1 Department of Burns, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
2 Wound Healing Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
3 Department of Orthopaedics, Shanghai Fengxian District Center Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Objectives: Treating chronic cutaneous wounds is challenging, and debridement is a central concept in treating them. Studies have shown that CO2 laser debridement can control local infection and promote the wound healing process. The present study aimed to investigate the efficacy and safety of fully ablative CO2 laser debridement compared to routine surgical debridement in the treatment of chronic wounds.
Methods: The retrospective cohort study was conducted on patients with chronic (>1 month) cutaneous wounds (≥1 cm2) between December 1, 2017, and December 1, 2020, in the Wound Healing Center at Shanghai Ruijin Hospital, China. Patients treated with CO2 laser debridement with a DEKA SmartXide2 C80 (DEKA) (the CO2 laser group) were compared with matched control patients with similar baseline characteristics who had undergone routine surgical debridement (the routine group). The primary outcome was time‐to‐heal (days) for chronic wounds in two groups, and secondary outcomes included the wound area and BWAT (Bates–Jensen wound assessment tool) score before treatment, and at 1, 2, 3, and 4 weeks after treatment.
Results: The study included 164 patients (82 in the CO2 laser group and 82 matched in the routine group). The time‐to‐heal for patients in the CO2 laser group (41.30 ± 17.11) was significantly shorter than that of the patients in the routine group (48.51 ± 24.32) (p = 0.015). At 3 and 4 weeks after treatment, the absolute wound area of the CO2 laser group was significantly smaller than that of the routine group. Also, the CO2 laser group exhibited a significantly lower relative area at 2, 3, and 4 weeks after treatment. The CO2 laser group yielded significantly lower BWAT scores at 2, 3, and 4 weeks after treatment. Additionally, the relative BWAT score was significantly lower in the CO2 laser group than the relative scores in the routine group at 2, 3, and 4 weeks after treatment. No adverse events related to the treatments were observed in either group during the study period.
Conclusions: The present study has shown that fully ablative CO2 laser debridement has several advantages over routine sharp surgical debridement. It is superior at ameliorating wound status and reducing wound area, and it also significantly reduces the time‐to‐heal for chronic wounds, without causing any adverse events.
#human-skin-woundsChronic cutaneous wounds are defined as wounds that fail to heal in an orderly and timely manner.1,2 Cases of patients suffering from chronic cutaneous wounds are on the rise due to changing lifestyle diseases such as diabetes, vascular disease, and prolonged pressure.3,4,5
In the United States alone, chronic wounds affected about 4.5 million people by 2018.6,7
In developed countries, it has been estimated that 2%–5% of total healthcare expenditure goes to chronic wound care.8,9
Disguised as co-morbid conditions, chronic cutaneous wounds incur significant medical, social, and financial costs, and pose enormous threats to patients, healthcare systems, and the worldwide economy.1,7
However, treating chronic cutaneous wounds is challenging, and a prominent concept in treating them is the role of debridement.10 The goal of debridement is to remove nonvital tissues, exudate, and bacterial biofilms from the wounds, and transform the chronic wounds into acute wounds, to initiate the wound‐healing process.11 This procedure is routinely accomplished through mechanical (sharp debridement), autolytic, enzymatic, chemical, or biological methods.11,12,13
Another alternative wound debridement method is the application of a carbon dioxide (CO2 ) laser, which has been widely used in scar treatment.14,15,16,17 Studies have shown that fully ablative CO2 laser debridement controls local infection due to its physical bactericidal effects.18,19 It may also increase fibroblast proliferation and stimulate growth factors secretion. 20,21,22
Nonetheless, clinical research on CO2 laser debridement for chronic cutaneous wounds has been scant, and most has been in case reports or small‐scale clinical trials.23,24,25,26,27,28 Furthermore, some of these studies have focused on fractionated ablation, which is quite different from confluent laser debridement. Based on this premise, we conducted the present study to assess the efficacy and safety of CO2 laser debridement in the treatment of chronic cutaneous wounds, as compared with routine mechanical debridement.
PATIENTS AND METHODS
Eighty‐two patients with chronic cutaneous wounds who had been treated with CO2 laser debridement between December 1, 2017, and December 1, 2020, in the Wound Healing Center at Shanghai Ruijin Hospital, China, were retrospectively enrolled in this study. We compared each case, consisting of patients treated with CO2 laser debridement (the CO2 laser group) with a matched control sample of patients with chronic cutaneous wounds who had undergone routine surgical debridement (the routine group) within the same period of time and at the same institution. Important variables such as age (±5), wound duration (±2 months), wound area (±2 cm2), and initial Bates–Jensen wound assessment tool (BWAT) score (±5) were matched exactly.
(1) Patients had wounds that failed to heal within 1 month despite appropriate wound care.
(2) Wound area ≥1 cm2.
(3) Patients had received CO2 laser debridement or routine surgical debridement without skin grafting.
(1) Patients with incomplete follow‐up records.
(2) Wounds had been caused by a severe vascular obstruction that required vascular intervention therapy.
(3) Patients had received amputation.
(4) Patients had received radiotherapy, chemotherapy, or immunosuppressive therapy.
(5) Patients had received a combination of surgical debridement and CO2 laser debridement.
(6) Patients had received debridement treatments including autolytic, enzymatic, chemical, or biological methods.
(7) Patients had received adjunctive treatments including hyperbaric oxygen therapy or platelet‐rich plasma application/injections.
(8) Patients with severe local or systemic infections requiring systemic antibiotic therapy.
As a standard wound care measure in our facility, all patients received wound cultures before operation during their initial visit to our hospital. All procedures were performed in the operating room by the same surgeon. Before debridement, patients in both groups received normal saline for topical cleansing, and the wound surface and surrounding skin were then disinfected with chlorhexidine. Preoperative topical local anesthesia with 2% lidocaine gel was adopted in both groups.
Patients in the CO2 laser group received fully ablative CO2 laser debridement with a DEKA SmartXide2 C80 (DEKA) ultra‐pulsed CO2 laser. This guaranteed high peak power and rapid pulse duration. The operating parameters included power (5–80 W), emission mode (ultra‐pulsed or high‐pulsed), exposure mode (continuous, single or repeated), scanning shapes (point, circle, or clover), dwell time, and frequency were decided by the treating surgeon, to induce different effects on diverse ulcer tissues.
(1) To remove necrotic tissue on the wound, we used the CO2 laser beam in ultra‐pulsed mode, continuous exposure mode, 8–15W power, clover scanning shapes, and 350 μs of dwell time, scanning over the target tissue for 3–5 seconds.
(2) To remove aging granulation tissue, we used ultrapulsed mode and continuous exposure mode at a lower energy of 5–7W, clover scanning shapes, and 350 μs of dwell time.
(3) We used fractional microablative resurfacing on the periphery of the central wound with the intent to stimulate epithelial tissue growth. The CO2 laser beam was used in high‐pulsed mode, repeated exposure mode (0.04 seconds on and 0.4 seconds off), 100 Hz frequency, and 15W power and point scanning shape. We focused the laser beam (diameter of 0.325 mm) to needle into the normal skin around the wound with a density of 3–5 pinholes per centimeter.
(4) For wounds with exposed bone, we used a CO2 laser to produce discontinuities in the periosteum. We focused the CO2 laser beam (diameter of 0.325 mm) on the bone until it bled, with a density of 5‐7 discontinuities per square centimeter in the periosteum. We operated the laser in ultra‐pulsed mode, single exposure mode (0.06 seconds on), 80W power, and point scanning shape. After laser debridement, the carbonized necrotic tissues on the wound surface gently debrided with a curette or cotton swab.
Routine surgical debridement with a scalpel, scissors, or curette was performed for patients in the routine group, aiming for complete removal of necrotic tissue, dense fibrous tissue, and aging granulations in the wounds.
Standardized wound care
After debridement, wounds in both groups were received standardized wound care and dressing changes. Before the dressing changes, the wound was cleaned with normal saline and scraped with a curette. Then, the appropriate antibacterial ointment was applied based upon findings of the wound cultures received before operation. In cases with Gram‐positive bacteria isolated, the mupirocin ointment (GSK) was selected. When Gram-negative bacteria was isolated, the compound polymyxin B ointment (Zhejiang Fonow Medicine Co., Ltd.) was applied. Wounds culture was performed again at 1 week after operation in patients with positive culture findings and then was performed per week until negative. Topical antibiotics were stopped when the results turned negative. For wounds with negative culture findings or dry wound bases, vaseline ointments were used to keep wounds moist.
In cases with a large quantity of necrotic tissue or aging granulations, the wound was covered by a silver-containing dressing (Aquacel Ag, ConvaTec). When the wound base was clean, and fresh granulations had developed, foam dressings (Mepilex Border Flex, Mölnlycke Health Care) were adopted. The wound care and dressing changes were performed by nurses every 2–3 days according to wound conditions. The debridement was performed every 4–7 days. In the case of significant exudation and persistent infection, the debridement was performed more frequently (every 4–5 days). Conversely, the debridement frequency was reduced (every 6–7 days).
The time (days) required for the wound to achieve complete epithelialization was recorded as time‐to‐heal.
Each wound was taken photographed with a camera (Nikon D7200; Nikon Corporation) before treatment, and at 1, 2, 3, 4 weeks after treatment. The photographs were analyzed with ImageJ software (The National Institutes of Health) to measure the wound area. The relative area (percentage of unhealed area) = wound area at each time point/baseline wound area × 100%.
The status of the wounds was scored via photograph using the. BWAT29 before treatment, and at 1, 2, 3, 4 weeks after treatment. Based on the BWAT tool, all wounds were scored on a scale of 1–5 for each of 13 items, including size, depth, edges, undermining, necrotic tissues type, necrotic tissues amount, exudate type, exudate amount, skin color surrounding the wound, peripheral tissues edema, induration, granulations, and epithelialization.29 The total BWAT score was the sum of all 13 items scores, with a range from 13 to 65. A higher BWAT score indicated a more severe wound. Two trained researchers scored all wounds independently, and the average served as the final score if the difference between the two scores was less than two; otherwise, the wound was scored by a more experienced researcher. All of the researchers conducting the BWAT scoring were blinded to the debridement technique and group assignment. The relative score = BWAT score at each time point/initial BWAT score × 100%.
Both groups’ patients were observed for any adverse events, such as local allergies, infection, or severe pain.
Statistical analysis was performed with SPSS Version 26 software package (IBM SPSS). The categorical variables are presented as numbers and percentages and compared using a χ2 test and Fisher’s exact test. Continuous variables are presented as mean ± SD or medians (interquartile ranges), with analysis by a Student’s t test or a Mann–Whitney U test, as appropriate. Interrater reliability was analyzed using intraclass correlation coefficients (ICC) for the BWAT score. We utilized a Shapiro–Wilk test to examine the distribution’s normality.p < 0.05 defined statistical significance.
|Characteristics||CO2 laser group (n = 82)||Routine group (n = 82)||p value*|
|Age (years)||52.35 ± 17.22||58.32 ± 22.07||0.056|
|Wound duration (months)||2.35 (1.58–4.00)||2.40 (2.00–4.08)||0.46|
|Wound area (cm2)||4.41 (3.16–8.00)||4.60 (3.67–7.37)||0.702|
|Initial BWAT score||40.51 ± 7.42||39.35 ± 4.50||0.229|
|Debridement times||6.23 ± 2.991||7.43 ± 4.07||0.034|
|Debridement frequency (days)||6.85 ± 1.234||6.72 ± 0.901||0.434|
|Wound cause n (%)|
|Vascular diseases||6 (7.32)||2 (2.44)||0.147|
|Diabetes||12 (14.63)||13 (15.85)||0.828|
|Infection||13 (15.85)||23 (28.05)||0.059|
|Burn||11 (13.41)||5 (6.10)||0.114|
|Trauma||24 (29.27)||13 (15.85)||0.04|
|Pressure||5 (6.10)||8 (9.76)||0.386|
|Surgery||8 (9.76)||16 (19.51)||0.077|
|Others||3 (3.66)||2 (2.44)||
location, n (%)
|Head and neck||1 (1.22)||6 (7.32)||0.053|
|Trunk||7 (8.54)||13 (15.85)||0.152|
|Rump and perineum||12 (14.63)||13 (15.85)||0.828|
|Arm||2 (2.44)||5 (6.10)||0.246|
|Hand||1 (1.22)||4 (4.88)||0.173|
|Leg||38 (46.34)||28 (34.15)||0.111|
|Foot||21 (25.61)||13 (15.85)||0.123|
Note: Data are presented as median (interquartile range), mean ± SD or n (%). Bold values indicate statistically signiﬁcant p values.
Abbreviation: BWAT, Bates–Jensen wound assessment tool.
*χ2 or Fisher’s exact test, except Mann–Whitney U test and Student’s t test.
|Characteristics||CO2 laser group (n = 82)||Routine group (n = 82)||p value*|
|Positive samples (%)||46 (0.56)||40 (0.49)||0.348|
|Gram‐positive ﬁndings, n (%)|
|Staphylococcus aureus||23 (28.05)||16 (19.51)||0.299|
|Staphylococcus caprae||0 (0)||1 (1.22)||0.205|
|Staphylococcus hominis||1 (1.22)||2 (2.44)||0.584|
|Staphylococcus lugdunensis||0 (0)||1 (1.22)||0.205|
|Staphylococcus epidermidis||1 (1.22)||0 (0)||0.269|
|Staphylococcus haemolyticus||1 (1.22)||0 (0)||0.269|
|Enterococcus faecalis||3 (3.66)||4 (4.88)||0.688|
|Gram‐negative ﬁndings, n (%)|
|Escherichia coli||4 (4.88)||5 (6.10)||0.708|
|Pseudomonas aeruginosa||6 (7.32)||3 (3.66)||0.438|
|Acinetobacter baumannii||1 (1.22)||2 (2.44)||0.601|
|Klebsiella pneumoniae||1 (1.22)||1 (1.22)||0.742|
|Proteus vulgaris||0 (0)||1 (1.22)||0.485|
|Proteus mirabilis||5 (6.10)||4 (4.88)||0.543|
|Topical ointments, n (%)|
|Mupirocin||29 (35.37)||24 (29.27)||0.404|
|Polymyxin B||17 (20.73)||16 (19.51)||0.846|
|Vaseline||36 (43.90)||42 (51.22)||0.348|
|Duration of ointments (days)|
|Mupirocin||7.93 ± 1.889||8.08 ± 1.909||0.772|
|Polymyxin B||7.29 ± 0.587||7.81 ± 1.760||0.259|
|Vaseline||12.61 ± 5.039||12.38 ± 11.231||0.91|
Note: Data are presented as mean ± SD or n (%).
*χ2 or Student’s t test.
A total of 164 patients (82 in the CO2 laser group and 82 matched in the routine group) were enrolled in this study and analyzed. The general characteristics of the 164 enrolled patients and wounds were well balanced and listed in Table 1. There was no significant difference in sex, age, wound duration, wound area, anatomic location, or initial BWAT score between the groups. However, the routine group had significantly more debridement times than the CO2 laser group. Meanwhile, there was no significant difference in debridement frequency, wounds culture findings, and the usage of topical ointments between the two groups (Tables 1 and 2).
The time‐to‐heal for patients in the CO2 laser group (41.30 ± 17.11) was significantly shorter than that of patients in the routine group (48.51 ± 24.32) (p = 0.015, Figure 1). Subgroup comparisons shown in Figure 1 indicate that the effects of CO2 laser treatment were moderated by neither age, wound duration nor initial BWAT score. Of note, we found that the CO2 laser was more effective in female patients.
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Wound area reductions
We observed a marked reduction in wound area from baseline in both groups (Table 3). However, at 3 and 4 weeks after treatment, the absolute wound area for the CO2 laser group was significantly smaller than that of the routine group (p < 0.05, Figure 2A). Also, the CO2 laser group exhibited a significantly lower relative area at 2, 3, and 4 weeks after treatment (p < 0.05, Figure 2B).
|CO2 laser group (n = 82)||Routine group (n = 82)||p value*|
|Endpoint Week 1|
|Absolute area (cm2)||3.42 (2.00–5.00)||3.80 (2.23–6.48)||0.126|
|Relative area (%)||72.11 (56.78–85.00)||82.61 (59.06–90.00)||0.07|
|Endpoint Week 2|
|Absolute area (cm2)||2.24 (1.37–4.08)||3.00 (1.60–4.70)||0.066|
|Relative area (%)||50.80 (38.81–70.74)||66.67 (43.33–83.65)||0.03|
|Endpoint Week 3|
|Absolute area (cm2)||1.54 (0.67–3.00)||2.3 (1.18–4.00)||0.02|
|Relative area (%)||35.65 (20.91–55.84)||49.17 (29.25–66.06)||0.013|
|Endpoint Week 4|
|Absolute area (cm2)||1.00 (0.23–2.03)||1.95 (0.40–3.28)||0.021|
|Relative area (%)||23.71 (9.61–40.42)||37.08 (13.83–60.00)||0.008|
Note: Data are presented as median (interquartile range). Bold values indicate statistically significant p values.
*Mann–Whitney U test.
|CO2 laser group (n = 82)||Routine group (n = 82)||p value*|
|Endpoint Week 1|
|BWAT score||34.37 ± 6.98||36.05 ± 8.28||0.16|
|Relative area (%)||71.84 ± 19.96||76.22 ± 24.16||0.207|
|Endpoint Week 2|
|BWAT score||29.67 ± 7.15||32.82 ± 9.22||0.018|
|Relative area (%)||55.39 ± 24.70||63.46 ± 26.82||0.047|
|Endpoint Week 3|
|BWAT score||27.11 ± 8.11||31.60 ± 8.46||0.001|
|Relative area (%)||39.54 ± 23.82||47.44 ± 22.41||0.03|
|Endpoint Week 4|
|BWAT score||23.40 ± 7.89||27.23 ± 11.14||0.012|
|Relative area (%)||26.25 ± 23.34||36.23 ± 25.39||0.01|
Note: Data are presented as mean ± SD. Bold values indicate statistically significant p values.
Abbreviations: BWAT, Bates–Jensen wound assessment tool; SD, standard deviation.
*Student’s t test.
BWAT score reductions
The interrater reliability of the BWAT score assessment was very good (ICC all >0.90). The CO2 laser group yielded significantly lower BWAT scores at 2, 3, and 4 weeks after treatment (p < 0.05, Figure 3A). Also, the relative BWAT score was lower in the CO2 laser group than the relative scores in the routine group at 2, 3, and 4 weeks after treatment (p < 0.05, Figure 3B). The BWAT score reductions were shown in Table 4. This indicated superior BWAT score reduction in the CO2 laser group.
There were no adverse events related to the treatments observed in either group during the study period.
Efficacy of CO2 laser has been reported in a variety of dermatologic conditions including acne scars, actinic keratoses, onychomycosis, and striae distensae.16,30,31,32 However, clinical research on CO2 laser debridement used for chronic cutaneous wounds has been scant. The present study is the largest clinical study to date comparing CO2 debridement with routine debridement for chronic cutaneous wounds. Consistent with previous studies, we found that CO2 laser debridement is correlated with a shorter time‐to‐heal than routine debridement treatment. It is also correlated with superior wound status and causes no adverse events.23,26,27
CO2 laser employs high levels of energy to vaporize biological tissues. Its wavelength is 10,600 nm for targeting water in the superficial tissues and rarely scatters or penetrates, depositing energy to a precise depth below the surface of the skin without affecting the deeper tissues. This provides precise and controlled ablation of target necrotic tissues and minimizes thermal damage to healthy tissues. Previous animal studies have shown that a CO2 laser at 6W in continuous mode can penetrate depths of 100–300 μm of porcine skin,33 and 300–500 μm of porcine oral mucosa with a continuous mode CO2 laser at 2–4W.34,35 Pulsed CO2 laser with high peak power and rapid pulse duration provides a precise and controlled ablation of target necrotic tissues and minimize the thermal damage to healthy tissues. For chronic wounds with a long duration, the necrotic tissues may develop a tough fiberboard that thwarts the wound healing process, and the demarcation between necrotic tissues and the underlying living tissues is indistinguishable.
Meanwhile, CO2 laser may play an important role in controlling local infection in the wound bed. Jiang etal3 found that CO2 laser treatment reduces bacterial culture-positive rate more than routine debridement. In a prospective study of 60 patients, Juri et al.21 also demonstrated a lower infection rate in a CO2 laser group than a conventional surgery group. Microbial infection is a major barrier to wound healing, and chronic wounds are often colonized by pathogenic bacteria. This often leads to biofilms, which contribute to wound chronicity.36,37,38 It is difficult for routine surgical debridement to clear the bacterial biofilms without damaging the normal tissues. On the other hand, the overuse of topical or systemic antibiotics has contributed to bacterial drug resistance. Due to the high temperatures the target tissues reach, CO2 laser allows for effective microbial destruction without the risk of drug resistance. This helps transform the chronic wound environment into an acute wound environment. Furthermore, compared to routine surgical debridement with a scalpel, scissors, or a curette, CO2 laser debridement leads to significant alleviated intraoperative discomfort. Pain relief improves patient compliance, which allows physicians to perform more meticulous wound treatment.
Phillips et al.26 postulated that ablative fractional CO2 laser may create an increase in oxygen and circulation in wounds and this may expedite healing. Manolis et al.,39 Qu et al.,40 and Yu et al.41 revealed that CO2 laser energy might increase secretion and recruitment of the growth factors and cytokines that facilitate the wound healing process. These include basic fibroblast growth factor, transforming growth factor‐β1, matrix metalloprotein‐1, interleukin (IL)‐1, and IL‐8. Shingyochi et al.42 found that CO2 laser treatment at 1.0 J/cm2 stimulates the proliferation and migration of fibroblasts. A prospective, uncontrolled study of patients with burn scars from Ozog et al.43 has shown a significant increase in Type III collagen and a decrease in Type I collagen following CO2 laser treatment. This resulted in improved collagen architecture which favors wound healing. In addition, previous studies have suggested that CO2 laser might promote angiogenesis, which plays a key role in the healing process.44,45 After wound tissues absorb the CO2 laser, the local laser temperature and energy decay with depth. The tissues on the wound surface carbonize or gasify due to the higher energy. Additionally, the deeper tissues absorb the lower energy, which may stimulate the secretion of the growth factors and cytokines that promote tissue regeneration.
We have summarized a series of laser technical parameters based on our clinical experience. For the purposes of removing necrotic tissues on the wound, the CO2 2 laser beam was set in ultra‐pulsed mode, with the continuous exposure mode, 8–15W power, clover scanning shape tissues. A typical case is shown in Figure 4. To remove aging granulation tissues, we recommend lower energy of 5–7W. A typical case is shown in Figure 5. We also used fractionated microablative resurfacing on the periphery of the central wound aimed to stimulate epithelial tissue growth with a higher energy of 15W (150 MJ power for each pulse). A typical case is shown in Figure 6. In addition, we used a CO2 laser to treat wounds with exposed bone, as has been reported in a previous study.25 CO2 laser beam was used to produce discontinuities in the periosteum. This procedure may have initiated the wound healing process by allowing blood rich in bone marrow stem cells and other growth factors to penetrate the surface of the periosteum. For this purpose, the highest energy of 80W was used. A typical case is shown in Figure 7. However, the laser technical parameters may vary according to the laser devices, wound conditions, purposes, and operators. Further studies will be required to compare different technical parameters for the treatment of wounds with the same wound status. This may guide physicians in selecting appropriate laser parameters.
Although our study suggests that CO2 laser offer significant advantages over routine surgical debridement, CO2 laser debridement of chronic wounds still has its limitations. First, for chronic sinus wounds with small openings in the skin, it is hard to enter the depths of the sinus with a laser. A more suitable scanning laser head may improve this. Second, laser debridement alone is insufficient in treating wounds with a large area, or a large amount of necrotic tissues. These wounds require a combination of CO2 laser and routine sharp debridement.
Our study also has several limitations. Due to the retrospective study design, we were unable to analyze the changes in wound infection, before and after the treatment, due to insufficient information, which needs to be considered in future inquiry. Furthermore, further studies are needed to explore more suitable laser parameters for different wounds.
In summary, the findings of the present study have shown that CO2 laser debridement has several advantages over routine sharp surgical debridement. It is superior at ameliorating wound status and reducing wound area, and it also significantly reduces the time‐to‐heal for chronic wounds, without causing any adverse events.
We are grateful to the Shanghai Burn Research Institute of Shanghai Ruijin Hospital for its support of our research.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Data acquisition, data analysis, and manuscript drafting: Haonan Guan. Data acquisition and interpretation:
Di Zhang, Xian Ma, Yechen Lu, Yiwen Niu, Yingkai Liu, and Jiaoyun Dong. Designing the research and critically revising important knowledge content and final approval of the version for publication: Jiping Xu, Jiajun Tang, and Shuliang Lu.
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