Dental abnormalities in rare genetic bone diseases: Literature review.

Currently, over 500 rare genetic bone disorders are identified. These diseases are often accompanied by dental abnormalities, which are sometimes the first clue for an early diagnosis. However, not many dentists are sufficiently familiar with phenotypic abnormalities and treatment approaches when they encounter patients with rare diseases. Such patients often need dental treatment but have difficulties in finding a dentist who can treat them appropriately. Herein we focus on major dental phenotypes and summarize their potential causes and mechanisms, if known. We discuss representative diseases, dental treatments, and their effect on the oral health of patients and on oral health-related quality of life. This review can serve as a starting point for dentists to contribute to early diagnosis and further investigate the best treatment options for patients with rare disorders, with the goal of optimizing treatment outcomes.

Risk factors associated with prognosis of patients with medication-related osteonecrosis of the jaw.

OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive and/or antiangiogenic agents. As the treatment application for MRONJ is controversial, we aimed to identify the risk factors for poor prognosis and to help determine appropriate management. METHODS: This study included 119 patients. Relevant clinical data were obtained for all the patients. In computed tomography images, osteosclerosis, osteolysis, cortical perforation (buccal or lingual), periosteal reaction, and sequestration were evaluated. RESULTS: Multivariate analyses showed statistically significant associations between poor prognosis in patients with MRONJ and conservative treatment alone (hazard ratio [HR] 1.89), osteolysis (HR 4.67), and the absence of sequestration (HR 5.33). CONCLUSIONS: Conservative treatment alone without clear objectives needs to be avoided, and osteolytic change could be the criteria for surgical intervention. As the boundary between the lesion and vital bone is indistinct, we recommend extensive surgery in cases with unpredictable sequestration.

Is the LRINEC score useful for predicting necrotizing fasciitis as a complication of MRONJ?

INTRODUCTION: Necrotizing fasciitis as a complication of medication-related osteonecrosis of the jaw (MRONJ), which we named "ONJ-NF", has been sometimes reported. This study aimed to investigate the usefulness of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score for predicting ONJ-NF. MATERIALS AND METHODS: We included patients with acute MRONJ who required hospitalization at a single institution from April 2013 to June 2022. They were divided into two groups: patients with ONJ-NF and those with severe cellulitis as a complication of MRONJ, which we named "ONJ-SC." LRINEC scores were compared between the groups and the cut-off value of the score was set by creating a receiver operating characteristic curve. RESULTS: Eight patients with ONJ-NF and 22 patients with ONJ-SC were included. The LRINEC score was significantly higher in patients with ONJ-NF (median: 8.0 points, range 6-10 points) than in those with ONJ-SC (median: 2.5 points, range 0-6 points). A LRINEC score of ≥ 6 points had a sensitivity of 100.0%, a specificity of 77.3%, and an area under the curve of 0.97. Among 6 parameters of LRINEC score, only C-reactive protein (CRP) and white blood cell count (WBC) had significant differences between two groups. Most of the patients with ONJ-NF were rescued by antibiotic therapy and surgical drainage including debridement of necrotic tissues, but unfortunately, one patient did not survive. CONCLUSION: Our results suggested that the LRINEC score may be a useful diagnostic tool to predict ONJ-NF but valuating only CRP and WBC may be sufficient particularly in patients with osteoporosis.

Risk factors for pathological fracture in patients with mandibular osteoradionecrosis.

Osteoradionecrosis (ORN) often results in pathological fractures through progression. We aimed to identify the risk factors for pathological fracture in patients with mandibular ORN. Seventy-four patients with mandibular ORN were included in this retrospective study. We investigated various risk factors for pathological fracture in patients with mandibular ORN, including number of mandibular teeth with a poor prognosis each at initial evaluation before radiation therapy (RT) and when fracture occurred, and the proportion of antibiotic administration period in a follow-up duration after RT. The rate of occurrence of pathological fractures in patients with mandibular ORN was 25.7%. The median of duration between RT completion and fracture occurrence was 74.0 months. We found that pathological fracture was significantly associated with a larger number of mandibular teeth with a poor prognosis at initial evaluation before RT (P = 0.024) and when fracture occurred (P = 0.009). Especially, a larger number of mandibular teeth with P4 periodontitis, in other words severe periodontal status, was related to pathological fracture in both timings. The proportion of antibiotic administration period in a follow-up duration was also significant risk factor (P = 0.002). Multivariate analyses showed statistically significant associations between pathological fracture and a larger number of mandibular teeth with a poor prognosis when fracture occurred (hazard ratio 3.669). The patient with a larger number of mandibular teeth with P4 periodontitis may have a risk of not only occurrence of ORN but resulting in pathological fracture by accumulation of infection. Surgeons should consider extraction of those teeth regardless of before/after RT if necessary for infection control.

Relationship between oral health and prognosis in patients with empyema: Single center retrospective study with propensity score matching analysis.

BACKGROUND: Empyema is a life-threatening infection often caused by oral microbiota. To the best of our knowledge, no reports have investigated the association between the objective assessment of oral health and prognosis in patients with empyema. MATERIALS AND METHODS: A total of 63 patients with empyema who required hospitalization at a single institution were included in this retrospective study. We compared non-survivors and survivors to assess risk factors for death at three months, including the Renal, age, pus, infection, diet (RAPID) score, and Oral Health Assessment Tool (OHAT) score. Furthermore, to minimize the background bias of the OHAT high-score and low-score groups determined based on the cut-off value, we also analyzed the association between the OHAT score and death at 3 months using the propensity score matching method. RESULTS: The 3-month mortality rate was 20.6% (13 patients). Multivariate analysis showed that a RAPID score ≥5 points (odds ratio (OR) 8.74) and an OHAT score ≥7 points (OR 13.91) were significantly associated with death at 3 months. In the propensity score analysis, a significant association was found between a high OHAT score (≥7 points) and death at 3 months (P = 0.019). CONCLUSION: Our results indicated that oral health assessed using the OHAT score may be a potential independent prognostic factor in patients with empyema. Similar to the RAPID score, the OHAT score may become an important indicator for the treatment of empyema.

Hematologic and inflammatory parameters for determining severity of odontogenic infections at admission: a retrospective study.

BACKGROUND: Severe odontogenic infections in the head and neck region, especially necrotizing soft tissue infection (NSTI) and deep neck abscess, are potentially fatal due to their delayed diagnosis and treatment. Clinically, it is often difficult to distinguish NSTI and deep neck abscess in its early stage from cellulitis, and the decision to perform contrast-enhanced computed tomography imaging for detection is often a challenge. This retrospective case-control study aimed to examine the utility of routine blood tests as an adjunctive diagnostic tool for NSTI in the head and neck region and deep neck abscesses. METHODS: Patients with severe odontogenic infections in the head and neck region that required hospitalization were classified into four groups. At admission, hematologic and inflammatory parameters were calculated according to the blood test results. In addition, a decision tree analysis was performed to detect NSTI and deep neck abscesses. RESULTS: There were 271 patients, 45.4% in Group I (cellulitis), 22.5% in Group II (cellulitis with shallow abscess formation), 27.3% in Group III (deep neck abscess), and 4.8% in Group IV (NSTI). All hematologic and inflammatory parameters were higher in Groups III and IV. The Laboratory Risk Indicator for Necrotizing Fasciitis score, with a cut-off value of 6 and C-reactive protein (CRP) + the neutrophil-to-lymphocyte ratio (NLR), with a cut-off of 27, were remarkably useful for the exclusion diagnosis for Group IV. The decision tree analysis showed that the systemic immune-inflammation index (SII) of ≥ 282 or < 282 but with a CRP + NLR of ≥ 25 suggests Group III + IV and the classification accuracy was 89.3%. CONCLUSIONS: Hematologic and inflammatory parameters calculated using routine blood tests can be helpful as an adjunctive diagnostic tool in the early diagnosis of potentially fatal odontogenic infections. An SII of ≥ 282 or < 282 but with a CRP + NLR of ≥ 25 can be useful in the decision-making for performing contrast-enhanced computed tomography imaging.

Prevalence of and risk factors for postoperative complications after lower third molar extraction: A multicenter prospective observational study in Japan.

Lower third molar extraction is the most common surgical treatment among routine dental and oral surgical procedures. while the surgical procedures for lower third molar extraction are well established, the difficulty of tooth extraction and the frequency of postoperative complications differ depending on the patient's background. To establish a management protocol for the lower third molars, the prevalence of and risk factors for postoperative complications after lower third molar extraction were investigated in a large number of Japanese patients in a multicenter prospective study. During 6 consecutive months in 2020, 1826 lower third molar extractions were performed at the 20 participating institutions. The medical records of the patients were reviewed, and relevant data were extracted. The prevalence of and risk factors for postoperative complications were analyzed. The prevalence of postoperative complications after lower third molar extraction was 10.0%. Multivariate analysis indicated that age (≤32 vs >32, odds ratio [OR]: 1.428, 95% confidence interval [95% CI]: 1.040-1.962, P < .05), the radiographic anatomical relationship between the tooth roots and mandibular canal (overlapping of the roots and canal vs no close anatomical relationship between the roots and the superior border of the canal, OR: 2.078, 95% CI: 1.333-3.238, P < .01; overlapping of the roots and canal vs roots impinging on the superior border of the canal, OR: 1.599, 95% CI: 1.050-2.435, P < .05), and impaction depth according to the Pell and Gregory classification (position C vs position A, OR: 3.7622, 95% CI: 2.079-6.310, P < .001; position C vs position B, OR: 2.574, 95% CI: 1.574-4.210, P < .001) are significant independent risk factors for postoperative complications after lower third molar extraction. These results suggested that higher age and a deeply impacted tooth might be significant independent risk factors for postoperative complications after lower third molar extraction.

Effect of compression on mandibular fracture haematoma-derived cells.

Mechanical stress induces a variety of biochemical and morphological reactions in bone cell biology. This study aimed to investigate appropriate pressures of osteogenesis on the biological responses of 3-dimensional cultured human mandibular fracture haematoma-derived cells by compressive loading. Six patients with mandibular fractures who underwent open reduction and internal fixation were included in the study. During the operation, fracture haematomas that formed fibrin clots were manually removed before irrigation. First, pressures were applied to human mandibular fracture haematoma-derived cell-seeded collagen sponges. The sponges were subjected to mechanical compression using loading equipment applied at no compression, 0.5, or 1 mm. Compressive loading was applied to the samples prior to compression for 0, 6, 12, or 24 hours. Collagen sponge samples were collected for quantification of mRNA using several parameters including alkaline phosphatase (ALP), osteopontin (OPN), osterix (OSX), runt-related gene 2 (RUNX2), protein level, and immunocytochemistry (anti-sclerostin). Among these the 0.5 mm compression group compared with the control and 1.0 mm compression groups upregulated mRNA expression of OPN and OSX after 24 hours. Additionally, compared with the control group, a significantly higher OSX gene expression was observed in both the 0.5 mm and 1.0 mm groups after 6, 12, and 24 hours of compression (p < 0.05). However, no significant differences were observed regarding ALP and RUNX2 expression. These results indicated increased stimulation of osteogenesis of the mandibular fracture-line gap in the 0.5 mm compression group compared with the control and 1.0 mm compression groups.

Factors Associated with Treatment Outcomes and Pathological Features in Patients with Osteoradionecrosis: A Retrospective Study.

A standard treatment for osteoradionecrosis (ORN) has not yet been established because of the diversity. Therefore, identifying the risk factors for a poor prognosis is essential. This study retrospectively investigated the factors associated with the prognosis of ORN in 68 patients. Relevant clinical data of all patients were obtained. Of the patients, 16 who underwent extensive surgery underwent histopathological analysis. The necrotic changes of the anterior and posterior margins in the cortical and cancellous bones were investigated. Multivariate analyses showed statistically significant associations between poor prognosis in patients with ORN and high radiation dose (hazard ratio [HR] 1.15), orocutaneous fistula (HR 2.93), and absence of sequestration (HR 2.49). Histopathological analysis showed a viable anterior margin of the middle portion of the cortical bone for all recovered cases; in contrast, most cases (75%) with a poor prognosis showed necrotic changes. The anterior margin of the cancellous bone was viable and resilient to high irradiation, regardless of the prognosis. These results suggest that patients with orocutaneous fistula should receive early surgical intervention, even if the affected area is limited or asymptomatic. In extensive surgery, a sufficient safety margin of necrotic bone, particularly in the anterior region, is required to improve the prognosis.

Risk factors associated with post-extraction bleeding in patients on warfarin or direct-acting oral anticoagulants: a retrospective cohort study.

PURPOSE: The purpose of this study was to investigate the risk factors associated with post-extraction persistent bleeding in patients on warfarin or direct-acting oral anticoagulants (DOACs) and the ability of risk scores to predict post-extraction bleeding. METHODS: Three hundred ninety-one patients taking warfarin or DOACs underwent tooth extractions. Various risk factors for post-extraction bleeding, including number of tooth extraction, with antiplatelet therapy, and risk scores, were investigated by univariate and multivariate analyses. A post-extraction bleeding was classified into grades 1-3. RESULTS: The incidence of post-extraction bleeding was 26.8% (77 out of 287 patients; grade 1: 63, grade 2:14) in patients taking warfarin, and 26.0% (27 out of 104 patients; grade 1: 20, grade 2:7) in patients taking warfarin DOACs. Multivariate analyses showed that multiple teeth extractions and HAS-BLED scores (above 3 points) in patients taking warfarin, and only multiple teeth extractions in patients taking DOAC, were significantly associated with post-extraction bleeding, respectively. CONCLUSION: Most of the post-extraction bleedings were grade 1, which can be stopped by eligibly pressing gauze by surgeons. If patients taking anticoagulants are scheduled to undergo multiple teeth extractions or their HAS-BLED score are above 3 points (if warfarin), we recommend informing patients risk of post-extraction bleeding before operation, taking carefully hemostasis, and instructing patients to bite down accurately on the gauze for longer than usual.

The characteristics of oro-cervical necrotizing fasciitis-Comparison with severe cellulitis of oro-cervical region and necrotizing fasciitis of other body regions.

BACKGROUND: Necrotizing fasciitis (NF) is an acute and life-threatening soft-tissue infection however rarely seen in oro-cervical region. Therefore, the details of oro-cervical NF (OCNF) are not well known. The purpose of this study was to investigate the characteristics of OCNF by comparing it with severe cellulitis of oro-cervical region (OCSC) or NF of other body regions (e.g., limb, perineum, and trunk) (BNF), respectively. MATERIALS AND METHODS: At first, various risk factors for OCNF in oro-cervical severe infection (OCSI; composed of OCNF and OCSC), including neutrophil-to-lymphocyte ratio (NLR) and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, were investigated by univariate and multivariate analyses. Next, the differences between OCNF and BNF, including inflammatory markers and mortality, were investigated. RESULTS: In the present study, 14 out of 231 OCSI patients had OCNF. Multivariate analyses of OCSI patients showed that NLR ≥15.3 and LRINEC score ≥6 points were significantly related to OCNF. During the same period, 17 patients had BNF. The OCNF group had significantly higher inflammatory markers than the BNF group when diagnosis, but significantly lower clinical stages at the time and mortality as outcomes. CONCLUSION: We found that compared to BNF, OCNF can be detected at lower clinical stage by using indexes, such as NLR and LRINEC score, besides clinical findings, which may help contributing to patient's relief.

Can CT predict the development of oroantral fistula in patients undergoing maxillary third molar removal?

PURPOSE: In maxillary wisdom tooth extraction, the necessity of CT is unknown. The purpose of this study was to investigate whether CT adding to orthopantomography is useful for predicting oroantral perforation during maxillary third molar extraction. METHODS: Various risk factors for oroantral perforation during maxillary third molar extraction were investigated by univariate and multivariate analyses. We analyzed those of all patients and the patients who underwent CT, respectively. The proximity of the roots to the maxillary sinus floor (root-sinus [RS] classification) and Archer classification were assessed using panoramic radiography. The number of roots and vertical relationship were assessed using CT. RESULTS: A total of 604 out of 3299 patients underwent CT adding to orthopantomography. In all cases, multivariate analyses except for CT findings showed that the RS classification type III/IV and the Archer classification Type B/C/D in panoramic findings were significantly correlated with oroantral perforation as radiological findings. In cases for which CT was performed, multivariate analyses showed that one root (OR 12.87) and the vertical relationship Type D (OR 5.63) in CT findings, besides the RS classification type III/IV (OR 4.47) in panoramic findings, were significantly related to oroantral perforation. CONCLUSION: The RS classification and the Archer classification in panoramic findings can predict the risk of oroantral perforation. The usefulness of CT adding to orthopantomography is limited. However, when the relationship between the upper wisdom tooth and maxillary sinus floor (RS classification) is unclear, to check whether the number of roots is one and the apex of one root is projecting into the maxillary sinus in CT findings, is useful for the prediction.

Does prophylactic antibiotic administration for tooth extraction affect PT-INR in patients taking warfarin?

BACKGROUND: Various antibiotics and analgesics have been reported to interact with warfarin. Reports that investigate the effects of medication taken for just a few days during tooth extraction on the prothrombin time-international normalized ratio are rare. METHODS: A total of 110 patients receiving long-term stable warfarin therapy underwent tooth extraction without interruption of warfarin treatment. INR values were measured 1 month before the tooth extraction, the day of the extraction, and 1 week after the extraction. We investigated the changes in INR values between the day of extraction and 1 week after extraction, as well as the various risk factors for increases in INR values. RESULTS: Before and after tooth extraction, the number of patients taking cefcapene pivoxil, amoxicillin, and azithromycin was 57, 36, and 8, respectively. Nine patients were administered ampicillin before tooth extraction and received amoxicillin after their tooth extraction. One week after tooth extraction, the INR values increased beyond the therapeutic range in 3 out of 110 patients (2.7%). The INR values before tooth extraction in these three patients were close to 3.0. The INR value increased by more than twice as much in 1 out of 110 patients (0.9%). CONCLUSION: Our results suggest that prophylactic antibiotic administration has little effect on INR values when patients on stable warfarin therapy undergo tooth extraction. Surgeons have to take attention if the patients whose INR values are close to 3.0 before their extraction.

Factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas: a retrospective multicenter study of 326 patients.

PURPOSE: The present retrospective multicenter study intended to investigate the factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas. METHODS: A total of 326 patients who underwent radiotherapy for oral and oropharyngeal cancers were enrolled in the study. The patients' age, sex, body mass index, primary site, diabetes, serum albumin, creatinine, hemoglobin, leukocyte and lymphocyte, concurrent cisplatin or cetuximab, method of radiation, total radiation dose, feeding route, use of spacers, pilocarpine hydrochloride, and corticosteroid ointment were examined, and the associations of each variable with oral mucositis and candidiasis were analyzed by multivariate Cox regression analysis. RESULTS: Grade 3 oral mucositis occurred in 136 (41.7%) patients. Male sex, oropharyngeal cancer, low hemoglobin levels, low leukocytes or lymphocytes, concurrent cisplatin or cetuximab, and oral feeding were found to be significantly associated with a higher incidence of severe oral mucositis. Oral candidiasis occurred in 101 (31.0%) patients. Oropharyngeal cancer, low leukocyte count, and oral mucositis of grade 2 or higher were found to be significantly associated with a higher incidence of oral candidiasis. The use of a topical steroid ointment was not found to be a risk factor for oral candidiasis. CONCLUSIONS: The present retrospective study demonstrated that certain factors may predispose patients with oral and oropharyngeal cancers receiving radiotherapy to develop severe oral mucositis and oral candidiasis. A preventive strategy for severe oral mucositis needs to be established in the future for high-risk cases.

Induced Pluripotent Stem Cell-related Genes Correlate With Poor Prognoses of Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: We recently investigated the contribution of the iPS-related genes SOX2, OCT4, and Nanog to de-differentiation by assaying for their mRNA levels. Given that mRNA expression does not always correlate with the protein levels, the aim of this study was to retrospectively determine the expression of these four iPS-related factors in human OSCC specimens by immunohistochemistry and examine their association with patient prognosis. MATERIALS AND METHODS: iPS cell-related gene expression in 89 OSCC patients by tissue microarray, and its correlation with clinicopathological factors, differentiation, metastasis, and poor prognoses were investigated. RESULTS: No evidence of statistically significant relationships was found between the expression of iPS cell-related genes and clinicopathological parameters. However, our data indicated that KLF4 expression was associated with survival, and poor tumor differentiation. In addition, high expression of KLF4 was an independent poor prognostic factor (p=0.004) for OSCC patients. CONCLUSION: In preoperative biopsies, higher KLF4 and poor differentiation may be clinically effective predictors for the prognosis of oral cancer.

Effects of perioperative oral care on prevention of postoperative pneumonia after lung resection: Multicenter retrospective study with propensity score matching analysis.

BACKGROUND: Postoperative pneumonia can be a fatal complication that may occur after lung resection in cancer patients. Some reports have shown that the incidence of postoperative pneumonia is decreased after esophageal surgery by perioperative oral care; however, there exist no data to suggest that a lack of perioperative oral care can be a risk factor for postoperative pneumonia after lung resection. To investigate the association between the preventive effect of oral care and postoperative pneumonia, we conducted a multicenter, retrospective study of lung cancer patients who underwent lung resection. METHODS: Between January 2014 and December 2016, a total of 721 patients underwent lung resections at 1 of the 6 hospitals included in our study. Among 721 patients, 280 (38.8%) received perioperative oral care, and the remaining 441 (61.2%) did not receive any such care. Propensity score matching was performed to minimize selection biases associated with the comparison of retrospective data between the oral care and control groups. RESULTS: Of the 721 patients, 54 (7.5%) experienced postoperative pneumonia involving 13 of the 280 patients (4.6%) in the oral care group and 41 of the 441 patients (9.3%) in the control group (P = .02). On propensity score analysis, a significant difference was also found between oral care intervention and incidence of postoperative pneumonia (P = .002). CONCLUSION: Our results suggest that perioperative oral care is an effective method to decrease the occurrence of postoperative pneumonia in patients who have undergone lung resection.

Gold nanoparticles enhance X-ray irradiation-induced apoptosis in head and neck squamous cell carcinoma in vitro.

Enhancing the antitumor effect of radiation, while reducing damage to organs, is a significant challenge in radiation therapy for head and neck malignancies. One promising radiosensitizer is gold. The present study aimed to determine whether gold nanoparticles (AuNPs) have the potential to enhance the effects of X-ray irradiation on head and neck cancer cells. The human head and neck carcinoma cell line HSC-3 was used. Total cell number and the levels of cell proliferation and apoptosis were compared between control cells and cells treated with 5-nm AuNPs alone at four concentrations (0.1, 0.4, 1.0 and 10.0 nM), X-ray irradiation alone at three doses (2, 4 and 8 Gy), or a combination of 4 Gy X-ray irradiation and 1.0 nM AuNPs. Analysis of variance and Tukey-Kramer testing were performed to compare the different groups. The total number of cells significantly decreased following 4 and 8 Gy X-ray irradiation, compared with in the control group (control vs. 4Gy, P=2.19×10-4; control vs. 8Gy, P=1.28×10-6). The combination of 4 Gy X-ray irradiation and 1.0 nM AuNPs significantly reduced the total number of cells compared with 4 Gy X-ray irradiation alone (P=2.95×10-4). Cell proliferation was not affected by AuNP treatment alone, 4 Gy X-ray irradiation alone or the combination of X-ray irradiation and AuNPs. The combination of 4 Gy irradiation and 1.0 nM AuNPs significantly increased the number of apoptotic cells compared with 4 Gy irradiation alone (P=0.0261). In conclusion, AuNPs combined with X-ray irradiation enhanced the cytotoxic effect on human head and neck cancer cells in vitro, through the induction of apoptosis, but not inhibition of cell proliferation.

Effect of local application of transcutaneous carbon dioxide on survival of random-pattern skin flaps.

INTRODUCTION: Skin flap procedures are widely used to reconstruct skin and soft tissue defects. Skin flap necrosis is a serious postoperative complication. Many researchers have introduced pharmacological agents to improve flap ischemia in experimental studies. However, outcomes of these studies remain controversial. We previously demonstrated that transcutaneous CO2 application improves hypoxia in fracture repair. In this study, we hypothesized that improving hypoxia by transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis. We investigated whether transcutaneous CO2 application can increase the survival of random-pattern skin flaps. MATERIALS AND METHODS: Six-week-old male Sprague-Dawley rats were divided into two equal groups: the control group (n = 6) and CO2 group (n = 6). A random-pattern skin flap was constructed in these rats. Topical CO2 was applied using a hydrogel every day for 5 days in the CO2 group. The flap survival area was measured on postoperative days 1, 3, and 5. The vessel density and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hypoxia-inducible factor-1α (HIF-1α) were evaluated on postoperative day 5. RESULTS: A statistically significant difference was found in the percentage of the flap survival area between the two groups on postoperative days 3 and 5 (p < 0.05). Furthermore, the expression of VEGF and bFGF was significantly higher and that of HIF-1α was significantly lower in the CO2 than in the control group (p < 0.05). CONCLUSIONS: Transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis, thus increasing the survival of random-pattern skin flaps.