TY - JOUR
AU1 - Cho, Yoon, Soo
AU2 - Seo, Cheong, Hoon
AU3 - Joo, So, Young
AU4 - Song,, Jimin
AU5 - Cha,, Eunsil
AU6 - Ohn, Suk, Hoon
AB - Abstract Fibroblasts, keratinocytes, mast cells, and other cells participate in hypertrophic scar formation and express the vitamin D receptor. We investigated the association between vitamin D deficiency and the biomechanical properties of hypertrophic burn scars. This cross-sectional study analyzed 486 participants enrolled from May 1, 2013 to April 30, 2017. When complete wound healing was agreed with by the two opinions, blood sampling and scar evaluation were performed. The values of melanin and erythema, trans-epidermal water loss (TEWL), and scar distensibility and elasticity were measured using pigment- and TEWL-measuring devices and a suction skin elasticity meter. 25(OH) vitamin D deficiency was defined as plasma level of <20 ng/ml. The vitamin D-deficient patients had significantly higher mean values of scar melanin and TEWL (P = .032, P = .007), whereas scar erythema level was similar. They also showed significantly lower values of Uf (final distensibility; P < .001), Ua/Uf (gross elasticity; P < .001) and Ur/Uf (biological elasticity; P = .014), and higher value of Uv/Ue (viscoelasticity or potency against interstitial fluid shift; P = .016). In multiple linear regression analysis, Uf, Ua/Uf, Uv/Ue, and Ur/Uf were significantly affected by 25(OH)-vitamin D level in deficient patients (Uf, P = .017; Ua/Uf, P = .045; Uv/Ue, P = .024; Ur/Uf, P = .021). Our results demonstrated that vitamin D deficiency was significantly related to increased pigmentation, decreased skin barrier function, low scar distensibility and elasticity, and slow interstitial fluid movement in burn patients. Hypertrophic scar is one of the common postburn complications and hypertrophic scar formation is reported between 32 and 72% of burn survivors.1 The prevalence of hypertrophic scar has increased as burn mortality decreased owing to development in acute burn care. Excessive scar formation is associated with slower wound healing following burn injury, dark skin, burn location of neck and upper limb, burn severity, young age, and meshed skin graph and it can result in the limitation of joint motion, thick and non-pliable scars, pain, and itch.2 Diverse cells, such as fibroblasts, keratinocytes, and mast cells,3 participate in this pathologic process; notably, each of these cell types expresses the vitamin D receptor.4,5 25(OH)-vitamin D is mainly derived from 7-dehydrocholesterol via cutaneous synthesis, although it can be produced from dietary sources.6 Thus, the loss in body surface area (BSA) caused by burns can reduce pre-vitamin D productivity in the skin. Furthermore, the conversion of cholesterol precursor to pre-vitamin D by ultraviolet light is hampered in burn scars as well as in normal skin adjacent to the scars, suggesting that biomechanical abnormality may be both burn scars and healthy skin adjacent to the scars.7 Therefore, burn patients are higher risk population for 25(OH)-vitamin D deficiency.8 In a previous study, we showed consistent reduction in plasma vitamin D concentration in 87.1% of burn patients hospitalized in the rehabilitation department.9 In burn care, vitamin D engages in a pleiotropic role besides its traditional role in bone and calcium homeostasis.10 In the skin, 1,25(OH)-vitamin D helps to maintain the epidermal permeability barrier.11 Furthermore, 1,25-(OH) vitamin D promotes keratinocyte proliferation and differentiation in human epidermis,12 and fibroblast growth in normal human dermis.13 Low vitamin D level contributes to prolonged wound healing in the early phase.4,6,14 However, to our knowledge, few studies have demonstrated the relationship between vitamin D deficiency and the biomechanical properties of hypertrophic scars. Therefore, we hypothesized that postburn vitamin D deficiency may be related to biomechanical scar properties as well as hypertrophic scar formation owing to abnormal regulation of keratinocytes and fibroblasts following burn wound closure. To objectively demonstrate the relationship between the vitamin D deficiency and biomechanical scar properties in burn patients, we investigated the values of melanin and erythema, trans-epidermal water loss (TEWL), and scar distensibility and elasticity as well as 25(OH)-vitamin D levels. MATERIALS AND METHODS Study Participants This cross-sectional study analyzed clinical data from medical records and a clinical data warehouse database of burn patients who were sent directly from the burn center to the rehabilitation unit without returning home. The study protocol was approved by the institutional review board and informed consent for participants was waived (IRB No.2017–110). Initially, 1,716 burn participants (1,407 men, 309 women) from May 1, 2013 to April 30, 2017 were enrolled, but 1230 subjects were excluded because they had at least one of the following criteria: 1) burned BSA < 20% (n = 321); 2) history disorders such as hypoparathyroidism, hyperthyroidism, tumors, and chronic kidney disease (n = 81); 3) intake of nutritional supplements, including vitamin D (n = 162); 4) age >50 years old, as patients of this age have decreased 7-dehydrocholesterol content in the skin (n = 534); 5) received sex hormone therapy for osteoporosis (n = 6); and 6) missing data regarding one or more clinical values (n = 126). Finally, 486 participants (438 men and 48 women) were included in the analysis (Figure 1). Data were collected for the levels of 25(OH)-vitamin D, burn type, percentage of burned BSA, duration from burn injury to examination, length of stay in intensive care unit (ICU), and biomechanical parameters of the burn scar. One surgeon and one rehabilitation specialist assessed the status of the burn wound. When the two opinions agreed that wound healed completely, participants were sent directly from the burn center to the rehabilitation unit for blood sampling and scar evaluation without returning home. Figure 1. View largeDownload slide Flow diagram of patient enrollment. Figure 1. View largeDownload slide Flow diagram of patient enrollment. Measurement of Plasma 25(OH)-Vitamin D As 25(OH)-vitamin D is the main circulating form, the plasma level of total 25(OH)-vitamin D is routinely measured to assess vitamin D status in clinical practice.15 25(OH)-vitamin D level was measured using a radioimmunoassay analyzer (ADVIA Centaur XPT, Siemens, Germany) within 24 hours of refrigerated storage of the plasma. As described by Holick in 2007,16 vitamin D deficiency was defined as a plasma level < 20 ng/ml. Measurement of Scar Biomechanical Properties Melanin and Erythema Levels Melanin and erythema levels of the scar were investigated using the Mexameter® (MX18 Courage-Khazaka Electronics GmbH, Cologne, Germany). The measurement was obtained as soon as the scar contacted with the sensor.17,18 A higher value represents a darker and redder scar. Skin barrier function Skin barrier function was evaluated using a Tewameter® (Courage-Khazaka Electronics GmbH), which measures the TEWL of the burn scar. Relative humidity was 40–50%, and room temperature was adjusted to 20–25℃. The probe was placed on the scar for 30 seconds.17,18 Scar deformation Scar vertical deformation was measured using a Cutometer SEM 5801® (Courage-Khazaka Electronic GmbH) with an 8-mm-diameter probe. This probe pulls skin upwards with negative pressure for 5 seconds, followed by a relaxation period of 3 seconds.19Figure 2 shows a skin deformation curve with its corresponding absolute parameters. In this study, two absolute and three relative parameters were selected to compare the distensibility, elasticity, and viscoelasticity of the burn scar19 as follows. 1) Uf (final distensibility) indicates the firmness of the skin, which is related to the ability to stretch collagen and elastin fibers. 2) Ua/Uf (gross elasticity) is the capacity of the skin returning to original shape. This is associated with elastin function. 3) Uv/Ue (viscoelasticity or potency against interstitial fluid shift) is linked to the displacement of interstitial fluid containing viscous glycosaminoglycan and the deformation of the viscoelastic component. The ratio between viscoelastic properties and elastic distension is higher in firmer skin. 4) Ur/Uf (biological elasticity) is frequently selected in the clinical environment. This is also associated with elastin fiber function. 5) Hysteresis (H) implies a tiring effect, which is the difference of skin distension between first and the last suction.20 Figure 2. View largeDownload slide Skin deformation curve with its corresponding absolute parameters measured using a Cutometer®. Ue: immediate distension; Uv: delayed distension; Uf: final distension; Ur: immediate retraction; Ua: final retraction; R: residual deformation; H: hysteresis.19 Figure 2. View largeDownload slide Skin deformation curve with its corresponding absolute parameters measured using a Cutometer®. Ue: immediate distension; Uv: delayed distension; Uf: final distension; Ur: immediate retraction; Ua: final retraction; R: residual deformation; H: hysteresis.19 Statistical Analysis Continuous variables present as mean ± standard deviation and categorical variables do as number (%). According to 25(OH)-vitamin D levels, burn patients were divided into deficient and non-deficient groups. The assumption of homogeneity of variance was tested using Levene’s test of equality of variances. Percentage of burned BSA, duration from burn injury to complete wound healing, length of stay in the ICU, and biomechanical parameters of the burn scar were compared based on vitamin D status using Student’s t-test. Analysis for smoking, depressive mood, and numerical rating score >3 of pain used Fisher’s exact test. The one-way analysis of variance (ANOVA) was used to compare with biomechanical properties of hypertrophic burn scars according to vitamin D level quartiles. The effect of vitamin D deficiency on biomechanical scar properties was investigated using multiple linear regression analysis. All analyses were performed with SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, United States) and significance was established at P < .05. RESULTS Participant Characteristics Demographic characteristics of the included participants are presented in Table 1. There were 438 men (mean age, 37.1 ± 7.8 years) and 48 women (mean age, 33.81 ± 9.4 years) analyzed in this study. The mean percentage of burned BSA was 35.9 ± 13.4%, the mean duration from burn injury to examination was 57.5 ± 34.5 days, and the mean length of stay in the ICU was 15.4 ± 8.3 days. Patients were classified as follows depending on the burn injury type: flame burn, 285; electrical burn, 114; scalding burn, 39; contact burn, 27; chemical burn, 18; friction burn, 3. Table 1. Demographic characteristics of the participants Male: female 438: 48 Age (years; male:female) 37.1 ± 7.8: 33.81 ± 9.4 Burned BSA (%) 35.9 ± 13.4 Duration from burn injury to examination (days) 57.5 ± 34.5 Length of stay in ICU (days) 15.4 ± 8.3 FB: EB: SB: CoB: ChB: friction burn (number) 285: 114: 39: 27: 18: 3 Male: female 438: 48 Age (years; male:female) 37.1 ± 7.8: 33.81 ± 9.4 Burned BSA (%) 35.9 ± 13.4 Duration from burn injury to examination (days) 57.5 ± 34.5 Length of stay in ICU (days) 15.4 ± 8.3 FB: EB: SB: CoB: ChB: friction burn (number) 285: 114: 39: 27: 18: 3 BSA, body surface area; ICU, intensive care unit; FB, flame burn; EB, electrical burn; SB, scalding burn; CoB, contact burn; ChB, chemical burn. Data for continuous variables are expressed as mean ± standard deviation. View Large Table 1. Demographic characteristics of the participants Male: female 438: 48 Age (years; male:female) 37.1 ± 7.8: 33.81 ± 9.4 Burned BSA (%) 35.9 ± 13.4 Duration from burn injury to examination (days) 57.5 ± 34.5 Length of stay in ICU (days) 15.4 ± 8.3 FB: EB: SB: CoB: ChB: friction burn (number) 285: 114: 39: 27: 18: 3 Male: female 438: 48 Age (years; male:female) 37.1 ± 7.8: 33.81 ± 9.4 Burned BSA (%) 35.9 ± 13.4 Duration from burn injury to examination (days) 57.5 ± 34.5 Length of stay in ICU (days) 15.4 ± 8.3 FB: EB: SB: CoB: ChB: friction burn (number) 285: 114: 39: 27: 18: 3 BSA, body surface area; ICU, intensive care unit; FB, flame burn; EB, electrical burn; SB, scalding burn; CoB, contact burn; ChB, chemical burn. Data for continuous variables are expressed as mean ± standard deviation. View Large Clinical characteristics of the participants depending on vitamin D status are shown in Table 2. 25(OH)-vitamin D deficiency (<20 ng/ml) was shown in 420 (86.4%) patients (the deficient group). Mean 25(OH)-vitamin D level was 13.3 ± 3.2 ng/ml in the deficient group and 24.2 ± 3.6 ng/ml in the non-deficient group (P < .001). The two groups were not significantly different in age (P = .382). The percentage of burned BSA, duration from burn injury to examination, and length of stay in the ICU were 36.1 ± 9.4%, 59.8 ± 34.1 days, and 16.6 ± 9.5 days, respectively, in the deficient group, and 35.9 ± 13.8%, 38.3 ± 17.2 days, and 7.8 ± 7.4 days, respectively, in the non-deficient group. The deficient group showed significantly longer duration from burn injury to wound healing and length of stay in the ICU compared to that in the non-deficient group (all P < .001), whereas the two groups was not significantly different in burned BSA (P = .964). There was a significant correlation between 25(OH)-vitamin D deficiency and smoking and depressive mood (P = .046 and P = .038), whereas there was no significant association between 25(OH)-vitamin D deficiency and pain (P = .765). Table 2. Clinical characteristics of the participants according to 25(OH) vitamin D status 25(OH) vitamin D P-value Deficiency Non-deficiency Number n (%); total = 486 (100.0) 420 (86.4) 66 (13.6) 25(OH) vitamin D (ng/ml) 13.3 ± 3.2 24.2 ± 3.6 <.001** Age (yr) 37.0 ± 8.1 35.8 ± 7.0 .382 Burned BSA (%) 36.1 ± 9.4 35.9 ± 13.8 .964 Duration to examination (days) 59.8 ± 34.1 38.3 ± 17.2 <.001** ICU length of stay (days) 16.6 ± 9.5 7.8 ± 7.4 <.001** Smoking, n (%) 47 (33.6) 3 (13.6) .046* Depressive mood, n (%) 56 (40.0) 4 (18.2) .038* NRS > 3 of pain, n (%) 38 (27.1) 7 (31.8) .765 25(OH) vitamin D P-value Deficiency Non-deficiency Number n (%); total = 486 (100.0) 420 (86.4) 66 (13.6) 25(OH) vitamin D (ng/ml) 13.3 ± 3.2 24.2 ± 3.6 <.001** Age (yr) 37.0 ± 8.1 35.8 ± 7.0 .382 Burned BSA (%) 36.1 ± 9.4 35.9 ± 13.8 .964 Duration to examination (days) 59.8 ± 34.1 38.3 ± 17.2 <.001** ICU length of stay (days) 16.6 ± 9.5 7.8 ± 7.4 <.001** Smoking, n (%) 47 (33.6) 3 (13.6) .046* Depressive mood, n (%) 56 (40.0) 4 (18.2) .038* NRS > 3 of pain, n (%) 38 (27.1) 7 (31.8) .765 The data are displayed as mean ± standard deviations for continuous variables and N (%) for categorical variables. Student t-test was used for analysis of 25(OH)-vitamin D level, age, burned BSA, duration from burn injury to wound healing, and length of stay in the ICU; smoking, depressive mood, and numerical rating scale >3 of pain were analyzed using Fisher’s exact test. BSA, body surface area; ICU, intensive care unit; NRS, numerical rating scale. *P < .05 and **P < .001. View Large Table 2. Clinical characteristics of the participants according to 25(OH) vitamin D status 25(OH) vitamin D P-value Deficiency Non-deficiency Number n (%); total = 486 (100.0) 420 (86.4) 66 (13.6) 25(OH) vitamin D (ng/ml) 13.3 ± 3.2 24.2 ± 3.6 <.001** Age (yr) 37.0 ± 8.1 35.8 ± 7.0 .382 Burned BSA (%) 36.1 ± 9.4 35.9 ± 13.8 .964 Duration to examination (days) 59.8 ± 34.1 38.3 ± 17.2 <.001** ICU length of stay (days) 16.6 ± 9.5 7.8 ± 7.4 <.001** Smoking, n (%) 47 (33.6) 3 (13.6) .046* Depressive mood, n (%) 56 (40.0) 4 (18.2) .038* NRS > 3 of pain, n (%) 38 (27.1) 7 (31.8) .765 25(OH) vitamin D P-value Deficiency Non-deficiency Number n (%); total = 486 (100.0) 420 (86.4) 66 (13.6) 25(OH) vitamin D (ng/ml) 13.3 ± 3.2 24.2 ± 3.6 <.001** Age (yr) 37.0 ± 8.1 35.8 ± 7.0 .382 Burned BSA (%) 36.1 ± 9.4 35.9 ± 13.8 .964 Duration to examination (days) 59.8 ± 34.1 38.3 ± 17.2 <.001** ICU length of stay (days) 16.6 ± 9.5 7.8 ± 7.4 <.001** Smoking, n (%) 47 (33.6) 3 (13.6) .046* Depressive mood, n (%) 56 (40.0) 4 (18.2) .038* NRS > 3 of pain, n (%) 38 (27.1) 7 (31.8) .765 The data are displayed as mean ± standard deviations for continuous variables and N (%) for categorical variables. Student t-test was used for analysis of 25(OH)-vitamin D level, age, burned BSA, duration from burn injury to wound healing, and length of stay in the ICU; smoking, depressive mood, and numerical rating scale >3 of pain were analyzed using Fisher’s exact test. BSA, body surface area; ICU, intensive care unit; NRS, numerical rating scale. *P < .05 and **P < .001. View Large Biomechanical Scar Properties According to Burn Types To investigate the differences in biomechanical properties of hypertrophic scars among burn types, burn types were divided into flame burn, electrical burn, and other burns. The parameters of biomechanical properties were similar among three burn groups with no significant differences (all P > .05 except Uf) and exceptionally, there was significant difference between electrical burn and others in Uf (final distensibility) after post hoc comparison (P = .46) (Supplementary Table 1). Mean Values of Melanin, Erythema, and TEWL According to 25(OH)-Vitamin D Status To demonstrate the relationship between vitamin D status and biomechanical properties of hypertrophic burn scars, we compared mean values of melanin, erythema, and TEWL according to viamin D level quartiles (Supplementary Table 2) and between the vitamin D-deficient and non-deficient groups (Table 3 and Figure 3). There were no significant differences in the mean values of melanin, erythema, and TEWL according to vitamin D level quartiles (P = .241, P = .356 and P = .091). Additionally, the mean values of melanin and TEWL were 197.5 ± 65.3 AU (range, 138–306) and 23.9 ± 3.3 g/hr/m2 (range, 20–28) in the deficient group and 161.4 ± 53.8 AU (range, 105–265) and 19.4 ± 3.2 g/hr/m2 (range, 16–24) in the non-deficient group. Vitamin D-deficient patients had significantly higher mean values of melanin and TEWL (P = .032, P = .007). The mean erythema level was 437.3 ± 53.6 AU (range, 369–504) in the deficient group and 434.5 ± 55.2 AU (range, 345–459) in the non-deficient group (P = .465). Therefore, the degree of scar pigmentation and dryness were more severe in the 25(OH)-vitamin D-deficient group, whereas the erythema value was similar between the two groups. Table 3. Mean values of melanin, erythema, and TEWL according to 25(OH) vitamin D status vit.D Deficiency Non-vit D Deficiency P-value N = 420 N = 66 Melanin value (AU) 197.5 ± 65.3 (138–306) 161.4 ± 53.8 (105–265) .032* Erythema value (AU) 437.3 ± 53.6 (369–504) 434.5 ± 55.2 (345–459) .465 TEWL (g/hr/m2) 23.9 ± 3.3 (20–28) 19.4 ± 3.2 (16–24) .007* vit.D Deficiency Non-vit D Deficiency P-value N = 420 N = 66 Melanin value (AU) 197.5 ± 65.3 (138–306) 161.4 ± 53.8 (105–265) .032* Erythema value (AU) 437.3 ± 53.6 (369–504) 434.5 ± 55.2 (345–459) .465 TEWL (g/hr/m2) 23.9 ± 3.3 (20–28) 19.4 ± 3.2 (16–24) .007* TEWL, trans-epidermal water loss; vit., vitamin; N, number; AU, arbitrary unit. Statistical significance was examined using Student’s t-test. *P < .05. View Large Table 3. Mean values of melanin, erythema, and TEWL according to 25(OH) vitamin D status vit.D Deficiency Non-vit D Deficiency P-value N = 420 N = 66 Melanin value (AU) 197.5 ± 65.3 (138–306) 161.4 ± 53.8 (105–265) .032* Erythema value (AU) 437.3 ± 53.6 (369–504) 434.5 ± 55.2 (345–459) .465 TEWL (g/hr/m2) 23.9 ± 3.3 (20–28) 19.4 ± 3.2 (16–24) .007* vit.D Deficiency Non-vit D Deficiency P-value N = 420 N = 66 Melanin value (AU) 197.5 ± 65.3 (138–306) 161.4 ± 53.8 (105–265) .032* Erythema value (AU) 437.3 ± 53.6 (369–504) 434.5 ± 55.2 (345–459) .465 TEWL (g/hr/m2) 23.9 ± 3.3 (20–28) 19.4 ± 3.2 (16–24) .007* TEWL, trans-epidermal water loss; vit., vitamin; N, number; AU, arbitrary unit. Statistical significance was examined using Student’s t-test. *P < .05. View Large Figure 3. View largeDownload slide To demonstrate the association between vitamin D deficiency on biomechanical properties of hypertrophic burn scars, we compared mean values of melanin, erythema, and TEWL according to 25(OH)-vitamin D status using Student’s t-test. Vitamin D-deficient patients had significantly higher mean values of melanin and TEWL. *P < .05. TEWL, trans-epidermal water loss. Figure 3. View largeDownload slide To demonstrate the association between vitamin D deficiency on biomechanical properties of hypertrophic burn scars, we compared mean values of melanin, erythema, and TEWL according to 25(OH)-vitamin D status using Student’s t-test. Vitamin D-deficient patients had significantly higher mean values of melanin and TEWL. *P < .05. TEWL, trans-epidermal water loss. Five Biomechanical Parameters According to 25(OH)-Vitamin D Status Two absolute and three relative parameters were compared according to vitamin D level quartiles (Supplementary Table 2) and between the vitamin D-deficient and non-deficient groups (Figure 4) to examine the association between 25(OH)-vitamin D status and biomechanical scar properties. There were significantly differences in the mean values of Uf (final distensibility; P < .001) and Uv/Ue (viscoelasticity; P = .009) according to vitamin D level quartiles and but not in the mean values of Ua/Uf and Ur/Uf (gross elasticity; P = .058 and biological elasticity; P = .370). according to vitamin D level quartiles. Furthermore, the burn scars in the vitamin D-deficient group showed significantly lower Uf (final distensibility; P < .001), Ua/Uf (gross elasticity; P < .001) and Ur/Uf (biological elasticity; P = .014), and higher Uv/Ue (viscoelasticity; P = .016), compared with values in the non-deficient group. These findings suggested that the vitamin D-deficient group had firmer fibrous scars. However, there was no significant difference in the mean value of H (tiring effect; P = .095) between the two groups. Multiple linear regression results demonstrated the influence of vitamin D level on biomechanical scar properties in burn patients with vitamin D deficiency (Table 4). 25(OH)-vitamin D status significantly affected Uf, Ua/Uf, Uv/Ue, and Ur/Uf in the deficient patients (Uf, P = .017; Ua/Uf, P = .045; Uv/Ue, P = .024 and Ur/Uf, P = .021). Uv/Ue and Ur/Uf were also affected by percentage of burned BSA (Uv/Ue, P = .037 and Ur/Uf, P = .023). However, vitamin D levels did not significantly influence dependent variables in the non-deficient patients. Table 4. Multiple linear regression analysis of vitamin D level and factors related to burn injury affecting biomechanical scar properties in burn patients with vitamin D deficiency Uf Ua/Uf Uv/Ue Ur/Uf β P-value β P-value β P-value β P-value 25(OH) vitamin D (ng/ml) 0.003 .017* 0.006 .045* −0.153 .024* 0.239 .021* Age (years) −0.005 .492 0.001 .591 −0.006 .896 −0.010 .897 Burned BSA (%) −0.001 .347 8.325 .683 0.063 .037* 0.116 .023* Duration to examination (days) −1.205 .830 1.913 .478 −4.862 .713 −9.131 .709 Adjusted R2 0.19 0.18 0.22 0.21 Uf Ua/Uf Uv/Ue Ur/Uf β P-value β P-value β P-value β P-value 25(OH) vitamin D (ng/ml) 0.003 .017* 0.006 .045* −0.153 .024* 0.239 .021* Age (years) −0.005 .492 0.001 .591 −0.006 .896 −0.010 .897 Burned BSA (%) −0.001 .347 8.325 .683 0.063 .037* 0.116 .023* Duration to examination (days) −1.205 .830 1.913 .478 −4.862 .713 −9.131 .709 Adjusted R2 0.19 0.18 0.22 0.21 Multiple linear regression analyses were used to demonstrate the influence of vitamin D level on parameters of dependent variables in burn patients with vitamin D deficiency. BSA, body surface area; ICU, intensive care unit; Uf, final distensibility; Ua/Uf, gross elasticity; Uv/Ue, viscoelasticity; Ur/Uf, biological elasticity. *P < .05 and **P < .001. View Large Table 4. Multiple linear regression analysis of vitamin D level and factors related to burn injury affecting biomechanical scar properties in burn patients with vitamin D deficiency Uf Ua/Uf Uv/Ue Ur/Uf β P-value β P-value β P-value β P-value 25(OH) vitamin D (ng/ml) 0.003 .017* 0.006 .045* −0.153 .024* 0.239 .021* Age (years) −0.005 .492 0.001 .591 −0.006 .896 −0.010 .897 Burned BSA (%) −0.001 .347 8.325 .683 0.063 .037* 0.116 .023* Duration to examination (days) −1.205 .830 1.913 .478 −4.862 .713 −9.131 .709 Adjusted R2 0.19 0.18 0.22 0.21 Uf Ua/Uf Uv/Ue Ur/Uf β P-value β P-value β P-value β P-value 25(OH) vitamin D (ng/ml) 0.003 .017* 0.006 .045* −0.153 .024* 0.239 .021* Age (years) −0.005 .492 0.001 .591 −0.006 .896 −0.010 .897 Burned BSA (%) −0.001 .347 8.325 .683 0.063 .037* 0.116 .023* Duration to examination (days) −1.205 .830 1.913 .478 −4.862 .713 −9.131 .709 Adjusted R2 0.19 0.18 0.22 0.21 Multiple linear regression analyses were used to demonstrate the influence of vitamin D level on parameters of dependent variables in burn patients with vitamin D deficiency. BSA, body surface area; ICU, intensive care unit; Uf, final distensibility; Ua/Uf, gross elasticity; Uv/Ue, viscoelasticity; Ur/Uf, biological elasticity. *P < .05 and **P < .001. View Large Figure 4. View largeDownload slide To demonstrate the relationship between vitamin D deficiency and biomechanical scar properties, five parameters were compared between vitamin D-deficient and non-deficient groups using Student’s t-test. Vitamin D-deficient patients showed significantly lower Uf, Ua/Uf and Ur/Uf, and higher Uv/Ue, indicating firmer fibrous scars. Uf, final distensibility; Ua/Uf, gross elasticity; Uv/Ue, viscoelasticity; Ur/Uf, biological elasticity; H, tiring effect. *P < .05. Figure 4. View largeDownload slide To demonstrate the relationship between vitamin D deficiency and biomechanical scar properties, five parameters were compared between vitamin D-deficient and non-deficient groups using Student’s t-test. Vitamin D-deficient patients showed significantly lower Uf, Ua/Uf and Ur/Uf, and higher Uv/Ue, indicating firmer fibrous scars. Uf, final distensibility; Ua/Uf, gross elasticity; Uv/Ue, viscoelasticity; Ur/Uf, biological elasticity; H, tiring effect. *P < .05. DISCUSSION Keratinocytes, fibroblasts, and mast cells actively participate in the pathogenesis of hypertrophic scarring following burn injury.21 Furthermore, growing evidence suggests that epidermal keratinocytes and dermal fibroblasts play a role in the conversion of cholesterol precursor to pre-vitamin D3 by the expression of vitamin D receptors.6 Thus, we hypothesized that the biomechanical properties of hypertrophic scars may be associated with vitamin D deficiency in burn patients. We investigated the values of melanin and erythema, TEWL, and distensibility and elasticity in hypertrophic scars as well as 25(OH)-vitamin D levels to demonstrate our hypotheses. Low vitamin D levels on burn center admission were related to increased length of stay in the ICU and hospital.22 When the innate immune system recognized microbial invasion, vitamin D-deficient patients showed decreased expression of the genes coding for the antimicrobial peptide cathelicidin and microbial pattern recognition receptors in epidermal keratinocytes surrounding a wound.23 Moreover, vitamin D deficiency was associated with higher blood culture positivity and sepsis rates.24,25 Therefore, a decrease in the antimicrobial and immunomodulatory roles of vitamin D could cause a longer length of stay.24 Additionally, added vitamin D intensified the effect of low TGF-β1 level in fibroblast-mediated dermal wound healing.14 In the current study, vitamin D-deficient patients showed prolonged healing time of burn wounds and an increased length of stay in the ICU. However, the time at which we assessed vitamin D level (after wound healing) is not consistent with that of a previous study22; accordingly, one interpretation may be that prolonged postburn wound healing and ICU length of stay may result in a low vitamin D level. Therefore, additional study should be performed with preinjury vitamin D levels on admission as well as postburn vitamin D levels in the rehabilitation unit. Of note, we demonstrated that the hypertrophic scars in vitamin D-deficient patients were associated with higher values of melanin and TEWL compared with those in non-deficient patients. Melanin in epidermal keratinocytes absorbs ultraviolet electromagnetic radiation competitively with 7-dehydrocholesterol; consequently, high melanin levels in pigmented skin cause a decrease in vitamin D production.26 Therefore, the increased melanin in hypertrophic burn scars is likely to reduce vitamin D production. TEWL is frequently measured to examine the integrity of the outermost skin, which is responsible for skin barrier function,27 and 1,25-dihydroxyvitamin D is essential to maintain permeability barrier in epidermis.11,28 Thus, an increased TEWL value indicates impaired epidermal barrier function in vitamin D-deficient patients. The present study provides the novel observation that there is a significant association between postburn vitamin D deficiency and biomechanical scar properties in burn patients. The reduced Uf reflects an increase in rigidity of the skin, whereas Ua/Uf and Ur/Uf are associated with the capacity of the elastin fibers to recover their original shape after distension. Decreased Ua/Uf and Ur/Uf indicate altered elastin fibers or increased skin thickness. Increased Uv/Ue represents the attenuated movement of interstitial fluid throughout the burn scar network and firmer skin. TGF-β is produced by many cells, such as fibroblasts and macrophages. TGF-β-activated keratinocytes stimulate collagen production in fibroblasts before wound closure, and promote wound healing.3,29 On the contrary, after wound closure, TGF-β inactivates keratinocytes and inactivated keratinocytes attenuate collagen production by fibroblasts.30,31 Vitamin D enhances the action of TGF-β14 and upregulates expression of cathelicidin in cultured keratinocytes.32 Cathelicidin plays a role in re-epithelialization and angiogenesis.33 Furthermore, vitamin D reduces the expression of profibrotic factor and collagen in mesenchymal multipotent cells.34 Therefore, vitamin D deficiency may result in impaired communication between epidermal keratinocytes and dermal fibroblasts, and perturbation of collagen and elastin production in burn scar. This study has some limitations. First, the amount of sun exposure was not considered because of the inability to control all participants’ activities in the hospital. To exclude the effect of sun exposure, we only enrolled burn inpatients who had never returned home in the burn center. Therefore, the participants rarely had the potential for sun exposure before blood sampling and scar evaluation. Second, differences in vitamin D levels according to sex and continuous vitamin D levels were not evaluated enough because of the small sample size for women and normal controls. Finally, the association between vitamin D deficiency and hypertrophic scarring in burns less than 20% BSA was not examined because of exclusion criteria. Further investigation with more samples from women and normal controls, and patients with burned BSA < 20% is required, with consideration of sun exposure, sex differences, smaller burn size and factors related to burn injury. In conclusion, our results demonstrated that vitamin D deficiency was significantly associated with biomechanical properties of hypertrophic scars, which were increased pigmentation, decreased skin barrier function, low scar distension and elasticity, and slow interstitial fluid movement, in burn patients. We suggest that vitamin D supplementation may positively affect the hypertrophic process of burn scar. However, further studies using continuous model of plasma vitamin D levels with a number of normal controls are warranted to demonstrate the influence of vitamin D deficiency on biomechanical properties of hypertrophic scars. This study was supported by Hallym University Research Fund 2017 (HURF-2017-64). The authors who have participated in this study declared that they have nothing to disclose with respect to conflict of interest regarding this article. 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TI - The Association Between Postburn Vitamin D Deficiency and the Biomechanical Properties of Hypertrophic Scars
JF - Journal of Burn Care & Research
DO - 10.1093/jbcr/irz028
DA - 2019-04-26
UR - https://www.deepdyve.com/lp/oxford-university-press/the-association-between-postburn-vitamin-d-deficiency-and-the-xbtxuZW9By
SP - 274
VL - 40
IS - 3
DP - DeepDyve
ER -