Sirolimus-coated Eustachian tube balloon dilatation for treating Eustachian tube dysfunction in a rat model.

Eustachian tube balloon dilatation (ETBD) has shown promising results in the treatment of ET dysfunction (ETD); however, recurrent symptoms after ETBD frequently occur in patients with refractory ETD. The excessive pressure of balloon catheter during ETBD may induce the tissue hyperplasia and fibrotic changes around the injured mucosa. Sirolimus (SRL), an antiproliferative agent, inhibits tissue proliferation. An SRL-coated balloon catheter was fabricated using an ultrasonic spray coating technique with a coating solution composed of SRL, purified shellac, and vitamin E. This study aimed to investigate effectiveness of ETBD with a SRL-coated balloon catheter to prevent tissue proliferation in the rat ET after ETBD. In 21 Sprague-Dawley rats, the left ET was randomly divided into the control (drug-free ETBD; n = 9) and the SRL (n = 9) groups. All rats were sacrificed for histological examination immediately after and at 1 and 4 weeks after ETBD. Three rats were used to represent the normal ET. The SRL-coated ETBD significantly suppressed tissue proliferation caused by mechanical injuries compared with the control group. ETBD with SRL-coated balloon catheter was effective and safe to maintain ET luminal patency without tissue proliferation at the site of mechanical injuries for 4 weeks in a rat ET model.

Novel self-expandable stent-based endobiliary radiofrequency ablation for unresectable malignant biliary obstruction.

BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) is an emerging endoscopic palliative adjunctive therapy used for the local treatment of unresectable malignant biliary obstruction (MBO). However, irregular ablation ranges caused by insufficient electrode-to-bile duct contact pose a significant obstacle. The aim was to investigate the feasibility of a self-expandable stent (SES)-based electrode with a customized RFA generator in the porcine liver and common bile duct (CBD). METHODS: A SES-RFA system with polarity-switching was developed to perform endobiliary RFA. The ablation ranges of 20 ablation protocols were evaluated to validate the feasibility of the newly developed RFA system in the porcine liver. Nine of the 20 ablation protocols were selected for evaluation in the porcine CBD with cholangiography, endoscopy, and histological and immunohistochemical analysis. RESULTS: The SES-RFA system with polarity-switching was successfully constructed and demonstrated high accuracy and reproducibility. The ablation area was clearly identified between the two SESs. The ablation ranges and degree of mucosal damage including TUNEL- and HSP70-positive depositions increased proportionally with ablation protocols in the porcine liver and CBD (all P < .05). Ablation length and depth linearly increased with ablation protocols from 8.74 ± 0.25 to 31.25 ± 0.67 mm and 1.61 ± 0.09 to 11.94 ± 0.44 mm, respectively. CONCLUSIONS: The SES-RFA system with polarity-switching between electrodes provided an even circumferential area of ablation and enhanced ablation depth between the electrodes. This novel endobiliary RFA system is a promising modality for local ablation in patients with unresectable MBO.

Balloon neck-plasty to create a wide-necked aneurysm in the elastase-induced rabbit model.

PURPOSE: The elastase-induced aneurysm (EIA) model in rabbits has been proposed for translational research; however, the adjustment of aneurysm neck size remains challenging. In this study, the technical feasibility and safety of balloon neck-plasty to create a wide-necked aneurysm in rabbit EIA model were investigated. METHODS: Male New Zealand White rabbits (N = 15) were randomly assigned to three groups: group A, EIA creation without neck-plasty; group B, neck-plasty immediately after EIA creation; group C, neck-plasty 4 weeks after EIA creation. The diameter of balloon used for neck-plasty was determined 1 mm larger than origin carotid artery diameter. All rabbits were euthanized 4 weeks after their final surgery. Aneurysm neck, height, dome-to-neck (D/N) ratio, and histologic parameters were compared among the groups. RESULTS: Aneurysm creation was technically successful in 14 out of 15 rabbits (93.3%), with one rabbit experiencing mortality due to an adverse anesthetic event during the surgery. Saccular and wide-necked aneurysms were successfully created in all rabbits. Aneurysm neck was significantly greater in groups B and C compared to group A (all P < .05). D/N ratio was significantly lower in groups B and C compared to group A (all P < .05). Additionally, tunica media thickness, vessel area, and luminal area were significantly greater in groups B and C compared to group A (all P < .05). These variables were found to be significantly greater in group B compared to group C (all P < .05). CONCLUSION: The creation of a wide-necked aneurysm using balloon neck-plasty after elastase induction in rabbits has been determined to be technically feasible and safe.

3D-printed versatile biliary stents with nanoengineered surface for anti-hyperplasia and antibiofilm formation.

Biliary strictures are characterized by the narrowing of the bile duct lumen, usually caused by surgical biliary injury, cancer, inflammation, and scarring from gallstones. Endoscopic stent placement is a well-established method for the management of biliary strictures. However, maintaining optimal mechanical properties of stents and designing surfaces that can prevent stent-induced tissue hyperplasia and biofilm formation are challenges in the fabrication of biodegradable biliary stents (BBSs) for customized treatment. This study proposes a novel approach to fabricating functionalized polymer BBSs with nanoengineered surfaces using 3D printing. The 3D printed stents, fabricated from bioactive silica poly(ε-carprolactone) (PCL) via a sol-gel method, exhibited tunable mechanical properties suitable for supporting the bile duct while ensuring biocompatibility. Furthermore, a nanoengineered surface layer was successfully created on a sirolimus (SRL)-coated functionalized PCL (fPCL) stent using Zn ion sputtering-based plasma immersion ion implantation (S-PIII) treatment to enhance the performance of the stent. The nanoengineered surface of the SRL-coated fPCL stent effectively reduced bacterial responses and remarkably inhibited fibroblast proliferation and initial burst release of SRL in vitro systems. The physicochemical properties and biological behaviors, including in vitro biocompatibility and in vivo therapeutic efficacy in the rabbit bile duct, of the Zn-SRL@fPCL stent demonstrated its potential as a versatile platform for clinical applications in bile duct tissue engineering.

Radiofrequency ablation via an implanted self-expandable metallic stent to treat in-stent restenosis in a rat gastric outlet obstruction model.

Background: In-stent restenosis caused by tissue hyperplasia and tumor growth through the wire meshes of an implanted self-expandable metallic stent (SEMS) remains an unresolved obstacle. This study aimed to investigate the safety and efficacy of SEMS-mediated radiofrequency ablation (RFA) for treating stent-induced tissue hyperplasia in a rat gastric outlet obstruction model. Methods: The ablation zone was investigated using extracted porcine liver according to the ablation time. The optimal RFA parameters were evaluated in the dissected rat gastric outlet. We allocated 40 male rats to four groups of 10 rats as follows: group A, SEMS placement only; group B, SEMS-mediated RFA at 4 weeks; group C, SEMS-mediated RFA at 4 weeks and housed until 8 weeks; and group D, SEMS-mediated RFA at 4 and 8 weeks. Endoscopy and fluoroscopy for in vivo imaging and histological and immunohistochemical analysis were performed to compare experimental groups. Results: Stent placement and SEMS-mediated RFA with an optimized RFA parameter were technically successful in all groups. Granulation tissue formation-related variables were significantly higher in group A than in groups B-D (all p < 0.05). Endoscopic and histological findings confirmed that the degrees of stent-induced tissue hyperplasia in group D were significantly lower than in groups B and C (all p < 0.05). Hsp70 and TUNEL expressions were significantly higher in groups B-D than in group A (all p < 0.001). Conclusion: The implanted SEMS-mediated RFA successfully managed stent-induced tissue hyperplasia, and repeated or periodic RFA seems to be more effective in treating in-stent restenosis in a rat gastric outlet obstruction model.

Efficacy of closed cell self expandable metallic stent for peripheral arterial disease in the porcine iliac artery.

This study aimed to investigate the efficacy of a closed-cell self-expandable metallic stent (SEMS) with or without expanded-polytetrafluoroethylene (e-PTFE)-covering membrane in a porcine iliac artery model. Twelve Yorkshire domestic pigs were divided into a bare closed-cell SEMS (B-SEMS) group (n = 6) and covered closed-cell SEMS (C-SEMS) group (n = 6). Both closed-cell SEMSs were placed in the right or left iliac artery. Thrombogenicity score in the C-SEMS group was significantly higher than that in the B-SEMS group (p = 0.004) after 4 weeks. Angiographic findings of mean luminal diameters at 4 weeks follow-up did not differ significantly between B-SEMS and C-SEMS groups. Neointimal hyperplasia thickness as well as degree of inflammatory cell infiltration and collagen deposition in the C-SEMS group was significantly greater than that in the B-SEMS group (p < 0.001). Closed-cell SEMSs successfully maintained patency for 4 weeks without stent-related complications in the porcine iliac artery. Although mild thrombus with neointimal hyperplasia was observed in the C-SEMS group, subsequent occlusion, and in-stent stenosis did not occur in any of the pigs until the end of the study. Closed-cell SEMS with or without the e-PTFE covering membrane is effective and safe for the porcine iliac artery.

Preliminary results of absorbable magnesium stent for treating eustachian tube dysfunction in a porcine model.

Absorbable magnesium (Mg) stents have an attractive biocompatibility and rapid degradation rate, but their degradable behavior and efficacy in the Eustachian tube (ET) have not yet been investigated. In this study, the degradable behavior of the Mg stent in artificial nasal mucus was evaluated. The Mg stents in the porcine ET model were also investigated to evaluate their safety and efficacy. Four Mg stents were placed into the four ETs of two pigs. The mass loss rate of the Mg stents gradually decreased over time. The decrease rates were 30.96% at one week, 49.00% at two weeks, and 71.80% at four weeks. On the basis of histological findings, the thickness of submucosal tissue hyperplasia and the degree of inflammatory cell infiltration significantly decreased at four weeks compared with two weeks. Biodegradation of the Mg stent occurred before tissue proliferative reactions, and the ET patency was successfully maintained without stent-induced tissue hyperplasia at four weeks. The Mg stent that biodegrades rapidly seems to be effective and safe in porcine ET. Further investigation is required to verify the optimal stent shape and indwell period in the ET.

A modified method of elastase-induced saccular aneurysm creation in rabbits: Schematic representation of the method.

BACKGROUND: The purpose of our study was to investigate the safety and effectiveness of a modified technique using a short guiding catheter for instillation of elastase in comparison with the previously described method of creating elastase-induced aneurysm in rabbits. METHODS: Following right common carotid artery (RCCA) access using an arterial sheath and inflating the Fogarty balloon in the subclavian artery, a short guiding catheter was used for the instillation of the elastase in the experimental group (n = 5) while it was performed with a microcatheter in the control group (n = 5). The procedure duration was recorded from the RCCA puncture to the sheath removal. The histological changes were characterized using H&E and Masson's trichrome (MT) staining. RESULTS: The procedure time was 23 ± 2 min in the experimental group and 29 ± 2 min in the control group. All the rabbits (100%) in the experimental group survived without neurologic deficits, but two rabbits (40%) survived in the control group. All aneurysms were created in the saccular shape (100%) with a neck size of 2.3 ± 0.29 mm, a width of 2.75 ± 0.36 mm, and height of 6.37 ± 0.46 mm, and a dome to neck ratio of 1.21 ± 0.23. The aneurysm walls were partly thickened due to the degradation of the media tunica and adventitia proliferation with loss of the internal elastic lamina. CONCLUSION: By using a short guiding catheter, we could instill the elastase in a more effective and safe manner in the creation of the elastase-induced aneurysm model in rabbits.

Different routes of administering EW-7197 versus EW-7197⋠HBr for preventing peritoneal adhesion in a rat model.

BACKGROUND: The relatively low aqueous solubility of EW-7197 that was administered orally may have affected the desired concentration in the systemic circulation for treating peritoneal adhesion. This experimental study aimed to compare the efficacy of different routes of administering EW-7197 (2-fluoro-N-[(5-[6-methylpyridin-2-yl]-4-[(1,2,4)triazolo(1,5-a)pyridin-6-yl]-1H-imidazol-2-yl)methyl]aniline) and EW-7197·hydrobromide (HBr), with improved aqueous solubility, for inhibiting peritoneal adhesion in a rat model. METHODS: After peritoneal adhesion induction, 30 male Sprague-Dawley rats were randomly divided into 5 groups with 6 rats in each: group A, sham control; group B, orally administered 25 mg/kg of EW-7197·HBr for 7 days; group C, locally administered 25 mg/kg of EW-7197·HBr; group D, orally administered 20 mg/kg of EW-7197 for 7 days; and group E, locally administered 20 mg/kg of EW-7197. Gross examination, histologic staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-smooth muscle actin marker [α-SMA]) were performed to evaluate the efficacy of both drugs. RESULTS: All procedures were technically successful. All treatment groups, except for group C, showed significantly reduced incidence, quality, tenacity, fibrosis, and collagen deposition scores and lowered expressions of Ki-67- and α-SMA-positive cells compared with group A. When comparing between groups, all scores were significantly lower in group B than in group C (all P < .001), whereas no significant difference was noted in any of the scores between groups D and E and groups B and E (all P > .05). CONCLUSION: Orally administering EW-7197·HBr and both orally and locally administering EW-7197 significantly prevented peritoneal adhesion formation, and orally administering EW-7197·HBr was the most effective overall.

Image-guided stent-directed irreversible electroporation for circumferential ablation in the rat esophagus.

Background: Irreversible electroporation (IRE) has been investigated in the alimentary tract; however, the lack of dedicated electrodes and insufficient tissue responses made its application limited. The aim of this study was to investigate the efficacy and safety of image-guided stent-directed IRE in the rat esophagus. Methods: The bipolar self-expandable electrode (SE) was developed using the braiding technique. A finite element analysis was performed to validate optimal electrical field strength for the rat esophagus. A total of 40 out of 50 rats received stent-directed IRE and were sacrificed at 10 h, 3 days, 7 days, and 28 days of 10 each. The remaining ten rats underwent a sham procedure. The outcomes of stent-directed IRE were assessed by esophagography and histological responses. Results: Stent-directed IRE was technically successful in all rats with mild muscle contraction. The heart rate dropped immediately and gradually recovered at 180 s. TUNEL and caspase-3 with submucosal thickness significantly increased at 10 h and Day 3 compared with those of the sham control (all p < 0.001). The thickness of epithelial layers with collagen deposition significantly decreased at 10 h and Day 3 (all p < 0.001), however, increased at Day 7 compared with that of the sham control (all p < 0.05). The Ki67-positive deposition significantly increased at Day 3 and 7 compared with that of the sham control (all p < 0.001). All variables were similar to those of the sham control at Day 28. Conclusion: Image-guided stent-directed IRE was effective and safe in the rat esophagus. It seems to have effectively and evenly induced cell death and gradually recovered with cellular regeneration.

Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model.

As a non-thermal ablation method, irreversible electroporation (IRE) has been widely investigated in the treatment of prostate cancer. However, no consensus has been achieved on the optimal parameters of IRE for prostate cancer. Since high voltage is known to carry risks of muscle contraction and patient discomfort, it is crucial to identify the minimum but effective and safer applied voltage to inhibit tumor growth. In this study, the effect of different applied voltages of IRE on prostate cancer was evaluated in BALB/c nude mice. Mathematical simulation and measurement of the actual ablation area revealed a larger ablation area at a higher voltage. In in vivo experiment, except for the three different voltages applied, all groups received identical electrical conditions: pulse number, 180 (20 groups × 9 pulses/group); pulse width, 100 µs; pulse interval, 2 ms; distance between the electrodes, 5 mm; and electrode exposure length, 15 mm. Whilst the tumor volume initially decreased in the 500 V (1000 V/cm) and 700 V (1400 V/cm) groups and subsequently increased, only a transient increase followed by a continuous decrease until the sacrifice was observed in the 900 V (1800 V/cm) group. This result demonstrated a lasting effect of a higher applied voltage on tumor growth inhibition. The histological, immunohistochemical, and western blot findings all confirmed IRE-induced apoptosis in the treatment groups. Taken together, 900 V seemed to be the minimum applied voltage required to reduce tumor growth, though subsequent studies are anticipated to further narrow the voltage intervals and lower the minimum voltage required for tumor inhibition.

Tapered self-expandable metallic stent optimized for Eustachian tube morphology in a porcine ET model.

Several investigations on the feasibility of stent placement into the Eustachian tube (ET) are being conducted. However, stents optimized for the anatomical structure of the ET have not yet been developed. In this study, the efficacy and safety of a self-expandable metallic stent (SEMS) optimized for porcine ET morphology was investigated. Silicone was injected into a cadaveric porcine ET to analyze the ET morphology. The three-dimensional-reconstructed porcine ET phantom images obtained after a computed tomography scan were measured to determine the dimensions of the porcine ET. The SEMS was designed as a tapered structure on the basis of the morphological findings of the porcine ET. The tapered SEMS (T-SEMS) and conventional SEMS (C-SEMS) were placed into the porcine ET to compare the safety and efficacy of the two types of SEMSs. Stent-induced tissue hyperplasia in the T-SEMS group was significantly lower than that in the C-SEMS group (p < 0.001). The T-SEMS optimized for the porcine ET was effective in maintaining stent patency. T-SEMS seems to be better than C-SEMS in suppressing stent-induced tissue hyperplasia, owing to the reduced stent-mediated mechanical injuries and maintaining ET patency.

Stent-based electrode for radiofrequency ablation in the rat esophagus: a preliminary study.

Endoluminal radiofrequency (RF) ablation has been widely used as a safe and effective treatment for Barrett's esophagus. However, inadequate RF ablation may occur due to insufficient contact between the electrode and target tissues. Herein, a stent-based monopolar RF electrode (SE) was developed to evenly deliver RF energy to the inner wall of the rat esophagus. The optimal RF parameters were evaluated in the exposed rat esophagus. The temperature in the rat esophagus reached 70 â„ƒ in 89 s at 30 W, 59 s at 40 W, and 34 s at 50 W. The technical feasibility and efficacy of RF ablation using SE were evaluated based on changes in histological transformation and immunohistochemical parameters of tissues compared at immediately, 1 and 2 weeks after the procedure. The degrees of inflammatory cell infiltration, fibrotic changes, TUNEL, and HSP70 in the RF-ablated rat esophagus were significantly higher than compared with sham control (all p < 0.05). TUNEL-positive deposition gradually decreased, but HSP 70-positive deposition maintained a similar level for 2 weeks. The stent-based RF ablation was technically feasible and effective in evenly inducing thermal damages to the rat esophagus. The RF ablation system using the SE may represent a promising treatment for endoluminal malignancies.

High-Frequency Pulsed Electric Field Ablation in Beagle Model for Treatment of Prostate Cancer.

Conventional irreversible electroporation (IRE) with low-frequency pulsed electric field (LF-PEF) is used to induce cell death; however, it has several disadvantages including a long procedure time and severe muscle contraction due to high-voltage electric field. This study investigates a novel IRE protocol with high-frequency pulsed electric field (HF-PEF) of 500 Hz repetition to ablate the prostate tissue in beagles for treatment of prostate cancer. A finite element analysis was performed to validate optimal electrical field strength for the procedure. In total, 12 beagles received HF-PEF of 500 Hz and were sacrificed at 4 h, 4 days, and 28 days (3 each). The remaining three beagles underwent sham procedure. The outcomes of HF-PEF were assessed by histological responses. HF-PEF successfully decellularized the prostate tissues 4 h after the treatment. The prostate glands, duct, and urethra were well preserved after IRE with HF-PEF. The ablated prostatic tissues were gradually regenerated and appeared similar to the original tissues 28 d after IRE with HF-PEF. Moreover, electrocardiography and hematology demonstrated that IRE with HF-PEF did not seriously affect the cardiac tissue. HF-PEF was effective and safe in the beagle prostate and effectively induced the ablation and gradually recovered with cellular regeneration.

Efficacy of thermoplastic polyurethane and gelatin blended nanofibers covered stent graft in the porcine iliac artery.

Stent-grafts composed of expanded polytetrafluoroethylene (e-PTFE), polyethylene terephthalate (PET) and polyurethane (PU) are characterized by poor endothelialization, high modulus, and low compliance, leading to thrombosis and intimal hyperplasia. A composite synthetic/natural matrix is considered a promising alternative to conventional synthetic stent-grafts. This study aimed to investigate the efficacy of thermoplastic polyurethane (TPU) and gelatin (GL) blended nanofibers (NFs) covered stent-graft in the porcine iliac artery. Twelve pigs were randomly sacrificed 7 days (n = 6) and 28 days (n = 6) after stent-graft placement. The thrombogenicity score at 28 days was significantly increased compared at 7 days (p < 0.001). The thickness of neointimal hyperplasia, degree of inflammatory cell infiltration, and degree of collagen deposition were significantly higher at 28 days than at 7 days (all p < 0.001). The TPU and GL blended NFs-covered stent-grafts successfully maintained the patency for 28 days in the porcine iliac artery. Although thrombosis with neointimal tissue were observed, no subsequent occlusion of the stent-graft was noted until the end of the study. Composite synthetic/natural matrix-covered stent-grafts may be promising for prolonging stent-graft patency.

Silver Nanofunctionalized Stent after Radiofrequency Ablation Suppresses Tissue Hyperplasia and Bacterial Growth.

Intraductal radiofrequency (RF) ablation combined with placement of a self-expandable metal stent (SEMS) for malignant biliary obstruction has risks such as stent- and heat-induced biliary sludge and restenosis. Here, we investigated the efficacy of a silver nanoparticles (AgNPs)-coated SEMS to inhibit tissue hyperplasia and bacterial growth caused by RF ablation with stent placement in the rabbit bile duct. The release behavior and antibacterial effects of AgNPs-coated SEMSs were evaluated. Then, SEMSs were successfully placed in all rabbits immediately after RF ablation. Ag ions were rapidly released at the beginning and then showed a gradual release behavior. The AgNPs-coated SEMS significantly inhibited bacterial activity compared to the uncoated SEMS (p < 0.05). Cholangiography and histological examination confirmed that the level of tissue hyperplasia was significantly lower in the AgNPs group than in the control group (all p < 0.05). Immunohistochemistry analyses revealed that TUNEL-, HSP 70-, and α-SMA-positive areas were significantly lower in the AgNPs group than in the control group (all p < 0.05). Intraductal RF ablation combined with nanofunctionalized stent placement represents a promising new approach for suppressing thermal damage as well as stent-induced tissue hyperplasia and bacterial growth.

Novel platinum bipolar electrode for irreversible electroporation in prostate cancer: preclinical study in the beagle prostate.

The exposure of the prostate to high electric field strength during irreversible electroporation (IRE) has been extensively investigated. Multiple monopolar electrodes, however, have risks of organ piercing and bleeding when placing electrodes. A novel bipolar electrode made of pure platinum and stainless steel was developed for prostate cancer ablation. Voltages of 500 and 700 V were applied to the beagle prostate with this electrode to evaluate ablated tissues and their characteristics. IRE procedures were technically successful in all dogs without procedure-related complications. The current that flowed through the anode and cathode while applying 500 and 700 V were 1.75 ± 0.25 A and 2.22 ± 0.35 A, respectively. TUNEL assays showed that the estimated ablated areas when applying 500 and 700 V were 0.78 cm2 and 1.21 cm2, respectively. The minimum electric field strength threshold required for induction of IRE was 800 V/cm. The platinum electrode was resistant to corrosion. The IRE procedure for beagle prostates using a single bipolar electrode was technically feasible and safe. The novel bipolar electrode has great potential for treating human prostate cancer with fewer IRE-related complications.