Background Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine. So far current methodologies, including the commonly used back excisional wound model (BEWM) and paw skin scald wound model, are focused on assessing the regeneration of either hair follicles (HFs) or sweat glands (SwGs). How to achieve de novo appendage regeneration by synchronized evaluation of HFs, SwGs and sebaceous glands (SeGs) is still challenging. Here, we developed a volar skin excisional wound model (VEWM) that is suitable for examining cutaneous wound healing with multiple-appendage restoration, as well as innervation, providing a new research paradigm for the perfect regeneration of skin wounds. Methods Macroscopic observation, iodine–starch test, morphological staining and qRT-PCR analysis were used to detect the existence of HFs, SwGs, SeGs and distribution of nerve fibres in the volar skin. Wound healing process monitoring, HE/Masson staining, fractal analysis and behavioral response assessment were performed to verify that VEWM could mimic the pathological process and outcomes of human scar formation and sensory function impairment. Results HFs are limited to the inter-footpads. SwGs are densely distributed in the footpads, scattered in the IFPs. The volar skin is richly innervated. The wound area of the VEWM at 1, 3, 7 and 10 days after the operation is respectively 89.17% ± 2.52%, 71.72% ± 3.79%, 55.09 % ± 4.94% and 35.74% ± 4.05%, and the final scar area accounts for 47.80% ± 6.22% of the initial wound. While the wound area of BEWM at 1, 3, 7 and 10 days after the operation are respectively 61.94% ± 5.34%, 51.26% ± 4.89%, 12.63% ± 2.86% and 6.14% ± 2.84%, and the final scar area accounts for 4.33% ± 2.67% of the initial wound. Fractal analysis of the post-traumatic repair site for VEWM vs human was performed: lacunarity values, 0.040 ± 0.012 vs 0.038 ± 0.014; fractal dimension values, 1.870 ± 0.237 vs 1.903 ± 0.163. Sensory nerve function of normal skin vs post-traumatic repair site was assessed: mechanical threshold, 1.05 ± 0.52 vs 4.90 g ± 0.80; response rate to pinprick, 100% vs 71.67% ± 19.92%, and temperature threshold, 50.34°C ± 3.11°C vs 52.13°C ± 3.54°C. Conclusions VEWM closely reflects the pathological features of human wound healing and can be applied for skin multiple-appendages regeneration and innervation evaluation.

中文翻译：

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用于原位评估多附属器再生和神经支配的掌侧皮肤切除伤口模型

背景促进伤口快速愈合并恢复所有皮肤附属器的功能是再生医学的主要目标。到目前为止，目前的方法，包括常用的背部切除伤口模型（BEWM）和爪子皮肤烫伤模型，都集中于评估毛囊（HF）或汗腺（SwG）的再生。如何通过同步评估 HF、SwG 和皮脂腺 (SeG) 来实现附属器从头再生仍然具有挑战性。在这里，我们开发了一种掌侧皮肤切除伤口模型（VEWM），适用于检查皮肤伤口愈合与多附件修复以及神经支配，为皮肤伤口的完美再生提供了新的研究范式。方法 肉眼观察、碘淀粉试验、采用形态学染色和qRT-PCR分析检测掌侧皮肤中HFs、SwGs、SeGs的存在以及神经纤维的分布。通过伤口愈合过程监测、HE/Masson染色、分形分析和行为反应评估来验证VEWM可以模拟人类疤痕形成和感觉功能损伤的病理过程和结果。结果 HF 仅限于脚垫间。SwG 密集分布于足垫，分散于 IFP。掌侧皮肤神经支配丰富。术后第1、3、7、10天VEWM的创面面积分别为89.17%±2.52%、71.72%±3.79%、55.09%±4.94%和35.74%±4.05%，最终疤痕面积占初始伤口的 47.80% ± 6.22%。而BEWM的伤口面积为1、3时，术后7天和10天分别为61.94%±5.34%、51.26%±4.89%、12.63%±2.86%和6.14%±2.84%，最终疤痕面积占初始伤口的4.33%±2.67%。对 VEWM 与人类的创伤后修复部位进行分形分析：空隙度值，0.040 ± 0.012 vs 0.038 ± 0.014；分形维数值，1.870 ± 0.237 与 1.903 ± 0.163。评估正常皮肤与创伤后修复部位的感觉神经功能：机械阈值，1.05 ± 0.52 vs 4.90 g ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。86%和6.14%±2.84%，最终疤痕面积占初始伤口的4.33%±2.67%。对 VEWM 与人类的创伤后修复部位进行分形分析：空隙度值，0.040 ± 0.012 vs 0.038 ± 0.014；分形维数值，1.870 ± 0.237 与 1.903 ± 0.163。评估正常皮肤与创伤后修复部位的感觉神经功能：机械阈值，1.05 ± 0.52 vs 4.90 g ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。86%和6.14%±2.84%，最终疤痕面积占初始伤口的4.33%±2.67%。对 VEWM 与人类的创伤后修复部位进行分形分析：空隙度值，0.040 ± 0.012 vs 0.038 ± 0.014；分形维数值，1.870 ± 0.237 与 1.903 ± 0.163。评估正常皮肤与创伤后修复部位的感觉神经功能：机械阈值，1.05 ± 0.52 vs 4.90 g ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。对 VEWM 与人类的创伤后修复部位进行分形分析：空隙度值，0.040 ± 0.012 vs 0.038 ± 0.014；分形维数值，1.870 ± 0.237 与 1.903 ± 0.163。评估正常皮肤与创伤后修复部位的感觉神经功能：机械阈值，1.05 ± 0.52 vs 4.90 g ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。对 VEWM 与人类的创伤后修复部位进行分形分析：空隙度值，0.040 ± 0.012 vs 0.038 ± 0.014；分形维数值，1.870 ± 0.237 与 1.903 ± 0.163。评估正常皮肤与创伤后修复部位的感觉神经功能：机械阈值，1.05 ± 0.52 vs 4.90 g ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。05 ± 0.52 与 4.90 克 ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。05 ± 0.52 与 4.90 克 ± 0.80；对针刺的响应率，100% vs 71.67% ± 19.92%，温度阈值，50.34°C ± 3.11°C vs 52.13°C ± 3.54°C。结论 VEWM密切反映人体伤口愈合的病理特征，可用于皮肤多附属器再生和神经支配评估。