than 75% and improved patients’ QoL, whereas ozonated blood via minor autohemotherapy improved significantly (p < 0.001) WOMAC and Lequesne’s parameters in knee os- teoarthritis. Conclusions. The models described, i.e., ozone autohemotherapy in wound antimicrobial treatment and ozonated blood in knee osteoarthrosis, following our protocols, share the outstanding ability of ozone to modulate the innate immune response and address bacterial clearance as well as inflammation and pain. Keywords: ozone; ozone therapy; SIOOT; Nrf2; clinics; hormesis 1. Introduction Ozone (O 3 ) is an allotrope of oxygen, which is usually known as a pollutant and a component of the terrestrial atmosphere [1–3], although the formation of ozone has also been reported in biological systems [4–8]. Biology 2023, 12, 1512. https://doi.org/10.3390/biology12121512 https://www.mdpi.com/journal/biology