EW-7197, transforming growth factor ß inhibitor, combined with irreversible electroporation for improving skin wound in a rat excisional model.

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague-Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes.

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.

Effects of bipolar irreversible electroporation with different pulse durations in a prostate cancer mouse model.

Irreversible electroporation (IRE) is a non-thermal ablation technique for local tumor treatment known to be influenced by pulse duration and voltage settings, affecting its efficacy. This study aims to investigate the effects of bipolar IRE with different pulse durations in a prostate cancer mouse model. The therapeutic effectiveness was assessed with in vitro cell experiments, in vivo tumor volume changes with magnetic resonance imaging, and gross and histological analysis in a mouse model. The tumor volume continuously decreased over time in all IRE-treated groups. The tumor volume changes, necroptosis (%), necrosis (%), the degree of TUNEL-positive cell expression, and ROS1-positive cell (%) in the long pulse duration-treated groups (300 µs) were significantly increased compared to the short pulse duration-treated groups (100 µs) (all p < 0.001). The bipolar IRE with a relatively long pulse duration at the same voltage significantly increased IRE-induced cell death in a prostate cancer mouse model.

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.

Self-Expandable Electrode Based on Chemically Polished Nickel-Titanium Alloy Wire for Treating Endoluminal Tumors Using Bipolar Irreversible Electroporation.

The application of irreversible electroporation (IRE) to endoluminal organs is being investigated; however, the current preclinical evidence and optimized electrodes are insufficient for clinical translation. Here, a novel self-expandable electrode (SE) made of chemically polished nickel-titanium (Ni-Ti) alloy wire for endoluminal IRE is developed in this study. Chemically polished heat-treated Ni-Ti alloy wires demonstrate increased electrical conductivity, reduced carbon and oxygen levels, and good mechanical and self-expanding properties. Bipolar IRE using chemically polished Ni-Ti wires successfully induces cancer cell death. IRE-treated potato tissue shows irreversibly and reversibly electroporated areas containing dead cells in an electrical strength-dependent manner. In vivo study using an optimized electric field strength demonstrates that endobiliary IRE using the SE evenly induces well-distributed mucosal injuries in the common bile duct (CBD) with the overexpression of the TUNEL, HSP70, and inflammatory cells without ductal perforation or stricture formation. This study demonstrates the basic concept of the endobiliary IRE procedure, which is technically feasible and safe in a porcine CBD as a novel therapeutic strategy for malignant biliary obstruction. The SE is a promising electrical energy delivery platform for effectively treating endoluminal organs.

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.

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.

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.

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.

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.

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.

Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Serial histological changes in the cartilaginous eustachian tube in the rat following balloon dilation.

Although balloon dilation has shown promising results in the treatment of dilatory Eustachian tube (ET) dysfunction, the histological effects of ET balloon dilation (ETBD) is unknown because histological examination of the whole human cartilaginous ET is impossible. Animal studies are needed to elucidate the effect of ETBD so we evaluated the histological changes after ETBD in a rat model. The left ET of 20 Wistar rats was dilated with a balloon catheter and the right ET was used as a control. Five rats were sacrificed immediately after ETBD, at 1, 4 and 12 weeks after the procedure for histological examination. The epithelial cells, presence of epithelial hyperplasia, and the proportion of the goblet cells in the epithelium; the vascular structures and dimensions of the submucosa; and presence of cartilage fracture and the area of the ET lumen were evaluated and compared between the groups. Desquamation of nearly all epithelial cells and the fracture of tubal cartilages were observed immediately after ETBD. At 1-week post-ETBD, the ciliated epithelial cells started to recover with epithelial hyperplasia. The goblet cells recovered by 4 weeks post-ETBD and epithelial hyperplasia decreased but was still present at 12 weeks post-ETBD. The depth of the submucosa increased and neovascularization in this region was observed at 1-week post-ETBD and persisted up to 12 weeks post-ETBD. The lumen of the cartilaginous ET increased immediately after ETBD but decreased at 1-week post-ETBD. The cartilaginous ET lumen recovered to the normal value at 4 weeks post-ETBD. This study is the first to describe the serial histological changes to the cartilaginous ET after ETBD and helps our understanding of the histological changes that occur after an ETBD intervention for intractable ET dysfunction.

Flexible 3D Nanonetworked Silica Film as a Polymer-Free Drug-Eluting Stent Platform to Effectively Suppress Tissue Hyperplasia in Rat Esophagus.

Loading and eluting drugs on self-expandable metallic stents (SEMSs) can be challenging in terms of fabrication, mechanical stability, and therapeutic effects. In this study, a flexible 3D nanonetworked silica film (NSF) capable of withstanding mechanical stress during dynamic expansion is constructed to function as a drug delivery platform on an entire SEMS surface. Despite covering a broad curved area, the synthesized NSF is defect-free and thin enough to increase the stent strut diameter (110 µm) by only 0.4 percent (110.45 µm). The hydrophobic modification of the surface enables loading of 4.7 times the sirolimus (SRL) concentration in NSF than Cypher, polymer-coated commercial stent, which is based on the same thickness of coating layer. Furthermore, SRL-loaded NSF exhibits a twofold delay in release compared to the control group without NSF. The SRL-loaded NSF SEMS significantly suppresses stent-induced tissue hyperplasia than the control SEMS in the rat esophagus (all variables, p < 0.05). Thus, the developed NSF is a promising polymer-free drug delivery platform to efficiently treat esophageal stricture.

Combination of Metal-Phenolic Network-Based Immunoactive Nanoparticles and Bipolar Irreversible Electroporation for Effective Cancer Immunotherapy.

To circumvent the limitations of conventional cancer immunotherapy, it is critical to prime antigen-presenting cells (APCs) to initiate the cancer-immune cycle. Here, the authors develop a metal-phenolic network (MPN)-based immunoactive nanoparticle in combination with irreversible electroporation (IRE) for an effective cancer immunotherapy. The MPN nanoparticles are synthesized by coordinating tannic acid with manganese (Mn) ions, and subsequent coating with CpG-oligodeoxynucleotides (CpG-ODNs) via hydrogen bonding. The CpG-ODN-coated Mn-phenolic network (CMP) nanoparticles are effectively internalized into macrophages, a type of APCs, and successfully trigger M1 polarization to promote release of proinflammatory cytokines. Notably, the CMP nanoparticles demonstrate an extended retention time period than the free CpG-ODN in the tumor. The tumor microenvironment tailored bipolar IRE, enhances the therapeutic efficacy by significantly broadening the ablation zone, which further increases immunogenic cell death (ICD). Ultimately, the simultaneous CMP nanoparticles and IRE treatment successfully inhibit tumor growth and prolong survival in a mouse tumor model. Thus, CMP nanoparticles are empowered with Mn and CpG-ODN immunomodulators and the tumor microenvironment tailored bipolar IRE will be a new tool for effective cancer immunotherapy to treat intractable malignancies.

Sirolimus-eluting cobalt-chrome alloy stent suppresses stent-induced tissue hyperplasia in a porcine Eustachian tube model.

Various preclinical studies with developed Eustachian tube (ET) stents are in progress but have not yet been clinically applied. ET stent is limited by stent-induced tissue hyperplasia in preclinical studies. The effectiveness of sirolimus-eluting cobalt-chrome alloy stent (SES) in suppressing stent-induced tissue hyperplasia after stent placement in the porcine ET model was investigated. Six pigs were divided into two groups (i.e., the control and the SES groups) with three pigs for each group. The control group received an uncoated cobalt-chrome alloy stent (n = 6), and the SES group received a sirolimus-eluting cobalt-chrome alloy stent (n = 6). All groups were sacrificed 4 weeks after stent placement. Stent placement was successful in all ETs without procedure-related complications. None of the stents was able to keep its round shape as original, and mucus accumulation was observed inside and around the stent in both groups. On histologic analysis, the tissue hyperplasia area and the thickness of submucosal fibrosis were significantly lower in the SES group than in the control group. SES seems to be effective in suppressing stent-induced tissue hyperplasia in porcine ET. However, further investigation was required to verify the optimal stent materials and antiproliferative drugs.