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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2019

Open Access 01-12-2019 | Research article

Topical cutaneous application of carbon dioxide via a hydrogel for improved fracture repair: results of phase I clinical safety trial

Authors: Takahiro Niikura, Takashi Iwakura, Takashi Omori, Sang Yang Lee, Yoshitada Sakai, Toshihiro Akisue, Keisuke Oe, Tomoaki Fukui, Takehiko Matsushita, Tomoyuki Matsumoto, Ryosuke Kuroda

Published in: BMC Musculoskeletal Disorders | Issue 1/2019

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Abstract

Background

Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2 absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2 therapy in patients with fractures.

Methods

Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2 absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2 was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter.

Results

Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2 therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner.

Conclusions

The findings of the present study revealed that CO2 therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs.

Trial registration

This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).
Literature
1.
Morison Z, Vicente M, Schemitsch EH, McKee MD. The treatment of atrophic, recalcitrant long-bone nonunion in the upper extremity with human recombinant bone morphogenetic protein-7 (rhBMP-7) and plate fixation: a retrospective review. Injury. 2016;47:356–63.PubMedCrossRef
2.
Dai J, Li L, Jiang C, Wang C, Chen H, Chai Y. Bone morphogenetic protein for the healing of tibial fracture: a meta-analysis of randomized controlled trials. PLoS One. 2015;10:e0141670.PubMedPubMedCentralCrossRef
3.
Papanagiotou M, Dailiana ZH, Karachalios T, Varitimidis S, Vlychou M, Hantes M, et al. RhBMP-7 for the treatment of nonunion of fractures of long bones. Bone Joint J. 2015;97:997–1003.PubMedCrossRef
4.
Moghaddam A, Elleser C, Biglari B, Wentzensen A, Zimmermann G. Clinical application of BMP 7 in long bone non-unions. Arch Orthop Trauma Surg. 2010;130:71–6.PubMedCrossRef
5.
Govender S, Csimma C, Genant HK, Valentin-Opran A. BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123–34.PubMedCrossRef
6.
Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83:S151–8.PubMedCrossRef
7.
8.
Leighton R, Watson JT, Giannoudis P, Papakostidis C, Harrison A, Steen RG. Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): a systematic review and meta-analysis. Injury. 2017;48:1339–47.PubMedCrossRef
9.
Jingushi S, Mizuno K, Matsushita T, Itoman M. Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures. J Orthop Sci. 2007;12:35–41.PubMedCrossRef
10.
Shi HF, Xiong J, Chen YX, Wang JF, Qiu XS, Wang YH, et al. Early application of pulsed electromagnetic field in the treatment of postoperative delayed union of long-bone fractures: a prospective randomized controlled study. BMC Musculoskelet Disord. 2013;14:35.PubMedPubMedCentralCrossRef
11.
Boyette MY, Herrera-Soto JA. Treatment of delayed and nonunited fractures and osteotomies with pulsed electromagnetic field in children and adolescents. Orthopedics. 2012;35:e1051–5.PubMedCrossRef
12.
Assiotis A, Sachinis NP, Chalidis BE. Pulsed electromagnetic fields for the treatment of tibial delayed unions and nonunions. A prospective clinical study and review of the literature. J Orthop Surg Res. 2012;7:24.PubMedPubMedCentralCrossRef
13.
Krishnakumar GS, Roffi A, Reale D, Kon E, Filardo G. Clinical application of bone morphogenetic proteins for bone healing: a systematic review. Int Orthop. 2017;41:1073–83.PubMedCrossRef
14.
von Rüden C, Morgenstern M, Friederichs J, Augat P, Hackl S, Woltmann A, et al. Comparative study suggests that human bone morphogenetic proteins have no influence on the outcome of operative treatment of aseptic clavicle non-unions. Int Orthop. 2016;40:2339–45.CrossRef
15.
von Rüden C, Morgenstern M, Hierholzer C, Hackl S, Gradinger FL, Woltmann A, et al. The missing effect of human recombinant bone morphogenetic proteins BMP-2 and BMP-7 in surgical treatment of aseptic forearm nonunion. Injury. 2016;47:919–24.CrossRef
16.
Starman JS, Bosse MJ, Cates CA, Norton HJ. Recombinant human bone morphogenetic protein-2 use in the off-label treatment of nonunions and acute fractures: a retrospective review. J Trauma Acute Care Surg. 2012;72:676–81.PubMedCrossRef
17.
Schandelmaier S, Kaushal A, Lytvyn L, Heels-Ansdell D, Siemieniuk RA, Agoritsas T, et al. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ. 2017;356:j656.PubMedPubMedCentral
18.
Busse JW, Bhandari M, Einhorn TA, Schemitsch E, Heckman JD, Tornetta P, et al. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. 2016;355:i5351.PubMedPubMedCentral
19.
Tarride JE, Hopkins RB, Blackhouse G, Burke N, Bhandari M, Johal H, et al. Low-intensity pulsed ultrasound for treatment of tibial fractures: an economic evaluation of the TRUST study. Bone Joint J. 2017;99:1526–32.PubMedCrossRef
20.
Hannemann PF, Essers BA, Schots JP, Dullaert K, Poeze M, Brink PR. Functional outcome and cost-effectiveness of pulsed electromagnetic fields in the treatment of acute scaphoid fractures: a cost-utility analysis. BMC Musculoskelet Disord. 2015;16:84.PubMedPubMedCentralCrossRef
21.
Hannemann PF, Van Wezenbeek MR, Kolkman KA, Twiss EL, Berghmans CH, Dirven PA, et al. CT scan-evaluated outcome of pulsed electromagnetic fields in the treatment of acute scaphoid fractures: a randomised, multicentre, double-blind, placebo-controlled trial. Bone Joint J. 2014;96:1070–6.PubMedCrossRef
22.
Hannemann PF, Mommers EH, Schots JP, Brink PR, Poeze M. The effects of low-intensity pulsed ultrasound and pulsed electromagnetic fields bone growth stimulation in acute fractures: a systematic review and meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2014;134:1093–106.PubMedCrossRef
23.
Hannemann PF, Göttgens KW, van Wely BJ, Kolkman KA, Werre AJ, Poeze M, et al. The clinical and radiological outcome of pulsed electromagnetic field treatment for acute scaphoid fractures: a randomised double-blind placebo-controlled multicentre trial. J Bone Joint Surg Br. 2012;94:1403–8.PubMedCrossRef
24.
Adie S, Harris IA, Naylor JM, Rae H, Dao A, Yong S, et al. Pulsed electromagnetic field stimulation for acute tibial shaft fractures: a multicenter, double-blind, randomized trial. J Bone Joint Surg Am. 2011;93:1569–76.PubMedCrossRef
25.
Koga T, Niikura T, Lee SY, Okumachi E, Ueha T, Iwakura T, et al. Topical cutaneous CO2 application by means of a novel hydrogel accelerates fracture repair in rats. J Bone Joint Surg Am. 2014;96:2077–84.PubMedCrossRef
26.
Sakai Y, Miwa M, Oe K, Ueha T, Koh A, Niikura T, et al. A novel system for transcutaneous application of carbon dioxide causing an "artificial Bohr effect" in the human body. PLoS One. 2011;6:e24137.PubMedPubMedCentralCrossRef
27.
Oe K, Ueha T, Sakai Y, Niikura T, Lee SY, Koh A, et al. The effect of transcutaneous application of carbon dioxide (CO2) on skeletal muscle. Biochem Biophys Res Commun. 2011;407:148–52.PubMedCrossRef
28.
Akahane S, Sakai Y, Ueha T, Nishimoto H, Inoue M, Niikura T, et al. Transcutaneous carbon dioxide application accelerates muscle injury repair in rat models. Int Orthop. 2017;41:1007–15.PubMedCrossRef
29.
Ueha T, Oe K, Miwa M, Hasegawa T, Koh A, Nishimoto H, et al. Increase in carbon dioxide accelerates the performance of endurance exercise in rats. J Physiol Sci. 2018;68:463–70.PubMedCrossRef
30.
Ueha T, Kawamoto T, Onishi Y, Harada R, Minoda M, Toda M, et al. Optimization of antitumor treatment conditions for transcutaneous CO2 application: An in vivo study. Oncol Rep. 2017;37:3688–94.PubMedCrossRef
31.
Iwata E, Hasegawa T, Takeda D, Ueha T, Kawamoto T, Akisue T, et al. Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma. Int J Oncol. 2016;48:1493–8.PubMedCrossRef
32.
Onishi Y, Kawamoto T, Ueha T, Kishimoto K, Hara H, Fukase N, et al. Transcutaneous application of carbon dioxide (CO2) induces mitochondrial apoptosis in human malignant fibrous histiocytoma in vivo. PLoS One. 2012;7:e49189.PubMedPubMedCentralCrossRef
33.
Takeda D, Hasegawa T, Ueha T, Imai Y, Sakakibara A, Minoda M, et al. Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo. PLoS One. 2014;9:e100530.PubMedPubMedCentralCrossRef
34.
Harada R, Kawamoto T, Ueha T, Minoda M, Toda M, Onishi Y, et al. Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. Exp Cell Res. 2013;319:1988–97.PubMedCrossRef
35.
Iwata E, Hasegawa T, Ueha T, Takeda D, Saito I, Kawamoto T, et al. Transcutaneous carbon dioxide enhances the antitumor effect of radiotherapy on oral squamous cell carcinoma. Oncol Rep. 2018;40:434–42.PubMed
36.
Onishi Y, Akisue T, Kawamoto T, Ueha T, Hara H, Toda M, et al. Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma. Int J Oncol. 2014;45:732–8.PubMedCrossRef
37.
Takemori T, Kawamoto T, Ueha T, Toda M, Morishita M, Kamata E, Fukase N, et al. Transcutaneous carbon dioxide application suppresses bone destruction caused by breast cancer metastasis. Oncol Rep. 2018;40:2079–87.PubMed
38.
39.
40.
Dickson K, Katzman S, Delgado E, Contreras D. Delayed unions and nonunions of open tibial fractures. Correlation with arteriography results. Clin Orthop Relat Res. 1994;302:189–93.
41.
Santolini E, West R, Giannoudis PV. Risk factors for long bone fracture non-union: a stratification approach based on the level of the existing scientific evidence. Injury. 2015;46:S8–19.PubMedCrossRef
42.
Giannoudis PV, Gudipati S, Harwood P, Kanakaris NK. Long bone non-unions treated with the diamond concept: a case series of 64 patients. Injury. 2015;46:S48–54.PubMedCrossRef
43.
Pountos I, Panteli M, Panagiotopoulos E, Jones E, Giannoudis PV. Can we enhance fracture vascularity: what is the evidence? Injury. 2014;45:S49–57.PubMedCrossRef
44.
45.
46.
Xue Z, Jiang C, Hu C, Qin H, Ding H, An Z. Effects of different surgical techniques on mid-distal humeral shaft vascularity: open reduction and internal fixation versus minimally invasive plate osteosynthesis. BMC Musculoskelet Disord. 2016;17:370.PubMedPubMedCentralCrossRef
47.
Ronga M, Longo UG, Maffulli N. Minimally invasive locked plating of distal tibia fractures is safe and effective. Clin Orthop Relat Res. 2010;468:975–82.PubMedCrossRef
48.
Perren SM. Evolution of the internal fixation of long bone fractures. The scientific basis of biological internal fixation: choosing a new balance between stability and biology. J Bone Joint Surg Br. 2002;84:1093–110.PubMedCrossRef
49.
Farouk O, Krettek C, Miclau T, Schandelmaier P, Tscherne H. Effects of percutaneous and conventional plating techniques on the blood supply to the femur. Arch Orthop Trauma Surg. 1998;117:438–41.PubMedCrossRef
Metadata
Title
Topical cutaneous application of carbon dioxide via a hydrogel for improved fracture repair: results of phase I clinical safety trial
Authors
Takahiro Niikura
Takashi Iwakura
Takashi Omori
Sang Yang Lee
Yoshitada Sakai
Toshihiro Akisue
Keisuke Oe
Tomoaki Fukui
Takehiko Matsushita
Tomoyuki Matsumoto
Ryosuke Kuroda
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2019
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-019-2911-7

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