以下文字版
At the end of the treatment period, the LIPUS group presented a mean WHR of +41%, i.e., the ulcer area decreased by an average of 41%, compared to an average decrease of 0% in the SDZ group. There was a signifificant difference in the WHR between groups (p < 0.05), indicating a benefificial action of LIPUS on tissue formation and ulcer healing. Ultrasound has been used in the healing process since the 1960s. In 1976, Dyson et al. corroborated these fifindings, demonstrating a reduction in the ulcer area following treatment with ultrasound. The effects of ultrasound (pulsed mode, 3.0 MHz frequency, intensity 1.0 W/cm2 SATA, 5–10 min, 3 times per week) on the healing of chronic varicose ulcers were evaluated [43]. Peschen et al. in 1997 observed that chronic venous ulcers that were treated with ultrasound at a frequency of 30 kHz, continuous 100 mW/cm2 , 10 min, 3 times per week for 12 weeks presented a mean 55.4% reduction in the area of the ulcer compared to a mean 16.5% reduction in a group that was treated conventionally with a topical application of hydrocolloids and compression therapy [33]. However, Franek et al. in 2004 evaluated venous ulcers treated with ultrasound at an intensity of 1.0 W/cm2 SATA and compressive therapy and ulcers treated with ultrasound at an intensity of 0.5 W/cm2 SATA and compressive therapy; in both groups, the patients were treated with a pulsed wave with a duty cycle of 1/5 (impulse time = 2 ms, pause time = 8 ms) and an frequency of 1.0 MHz. The treatment was performed for approximately 5–10 min daily for 3 weeks. It was observed that 0.5 W/ cm2 ultrasound makes larger and faster changes in the healing process than 1.0 W/cm2 ultrasound [44]. These studies are in agreement with our fifindings, reaffifirming that a LIPUS treatment of at least 20 min 3 times per week for approximately 12 weeks can be an effective protocol for the treatment of chronic venous ulcers.
在治疗期结束时，LIPUS组的平均WHR为+ 41％，即溃疡面积平均减少，与SDZ组的平均下降0％相比，下降了41％。两组之间的WHR有显着差异（p <0.05），表明LIPUS对组织形成和溃疡愈合具有有益作用。自20世纪60年代以来，超声波已被用于治疗过程。1976年，戴森（Dyson）等人证实了这些发现，结果显示，经超声波治疗后溃疡面积减少。超声波（脉冲模式，3.0 MHz频率，强度1.0 W / cm2 SATA，5-10分钟，每周3次。对慢性静脉曲张溃疡的愈合进行了评估[43].Peschen等在1997年观察到以30 kHz的频率，连续100 mW / cm2，每次10分钟，每周3次，连续12周进行超声治疗的慢性静脉溃疡，平均溃疡面积减少了55.4％。相比之下，常规应用水胶体和加压疗法治疗组的溃疡面积平均减少16.5％[33].但是，Franek等在2004年，评估了以1.0 W / cm2 SATA的超声强度和压迫疗法治疗的静脉溃疡和以0.5 W / cm2 SATA的强度的超声疗法和压迫疗法治疗的溃疡；在两组中，患者均使用占空比为1/5（脉冲时间= 2 ms，暂停时间= 8 ms）和频率为1.0 MHz的脉冲波治疗。每天进行大约5-10分钟的治疗，持续3周。观察到，与1.0 W / cm2 超声相比，0.5 W / cm2 超声在愈合过程中产生更大，更快的变化[44].这些研究与我们的发现一致，重申了LIPUS治疗。每周至少20分钟3次，持续大约12周，可以有效治疗慢性静脉溃疡。
Fibrin/sphacel is initially characterized by necrotic tissue, cell remnants and inflflammatory cells; its persistence delays ulcer healing. On the other hand, granulation tissue is fundamentally important for healing, as it clinically corresponds to neo-angiogenesis, which is necessary to guarantee an adequate nutritional supply to newly formed tissue. Monitoring the clinical changes that occur in the fifibrin/sphacel and granulation areas in the bottom surface of a wound can also assess the initial healing response to the proposed treatment. A reduction in devitalized tissue (sphacel) is expected, with consequent replacement with increased granulation tissue. Initially, these changes can occur with no reduction in the ulcerated area, which suggests changes in the epidermis (reepithelialization).
纤维蛋白/残渣最初的特征是坏死组织，细胞残留物和炎性细胞。它的持续存在会延迟溃疡的愈合。另一方面，肉芽组织从根本上来说对于愈合至关重要，因为它在临床上与新血管生成相对应，这是保证向新形成的组织提供足够营养的必要条件。监测伤口底部表面的纤维蛋白/杂物和肉芽区域中发生的临床变化，也可以评估对所提议治疗的初始治愈反应。预计失活的组织（残渣）会减少，并随后被增加的肉芽组织代替。最初，这些变化可以在溃疡面积没有减少的情况下发生，这表明表皮发生了变化（重新
上皮化）。
The analysis of sphacel and fifibrin of ulcers was evaluated by the quantifification of the yellow and red areas, respectively, by ImageJ. Fig. 4 shows a signifificant increase in the area of granulation tissue and a respective reduction in the fifibrin/sphacel tissue area (FGR < 1) in the LIPUS group starting on day 30 until the end of the treatment period compared to the SDZ group.
通过ImageJ分别对黄色和红色区域进行定量评估来评估溃疡的残渣和纤维蛋白。图4显示肉芽组织面积显著增加，与SDZ组相比，LIPUS组从第30天开始直至治疗期结束，分别降低了血纤蛋白/纤维组织面积（FGR <1）。
LIPUS also tended to increase the amount of granulation tissue compared to SDZ, suggesting an increase in neovascularization. Swist-Chmielewska et al. in 2002 did not detect a signifificant difference between ulcers treated with ultrasound (1.0 W/cm2 and 0.5 W/cm2 ) and ulcers treated by conventional methods for debridement in terms of the development of granulation over a treatment period of 12 weeks. The treatments were applied 3, 2 and 1 times per week during the fifirst, second and third month of treatment, respectively. However, the ulcers that were treated with ultrasound at an intensity of 0.5 W/cm2 SATA showed reductions in area and volume that were statistically signifificant compared to the group that was treated with ultrasound at an intensity of 1.0 W/cm2 SATA [45]. Other studies have detected increased capillary growth when histologically analyzing ulcers induced in female rats. This growth was observed in regions equivalent to granulation tissue that was treated for 5 min/day with ultrasound at a frequency of 0.75 MHz and an intensity of 0.1 W/cm2 SATA for 5 days [46]. It is possible that the US (ultrasound) mechanical waves stimulate integrins that sense extracellular signals, resulting in fifibroblast proliferation. It was previously reported that low-intensity US promotes the activation of extracellular signal-regulated kinase (ERK) 1/2, inhibition of Rho-associated coiled-coil-containing protein kinase (ROCK) and activation of the integrin receptor; these changes are essential for fifibroblast proliferation [47]. These studies reaffifirm the fifindings that US intensities below 1.0 W/cm2 SATA are better able to induce the appearance of granulation tissue.
与SDZ相比，LIPUS还倾向于增加肉芽组织的数量，表明新血管形成的增加。Swist-Chmielewska等在2002年没有发现超声治疗（1.0 W / cm2 和0.5 W / cm2）之前存在差异。用传统方法治疗溃疡清创术指的是一个月内肉芽的形成，治疗期为12周。在治疗的第一个月，第二个月和第三个月，每周分别进行3、2和1次治疗。然而，与以1.0 W / cm2 强度超声处理的组相比，以0.5 W / cm2 SATA强度进行超声处理的溃疡显示面积和体积的减少具有统计学意义）SATA[45].其他研究在组织学分析雌性大鼠溃疡时发现毛细血管生长增加。在相当于肉芽组织的区域观察到这种生长，肉芽组织以0.75 MHz的频率和0.1 W /cm2 SATA 5天[46].US（超声波）机械波可能会刺激感知细胞外信号的整联蛋白，从而导致成纤维细胞增殖。以前有报道说，低强度超声促进细胞外信号调节激酶（ERK）1/2的激活，Rhoassociated含卷曲螺旋蛋白激酶（ROCK）的抑制和整联蛋白受体的激活。这些变化对于成纤维细胞的增殖至关重要[47].这些研究重申了以下发现：强度低于1.0 W / cm2 SATA能够更好地诱导肉芽组织的出现。
In the present study, picrosirius staining, which is specifific for the detection of collagen formation, revealed quantitatively higher numbers of hypertrophic collagen fifibers in the ulcers of the LIPUS group compared to the SDZ group on day 45 of treatment, as shown in Fig. 5. These fifindings indicate that LIPUS stimulates fifibroplasias, with fifibroblast proliferation improving the extracellular matrix and supporting new tissue, possibly positively affecting ulcer healing [2].
在本研究中，特异于检测胶原蛋白形成的picrosirius染色显示，在治疗的第45天，与SDZ组相比，LIPUS组溃疡中的肥大性胶原纤维数量更高。图5.这些发现表明，LIPUS刺激纤维化，纤维母细胞增殖改善细胞外基质并支持新组织，可能对溃疡愈合产生积极影响[2].
Immunohistochemical evaluation revealed that an increase in CD68+ cells occurred on day 45, indicating increased macrophage activation in the LIPUS group compared to the SDZ group (Fig. 6). This result suggests that LIPUS plays an important role in the stimulation of the inflflammatory phase during the fifirst 45 days of treatment, which explains the increase in ulcer areas observed on previous evaluation days, corresponding to the wound debridement that is inherent to this phase. These tissue modififications are necessary to modify chronic ulcers from an indolence state and to give them the characteristics of acute ulcers with regard to the healing process [48]. The inflflammatory cells (macrophages expressing the CD68 marker) that were found in our study indicate an inflflammatory healing process stimulated by LIPUS, corroborating previous fifindings that inflflammation is necessary to change the indolence status of chronic ulcers.
免疫组化评估显示，第45天CD68+ 细胞增加，与SDZ组相比，LIPUS组的巨噬细胞活化增加。（图6).该结果表明，在治疗的前45天，LIPUS在炎症期的刺激起着重要作用，这解释了在先前评估日观察到的溃疡面积增加，这对应于该阶段固有的伤口清创。这些组织修饰对于使慢性溃疡从惰性状态改变并使其具有急性溃疡的愈合过程特征是必需的[48].在我们的研究中发现的炎症细胞（表达CD68标记的巨噬细胞）表明LIPUS刺激了炎症的愈合过程，从而证实了炎症对于改变慢性溃疡的惰性状态是必需的。
With regard to angiogenesis, Reher et al. in 1999 investigated the effect of ultrasound (15.0 mW/cm2 SATA and 30.0 mW/cm2 SATA) at a frequency of 45 kHz in continuous mode on the in vitro production of IL-8, FGF and VEGF in monocytes, fifibroblasts and osteoblasts and concluded that VEGF reached the highest production rate in the three cell types regardless of ultrasound intensity [49]. Lu et al. in 2008 studied US activity on bone-tendon junction healing at 2, 4, 8 and 16 weeks after treatment. In 2 experimental groups, with or without LIPUS treatment, the authors observed a 35.6% increase in VEGF (p < 0.05) in the 4th week in cells in the newly formed bone that was treated with LIPUS. They observed a simultaneous increase in VEGF in cells in the newly regenerated fifibrocartilage zone, although this increase was not statistically signifificant. The authors concluded that LIPUS might inflfluence the healing process by accelerating early angiogenesis [25]. Similarly, a clinical tendency toward neoangiogenesis was also demonstrated by immunohistochemical evaluations of VEGF in ulcers that were treated with ultrasound (Figs. 3 and 7), which suggests a role for LIPUS in granulation tissue formation, with VEGF accelerating wound healing, as suggested previously [27,50].
关于血管生成，Reher等1999年研究了以连续模式在45 kHz频率下超声（15.0 mW / cm2 SATA和30.0 mW / cm2 SATA）对单核细胞中IL-8，FGF和VEGF体外产生的影响，成纤维细胞和成骨细胞，并得出结论：不管超声强度如何，VEGF在三种细胞类型中均达到最高生产率[49].Lu等2008年在美国研究了在治疗后第2、4、8和16周对骨-腱连接愈合的活性。在2个实验组中，无论是否接受LIPUS治疗，作者均观察到VEGF在第四周增加了35.6%（p <0.05），他们观察到用LIPUS治疗的新形成的骨细胞中VEGF升高了35.6％，新再生的纤维软骨区细胞中的VEGF同时增加，尽管这种增加在统计学上并不显着。作者得出结论，LIPUS可能会通过加速早期血管生成来影响愈合过程[25].同样，通过超声治疗的溃疡中VEGF的免疫组织化学评估，也证明了新血管生成的临床趋势（图3和7），这提示LIPUS在肉芽组织形成中的作用，如前所述，VEGF促进伤口愈合[27,50].
5. Conclusion 结论
Low-intensity ultrasound Accelerates the healing process of chronic venous ulcers, acting on the inflflammatory phase, as observed by the increase in CD68+ cells. Additionally, it seems to be actively promoting tissue formation, as characterized by an increase in the granulation tissue area, a tendency toward higher VEGF expression, increased thickness of collagen fifibers and reduction of wound healing rates compared to sulfadiazine treatment.
低强度超声可加速慢性静脉溃疡的愈合过程，作用于炎症期，这可以通过CD68+ 细胞的增加来观察。另外，与磺胺嘧啶治疗相比，它似乎正在积极地促进组织形成，其特征在于肉芽组织面积的增加，趋于更高的VEGF表达的趋势，胶原纤维的厚度增加和伤口愈合速率的降低。
Acknowledgments 致谢
The authors would like to thank Rosangela Orlandin Lopes of the Pathology Department of FMRP-USP for immunohistological technical assistance and Anand Iyer from Academic Medical Center – University of Amsterdam for English translation assistance.
作者要感谢FMRP-USP病理学部门的Rosangela Orlandin Lopes提供的免疫组织学技术援助以及学术医学中心的Anand Iyer
–阿姆斯特丹大学，提供英语翻译帮助。
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