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Topical Cutaneous CO2 Application by Means of a Novel Hydrogel Accelerates Fracture Repair in Rats

Koga, Takaaki MD, PhD; Niikura, Takahiro MD, PhD; Lee, Sang Yang MD, PhD; Okumachi, Etsuko MD; Ueha, Takeshi MS, MOT; Iwakura, Takashi MD, PhD; Sakai, Yoshitada MD, PhD; Miwa, Masahiko MD, PhD; Kuroda, Ryosuke MD, PhD; Kurosaka, Masahiro MD, PhD

Journal of Bone & Joint Surgery - American Volume: 17 December 2014 - Volume 96 - Issue 24 - p 2077–2084
doi: 10.2106/JBJS.M.01498
Scientific Articles
Supplementary Content

Background: We previously demonstrated that topical cutaneous application of CO2, by means of a hydrogel in which the CO2 readily dissolves, increases blood flow and oxygen dissociation from hemoglobin in the soft tissues surrounding bone. In the present study, we utilized a rat fracture model to test the hypothesis that application of this treatment to fractured limbs would accelerate fracture repair.

Methods: A closed femoral shaft fracture was created in each rat. Topical cutaneous application of CO2 by means of a hydrogel was performed five times a week for up to four weeks in the CO2/hydrogel group (n = 60). Sham treatments were performed in the control group (n = 60). Radiographic, histological, immunohistochemical, laser Doppler perfusion imaging, real-time polymerase chain reaction, and biomechanical assessments were performed.

Results: Radiographic fracture union was evident at week 3 in twelve (86%) of fourteen animals in the CO2/hydrogel group compared with five (36%) of fourteen in the control group (p < 0.05; 95% CI [confidence interval] for the difference in union rate, 2.26% to 99.64%). Histological assessment revealed promotion of endochondral ossification in the CO2/hydrogel group. Immunohistochemical assessment at week 2 showed significantly greater capillary density in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 161 to 258 per mm2). Laser Doppler perfusion imaging demonstrated that the blood flow in the fractured limb was significantly greater at weeks 2 and 3 in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 8.4% to 22.4% and 6.7% to 19.0%, respectively). Gene expression of chondrogenic, osteogenic, and angiogenic markers was significantly greater in the CO2/hydrogel group at several time points. Ultimate stress, extrinsic stiffness, and failure energy (relative to the contralateral limb) were significantly greater in the CO2/hydrogel group at week 3 (p < 0.05; 95% CI for the difference, 24.8% to 67.5%, 4.0 % to 22.7%, and 9.6% to 58.8%, respectively). There were no significant differences between the groups with respect to any outcome measure at week 4.

Conclusions: Topical cutaneous application of CO2 by means of a hydrogel accelerated fracture repair in association with the promotion of angiogenesis, blood flow, and endochondral ossification.

Clinical Relevance: Topical cutaneous application of CO2 by this method is a novel and potentially useful therapy for accelerating fracture repair.

1Department of Orthopaedic Surgery (T.K., T.N., S.Y.L., E.O., T.I., M.M., R.K., and M.K.) and Division of Rehabilitation Medicine (T.U. and Y.S.), Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail address for T. Niikura:

Copyright 2014 by The Journal of Bone and Joint Surgery, Incorporated
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