Biliary stents for active materials and surface modification: Recent advances and future perspectives

Abstract

Demand for biliary stents has expanded with the increasing incidence of biliary disease. The implantation of plastic or self-expandable metal stents can be an effective treatment for biliary strictures. However, these stents are nondegradable and prone to restenosis. Surgical removal or replacement of the nondegradable stents is necessary in cases of disease resolution or restenosis. To overcome these shortcomings, improvements were made to the materials and surfaces used for the stents. First, this paper reviews the advantages and limitations of nondegradable stents. Second, emphasis is placed on biodegradable polymer and biodegradable metal stents, along with functional coatings. This also encompasses tissue engineering & 3D-printed stents were highlighted. Finally, the future perspectives of biliary stents, including pro-epithelialization coatings, multifunctional coated stents, biodegradable shape memory stents, and 4D bioprinting, were discussed.

Keywords: Biliary stent; Biodegradable; Functional coatings; Shape memory; Tissue engineering & 3D-printed stent.

Fig. 1

Etiology of biliary strictures [2].

Fig. 2

Typical types of biliary stents. A-E: Nondegradable plastic stents. A: Double pigtails. B: Single pigtail. C: Curved. D: Straight. E: Amsterdam. F-K: Nondegradable metal stents. F: Uncovered self-expandable metal stent. G: Partially covered. H: Fully covered. I: Cross type, closed-cell (red mark), braided. J: Open cell (green mark), laser-cut. K: Cross & hook, braided. L: Biliary stent made of magnesium alloy (UNITY-B; AMG International, Winsen, Germany). M-N: Biodegradable polymer stents. M: Archimedes stent (Amg International GmbH, Winsen, Germany). N: Ella-DV biliary stent made of polydioxanone (Ella-CS, Hradec Králové, Czech Republic).

Fig. 3

Schematic for preventing stent migration. A: Fully covered SEMS with flared ends (red dashed boxes) [30]. B: Outward projecting wires as anchoring fins (green arrows) [30]. C: Fully covered SEMS with anchoring flaps at the proximal end of the stent (blue arrows) [29]. D: An externally anchored PS for extending the patency of fully covered SEMS [32]. SEMS: self-expandable metal stent. PS: plastic stent. CBD: common bile duct.

Fig. 4

Typical functional coatings of biliary stents. EDTA: ethylenediaminetetraacetic acid; SC: sodium cholate.

Fig. 5

Coating preparation techniques commonly used for biliary stents. A: Dip coating. B: Layer by layer [137]. C: Covalent immobilization [138]. (a): Direct covalent immobilization through wet chemical methods. (b): Covalent immobilization using chemical linkers. D:Four steps of electrophoretic deposition [139]. (a) dispersion, (b) electrochemical charging, (c) electrophoresis and (d) deposition. E: Schematic illustration of four electrospinning methods [140]. (a) Single nozzle electrospinning. (b) Single nozzle electrospinning with emulsion. (c) Side-by-side nozzle electrospinning. (d) Coaxial nozzles electrospinning.

Fig. 6

Antitumor activity of GEM & CIS coatings in vivo [141]. A: Schematic diagram of the coated stent. The inner, middle and outer layer of the coating is PTFE membrane (as a barrier to prevent drug loss), PLCL layer (as the primary drug carrier), and PLCL-unloaded outer membrane (as a barricade to avoid burst release), respectively. B: HE staining ( × 200, 100 μm scale bar), immunohistochemical detection of p53 upregulated modulator of apoptosis and cleaved caspase-3 ( × 400, 50 μm scale bar), and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ( × 200, 50 μm scale bar) in subcutaneous tumor tissues. C: Subcutaneous tumors in nude mice after 4 weeks of drug-loaded nanofilm implantation. PTFE: polytetrafluoroethylene; GEM: gemcitabine; CIS: cisplatin; HE: hematoxylin and eosin; PLCL: poly L-lactide-caprolactone; PUMA: p53 upregulated modulator of apoptosis; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

Fig. 7

Coated stents for stone dissolution in pigs [147]. A: Schematic illustration of the establishment of a CBD stone model and stent placement. (a) The distal part of the CBD was partially ligated to construct biliary stricture. (b) After longitudinal incision of the dilated CBD, the stone was placed in it. (c) A plastic stent was implanted. B: Stone weight changed in different stent groups. (a) Three groups of stone weight change (mg). Greater stone weight reduction was achieved in the 50 % coating group. (b) Similar results were obtained for the percentage change in stone weight. C: Histological findings in CBD that receiving a 50 % EDTA & SC-coated stent. (a) The CBD macroscopic appearance. (b) & (c) HE staining of CBD in the implanted portion of the stent, mucosa was smooth, but presence of mild inflammatory cell infiltration; × 100 (b), × 250 (c). HE: hematoxylin and eosin stain; CBD: common bile duct; EDTA: ethylenediaminetetraacetic acid; SC: sodium cholate.

Fig. 8

Structure of a biliary stent with anti-reflux system [158]. A: Stent equipped with retractable valves. B: The state of the valve during the forward flow of bile, which passes smoothly through the valve. C: Valve status during reflux of duodenal contents, capable of preventing reflux effectively.

Fig. 9

Schematic diagram of biofilm formation [160]. Biofilm formation involves reversible and irreversible attachment, biofilm maturation, and eventually dispersion. EPS: extracellular polymeric substances.

Fig. 10

Implantation of AgNPs-coated SEMS after RF ablation effectively blocked tissue hyperplasia and bacterial growth [169]. A: Schematic representation of SEMS coated with AgNPs placed immediately following RF ablation. B: Histological results and gross findings. (a) Representative pictures of the histological and gross results indicated that the extent of tissue hyperplasia in the AgNPs group was lower than in the control group. (b–e) Histological findings of the bile ducts in the stent-implanted portion of the control and AgNPs groups. C: The representative diagrams of the IHC staining and findings. (a) The photographs of TUNEL-, HSP 70-, and α-SMA-stained sections. (b) Results of quantitative analysis of histograms. AgNPs: silver nanoparticles; SEMS: self-expandable metal stent; RF: radiofrequency; PDA: polydopamine; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling; HSP 70: heat shock protein 70; α-SMA: α-smooth muscle actin. CI: confidence interval; **p < 0.01; ***p < 0.001.

Fig. 11

The HAp/MgF double-layer coating on biodegradable high-purity Mg [224]. A: Surface morphologies and element components of HT-Mg (a–c) and FH-Mg (d–f). B: Polarization curves (a) and (b) corrosion rate for Mg, HF-Mg, HT-Mg, and FH-Mg after immersion test in SBF solution for 7, 14, and 21 days. C: Cytocompatibility of HF-Mg, HT-Mg, and FH-Mg. (a) MG63 cells proliferation after 1-, 4-, and 7-days incubation. Live-dead staining of MG63 cells cultured on the surface of HF-Mg (b, e, h), HT-Mg (c, f, i), and FH-Mg (d, g, j) at day 1, 4, and 7. *p < 0.05.

Fig. 12

Replacement of bile duct with ECO-populated densified collagen tubes [242]. A: Schematic illustration of the procedure for the replacement of the bile duct. B: Postmortem pictures of mice receiving a collagen tube populated with ECOs (ECOs) compared to a FPT (fibroblasts). Yellow pigmentation of EPT due to bile flow. Luminal obstruction causing bile leakage (yellow peritoneal pigmentation, white dashed line) is indicated by the white color of the fibroblast-populated conduit and the expanded, and bile-laden (yellow color) PBD, (scale bars, 500 μm). C: Pictures of a thin-walled native bile duct-like construct from a mouse that received an EPT compared to a thick construct with no discernible lumen generated from a mouse that received the FPT. D: qRT-PCR analyses demonstrating bile duct marker expression by ECOs from ECO-populated transplanted tubes (ECOs in vivo) versus cultivated ECOs (ECOs in vitro) and bile duct tissue from mice as the negative control.; n = 4 tubes. Box, IQR; center line, median; whiskers, range (minimum to maximum). The values are relative to the expression of HMBS. E: IF analyses revealing lumen lining of GFP + CK19+ epithelium in the EPC compared to lumen obliteration by fibroblasts in the FPC. F: H&E staining showing the existence of biliary epithelium and patent ductal lumen in EPT but not in FPC. G: Cholangiography with FITC demonstrating luminal patency in EPT as opposed to luminal occlusion in FPC. H: The activity of ALP is observed exclusively in EPT, but not in FPC. ECOs: extrahepatic cholangiocyte organoids; PBD: proximal bile duct. SC: collagen tubular scaffold; DBD: distal bile duct. HMBS: housekeeping gene hydroxymethylbilane synthase; EPC: ECO-populated construct; EPT: ECO-populated tube; FPC: fibroblast populated construct; FPT: fibroblast-populated tube; ALP: alkaline phosphatase.

Fig. 13

3D-printed biliary stents for anti-hyperplasia and antibiofilm formation. A: The elliptical strut promotes bile flow to reduce precipitate formation, and the hydrophilic surface and antibacterial Zn ions inhibit bacterial adhesion and biofilm formation. B: Representative FE-SEM images of 3D-printed fPCL stent (a) and chemical compositions of 3D-printed fPCL and pristine PCL stents (b). C: Anti-fibroblast proliferative activity. (a): CLSM micrographs of fibroblasts on different specimens after 24 h of culturing and (b) proliferation of fibroblasts on different specimens after 3 and 5 d of culturing. D: Macroscopic and microscopic images 4 weeks after stent placement in rabbit common bile duct. (b) Histological results of 3D-printed PCL, fPCL, SRL@fPCL, and Zn-SRL@fPCL stent groups in the stented bile duct. E: Evaluation of bactericidal activity. (a) Optical pictures and (b) mean colony counts of E. coli. (c) Optical pictures and (d) average colony counts of S. aureus. *p < 0.05, **p < 0.01, ***p < 0.005, and ****p < 0.001.

Fig. 14

3D printing-based biodegradable shape memory biliary stents [61]. A: The stent manufacturing process. B: Shape recovery of the P(3HB-co-4HB) stent in 37 °C PBS, bile, and alcohol at different time points. C: Stent morphology after insertion of 2 months (under endoscope). D: The position of the stent and common bile duct. E: Shape memory characteristics of the stent at different times. c1) The initial stent. c2) Fresh stent just removed from bile duct. c3) The dried stent removed from bile duct. F: Histologic staining of bile duct. TA: triamcinolone acetonide; PEG: polyethylene glycol; EPSO: ethiodized poppy seed oil.

Fig. 15

Schematic representation of 4D bioprinting [275]. The printed bioconstruct can alter its size, shape or functionality in response to external stimuli.