Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits
Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have...
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| creator | Kumabe, Yohei Fukui, Tomoaki Takahara, Shunsuke Kuroiwa, Yu Arakura, Michio Oe, Keisuke Oda, Takahiro Sawauchi, Kenichi Matsushita, Takehiko Matsumoto, Tomoyuki Hayashi, Shinya Kuroda, Ryosuke Niikura, Takahiro |
| description | Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported.
We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy?
Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantif |
| doi_str_mv | 10.1097/CORR.0000000000001288 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7371043</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2429772301</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3817-d3138fd9875cffe2e077d95a394bdf122c0bffd4eb4cee70497f9736172d37503</originalsourceid><addsrcrecordid>eNpdkU9vEzEQxS0EoqHwEUCWuPSyxX8zuxekkkJBqpQqKhI3y-udTVw262J7W_HtcZpStfXFmuffPHnmEfKes2POGvi0WK5Wx-zR4aKuX5AZ16KuOJfiJZkVtakawX8dkDcpXZVSKi1ekwMpQAoNMCP2AqObsh0xTIkuloJeRrR5i2OmJ87hgNFmTPRLGJGe4bgrfRjp6RT9uKanPuVo3Z20TBnDuiDJJ-pHurJt63N6S171dkj47v4-JD-_fb1cfK_Ol2c_FifnlZM1h6qTXNZ919SgXd-jQAbQNdrKRrVdz4VwrO37TmGrHCIw1UDfgJxzEJ0EzeQh-bz3vZ7aLXauTBDtYK6j39r41wTrzdOX0W_MOtwYkMCZksXg6N4ghj8Tpmy2PpUNDPvlGKFEAyAk4wX9-Ay9ClMcy3hGaAZqDkzrQuk95WJIKWL_8BnOzC5EswvRPA-x9H14PMlD1__UCqD2wG0YMsb0e5huMZoN2iFv7vwkq-eVYIKxulTVTgH5DycUqIM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2507467055</pqid></control><display><type>article</type><title>Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits</title><source>MEDLINE</source><source>PubMed (Medline)</source><source>EZB Electronic Journals Library</source><creator>Kumabe, Yohei ; Fukui, Tomoaki ; Takahara, Shunsuke ; Kuroiwa, Yu ; Arakura, Michio ; Oe, Keisuke ; Oda, Takahiro ; Sawauchi, Kenichi ; Matsushita, Takehiko ; Matsumoto, Tomoyuki ; Hayashi, Shinya ; Kuroda, Ryosuke ; Niikura, Takahiro</creator><creatorcontrib>Kumabe, Yohei ; Fukui, Tomoaki ; Takahara, Shunsuke ; Kuroiwa, Yu ; Arakura, Michio ; Oe, Keisuke ; Oda, Takahiro ; Sawauchi, Kenichi ; Matsushita, Takehiko ; Matsumoto, Tomoyuki ; Hayashi, Shinya ; Kuroda, Ryosuke ; Niikura, Takahiro</creatorcontrib><description><![CDATA[Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported.
We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy?
Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantification on the plain radiographs to evaluate consolidation in the distraction gap with image analyzing software. Callus parameters were measured with micro-CT to assess callus microstructure. The newly formed bone area and cartilage area were measured histologically with safranin O/fast green staining to assess the progress of ossification. We also performed immunohistochemical staining of endothelial cells with fluorescein-labeled isolectin B4 and examined capillary density to evaluate angiogenesis. Gene expressions in newly generated callus were analyzed by real-time polymerase chain reaction. Biomechanical strength, stiffness, and energy were determined from a three-point bend test to assess the mechanical strength of the callus.
Radiographs showed higher pixel values in the distracted area in the CO2 group than the control group at Week 4 of the consolidation phase (0.98 ± 0.11 [95% confidence interval 0.89 to 1.06] versus 1.19 ± 0.23 [95% CI 1.05 to 1.34]; p = 0.013). Micro-CT demonstrated that bone volume fraction in the CO2 group was higher than that in the control group at Week 4 (5.56 ± 3.21 % [95% CI 4.32 to 6.12 %] versus 11.90 ± 3.33 % [95% CI 9.63 to 14.25 %]; p = 0.035). There were no differences in any other parameters (that is, callus bone mineral content at Weeks 2 and 4; volumetric bone mineral density at Weeks 2 and 4; bone volume fraction at Week 2). At Week 2, rabbits in the CO2 group had a larger cartilage area compared with those in the control group (2.09 ± 1.34 mm [95% CI 1.26 to 2.92 mm] versus 5.10 ± 3.91 mm [95% CI 2.68 to 7.52 mm]; p = 0.011). More newly formed bone was observed in the CO2 group than the control group at Week 4 (68.31 ± 16.32 mm [95% CI 58.19 to 78.44 mm] versus 96.26 ± 19.37 mm [95% CI 84.25 to 108.26 mm]; p < 0.001). There were no differences in any other parameters (cartilage area at Weeks 0 and 4; newly formed bone area at Weeks 0 and 2). Immunohistochemical isolectin B4 staining showed greater capillary densities in rabbits in the CO2 group than the control group in the distraction area at Week 0 and surrounding tissue at Weeks 0 and 2 (distraction area at Week 0, 286.54 ± 61.55 /mm [95% CI 232.58 to 340.49] versus 410.24 ± 55.29 /mm [95% CI 361.78 to 458.71]; p < 0.001; surrounding tissue at Week 0 395.09 ± 68.16/mm [95% CI 335.34 to 454.83] versus 589.75 ± 174.42/mm [95% CI 436.86 to 742.64]; p = 0.003; at Week 2 271.22 ± 169.42 /mm [95% CI 122.71 to 419.73] versus 508.46 ± 49.06/mm [95% CI 465.45 to 551.47]; p < 0.001 respectively). There was no difference in the distraction area at Week 2. The expressions of BMP -2 at Week 2, HIF1-α at Week 2 and VEGF at Week 0 and 2 were greater in the CO2 group than in the control group (BMP -2 at Week 2 3.84 ± 0.83 fold [95% CI 3.11 to 4.58] versus 7.32 ± 1.63 fold [95% CI 5.88 to 8.75]; p < 0.001; HIF1-α at Week 2, 10.49 ± 2.93 fold [95% CI 7.91 to 13.06] versus 20.74 ± 11.01 fold [95% CI 11.09 to 30.40]; p < 0.001; VEGF at Week 0 4.80 ± 1.56 fold [95% CI 3.43 to 6.18] versus 11.36 ± 4.82 fold [95% CI 7.13 to 15.59]; p < 0.001; at Week 2 31.52 ± 8.26 fold [95% CI 24.27 to 38.76] versus 51.05 ± 15.52 fold [95% CI 37.44 to 64.66]; p = 0.034, respectively). There were no differences in any other parameters (BMP-2 at Week 0 and 4; BMP -7 at Weeks 0, 2 and 4; HIF-1α at Weeks 0 and 4; IL-6 at Weeks 0, 2 and 4; VEGF at Week 4). In the biomechanical assessment, ultimate stress and failure energy were greater in the CO2 group than in the control group at Week 4 (ultimate stress 259.96 ± 74.33 N [95% CI 167.66 to 352.25] versus 422.45 ± 99.32 N [95% CI 299.13 to 545.77]; p < 0.001, failure energy 311.32 ± 99.01 Nmm [95% CI 188.37 to 434.25] versus 954.97 ± 484.39 Nmm [95% CI 353.51 to 1556.42]; p = 0.003, respectively). There was no difference in stiffness (216.77 ± 143.39 N/mm [95% CI 38.73 to 394.81] versus 223.68 ± 122.17 N/mm [95% CI 71.99 to 375.37]; p = 0.92).
Transcutaneous application of CO2 accelerated bone generation in a distraction osteogenesis model of rabbit tibias. As demonstrated in previous studies, CO2 treatment might affect bone regeneration in distraction osteogenesis by promoting angiogenesis, blood flow, and endochondral ossification.
The use of the transcutaneous application of CO2 may open new possibilities for shortening healing time in patients with distraction osteogenesis. However, a deeper insight into the mechanism of CO2 in the local tissue is required before it can be used in future clinical practice.]]></description><identifier>ISSN: 0009-921X</identifier><identifier>EISSN: 1528-1132</identifier><identifier>DOI: 10.1097/CORR.0000000000001288</identifier><identifier>PMID: 32732577</identifier><language>eng</language><publisher>United States: Wolters Kluwer</publisher><subject>Angiogenesis ; Animals ; Basic Research ; Biomechanics ; Blood flow ; Bone blood flow ; Bone density ; Bone Density - physiology ; Bone growth ; Bone healing ; Bone mineral content ; Bone mineral density ; Bone morphogenetic protein 2 ; Bone morphogenetic protein 7 ; Bone Morphogenetic Proteins - metabolism ; Bone Regeneration - physiology ; Callus ; Carbon dioxide ; Carbon Dioxide - administration & dosage ; Cartilage ; Computed tomography ; Distraction osteogenesis ; Endochondral bone ; Endothelial cells ; Energy ; Female ; Fluorescein ; Hypoxia-Inducible Factor 1 - metabolism ; Hypoxia-inducible factor 1a ; Interleukin 6 ; Interleukin-6 - metabolism ; Mechanical properties ; Osteogenesis - physiology ; Osteogenesis, Distraction - methods ; Polymerase chain reaction ; Rabbits ; Radiography ; Tibia - metabolism ; Tibia - physiology ; Ultrasound ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism ; X-Ray Microtomography</subject><ispartof>Clinical orthopaedics and related research, 2020-08, Vol.478 (8), p.1922-1935</ispartof><rights>Wolters Kluwer</rights><rights>2020 by the Association of Bone and Joint Surgeons</rights><rights>2020 by the Association of Bone and Joint Surgeons 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3817-d3138fd9875cffe2e077d95a394bdf122c0bffd4eb4cee70497f9736172d37503</citedby><cites>FETCH-LOGICAL-c3817-d3138fd9875cffe2e077d95a394bdf122c0bffd4eb4cee70497f9736172d37503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371043/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371043/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32732577$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumabe, Yohei</creatorcontrib><creatorcontrib>Fukui, Tomoaki</creatorcontrib><creatorcontrib>Takahara, Shunsuke</creatorcontrib><creatorcontrib>Kuroiwa, Yu</creatorcontrib><creatorcontrib>Arakura, Michio</creatorcontrib><creatorcontrib>Oe, Keisuke</creatorcontrib><creatorcontrib>Oda, Takahiro</creatorcontrib><creatorcontrib>Sawauchi, Kenichi</creatorcontrib><creatorcontrib>Matsushita, Takehiko</creatorcontrib><creatorcontrib>Matsumoto, Tomoyuki</creatorcontrib><creatorcontrib>Hayashi, Shinya</creatorcontrib><creatorcontrib>Kuroda, Ryosuke</creatorcontrib><creatorcontrib>Niikura, Takahiro</creatorcontrib><title>Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits</title><title>Clinical orthopaedics and related research</title><addtitle>Clin Orthop Relat Res</addtitle><description><![CDATA[Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported.
We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy?
Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantification on the plain radiographs to evaluate consolidation in the distraction gap with image analyzing software. Callus parameters were measured with micro-CT to assess callus microstructure. The newly formed bone area and cartilage area were measured histologically with safranin O/fast green staining to assess the progress of ossification. We also performed immunohistochemical staining of endothelial cells with fluorescein-labeled isolectin B4 and examined capillary density to evaluate angiogenesis. Gene expressions in newly generated callus were analyzed by real-time polymerase chain reaction. Biomechanical strength, stiffness, and energy were determined from a three-point bend test to assess the mechanical strength of the callus.
Radiographs showed higher pixel values in the distracted area in the CO2 group than the control group at Week 4 of the consolidation phase (0.98 ± 0.11 [95% confidence interval 0.89 to 1.06] versus 1.19 ± 0.23 [95% CI 1.05 to 1.34]; p = 0.013). Micro-CT demonstrated that bone volume fraction in the CO2 group was higher than that in the control group at Week 4 (5.56 ± 3.21 % [95% CI 4.32 to 6.12 %] versus 11.90 ± 3.33 % [95% CI 9.63 to 14.25 %]; p = 0.035). There were no differences in any other parameters (that is, callus bone mineral content at Weeks 2 and 4; volumetric bone mineral density at Weeks 2 and 4; bone volume fraction at Week 2). At Week 2, rabbits in the CO2 group had a larger cartilage area compared with those in the control group (2.09 ± 1.34 mm [95% CI 1.26 to 2.92 mm] versus 5.10 ± 3.91 mm [95% CI 2.68 to 7.52 mm]; p = 0.011). More newly formed bone was observed in the CO2 group than the control group at Week 4 (68.31 ± 16.32 mm [95% CI 58.19 to 78.44 mm] versus 96.26 ± 19.37 mm [95% CI 84.25 to 108.26 mm]; p < 0.001). There were no differences in any other parameters (cartilage area at Weeks 0 and 4; newly formed bone area at Weeks 0 and 2). Immunohistochemical isolectin B4 staining showed greater capillary densities in rabbits in the CO2 group than the control group in the distraction area at Week 0 and surrounding tissue at Weeks 0 and 2 (distraction area at Week 0, 286.54 ± 61.55 /mm [95% CI 232.58 to 340.49] versus 410.24 ± 55.29 /mm [95% CI 361.78 to 458.71]; p < 0.001; surrounding tissue at Week 0 395.09 ± 68.16/mm [95% CI 335.34 to 454.83] versus 589.75 ± 174.42/mm [95% CI 436.86 to 742.64]; p = 0.003; at Week 2 271.22 ± 169.42 /mm [95% CI 122.71 to 419.73] versus 508.46 ± 49.06/mm [95% CI 465.45 to 551.47]; p < 0.001 respectively). There was no difference in the distraction area at Week 2. The expressions of BMP -2 at Week 2, HIF1-α at Week 2 and VEGF at Week 0 and 2 were greater in the CO2 group than in the control group (BMP -2 at Week 2 3.84 ± 0.83 fold [95% CI 3.11 to 4.58] versus 7.32 ± 1.63 fold [95% CI 5.88 to 8.75]; p < 0.001; HIF1-α at Week 2, 10.49 ± 2.93 fold [95% CI 7.91 to 13.06] versus 20.74 ± 11.01 fold [95% CI 11.09 to 30.40]; p < 0.001; VEGF at Week 0 4.80 ± 1.56 fold [95% CI 3.43 to 6.18] versus 11.36 ± 4.82 fold [95% CI 7.13 to 15.59]; p < 0.001; at Week 2 31.52 ± 8.26 fold [95% CI 24.27 to 38.76] versus 51.05 ± 15.52 fold [95% CI 37.44 to 64.66]; p = 0.034, respectively). There were no differences in any other parameters (BMP-2 at Week 0 and 4; BMP -7 at Weeks 0, 2 and 4; HIF-1α at Weeks 0 and 4; IL-6 at Weeks 0, 2 and 4; VEGF at Week 4). In the biomechanical assessment, ultimate stress and failure energy were greater in the CO2 group than in the control group at Week 4 (ultimate stress 259.96 ± 74.33 N [95% CI 167.66 to 352.25] versus 422.45 ± 99.32 N [95% CI 299.13 to 545.77]; p < 0.001, failure energy 311.32 ± 99.01 Nmm [95% CI 188.37 to 434.25] versus 954.97 ± 484.39 Nmm [95% CI 353.51 to 1556.42]; p = 0.003, respectively). There was no difference in stiffness (216.77 ± 143.39 N/mm [95% CI 38.73 to 394.81] versus 223.68 ± 122.17 N/mm [95% CI 71.99 to 375.37]; p = 0.92).
Transcutaneous application of CO2 accelerated bone generation in a distraction osteogenesis model of rabbit tibias. As demonstrated in previous studies, CO2 treatment might affect bone regeneration in distraction osteogenesis by promoting angiogenesis, blood flow, and endochondral ossification.
The use of the transcutaneous application of CO2 may open new possibilities for shortening healing time in patients with distraction osteogenesis. However, a deeper insight into the mechanism of CO2 in the local tissue is required before it can be used in future clinical practice.]]></description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Basic Research</subject><subject>Biomechanics</subject><subject>Blood flow</subject><subject>Bone blood flow</subject><subject>Bone density</subject><subject>Bone Density - physiology</subject><subject>Bone growth</subject><subject>Bone healing</subject><subject>Bone mineral content</subject><subject>Bone mineral density</subject><subject>Bone morphogenetic protein 2</subject><subject>Bone morphogenetic protein 7</subject><subject>Bone Morphogenetic Proteins - metabolism</subject><subject>Bone Regeneration - physiology</subject><subject>Callus</subject><subject>Carbon dioxide</subject><subject>Carbon Dioxide - administration & dosage</subject><subject>Cartilage</subject><subject>Computed tomography</subject><subject>Distraction osteogenesis</subject><subject>Endochondral bone</subject><subject>Endothelial cells</subject><subject>Energy</subject><subject>Female</subject><subject>Fluorescein</subject><subject>Hypoxia-Inducible Factor 1 - metabolism</subject><subject>Hypoxia-inducible factor 1a</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Mechanical properties</subject><subject>Osteogenesis - physiology</subject><subject>Osteogenesis, Distraction - methods</subject><subject>Polymerase chain reaction</subject><subject>Rabbits</subject><subject>Radiography</subject><subject>Tibia - metabolism</subject><subject>Tibia - physiology</subject><subject>Ultrasound</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>X-Ray Microtomography</subject><issn>0009-921X</issn><issn>1528-1132</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU9vEzEQxS0EoqHwEUCWuPSyxX8zuxekkkJBqpQqKhI3y-udTVw262J7W_HtcZpStfXFmuffPHnmEfKes2POGvi0WK5Wx-zR4aKuX5AZ16KuOJfiJZkVtakawX8dkDcpXZVSKi1ekwMpQAoNMCP2AqObsh0xTIkuloJeRrR5i2OmJ87hgNFmTPRLGJGe4bgrfRjp6RT9uKanPuVo3Z20TBnDuiDJJ-pHurJt63N6S171dkj47v4-JD-_fb1cfK_Ol2c_FifnlZM1h6qTXNZ919SgXd-jQAbQNdrKRrVdz4VwrO37TmGrHCIw1UDfgJxzEJ0EzeQh-bz3vZ7aLXauTBDtYK6j39r41wTrzdOX0W_MOtwYkMCZksXg6N4ghj8Tpmy2PpUNDPvlGKFEAyAk4wX9-Ay9ClMcy3hGaAZqDkzrQuk95WJIKWL_8BnOzC5EswvRPA-x9H14PMlD1__UCqD2wG0YMsb0e5huMZoN2iFv7vwkq-eVYIKxulTVTgH5DycUqIM</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Kumabe, Yohei</creator><creator>Fukui, Tomoaki</creator><creator>Takahara, Shunsuke</creator><creator>Kuroiwa, Yu</creator><creator>Arakura, Michio</creator><creator>Oe, Keisuke</creator><creator>Oda, Takahiro</creator><creator>Sawauchi, Kenichi</creator><creator>Matsushita, Takehiko</creator><creator>Matsumoto, Tomoyuki</creator><creator>Hayashi, Shinya</creator><creator>Kuroda, Ryosuke</creator><creator>Niikura, Takahiro</creator><general>Wolters Kluwer</general><general>Lippincott Williams & Wilkins Ovid Technologies</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200801</creationdate><title>Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits</title><author>Kumabe, Yohei ; Fukui, Tomoaki ; Takahara, Shunsuke ; Kuroiwa, Yu ; Arakura, Michio ; Oe, Keisuke ; Oda, Takahiro ; Sawauchi, Kenichi ; Matsushita, Takehiko ; Matsumoto, Tomoyuki ; Hayashi, Shinya ; Kuroda, Ryosuke ; Niikura, Takahiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3817-d3138fd9875cffe2e077d95a394bdf122c0bffd4eb4cee70497f9736172d37503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Basic Research</topic><topic>Biomechanics</topic><topic>Blood flow</topic><topic>Bone blood flow</topic><topic>Bone density</topic><topic>Bone Density - physiology</topic><topic>Bone growth</topic><topic>Bone healing</topic><topic>Bone mineral content</topic><topic>Bone mineral density</topic><topic>Bone morphogenetic protein 2</topic><topic>Bone morphogenetic protein 7</topic><topic>Bone Morphogenetic Proteins - metabolism</topic><topic>Bone Regeneration - physiology</topic><topic>Callus</topic><topic>Carbon dioxide</topic><topic>Carbon Dioxide - administration & dosage</topic><topic>Cartilage</topic><topic>Computed tomography</topic><topic>Distraction osteogenesis</topic><topic>Endochondral bone</topic><topic>Endothelial cells</topic><topic>Energy</topic><topic>Female</topic><topic>Fluorescein</topic><topic>Hypoxia-Inducible Factor 1 - metabolism</topic><topic>Hypoxia-inducible factor 1a</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - metabolism</topic><topic>Mechanical properties</topic><topic>Osteogenesis - physiology</topic><topic>Osteogenesis, Distraction - methods</topic><topic>Polymerase chain reaction</topic><topic>Rabbits</topic><topic>Radiography</topic><topic>Tibia - metabolism</topic><topic>Tibia - physiology</topic><topic>Ultrasound</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>X-Ray Microtomography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumabe, Yohei</creatorcontrib><creatorcontrib>Fukui, Tomoaki</creatorcontrib><creatorcontrib>Takahara, Shunsuke</creatorcontrib><creatorcontrib>Kuroiwa, Yu</creatorcontrib><creatorcontrib>Arakura, Michio</creatorcontrib><creatorcontrib>Oe, Keisuke</creatorcontrib><creatorcontrib>Oda, Takahiro</creatorcontrib><creatorcontrib>Sawauchi, Kenichi</creatorcontrib><creatorcontrib>Matsushita, Takehiko</creatorcontrib><creatorcontrib>Matsumoto, Tomoyuki</creatorcontrib><creatorcontrib>Hayashi, Shinya</creatorcontrib><creatorcontrib>Kuroda, Ryosuke</creatorcontrib><creatorcontrib>Niikura, Takahiro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical orthopaedics and related research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumabe, Yohei</au><au>Fukui, Tomoaki</au><au>Takahara, Shunsuke</au><au>Kuroiwa, Yu</au><au>Arakura, Michio</au><au>Oe, Keisuke</au><au>Oda, Takahiro</au><au>Sawauchi, Kenichi</au><au>Matsushita, Takehiko</au><au>Matsumoto, Tomoyuki</au><au>Hayashi, Shinya</au><au>Kuroda, Ryosuke</au><au>Niikura, Takahiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits</atitle><jtitle>Clinical orthopaedics and related research</jtitle><addtitle>Clin Orthop Relat Res</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>478</volume><issue>8</issue><spage>1922</spage><epage>1935</epage><pages>1922-1935</pages><issn>0009-921X</issn><eissn>1528-1132</eissn><abstract><![CDATA[Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported.
We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy?
Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantification on the plain radiographs to evaluate consolidation in the distraction gap with image analyzing software. Callus parameters were measured with micro-CT to assess callus microstructure. The newly formed bone area and cartilage area were measured histologically with safranin O/fast green staining to assess the progress of ossification. We also performed immunohistochemical staining of endothelial cells with fluorescein-labeled isolectin B4 and examined capillary density to evaluate angiogenesis. Gene expressions in newly generated callus were analyzed by real-time polymerase chain reaction. Biomechanical strength, stiffness, and energy were determined from a three-point bend test to assess the mechanical strength of the callus.
Radiographs showed higher pixel values in the distracted area in the CO2 group than the control group at Week 4 of the consolidation phase (0.98 ± 0.11 [95% confidence interval 0.89 to 1.06] versus 1.19 ± 0.23 [95% CI 1.05 to 1.34]; p = 0.013). Micro-CT demonstrated that bone volume fraction in the CO2 group was higher than that in the control group at Week 4 (5.56 ± 3.21 % [95% CI 4.32 to 6.12 %] versus 11.90 ± 3.33 % [95% CI 9.63 to 14.25 %]; p = 0.035). There were no differences in any other parameters (that is, callus bone mineral content at Weeks 2 and 4; volumetric bone mineral density at Weeks 2 and 4; bone volume fraction at Week 2). At Week 2, rabbits in the CO2 group had a larger cartilage area compared with those in the control group (2.09 ± 1.34 mm [95% CI 1.26 to 2.92 mm] versus 5.10 ± 3.91 mm [95% CI 2.68 to 7.52 mm]; p = 0.011). More newly formed bone was observed in the CO2 group than the control group at Week 4 (68.31 ± 16.32 mm [95% CI 58.19 to 78.44 mm] versus 96.26 ± 19.37 mm [95% CI 84.25 to 108.26 mm]; p < 0.001). There were no differences in any other parameters (cartilage area at Weeks 0 and 4; newly formed bone area at Weeks 0 and 2). Immunohistochemical isolectin B4 staining showed greater capillary densities in rabbits in the CO2 group than the control group in the distraction area at Week 0 and surrounding tissue at Weeks 0 and 2 (distraction area at Week 0, 286.54 ± 61.55 /mm [95% CI 232.58 to 340.49] versus 410.24 ± 55.29 /mm [95% CI 361.78 to 458.71]; p < 0.001; surrounding tissue at Week 0 395.09 ± 68.16/mm [95% CI 335.34 to 454.83] versus 589.75 ± 174.42/mm [95% CI 436.86 to 742.64]; p = 0.003; at Week 2 271.22 ± 169.42 /mm [95% CI 122.71 to 419.73] versus 508.46 ± 49.06/mm [95% CI 465.45 to 551.47]; p < 0.001 respectively). There was no difference in the distraction area at Week 2. The expressions of BMP -2 at Week 2, HIF1-α at Week 2 and VEGF at Week 0 and 2 were greater in the CO2 group than in the control group (BMP -2 at Week 2 3.84 ± 0.83 fold [95% CI 3.11 to 4.58] versus 7.32 ± 1.63 fold [95% CI 5.88 to 8.75]; p < 0.001; HIF1-α at Week 2, 10.49 ± 2.93 fold [95% CI 7.91 to 13.06] versus 20.74 ± 11.01 fold [95% CI 11.09 to 30.40]; p < 0.001; VEGF at Week 0 4.80 ± 1.56 fold [95% CI 3.43 to 6.18] versus 11.36 ± 4.82 fold [95% CI 7.13 to 15.59]; p < 0.001; at Week 2 31.52 ± 8.26 fold [95% CI 24.27 to 38.76] versus 51.05 ± 15.52 fold [95% CI 37.44 to 64.66]; p = 0.034, respectively). There were no differences in any other parameters (BMP-2 at Week 0 and 4; BMP -7 at Weeks 0, 2 and 4; HIF-1α at Weeks 0 and 4; IL-6 at Weeks 0, 2 and 4; VEGF at Week 4). In the biomechanical assessment, ultimate stress and failure energy were greater in the CO2 group than in the control group at Week 4 (ultimate stress 259.96 ± 74.33 N [95% CI 167.66 to 352.25] versus 422.45 ± 99.32 N [95% CI 299.13 to 545.77]; p < 0.001, failure energy 311.32 ± 99.01 Nmm [95% CI 188.37 to 434.25] versus 954.97 ± 484.39 Nmm [95% CI 353.51 to 1556.42]; p = 0.003, respectively). There was no difference in stiffness (216.77 ± 143.39 N/mm [95% CI 38.73 to 394.81] versus 223.68 ± 122.17 N/mm [95% CI 71.99 to 375.37]; p = 0.92).
Transcutaneous application of CO2 accelerated bone generation in a distraction osteogenesis model of rabbit tibias. As demonstrated in previous studies, CO2 treatment might affect bone regeneration in distraction osteogenesis by promoting angiogenesis, blood flow, and endochondral ossification.
The use of the transcutaneous application of CO2 may open new possibilities for shortening healing time in patients with distraction osteogenesis. However, a deeper insight into the mechanism of CO2 in the local tissue is required before it can be used in future clinical practice.]]></abstract><cop>United States</cop><pub>Wolters Kluwer</pub><pmid>32732577</pmid><doi>10.1097/CORR.0000000000001288</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0009-921X |
| ispartof | Clinical orthopaedics and related research, 2020-08, Vol.478 (8), p.1922-1935 |
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| source | MEDLINE; PubMed (Medline); EZB Electronic Journals Library |
| subjects | Angiogenesis Animals Basic Research Biomechanics Blood flow Bone blood flow Bone density Bone Density - physiology Bone growth Bone healing Bone mineral content Bone mineral density Bone morphogenetic protein 2 Bone morphogenetic protein 7 Bone Morphogenetic Proteins - metabolism Bone Regeneration - physiology Callus Carbon dioxide Carbon Dioxide - administration & dosage Cartilage Computed tomography Distraction osteogenesis Endochondral bone Endothelial cells Energy Female Fluorescein Hypoxia-Inducible Factor 1 - metabolism Hypoxia-inducible factor 1a Interleukin 6 Interleukin-6 - metabolism Mechanical properties Osteogenesis - physiology Osteogenesis, Distraction - methods Polymerase chain reaction Rabbits Radiography Tibia - metabolism Tibia - physiology Ultrasound Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism X-Ray Microtomography |
| title | Percutaneous CO2 Treatment Accelerates Bone Generation During Distraction Osteogenesis in Rabbits |
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