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Research Article
24 January 2020

Meta-analysis of short-term outcomes comparing robot-assisted and laparoscopic distal pancreatectomy

Abstract

Aim: To evaluate and compare the short-term outcomes of robotic surgery and laparoscopic approach in distal pancreatectomy (DP). Materials & methods: EMBASE, PubMed, the Cochrane Library, CNKI and Wan Fang database were retrieved from the inception of electronic databases to June 2019. All analyses were performed using Stata/SE 15.1 version (StataCorp). Results: Twenty-two papers were included, four of which were prospective studies and the rest were retrospective studies. There was significant difference in spleen preservation rate (odds ratio: 2.020; 95% CI: 1.085–3.758; p = 0.027), operation time (mean difference [MD]: 27.372; 95% CI: 8.236–47.210; p = 0.000), the length of hospital stay (MD: -0.911; 95% CI: -1.287 to -0.535; p = 0.000), conversion rate (rate difference: -0.090; 95% CI: -1.287 to -0.535; p = 0.000), operation cost (MD: 2816.564; 95% CI: 1782.028–3851.064; p = 0.000). However, no significant difference was detected in estimated blood loss, total complication, severe complication, lymph nodules harvest, blood transfusion rate, total pancreatic fistula, severe pancreatic fistula, R0 resection rate and mortality. Conclusion: Both robotic and laparoscopic DP are safe and feasible. Although robotic DP increases the operation cost, the spleen-preserving rate is much higher. Robotic surgery may be an alternative approach to DP.
Due to the complexity of the anatomical location and adjacency, distal pancreatectomy (DP) has already become one of the most challenging procedure in the abdomen, with perioperative mortality and complication rates of 2 and 30–40%, respectively [1–3]. Open DP (ODP) used to be the only choice for those patients who need DP. While Cuschieri [4] successfully applied laparoscopic surgery to DP for the first time in 1994, laparoscopic DP (LDP) has become the most widely used minimally invasive technique in pancreatic surgery. Thanks to the advance of technology, another minimally invasive technique, the robotic surgical system (Da Vinci System) was invented. Compared with ODP, minimally invasive pancreatectomy could evidently reduce intraoperative bleeding, improve spleen-preserving rate, reduce postoperative pain, accelerate postoperative recovery and shorten hospital stay [5,6]. A systematic review including 561 patients with ODP and 895 patients with LDP showed that laparoscopic resection could improve operative and postoperative outcomes [7]. Furthermore, LDP had the same rate of margin positive, lymph nodules harvested and overall survival as ODP [5,8,9]. Although achieving good clinical results, in the past 20 years, LDP also showed some limitations, such as 2D planar imaging, less freedom of movement of surgical instruments and long learning curve [10]. The emergence of robotic surgery system partly overcame the shortcomings of laparoscopic surgery through a 3D high-definition surgical view, tremor filtration and seven degrees-of-freedom manipulator arm [11–13]. Melvin et al. [14] performed the first DP with robotic surgical system in 2003. Some authors believed that compared with LDP, robotic DP (RDP) has less bleeding, lower conversion rate and higher rate of lymph node harvested and spleen preservation but has no significant differences in operation time and pancreatic fistula [4,15,16]. While other studies showed different tendencies in comparing LDP with RDP in terms of operation time, pancreatic fistula, blood loss and other outcome indicators [17,18]. Recently, a meta-analysis focusing on LDP and RDP pooled the results from studies with finite sample sizes. Therefore, we performed a more comprehensive meta-analysis concerning whether patients benefit more from RDP compared with LDP.

Materials & methods

The present study was completed according to the Preferred Reported Items for Systematic Reviews and Meta-Analyses guideline.

Literature & search strategy

Two independent researchers (Y-H Hu, Y-M Zhao) performed a systematic search of the electronic databases including EMBASE, PubMed, the Cochrane Library, CNKI and Wan Fang databases to identify randomized controlled trials (RCTs), retrospective controlled study (RCS) and prospective observational studies exploring the safety and efficacy of RDP and LDP from the inception of electronic databases to June 2019. We used a structured search strategy in combination with Boolean logic: (robotics OR robotic) AND (laparoscopy OR laparoscopic) AND (pancreatectomy OR pancreatectomies OR distal pancreatectomy). In addition, we checked the reference list of the studies to identify other trials that might potentially qualify for inclusion in the meta-analysis. The process was completed when no further studies could be determined. In case of more than one publication was available for a study, we used either the most recent publication or the one with the most relevant information.

Inclusion & exclusion criteria

If the literatures met the following criteria in accordance with PICOS, the literature was considered to be included in the present meta-analysis. Population: patients underwent surgeries for lesions in the body or tail of the pancreas; Intervention: patients who received RDP; Comparison intervention: LDP or RDP; Outcome measures: operation time, the length of hospital stay, spleen preservation rate, pancreatic fistula, estimated blood loss, conversion rate, lymph nodules harvest, operation time, blood transfusion rate, operation cost and mortality; Study design: RCTs or RCS. Exclusion criteria: abstracts, letters, editorials and expert opinions, case reports; noncomparative studies; insufficient data and unexplained results and parameters; the scores of Newcastle–Ottawa scale (NOS) <6 [19]; inadequate raw data. Diagnostic criteria for pancreatic leakage: the drainage volume of anastomotic or pancreatic residual fluid was more than 10 ml per day on the 3rd day or later after operation, and the concentration of amylase in drainage fluid was three-times higher than the upper limit of normal plasma amylase and lasted for more than 3 days [20]. Class B and Class C fistulas are thought to be severe pancreatic fistulas according to the criteria of the International Study Group on Pancreatic Surgery. Complications of grade III and IV are considered serious complications after abdominal surgery according to the Clavien–Dindo classification system [21].

Data extraction & outcome measures

We created an electronic data extraction spreadsheet that consisted of the following information: general trial parameters, demographic characteristics, diagnostic measurements, treatment regimens and outcomes. Two independent authors conducted data collection and disagreements were settled by discussion. Intraoperative outcome measures: operation time, estimated blood loss, spleen preservation rate, pancreatic fistula, lymph nodules harvest, blood transfusion rate, conversion rate and operation cost. Postoperative outcome measures: the length of hospital stay, pancreatic fistula, complication and mortality.

Quality assessment & statistical analysis

Two independent authors evaluated the methodological quality of the included RCTs and RCS, respectively, using the NOS. Evidence quality assessment using GRADEpro software Version 3.6 (https://community.cochrane.org/help/tools-and-software/gradepro-gdt). The results of continuous data (operation time, estimated blood loss, lymph nodules harvest, operation cost and the length of hospital stay) were calculated as the mean difference (MD) with 95% CIs. For dichotomous outcome variables (spleen preservation rate, pancreatic fistula, blood transfusion rate, conversion rate, complication and mortality), we used an odds ratio (OR) or rate difference (RD) with 95% CIs. All analyses were performed using Stata/SE 15.1 version (StataCorp). If there was proof of significant heterogeneity (I2 >50%), random-effects models were used. If not, fixed-effects models were used for analysis in accordance with the Cochrane Handbook for systematic reviews of Interventions (Version 5.1.0, https://training.cochrane.org/handbook). If p-value was <0.05, the difference was considered as statistically significant.

Results

Search results

According to the proposed retrieval strategy and method, 1642 research articles were retrieved. Four hundred and thirty duplicated articles are deleted. 1121 papers were removed by reading titles and abstracts; the full text was read and the nonconforming papers were deleted; the full text was re-read and screened according to inclusion criteria, exclusion criteria and data integrity. Finally, 22 [22–43] papers were included, four of which are prospective studies and the rest were retrospective studies. The specific screening process is shown in the Figure 1.
Figure 1. Flowchart of the study selection process.

Characteristics of included studies

We summarized the characteristics of the 22 included studies as follows: 3298 individuals were incorporated into our trial of whom 2519 cases underwent an LDP and 779 cases underwent RDP. The general trial parameters, demographic characteristics, are shown in Table 1.
Table 1. The basic characteristics of included studies.
StudyYearCountryStudy designStudy groupGenderAge
    RDPLDPRDP (M/F)LDP (M/F)RDPLDP
Goh et al.2016SingaporeRetrospective8312/618/13NANA
Eckhardt et al.2015GermanyRetrospective12294/812/1748.5 (29–76)59 (17–85)
Lee et al.2016ChinaRetrospective1869/93/358 (39–80)54.5 (23–80)
Deng et al.2015ChinaRetrospective12223/96/1646.5 ± 16.0848.5 ± 14.8
Adam et al.2015USARetrospective6147428/33248/22665 ± 1464 ± 13
Ryan et al.2015USAProspective18169/96/1067 ± 12.560 ± 17
Lee et al.2015USARetrospective3713110/2757/7458 ± 11.158 ± 15.0
Lai and Tang2015ChinaRetrospective171810/74/1461.2 ± 10.463.2 ± 17.9
Chen et al.2015ChinaRetrospective695023/4618/3256.2 ± 13.356.5 ± 15.0
Butturini et al.2015ItalyProspective22215/176/15NANA
Benizri et al.2014FranceRetrospective11233/810/1350.1 ± 21.152.3 ± 14.7
Duran et al.2014SpainRetrospective16189/79/961 ± 11.658.3 ± 10.0
Daouadi et al.2013USARetrospective309410/2033/6159 ± 1359 ± 16
Kang et al.2010KoreaRetrospective20258/1211/1444.5 ± 15.956.5 ± 13.9
Waters et al.2010USAProspective17186/119/9NANA
Balzano et al.2014ItalyRetrospective31140NANANANA
Ito et al.2014JapanRetrospective410NANA52.768.0
Lin et al.2019ChinaRetrospective414114/2715/2945.2 ± 16.447.4 ± 14.9
Souche et al.2018FranceProspective15233/129/1457 (34–72)66 (44–83)
Raoof et al.2018USARetrospective9960545/54322/283NANA
Zhan et al.2013ChinaRetrospective21305/1611/1952.2 ± 9.244.0 ± 16.8
Xourafas et al.2017USARetrospective20069483/117275/41962 (22–88)62 (19–89)
F: Female; LDP: Laparoscopic distal pancreatectomy; M: Male; NA: Not available; RDP: Robotic distal pancreatectomy.

Study quality & risk of bias

The quality of the included studies was evaluated by the scale of NOS. The details are showed in Table 2. NOS scores for all studies were greater than 7.
Table 2. The Newcastle–Ottawa scale assessment of the included studies.
StudyYearSelectionComparabilityExposureTotal
Goh et al.20164239
Eckhardt et al.20154228
Lee et al.20163137
Deng et al.20153227
Adam et al.20154228
Ryan et al.20153227
Lee et al.20154228
Lai and Tang20154239
Chen et al.20154239
Butturini et al.20153238
Benizri et al.20144239
Duran et al.20143227
Daouadi et al.20134228
Kang et al.20103238
Waters et al.20103238
Balzano et al.20144037
Ito et al.20144138
Lin et al.20194228
Souche et al.20183224
Raoof et al.20184138
Zhan et al.20133227
Xourafas et al.20173227

Methodological quality assessment

Table 3 indicated that the total qualities of the evidence were low for the spleen preservation rate, total pancreatic fistula, total complication, estimated blood loss and operation time.
Table 3. Robotic distal pancreatectomy compared with laparoscopy distal pancreatectomy.
Robotic distal pancreatectomy compared with laparoscopy distal pancreatectomy
Patient or population: patients with distal pancreatectomy
Settings: robotic distal pancreatectomy
Intervention: laparoscopy distal pancreatectomy
OutcomesIllustrative comparative risks (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
 Assumed riskCorresponding risk    
 ControlNew comparison    
Spleen preservation rateStudy populationOR: 2.06
(1.07–3.98)
1940
(16 studies)
⊕⊕⊝⊝
low
 
 184 per 1000317 per 1000
(194–472)
    
 Moderate    
 260 per 1000420 per 1000
(273–583)
    
Total pancreatic fistulaStudy populationOR: 1.09
(0.84–1.4)
1777
(17 studies)
⊕⊕⊝⊝
low
 
 226 per 1000241 per 1000
(197–290)
    
 Moderate    
 320 per 1000339 per 1000
(283–397)
    
Total complicationStudy populationOR: 0.88
(0.72–1.09)
2034
(17 studies)
⊕⊕⊝⊝
low
 
 417 per 1000387 per 1000
(340–438)
    
 Moderate    
 478 per 1000446 per 1000
(397–500)
    
Estimated blood loss The mean estimated blood loss in the intervention groups was
36.25 lower
(79.44 lower to 6.95 higher)
 1071
(17 studies)
⊕⊕⊝⊝
low
 
Operation time The mean operation time in the intervention groups was
27.74 higher
(8.31–47.17 higher)
 2008
(19 studies)
⊕⊕⊝⊝
low
 
The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
OR: Odds ratio.

Outcomes of meta-analysis

Spleen preservation rate

The spleen preservation rates of RDP and LDP were compared in 16 literatures. Meta-analysis showed that there was significant heterogeneity (I2 = 73.4%; p = 0.000) and the results of the random effect model showed that the RDP group had higher spleen-preserving rate (OR: 2.020; 95% CI: 1.085–3.758; p = 0.027; Figure 2).
Figure 2. The spleen preservation rate.
OR: Odds ratio.

Operation time

The operation time between the two groups was conducted among 19 of the included studies. The result showed that the operation time of the RDP group was approximately 30 min longer than the LDP group (heterogeneity p = 0.000; I2 = 85.9%; MD: 27.372; 95% CI: 8.236–47.210; p = 0.000; Figure 3).
Figure 3. The operation time.
WMD: Weighted mean difference.

The length of hospital stay

Twenty-one articles published on the length of hospital stay. There is no heterogeneity in the statistical results of the pooled literatures (I2 = 44.5%, p = 0.611). The result of the fixed effect model showed that the RDP group had shorter hospital stay (MD: -0.911; 95% CI: -1.287 to -0.535; p = 0.000; Figure 4).
Figure 4. The length of hospital stay.
WMD: Weighted mean difference.

Conversion rate

Figure 6 showed the consequences of the conversion rate. There was a significant difference between the RDP group and the LDP group (heterogeneity p = 0.007; I2 = 51.9%; RD: -0.090; 95% CI: -1.287 to -0.535; p = 0.000; Figure 5). The conversion rate in the LDP group was significantly lower than that in the RDP group.
Figure 5. The conversion rate.
RD: Rate difference.

Estimated blood loss

The estimated blood loss between the two groups was conducted among 18 of the included studies. The results showed that there were no significant differences (heterogeneity p = 0.000; I2 = 74.4%; MD: -14.619; 95% CI: -58.019–28.781; p = 0.509; Figure 6).
Figure 6. The estimated blood loss.
WMD: Weighted mean difference.

Total complication

Complications, including postoperative hemorrhage, biliary fistula and chylous fistula and so on, were evaluated in 17 studies. No significant differences were observed between the two groups (OR: 0.884; 95% CI: 0.716–1.092; p = 0.253; Figure 7) with no heterogeneity (p = 0.563; I2 = 0.0%).
Figure 7. The complication.
OR: Odds ratio.

Severe complication

Severe complications were defined according to Clavien-Dindo classification system. No significant differences were observed between the two groups (OR: 1.337; 95% CI: 0.858–2.084; p = 0.199; Figure 7) with no heterogeneity (p = 0.093; I2 = 41.1%).

Operation cost

Only five literatures provided the adequate data about the operation cost. The result of the meta-analysis showed that there was significant difference (MD: 2816.564; 95% CI: 1782.028–3851.064; p = 0.000; Figure 8) with obvious heterogeneity (p = 0.000; I2 = 98.6%).
Figure 8. The operation cost.
WMD: Weighted mean difference.

Lymph nodules harvest

Ten articles published on the lymph nodules harvest. There was heterogeneity in the statistical results of the pooled literatures (I2 = 67.6%; p = 0.001). The result of the random effect model showed that the RDP group had similar lymph nodules harvest compared with the LPD group (MD: 0.826; 95% CI: -1.131–2.783; p = 0.408; Figure 9).
Figure 9. The lymph nodules harvest.
WMD: Weighted mean difference.

Blood transfusion rate

The blood transfusion rate was reported in 13 included studies. A fixed-effects model was performed with no heterogeneity (I2 = 0.0%; p = 0.454). There was no significant difference between the two groups (RD: 0.000; 95% CI: -0.030–0.030; p = 0.998; Figure 10).
Figure 10. The blood transfusion rate.
RD: Rate difference.

Total pancreatic fistula

The total pancreatic fistula could be extracted from 17 studies. There was no heterogeneity in the statistical results of the pooled literatures (I2 = 0.0%; p = 0.957). The result of the fixed effect model showed that the incidence of the total pancreatic fistula was similar between the two groups (OR: 1.086; 95% CI: 0.839–1.404; p = 0.531; Figure 11).
Figure 11. The pancreatic fistula.
OR: Odds ratio.

Severe pancreatic fistula

Severe pancreatic fistula including Class B and Class C fistulas was assessed in 10 articles. A fixed-effects model was performed with no heterogeneity (I2 = 0.0%; p = 0.602). There was no significant difference between the two groups (OR: 1.051; 95% CI: 0.656–1.686; p = 0.835, Figure 11).

R0 resection rate

R0 resection was evaluated in eight literatures. A random effect model was performed with significant heterogeneity (I2 = 82.7%; p = 0.000). There was no significant difference between the two groups (RD: -0.041, 95% CI: -0.151–0.096; p = 0.462; Figure 12).
Figure 12. The R0 resection rate.
RD: Rate difference.

Mortality

Seventeen articles have been published on the mortality. There was no heterogeneity in the statistical results of the pooled literatures (I2 = 0.0%; p = 1.00000). The result of the fixed effect model showed that there was no significant difference (RD: -0.007; 95% CI: -0.020–0.007; p = 0.314; Figure 13).
Figure 13. The mortality.
RD: Rate difference.

Discussion

The DP spleen preserving is indicated only for benign tumors, neuroendocrine tumors or borderline malignancy tumors. With the emphasis on the immune function of spleen, more and more surgeons advocate preserving the spleen while performing DP to reduce the risk of infection, thrombosis and hematological tumors after splenectomy [44–47]. There are two main types of splenic surgery: the Kimura method with preservation of splenic arteries and veins, and the Warshaw method with excision of splenic arteries and veins but preservation of gastric short vessels [48,49]. Spleen preservation and conversion rates are the key indexes for the success of minimally invasive DP. Chen et al. [24] compared the surgical effects of minimally invasive DP among matched patients scheduled for spleen preservation. It was found that the success rate of spleen preservation by RDP was significantly higher than that by LDP (95.7 vs 39.4%). In the RDP group, the Kimura method was used for spleen preservation, accounting for 75.6% (34/45). Liu et al. [50] observed that the spleen-preserving rate of the RDP group was 95.5% for nonmalignant distal pancreatic tumors with a maximum diameter of 3–5 cm and 61.9% were preserved by the Kimuma method. Both data were higher than that of the LDP group in a propensity score-matched study. In contrast, a prospective nonrandomized study of 43 patients indicated that RDP did not have a significant advantage over LDP [23]. The results of our meta-analysis showed that RDP did increase the success rate of spleen preservation (OR: 2.02; 95% CI: 1.09–3.76) and reduce the conversion rate (RD: -0.09; 95% CI: -0.13 to -3.76) compared with LDP. The incidence of splenic infarction and gastric varices after spleen-preserving operation with the Kimuma method was lower and became the first choice of many surgeons [51–53]. The RDP had a 3D high-definition field of vision and was more stable, so it was helpful for a more accurate operation. In the process of separating the pancreatic parenchyma from the splenic artery and vein, for the Kimura method, the blood vessels could be treated separately, which effectively reduced the risk of bleeding and improved the success rate of preserving the spleen [26,32].
This meta-analysis showed that patients underwent RDP had a longer period of operation time than LDP (weighted mean difference [WMD]: 27.72; 95% CI: 8.24–47.21). The combined results were consistent with most clinical studies in the literatures [54,55]. The longer operation time of RDP may be related to the following reasons. First of all, the RDP relevant research is still in the learning stage, which inevitably requires a longer learning curve, including the time required to adapt to new technologies. Second, since additional settings required by robots usually take half an hour to complete, the time spent in the operating room of robotic surgery is extended. Third, most current studies do not describe surgeon proficiency clearly [56].
Pancreatic fistula is the most common abdominal complication after DP [57]. At present, most studies demonstrated that there were no significant differences in the incidence of total complications and pancreatic fistula between RDP and LDP [15,28]. No significant difference was observed in the incidence of total complications, severe complications, total pancreatic fistula and severe pancreatic fistula between RDP and LDP groups according to the results of subgroup analysis. As for transection of the pancreas, some surgeons chose to use the ultrasound scalpel [23]. The overall incidence of pancreatic fistula was 53.5%, of which the incidence of B grade and C grade pancreatic fistula is 16.3%. While other doctors who made up the majority chose to use a linear incision closure device. For those operations, the overall incidence of pancreatic fistula was 27.7–42.1%, of which the incidence of B grade and C grade pancreatic fistula was 7.9 and 9.8% [22,24,50]. It indicated that linear incision closure was more suitable for transection of pancreas than ultrasonic scalpel. The incision edge of pancreas with linear cutting stapler was smoother, the incidence of bleeding and pancreatic fistula was lower and different types of nail silos could be selected according to different thickness of the pancreas.
Kang et al. [26] considered that RDP total cost the patients about USD 8300, which was more than twice the amount for the LDP group. The results of this meta-analysis also showed that the operation cost of RDP was significantly higher than that of LDP (MD: 2816.546; 95% CI: 1782.028–3851.064). This is also one of the important reasons that restrict the application of robotic surgery at present. Studies showed that patients in the RDP group had a shorter length of hospital stay [24,50]. In our study, the hospital stay in the RDP group was nearly 1 day shorter than the LDP group (MD: -0.91; 95% CI: -1.29 to -0.53), which was consistent with previous studies.
This study had following limitations: First, there was heterogeneity in operation time, estimated blood loss, operation cost and spleen preservation rate between the two groups. Robot surgery system, including initial learning period, may lead to unequal operation quality comparison. Second, some literatures included in this meta-analysis had relative small sample size. In addition, the focus of this meta-analysis was to provide a short-term outcome to clarify the value of RDP in DP, and the long-term efficacy of surgical treatment has not been thoroughly discussed in some included studies. Therefore, further attention should be paid to long-term efficacy of RCTs to determine the potential advantages of RDP. Further studies on the long-term outcomes of two surgical techniques are warranted.

Conclusion

Both robotic and LDP are safe and feasible. Although RDP increases the operation cost, the spleen-preserving rate is higher. Robotic surgery may be an alternative approach to DP.
Summary points
Compared with open distal pancreatectomy (ODP), minimally invasive pancreatectomy could evidently reduce intraoperative bleeding, improve spleen-preserving rate, reduce postoperative pain, accelerate postoperative recovery and shorten hospital stay.
The emergence of robotic surgery system partly overcame the shortcomings of laparoscopic surgery.
Recently, a meta-analysis focusing on laparoscopic distal pancreatectomy (LDP) and robotic distal pancreatectomy (RDP) pooled the results from studies with finite sample sizes.
Therefore, we performed a more comprehensive meta-analysis concerning whether patients benefit more from RDP compared with LDP.
There was significant difference in spleen preservation rate, operation time, the length of hospital stays, conversion rate and operation cost.
No significant difference was detected in estimated blood loss, total complication, severe complication, lymph nodules harvest, blood transfusion rate, total pancreatic fistula, severe pancreatic fistula, R0 resection rate and mortality.
Both RDP and LDP are safe and feasible.
Although RDP increases the operation cost, the spleen-preserving rate is much higher. Robotic surgery may be an alternative approach to distal pancreatectomy.

Author contributions

YH Hu and YF Qin conceived of the design of the study. YM Zhao, W Jin, DJ Kong and DD Yu performed and collected the data and contributed to the design of the study. X Li and H Wang prepared and revised the manuscript. All the authors read and approved the final content of the manuscript.

Financial & competing interests disclosure

This work was supported by grants to H Wang from National Natural Science Foundation of China (nos. 81273257 and 81471584), Tianjin Application Basis and Cutting-Edge Technology Research Grant (no. 14JCZDJC35700), Li Jieshou Intestinal Barrier Research Special Fund (no. LJS_201412), Natural Science Foundation of Tianjin (no. 18JCZDJC35800) and Tianjin Medical University Talent Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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