Pancreatoscopy-assisted endoscopic mucosal resection combined with tetra-PEG hydrogel sealant spray in a porcine model: An innovative treatment method for main duct pancreatic intraductal neoplasms

To the Editor: With the improvement and popularization of medical imaging, an increasing number of main duct pancreatic intraductal neoplasms (MD-PINs), including intraductal oncocytic papillary, intraductal tubulopapillary neoplasms, and intraductal papillary mucinous neoplasms, are being detected.[1] The management of these patients has long posed a clinical dilemma. Surgical treatment requires extensive resection, while follow-up observation is associated with the risk of lesion progression.[2] Therefore, this study introduced an innovative technique, namely, pancreatoscopy-assisted endoscopic mucosal resection combined with tetra-poly(ethylene glycol) (PEG)-based hydrogel sealant spraying, in a porcine model to remove MD-PINs precisely while maintaining the anatomic integrity of the digestive system [Figure 1, Supplementary Figure 1, https://links.lww.com/CM9/C788].Figure 1: Pancreatoscopy-assisted endoscopic mucosal resection combined with tetra-PEG hydrogel sealant spray for main duct pancreatic intraductal neoplasms in a porcine model. (A) MPD intubation was conducted in a male pig. (B) An SOP was inserted into the MPD through the working channel of the duodenoscope along a guidewire. (C) An electrocautery snare was inserted into the MPD through the working channel of the SOP. (D) Electrocoagulation was performed using the electrocautery snare at 30 W under soft electrocoagulation mode to treat part of the MPD mucosa. (E) Two weeks later, single-operator pancreatoscopy was performed again to confirm the successful establishment of the MD-PIN model. (F) The electrocautery snare was inserted through the working channel of the SOP to the location of the MD-PIN model. (G) The lesion was then resected using an electrocautery snare at 35 W under ENDO CUT Q mode; bleeding was observed immediately after resection. (H) Negative pressure suction was performed to keep the visual field clear, and a spray tube was inserted into the MPD through the working channel of the SOP. (I) The injectable tetra-PEG hydrogel sealant was subsequently prepared by mixing the two components using a syringe and delivered through the spray tube to the MPD wound, after which the wound bleeding stopped. (J) A follow-up with SOP was performed at 4 weeks after the surgery, and the wound had healed well. MD-PIN: Main duct pancreatic intraductal neoplasm; MPD: Main pancreatic duct; PEG: Poly(ethylene glycol); SOP: Single-operator pancreatoscope.This study was approved by the Ethics Committee of the Chinese People’s Liberation Army (PLA) General Hospital (No. SQ2024888). The MD-PIN model was established as follows: (1) Main pancreatic duct (MPD) intubation was conducted in a male pig [Figure 1A]; (2) a single-operator pancreatoscope (SOP) was inserted into the MPD through the working channel of the duodenoscope along a guidewire [Figure 1B]; (3) an electrocautery snare was inserted into the MPD through the working channel of the SOP [Figure 1C]; and (4) electrocoagulation was performed using the electrocautery snare at 30 W under soft electrocoagulation mode to treat part of the MPD mucosa [Figure 1D]. Two weeks later, single-operator pancreatoscopy was performed again to confirm the successful establishment of the MD-PIN model [Figure 1E]. Pancreatoscopy-assisted endoscopic mucosal resection combined with tetra-PEG hydrogel sealant spray was performed immediately as follows: (1) The electrocautery snare was inserted through the working channel of the SOP to the location of the MD-PIN model [Figure 1F]; (2) The lesion was then resected using an electrocautery snare at 35 W under ENDO CUT Q mode; bleeding was observed immediately after resection [Figure 1G]; (3) Negative pressure suction was performed to keep the visual field clear, and a spray tube was inserted into the MPD through the working channel of the SOP [Figure 1H]; (4) Four-armed poly(ethylene glycol) amine (tetra-PEG-NH2) and four-armed poly (ethylene glycol) succinimidyl succinamide (tetra-PEG-SSA) polymers were each dissolved in phosphate buffered saline (PBS) (pH 7.4) at 6 weight (wt)% in two sample bottles. The injectable tetra-PEG hydrogel sealant was subsequently prepared by mixing the two components using a syringe and delivered through the spray tube to the MPD wound [Figure 1I], after which the wound bleeding stopped. The pig underwent serum amylase and lipase tests 24 h before the procedure, 24 h after the procedure, and one week after the procedure. Amylase and lipase levels were evaluated 24 h after the procedure and returned to normal levels after one week. A follow-up with SOP was performed at 4 weeks after the surgery, and the wound had healed well [Figure 1J]. The greatest advantage of pancreatoscopy-assisted endoscopic mucosal resection over surgical resection is that the anatomic integrity of the digestive system can be preserved postoperatively. In theory, the most concerning adverse events of this technique are postoperative pancreatic fistula and wound bleeding in the MPD. Hydrogel bioadhesives, which have been widely applied to promote the healing of various wounds and prevent postoperative bleeding in the field of biomedicine, have the potential to revolutionize medical procedures because of their noninvasive nature and ease of application without specialized requirements.[3] However, there are two technological bottlenecks in its application in the MPD. On the one hand, there are few clinical adhesive products that are both biosafe and effective at adhesion. Currently, tissue bioadhesives approved for medical use present significant limitations, including inadequate mechanical strength on tissue surfaces, potential risks of viral and disease transmission, and allergic reactions.[4] On the other hand, the blood-resistant hydrogel bioadhesives reported in the literature are severely limited by required external instruments, such as ultraviolet irradiation and/or the continuous application of constant pressure;[5] therefore, delivery into the wound in the MPD with simultaneously controlled gelation time and high adhesion strength is significantly difficult, particularly when the papilla of the duodenum is subjected to pancreatoscopy-assisted procedures. More importantly, the majority of hydrogel bioadhesives still struggle to maintain stability and cohesion within the MPD in pancreatic fluid environments. Therefore, ideal tissue bioadhesives should be easy for novice clinicians to operate, gelatinize, and solidify on demand, firmly adhere to targeted wound tissues, and maintain a high level of durable stability even with exposure to a fluidically, chemically, and mechanically dynamic environment. In the present study, our group developed a biocompatible tetra-PEG hydrogel sealant by an ammonolysis reaction between tetra-PEG-NH2 and tetra-PEG-SSA. These two components approved by the USA Food and Drug Administration were entirely synthetic without other transferring diseases. Once they were synchronously sprayed onto the wound in the MPD, the amine groups of the tetra-PEG-NH2 polymer quickly reacted with the N-hydroxysuccinimide (NHS)-ester of the tetra-PEG-SSA polymer to generate crosslinking amide bonds within seconds; thus, the strong tissue adhesion and good haemostasis properties of this hydrogel allow it to maintain a longer degradation time within the MPD in the pancreatic fluid environment. Moreover, our group developed special spray tubes that can pass through the working channel of the SOP to deliver tetra-PEG hydrogel sealants to the wound in the MPD. Based on the above efforts, this study further introduced pancreatoscopy-assisted tetra-PEG hydrogel sealant spray to promote wound healing and prevent wound bleeding in the MPD after pancreatoscopy-assisted endoscopic mucosal resection. In addition, this technology has the potential to further treat biliopancreatic fistulas in the clinic. Our group successfully established an animal model of biliopancreatic fistulas using a single-operator cholangiopancreatoscope [Supplementary Figure 2A, B, https://links.lww.com/CM9/C788]. Moreover, the present study provided a novel animal model of MD-PIN which was very similar to the actual lesion. In conclusion, this study preliminarily confirmed the feasibility and safety of pancreatoscopy-assisted endoscopic mucosal resection combined with tetra-PEG hydrogel sealant spray for MD-PINs in a novel porcine model, although further clinical studies are warranted. Funding This study was supported by the General Funding Program (78th Batch) of the China Postdoctoral Science Foundation and the Young Talent Program, The First Medical Center, Chinese PLA General Hospital. Conflicts of interest None. Data statement The data, analytic methods, and study materials will be made available to other researchers from the corresponding author.