Autologous Platelet- and Extracellular Vesicle-Rich Plasma Is an Effective Treatment Modality for Chronic Postoperative Temporal Bone Cavity Inflammation: Randomized Controlled Clinical Trial

Domen Vozel, Darja Božič, Marko Jeran, Zala Jan, Manca Pajnič, Ljubiša Pađen, Nejc Steiner, Veronika Kralj-Iglič, Saba Battelino, Domen Vozel, Darja Božič, Marko Jeran, Zala Jan, Manca Pajnič, Ljubiša Pađen, Nejc Steiner, Veronika Kralj-Iglič, Saba Battelino

Abstract

Purpose: To determine the efficacy of autologous platelet- and extracellular vesicle-rich plasma (PVRP) to treat chronic postoperative temporal bone cavity inflammation (CPTBCI) after exhausting surgical and standard conservative therapies.

Materials and methods: Patients were randomly allocated to treatment with PVRP (PVRP group) or standard conservative methods (control group) in a setting of four once-monthly checkups and subsequent follow-up. The treatment outcome was measured with the Chronic Otitis Media Questionnaire-12 (COMQ-12), CPTBCI focus surface area, and CPTBCI symptom-free time after the fourth checkup.

Results: Eleven patients from each group completed the trial; 95% of patients suffered from chronically discharging mastoid cavity (the type of CPTBCI). Within four checkups, the COMQ-12 score decreased statistically significantly in the PVRP group (p < 0.001) but not in the control group (p = 0.339). The CPTBCI foci surface area decreased statistically significantly between the first and second checkups (p < 0.0005) but not between other checkups (p > 0.05) in the PVRP group. No statistically significant differences in CPTBCI foci surface area were detected between checkups in the control group (p = 0.152). Nine patients from the PVRP group and three patients from the control group were CPTBCI symptom-free at the fourth checkup. The median symptom-free time was 9.2 months (95% CI [7.4, 11.9]) in the PVRP group. Cumulatively, 49% of patients in the PVRP group remained CPTBCI symptom-free for 12.7 months after the fourth checkup.

Conclusion: Autologous PVRP represents a novel additional and successful treatment modality for a chronically discharging radical mastoid cavity when the surgical and standard conservative treatment methods have been exhausted.

Trial number: https://ichgcp.net/clinical-trials-registry/NCT04281901" title="See in ClinicalTrials.gov">NCT04281901).

Keywords: cholesteatoma; extracellular vesicles; mastoidectomy; platelet-rich plasma; quality of life; regenerative medicine; temporal bone; theranostic nanomedicine.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Vozel, Božič, Jeran, Jan, Pajnič, Pađen, Steiner, Kralj-Iglič and Battelino.

Figures

FIGURE 1
FIGURE 1
Flowchart of a prospective randomized controlled clinical trial for treating patients with chronic postoperative temporal bone cavity inflammation. Data are presented according to the CONSORT statement (Schulz et al., 2010). Control group represented intervention A and PVRP intervention B. CPTBCI: chronic postoperative temporal bone cavity inflammation; PVRP: platelet- and extracellular vesicle-rich plasma; COVID-19: coronavirus disease 2019.
FIGURE 2
FIGURE 2
Chronic postoperative temporal bone cavity inflammation focus surface area measurements. Otomicroscopical photographs of CPTBCI (i.e., chronically discharging radical mastoid cavity) in a patient at four checkups depict surface areas (mm2) transformed to percentages (italics) according to the baseline. The figure represents a regression of inflammation (i.e., spherical granulation) in a patient treated with PVRP. D5 marks the anatomical area of CPTBCI focus according to the anatomical classification (Supplementary Material 2) and in the upper left corner, an ID of the patient (Supplementary Materials 7–10). CPTBCI: chronic postoperative temporal bone cavity inflammation; PVRP: platelet- and extracellular vesicle-rich plasma.
FIGURE 3
FIGURE 3
Autologous PVRP preparation protocol. Four citrated blood tubes were used to prepare two units of PVRP in parallel. Panels 1–6 denote preparation steps. PVRP: platelet- and extracellular vesicle-rich plasma; PPP: platelet-poor plasma. Adapted from Vozel et al. (2020b).
FIGURE 4
FIGURE 4
Treatment outcome and symptoms at follow-up. (A) COMQ-12 average sum scores (Vozel et al., 2020a); (B) CPTBCI focus area percentages; (C) Kaplan–Meier curve. 95% CIs are included in graphs (A,B). Graph (C) is based on the data of 9 of 11 (82%) patients treated with PVRP who were symptom-free after the fourth checkup of the trial. Cumulatively, 49% of patients from the PVRP group remained symptom-free for 12.7 months after the fourth checkup. COMQ-12: chronic otitis media questionnaire 12; CPTBCI: chronic postoperative temporal bone cavity inflammation; PVRP: platelet- and extracellular vesicle-rich plasma; *statistically significant difference between groups within checkup; #statistically significant difference between the first and second checkups in the PVRP group.
FIGURE 5
FIGURE 5
Scanning electron microscopy of PVRP. Panel (A) depicts high platelet and extracellular vesicle (EV) count. The white arrow on panel (A) depicts leukocytes, the white arrow on panel (B) depicts a platelet forming a tubular protrusion prior to EV shedding, triangles on panels (C,D) depict EVs. Panel (D) depicts platelets and EVs, which are globular fragments sized 300–1,000 nm, formed after platelet activation and shedding of their tubular protrusions. PVRP: platelet- and extracellular vesicle-rich plasma.

References

    1. Altamura S. A., Di Martino A., Andriolo L., Boffa A., Zaffagnini S., Cenacchi A., et al. (2020). Platelet-Rich plasma for sport-active patients with knee osteoarthritis: limited return to sport. Biomed. Res. Int. 2020:8243865. 10.1155/2020/8243865
    1. Chahla J., Cinque M. E., Piuzzi N. S., Mannava S., Geeslin A. G., Murray I. R., et al. (2017). A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J. Bone. Joint. Surg. Am. 99 1769–1779. 10.2106/JBJS.16.01374
    1. Cobden S. B., Oztürk K., Duman S., Esen H., Aktan T. M., Avunduk M. C., et al. (2016). Treatment of acute vocal fold injury with platelet-rich plasma. J. Voice 30 731–735. 10.1016/j.jvoice.2015.07.012
    1. DeLong J. M., Russell R. P., Mazzocca A. D. (2012). Platelet-Rich plasma: the PAW classification system. Arthroscopy 28 998–1009. 10.1016/j.arthro.2012.04.148
    1. Demir B., Sahin A., Binnetoglu A., Batman C. (2020). The utilization of chronic otitis media Questionnaire-12 in chronic otitis media with or without cholesteatoma. Eur. Arch. Otorhinolaryngol. 277 3037–3043. 10.1007/s00405-020-06030-7
    1. Dettori J. R. (2011). Loss to follow-up. Evid. Based Spine Care J. 2 7–10. 10.1055/s-0030-1267080
    1. Dornhoffer J. L., Smith J., Richter G., Boeckmann J. (2008). Impact on quality of life after mastoid obliteration. Laryngoscope 118 1427–1432. 10.1097/MLG.0b013e318173dd7e
    1. Eid A. M., Ebada H. A., El-Fattah A. M. A., Tawfik A. (2020). Platelet-rich fibrin: an autologous biomaterial for healing assistance of pharyngeal repair in total laryngectomy. Eur. Arch. Otorhinolaryngol. 278 463–470. 10.1007/s00405-020-06404-x
    1. Eryılmaz A., Demirci B., Gunel C., Doger F. K., Yukselen O., Omurlu I. K., et al. (2016). Can tissue adhesives and platelet-rich plasma prevent pharyngocutaneous fistula formation? Auris Nasus Larynx 43 62–67. 10.1016/j.anl.2015.06.012
    1. Fais S., O’Driscoll L., Borras F. E., Buzas E., Camussi G., Cappello F., et al. (2016). Evidence-Based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 10 3886–3899. 10.1021/acsnano.5b08015
    1. Gluth M. B., Tan B. Y. B., Santa Maria P. L., Atlas M. D. (2013). Unique microbiology of chronically unstable canal wall down tympanomastoid cavities: considerations for surgical revision. J. Laryngol. Otol. 127 458–462. 10.1017/S0022215113000583
    1. Gökçe Kütük S., Özdaş T. (2019). The impact of platelet-rich plasma therapy on short-term postoperative outcomes of pediatric tonsillectomy patients. Eur. Arch. Otorhinolaryngol. 276 489–495. 10.1007/s00405-018-5211-1
    1. Guo S.-C., Tao S.-C., Yin W.-J., Qi X., Yuan T., Zhang C.-Q. (2017). Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics 7 81–96. 10.7150/thno.16803
    1. Henatsch D., Wesseling F., Briedé J. J., Stokroos R. J. (2015). Treatment of chronically infected open mastoid cavities with medical honey: a randomized controlled trial. Otol. Neurotol. 36 782–787. 10.1097/MAO.0000000000000728
    1. Kalinec G. M., Gao L., Cohn W., Whitelegge J. P., Faull K. F., Kalinec F. (2019). Extracellular vesicles from auditory cells as nanocarriers for anti-inflammatory drugs and pro-resolving mediators. Front. Cell Neurosci. 13:530. 10.3389/fncel.2019.00530
    1. Khafagy Y. W., Abd Elfattah A. M., Moneir W., Salem E. H. (2018). Leukocyte- and platelet-rich fibrin: a new graft material in endoscopic repair of spontaneous CSF leaks. Eur. Arch. Otorhinolaryngol. 275 2245–2252. 10.1007/s00405-018-5048-7
    1. Khalil H. S., Windle-Taylor P. C. (2003). Canal wall down mastoidectomy: a long term commitment to the outpatients? BMC Ear Nose Throat Disord. 3:1. 10.1186/1472-6815-3-1
    1. Machin D., Fayers P. M. (2010). Randomized Clinical Trials: Design, Practice and Reporting. New Jersey: John Wiley & Sons Ltd, 95–111.
    1. Ogorevc E., Hudoklin S., Veraniè P., Kralj-Iglič V. (2014). Extracellular vesicle-mediated transfer of membranous components from the highly malignant T24 urinary carcinoma cell line to the non-malignant RT4 urinary papilloma cell line. Protoplasma 251 699–702. 10.1007/s00709-013-0544-5
    1. Otahal A., Kramer K., Kuten-Pella O., Weiss R., Stotter C., Lacza Z., et al. (2020). Characterization and chondroprotective effects of extracellular vesicles from plasma- and serum-based autologous blood-derived products for osteoarthritis therapy. Front. Bioeng. Biotechnol. 8:584050. 10.3389/fbioe.2020.584050
    1. Özgürsoy S. K., Tunçkaşık F., Tunçkaşık M. E., Akıncıoğlu E., Doğan H., Beriat G. K. (2018). Histopathologic evaluation of hyaluronic acid and plasma-rich platelet injection into rabbit vocal cords: an experimental study. Turk Arch. Otorhinolaryngol. 56 30–35. 10.5152/tao.2018.2942
    1. Pachito D. V., Latorraca C., de Oc, Riera R. (2019). Efficacy of platelet-rich plasma for non-transfusion use: overview of systematic reviews. Int. J. Clin. Pract. 73:e13402. 10.1111/ijcp.13402
    1. Pareschi R., Lepera D., Nucci R. (2019). Canal wall down approach for tympano-mastoid cholesteatoma: long-term results and prognostic factors. Acta Otorhinolaryngol. Ital. 39 122–129. 10.14639/0392-100X-2237
    1. Phillips J. S., Haggard M., Yung M. (2014). A new health-related quality of life measure for active chronic otitis media (COMQ-12): development and initial validation. Otol. Neurotol. 35 454–458. 10.1097/MAO.0000000000000205
    1. Piao L., Park H., Jo C. H. (2017). Theoretical prediction and validation of cell recovery rates in preparing platelet-rich plasma through a centrifugation. PLoS One 12:e0187509. 10.1371/journal.pone.0187509
    1. Rachul C., Rasko J. E. J., Caulfield T. (2017). Implicit hype? representations of platelet rich plasma in the news media. PLoS One 12:e0182496. 10.1371/journal.pone.0182496
    1. Sahin Onder S., Sahin Yilmaz A., Erkmen B., Topal C. S., Gergin O., Canpolat M. S. (2020). Platelet-rich plasma for laryngotracheal reconstruction: an experimental study. Eur. Arch. Otorhinolaryngol. 277 3103–3109. 10.1007/s00405-020-06091-8
    1. Sánchez M., Garate A., Bilbao A. M., Oraa J., Yangüela F., Sánchez P., et al. (2018). Platelet-Rich Plasma for Injured Peripheral Nerves: Biological Repair Process and Clinical Application Guidelines. Demystifying Polyneuropathy - Recent Advances and New Directions. Available online at: (Accessed September 25, 2019)
    1. Schulz K. F., Altman D. G., Moher D. Consort Group (2010). CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann. Intern. Med. 152 726–732.
    1. Smith C. W., Binford R. S., Holt D. W., Webb D. P. (2007). Quality assessment of platelet rich plasma during anti-platelet therapy. Perfusion 22 41–50. 10.1177/0267659107077950
    1. Stolle M., Schulze J., Roemer A., Lenarz T., Durisin M., Warnecke A. (2018). Human plasma rich in growth factors improves survival and neurite outgrowth of spiral ganglion neurons in vitro. Tissue Eng. Part A 24 493–501. 10.1089/ten.TEA.2017.0120
    1. Šuštar V., Bedina-Zavec A., Štukelj R., Frank M., Bobojević G., Janša R., et al. (2011). Nanoparticles isolated from blood: a reflection of vesiculability of blood cells during the isolation process. Int. J. Nanomed. 6 2737–2748. 10.2147/IJN.S24537
    1. Tambella A. M., Attili A. R., Dupré G., Cantalamessa A., Martin S., Cuteri V., et al. (2018). Platelet-rich plasma to treat experimentally-induced skin wounds in animals: a systematic review and meta-analysis. PLoS One 13:e0191093. 10.1371/journal.pone.0191093
    1. Tao S.-C., Guo S.-C., Zhang C.-Q. (2017). Platelet-derived extracellular vesicles: an emerging therapeutic approach. Int. J. Biol. Sci. 13 828–834. 10.7150/ijbs.19776
    1. Vidovic A., Delling U. (2017). Aryepiglottic fold augmentation as treatment for late-onset dysphagia following surgical treatment of recurrent laryngeal neuropathy. Tierarztl Prax Ausg G Grosstiere Nutztiere 45 219–225. 10.15653/TPG-160712
    1. Vozel D., Božič D., Jeran M., Jan Z., Pajnič M., Paðen L., et al. (2020a). “The role of platelet- and extracellular vesicle-rich plasma in the treatment of chronic postoperative temporal bone cavity inflammation: a randomized controlled clinical trial,” in Socratic Lectures: 3rd International Minisymposium: Peer Reviewed Proceedings, (Ljubljana: Faculty of Health Sciences, University of Ljubljana, Slovenia; ).
    1. Vozel D., Božič D., Jeran M., Jan Z., Pajnič M., Paðen L., et al. (2020b). “Treatment with platelet- and extracellular vesicle-rich plasma in otorhinolaryngology-a review and future perspectives,” in Advances in Biomembranes and Lipid Self-Assembly, eds Bongiovanni A., Pocsfalvi G., Manno M., Kralj-Igli? V. (Amsterdam: Elsevier; ), 10.1016/bs.abl.2020.05.003
    1. Vozel D., Steiner N., Božanić Urbančič N., Mladenov D., Battelino S. (2020c). Slovenian cross-cultural adaptation and validation of health-related quality of life measures for chronic otitis media (COMQ-12), vertigo (DHI, NVI) and tinnitus (THI). Zdr Varst 59 120–127. 10.2478/sjph-2020-0016
    1. Wang C., Xu M., Guo W., Wang Y., Zhao S., Zhong L. (2019). Clinical efficacy and safety of platelet-rich plasma in arthroscopic full-thickness rotator cuff repair: a meta-analysis. PLoS One 14:e0220392. 10.1371/journal.pone.0220392
    1. Wilkie M. D., Chudek D., Webb C. J., Panarese A., Banhegyi G. (2019). Canal wall down mastoidectomy with obliteration versus canal wall up mastoidectomy in primary cholesteatoma surgery. J. Laryngol. Otol. 133 1074–1078. 10.1017/S0022215119002408
    1. Yáñez-Mó M., Siljander P. R.-M., Andreu Z., Zavec A. B., Borràs F. E., Buzas E. I., et al. (2015). Biological properties of extracellular vesicles and their physiological functions. J. Extracell Vesicles 4:27066. 10.3402/jev.v4.27066
    1. Yasak A. G., Yigit O., Araz Server E., Durna Dastan S., Gul M. (2018). The effectiveness of platelet-rich plasma in an anosmia-induced mice model. Laryngoscope 128 E157–E162. 10.1002/lary.27029
    1. Yung M. (2016). The use of temporoparietal fascial flap to eliminate wound breakdown in subtotal petrosectomy for chronic discharging ears. Otol. Neurotol. 37 248–251. 10.1097/MAO.0000000000000959

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