A new agent for contrast-enhanced intravascular ultrasound imaging in vitro: polybutylcyanoacrylate nanoparticles with drug-carrying capacity.

This study prepared and evaluated polymeric polybutylcyanoacrylate (PBCA) nanoparticles (NPs) that can be used as a new agent for contrast-enhanced intravascular ultrasound (IVUS) imaging with drug delivery capacity. The nanoformulation was successfully developed using suspension polymerisation and characterised in terms of size, size distribution, zeta potential, morphology, stability, toxicity effects, imaging effects and drug release study. The results showed that the nanoparticles were round and hollow, with a particle diameter of 215.8 ± 25.3 nm and a zeta potential of -22.2 ± 4.1 mV. In vitro experiments, the nanoparticles were safe, non-toxic, and stable in nature with the capacity to carry and release drug (ant-miR-126). Moreover, the nanoparticles can match the high-frequency probe of commercially IVUS as a contrast agent to improve the resolution of imaging (the mean echo intensity ratio in the vascular wall increased significantly from 10.89 ± 1.10 at baseline, to 24.51 ± 1.91 during injection and 43.70 ± 0.88 after injection, respectively p < .0001). Overall, a new nano agent with drug-carrying capacity was prepared, which can be used in combination with IVUS for simultaneous diagnosis and targeted therapy of coronary atherosclerosis.

Blood-Nanoparticle Interactions Create a Brain Delivery Superhighway for Doxorubicin.

Purpose: This study investigated the brain targeting mechanism of doxorubicin-loaded polybutyl cyanoacrylate (PBCA) nanoparticles, particularly their interactions with the blood-brain barrier (BBB). The BBB protects the brain from drugs in the bloodstream and represents a crucial obstacle in the treatment of brain cancer. Methods: An advanced computer model analyzed the brain delivery of two distinct formulations, Doxil® and surfactant-coated PBCA nanoparticles. Computational learning was combined with in vitro release and cell interaction studies to comprehend the underlying brain delivery pathways. Results: Our analysis yielded a surprising discovery regarding the brain delivery mechanism of PBCA nanoparticles. While Doxil® exhibited the expected behavior, accumulating in the brain through extravasation in tumor tissue, PBCA nanoparticles employed a unique and previously uncharacterized mechanism. They underwent cell hitchhiking, resulting in a remarkable more than 1000-fold increase in brain permeation rate compared to Doxil® (2.59 × 10-4 vs 0.32 h-1). Conclusion: The nonspecific binding to blood cells facilitated and intensified interactions of surfactant-coated PBCA nanoparticles with the vascular endothelium, leading to enhanced transcytosis. Consequently, the significant increase in circulation time in the bloodstream, coupled with improved receptor interactions, contributes to this remarkable uptake of doxorubicin into the brain.

Transcatheter arterial embolization with N-butyl cyanoacrylate for postoperative hemorrhage treatment following pancreatoduodenectomy.

PURPOSE: Postoperative hemorrhage (PPH) is a severe complication of pancreatoduodenectomy (PD) with a mortality rate of 5-20.2% and mortality due to hemorrhage of 11-58%. Transcatheter arterial embolization (TAE) has been widely recommended for PPH, however, TAE with N-butyl cyanoacrylate (NBCA) for PPH treatment has been reported rarely. Therefore, this study aimed to evaluate the safety and efficacy of TAE with NBCA for PPH treatment following PD. METHODS: This retrospective study included 14 male patients (mean age, 60.93 ± 10.97 years) with postoperative hemorrhage following PD treated with TAE using NBCA as the main embolic agent from October 2019 to February 2022. The clinical data, technical and success rate, and complications were analyzed. RESULTS: Among the 14 patients who underwent TAE, the technical and clinical success rates were 100 and 85.71%, respectively. Angiography revealed contrast extravasation in 12 cases and a pseudoaneurysm in 3 cases. One patient developed a serious infection and died 2 days after the TAE. CONCLUSION: TAE with NBCA for PPH treatment following PD, especially for massive hemorrhage caused by a pancreatic fistula, biliary fistula, or inflammatory corrosion, can result in rapid and effective hemostasis with high safety.

mRNA Sonotransfection of Tumors with Polymeric Microbubbles: Co-Formulation versus Co-Administration.

Despite its high potential, non-viral gene therapy of cancer remains challenging due to inefficient nucleic acid delivery. Ultrasound (US) with microbubbles (MB) can open biological barriers and thus improve DNA and mRNA passage. Polymeric MB are an interesting alternative to clinically used lipid-coated MB because of their high stability, narrow size distribution, and easy functionalization. However, besides choosing the ideal MB, it remains unclear whether nanocarrier-encapsulated mRNA should be administered separately (co-administration) or conjugated to MB (co-formulation). Therefore, the impact of poly(n-butyl cyanoacrylate) MB co-administration with mRNA-DOTAP/DOPE lipoplexes or their co-formulation on the transfection of cancer cells in vitro and in vivo is analyzed. Sonotransfection improved mRNA delivery into 4T1 breast cancer cells in vitro with co-administration being more efficient than co-formulation. In vivo, the co-administration sonotransfection approach also resulted in higher transfection efficiency and reached deeper into the tumor tissue. On the contrary, co-formulation mainly promoted transfection of endothelial and perivascular cells. Furthermore, the co-formulation approach is much more dependent on the US trigger, resulting in significantly lower off-site transfection. Thus, the findings indicate that the choice of co-administration or co-formulation in sonotransfection should depend on the targeted cell population, tolerable off-site transfection, and the therapeutic purpose.

Comparison of outcomes with/without preoperative embolization for meningiomas with diluted N-butyl-2-cyanoacrylate.

BACKGROUND: Preoperative embolization for meningiomas is controversial regarding its effectiveness in reducing intraoperative blood loss and operative time. In contrast, some reports have documented improved surgical outcomes in large meningiomas. In this study, we retrospectively compared the outcomes of craniotomy for meningiomas with/without preoperative embolization with diluted N-butyl-2-cyanoacrylate (NBCA) primarily in a single institution. METHODS: Data (World Health Organization grade, Simpson grade, maximum tumor diameter, intraoperative bleeding, operative time, history of hypertension, and time from embolization to craniotomy) of patients with initial intracranial meningiomas were compared with or without preoperative embolization from January 2015 to April 2022. RESULTS: The embolization group consisted of 56 patients and the nonembolization group included 76 patients. Diluted NBCA (13% concentration for all patients) was used in 51 of 56 patients (91.1%) who underwent transarterial embolization. Permanent neurological complications occurred in 2 (3.6%) patients. Intraoperative bleeding was significantly lower in the embolization group for a maximum tumor diameter ≥40 mm (155 vs. 305 ml, respectively, p < 0.01). In the nonembolization group, for a maximum tumor diameter ≥30 mm, patients with hypertension had more intraoperative bleeding than non-hypertensive ones. CONCLUSIONS: Despite its limitations, the present results showed that, under certain conditions, preoperative embolization for intracranial meningiomas caused less intraoperative bleeding. The safety of treatment was comparable with that reported in the Japan Registry of NeuroEndovascular Therapy 3 (JR-NET3) with a complication rate of 3.7% for preoperative embolization of meningiomas, despite the treatment focused on the liquid embolization material.

Hypersensitivity reactions following vein closure therapy with venasealTM (n-butyl- 2-cyanoacrylate).

VenaSealTM is composed of a cyanoacrylate adhesive compound often utilized for chronic venous stasis treatment. Rare case reports of hypersensitivity reactions to this compound exist. We present the first case of dermatographism and angioedema after utilization of VenaSealTM successfully treated via high dose antihistamines. We also present a case of type IV hypersensitivity to VenaSealTM, a cyanoacrylate, occurring in a patient with known meth(acrylate) allergy indicating a possible cross reactivity between these acrylate groups.

Blocked-flow vs. free-flow cyanoacrylate glue embolization: Histological differences in an in vivo rabbit renal artery model.

PURPOSE: The purpose of this in vivo animal study was to compare the acute histological effects on the arterial vessel wall of free-flow vs. blocked-flow embolization with metacryloxysulfolane-n­butyl cyanoacrylate (MS-NBCA) in several concentrations. MATERIALS AND METHODS: A total of 42 rabbit renal arteries were embolized using MS-NBCA mixed with ethiodized oil. The MS-NBCA concentration was 12.5%, 25%, or 50%. All mixtures were injected under both free-flow and blocked-flow conditions. The rabbits were euthanised 30 min after arterial embolization. Arterial-lumen distension, intimal inflammation and necrosis, peri­arterial edema, and distality of MS-NBCA penetration were assessed histologically. Multivariable regression analyses were performed using a manual backward procedure, with linear, ordinal and logistic regression to search for factors associated with these outcomes RESULTS: Marked or severe dilatation was observed in 36 out of 42 arteries (86%) and marked or transmural intimal arteritis in all 42 arteries (42/42; 100%). Lumen dilatation caused focal vessel-wall flattening, which resulted in intimal necrosis. Multifocal necrosis extending from the intima to the media occurred in 23 out of 42 kidneys (55%) and peri­arterial edema with multifocal vascular leakage in 19 out of 42 kidneys (45%). At multivariable analysis, blocked-flow MS-NBCA injection was associated with greater severity of vessel-wall lesions, including intimal arteritis (P = 0.003) and intimal necrosis (P = 0.014), compared to free-flow injection. Blocked-flow injection was also associated with peri­arterial edema (P = 0.008) and greater distality of MS-NBCA penetration (P = 0.001). CONCLUSION: Blocked-flow MS-NBCA injection during renal artery embolization is significantly associated with more acute arterial-wall damage and greater distality of glue penetration compared to free-flow injection in a rabbit model. These preliminary findings may have clinical implications, as blocked-flow injection is routinely used to treat specific vascular diseases or malformations in human.

Bronchial artery embolization in patients with life-threatening massive hemoptysis: comparison of the efficacy and safety of particulate embolizing agents and n-2-butyl-cyanoacrylate.

OBJECTIVE: Comparing the efficacy and safety of particulate [microspheres/polyvinyl alcohol (PVA)] and non-particulate [n-butyl-2-cyanoacrylate (NBCA)] agents used as the embolic agents for bronchial artery embolization (BAE) intervention in patients experiencing massive hemoptysis. PATIENTS AND METHODS: A total of 58 individuals (47 male, 11 female, standard deviation = 53.9 ± 14.8, age range = 18-84) were recruited for a retrospective study in a single unit. Thirty (51.7%) of the patients underwent BAE intervention with NBCA, and 28 (48.3%) underwent the same procedure with a particulate embolizing agent (microspheres/PVA). The demographic distribution of the patients, the etiological factors, the technical and clinical success rates, and complications were documented, with the two groups subsequently compared. RESULTS: The technical and clinical success rates following the procedure were 100% for both groups. The average follow-up duration was 34 months in the NBCA group and 33.5 months in the particulate embolizing agent group. In comparison, the rate of recurrent hemoptysis was 3.3% in the former and 17.9% in the latter, with the presence of recurrent hemoptysis not statistically different between the two groups (p = 0.097). Major complications and procedural death did not occur in either of the samples. CONCLUSIONS: The use of NBCA in BAE presents a safe and effective method. The combination of NBCA and particulate embolizing agents (PVA/microspheres) achieved equal technical and clinical success and significantly increased the hemoptysis-free survival rates in terms of life-threatening hemoptysis. MAIN POINTS: (1) In managing massive hemoptysis, using NBCA is a safe and effective method similar to using particulate embolizing agents. (2) Although not statistically significant, recurrent hemoptysis is observed less frequently in the NBCA group. (3) Technique and clinical success were relatively high and similar in the groups where NBCA and particulate embolizing agents were used.

Suturing with or without surgical glue is superior to surgical glue alone for sealing ex vivo swine gallbladders.

OBJECTIVE: To assess the effectiveness of various sealing techniques in cholecystotomies under maximum intraluminal pressure stress using an ex vivo swine model. SAMPLE: 30 gallbladders from different animals were used. METHODS: The experiment was conducted ex vivo, with the formation of 3 groups, each comprising 10 samples. Group 1 utilized a traditional single-layer Cushing suture made from polydioxanone material. Group 2 employed a single layer of Cushing suture, also made from polydioxanone material, but in conjunction with surgical glue (n-butyl cyanoacrylate). Group 3 relied solely on the use of surgical glue (n-butyl cyanoacrylate) for sealing the edges of the surgical wound. The intraluminal pressure was gauged with a pressure transducer. RESULTS: The maximum intraluminal pressures (mean ± SD) sustained in G1, G2, and G3 were, respectively, 48.70 ± 21.32 mm Hg, 110.90 ± 37.52 mm Hg, and 10.9 ± 4.07 mm Hg. Comparisons between groups showed that G2 supported significantly higher pressures (56.1% higher) than G1 (P < .001) and G3 (90.2% higher; P < .001). When G1 was compared with G3, a significantly higher pressure (77.6%) was also observed (P < .01). CLINICAL RELEVANCE: The study's conclusions demonstrated the safest suture techniques for the gallbladder and provided advice regarding the use of surgical glue.

Polymerisation of cyanoacrylates: The effect of sclero-embolic and contrast agents.

OBJECTIVES: The objective is to investigate the interaction of sclero-embolic and contrast agents with the polymerisation of medical grade n-butyl-cyanoacrylates. METHODS: An in vitro spectrophotometric absorbance method was developed to detect changes in light transmission to measure n-BCA polymerisation. The initiation and the rate-of-polymerisation of mixtures of n-BCA with sclero-embolic and contrast agents were investigated. RESULTS: Initiation of polymerisation: VENABLOCK™ and HISTOACRYL® were the fastest agents to polymerise, while VENASEAL™ was the slowest. Rate of polymerisation: Hypertonic saline inhibited the polymerisation of all n-BCAs, while hypertonic glucose prolonged the polymerisation rate. ETHANOL and detergent sclerosants had no effect. Contrast agents OMNIPAQUE™ and ULTRAVIST® initiated and prolonged the polymerisation of n-BCA, but in contrast, LIPIODOL® failed to initiate the process. CONCLUSIONS: The commercially available medical cyanoacrylates differ in their polymerisation rates. These polymerisation rates are further affected when these products are used in conjunction with other compounds, such as sclero-embolic and contrast agents.

Balloon-Assisted Portal Vein Embolization Using n-Butyl-2-Cyanoacrylate-Lipiodol-Iopamidol Mixture in Swine: A Comparison of 2 Formulations.

PURPOSE: To compare 2 ratios of n-butyl-2-cyanoacrylate (nBCA)-ethiodized oil (Lipiodol)-iopamidol (NLI) in balloon-assisted portal vein embolization (PVE) in swine. MATERIALS AND METHODS: In an in vitro study, NLI prepared at a ratio of 2:3:1 (NLI231) or 1:4:1 (NLI141) was injected into 2.5- or 10-mL syringes filled with swine blood, and the viscosity of NLI was measured to determine an appropriate balloon occlusion time. Two portal vein branches in 8 female swine (n = 16 vein branches) were embolized with NLI231 (n = 8) or NLI141 (n = 8) under balloon occlusion. Portal venography was performed before, immediately after, and 3 days after PVE to evaluate the migration of NLI and the recanalization of embolized portal vein branches. Then, the livers were removed for histopathologic evaluation. RESULTS: The times to peak viscosity of NLI231 in the 2.5- and 10-mL syringes were 55.8 seconds (SD ± 7.0) and 85.2 seconds (SD ± 6.3), and those to peak viscosity of NLI141 were 129.2 seconds (SD ± 11.8) and 254.0 seconds (SD ± 21.8), respectively. No migration of NLI231 was observed in all 8 procedures immediately or 3 days after PVE. Migration of NLI141 was observed in 6 of 8 procedures within 3 days after PVE. The migration frequency of the embolic material was lower in the NI231 group than in the NLI141 group (0/8 vs 6/8; P = .051). Histologically, NLI231 occupied the portal veins without any thrombi, whereas NLI141 was accompanied by thrombi in the portal veins. CONCLUSIONS: NLI231 may be more suitable than NLI141 for balloon-assisted PVE in swine.

Prostate artery embolization using n-butyl cyanoacrylate glue for symptomatic benign prostatic hyperplasia: A six-month outcome analysis in 103 patients.

PURPOSE: The purpose of this study was to assess the feasibility, safety, and 6-month outcomes of prostate artery embolization (PAE) using N-butyl-cyanoacrylate (NBCA) glue as the only embolic agent in patients with benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms. MATERIALS AND METHODS: Patients with BPH-related lower urinary tract symptoms who were treated by PAE using methacryloxysulfolane-NBCA mixed with ethiodized oil (1:8 ratio) between September 2018 and January 2023 were retrospectively included. Vascular mapping was made using cone-beam computed tomography angiography. PAEs were performed as an outpatient procedure, under local anaesthesia. Outcomes were assessed at six months using the International Prostate Symptoms Score (IPSS) and associated quality-of-life score (IPSS-QoL), prostate-specific antigen (PSA) level, prostate volume, and International Index of Erectile Function form 5 (IIEF5). RESULTS: A total of 103 men with a mean age of 68.4 ± 6 (standard deviation [SD]) years were included. Technical success rate was 100%. The mean fluoroscopy time was 26.4 ± 12.5 (SD) min and the median radiation dose was 23 980 mGy·cm (Q1, Q3: 16 770, 38 450). Compared to baseline, statistically significant improvements were observed at six months for the IPSS (8.9 ± 6.2 [SD] vs. 20.2 ± 6.5 [SD]; P = 0.01), IPSS-QoL (2.1 ± 1.4 [SD] vs. 5.1 ± 0.9 [SD]; P = 0.01), PSA level (3.6 ± 3.2 [SD] ng/mL vs. 4.8 ± 4.2 [SD] ng/mL; P = 0.0001), and prostate volume (78.6 ± 43.5 [SD] mL vs. 119.1 ± 65.7 [SD] mL; P = 0.01). Minor adverse events developed in 19/103 (18.4%) patients. No major complications occurred. Compared to baseline, the IIEF5 did not change significantly at six months (15.3 ± 6.8 [SD] vs. 15.8 ± 6.8 [SD]; P = 0.078). CONCLUSION: PAE with NBCA is a feasible and safe method that provides good outcomes at six months in patients with BPH-related lower urinary tract symptoms. This method deserves further evaluation in randomized trials with longer follow-up.

Closure of Long Surgical Incisions with Hemostatic Tissue Adhesive in a Porcine Skin Model.

OBJECTIVE: Skin adhesives offer many advantages over traditional wound-closure devices. Recently, the current research group reported on tissue adhesives composed of natural polymers (gelatin and alginate), which are biocompatible with mechanical properties suitable for tissue adhesion. The objective of the present study was to conduct clinical and histologic assessment of this hemostatic bioadhesive in the healing of long skin incisions (≥4 cm) in comparison with traditional and commercially available methods. METHODS: Researchers created 24 long incisions on the ventral side of two domestic pigs to compare four different treatment modalities: two topical bioadhesives based on gelatin and alginate combined with the hemostatic agent kaolin, nylon sutures, and commercial tissue adhesive N-butyl-2-cyanoacrylate. The bioadhesive compounds were spread on the incision surface and then mixed either manually or with a double-headed syringe. After 14 days, clinical and histologic measurements were performed to evaluate the healing phase of the wounds. RESULTS: The bioadhesive formulation that contained a relatively low crosslinker concentration demonstrated superior results to the formulation that contained a standard crosslinker concentration. However, no significant statistical differences were observed compared with the control incisions (sutures and commercial adhesive N-butyl-2-cyanoacrylate). This was verified by immunohistochemical analysis for epithelial integrity and scar formation as well as by clinical assessment. CONCLUSIONS: This newly developed bioadhesive demonstrated suitable properties for the closure of long incisions in a porcine skin model.

Unraveling the enigma of Adamkiewicz: exploring the prevalence, anatomical variability, and clinical impact in spinal embolization procedures for bone metastases.

BACKGROUND: The artery of Adamkiewicz (AKA) is vital for spinal cord blood supply. Its role in embolization procedures for bone metastases can cause serious complications. We explored its prevalence, anatomical variation, and effect on spinal embolization using N-butyl cyanoacrylate (NBCA) in patients with bone metastases. PURPOSE: To understand the impact and variability of AKA in spinal embolizations in cases of bone metastases to reduce complications and improve patient outcomes. MATERIAL AND METHODS: We examined data from 454 patients who underwent spinal embolization with NBCA between 2009 and 2018. The presence, anastomoses, and tumor features of AKA were assessed via pre-procedure imaging and angiography. Complications were classified per the CIRSE Classification System. RESULTS: AKA was found in 22.8% of patients, predominantly left-sided and originating from T8 to L1. Direct and indirect anastomoses were present in 66.6% and 33.4% of patients, respectively. Extra-compartmental invasion was linked with direct anastomosis (P = 0.004). High-grade complications were rare but included one instance of bilateral lower limb paralysis. Partial embolization was necessary in 22.8% of cases due to AKA. CONCLUSION: The study underscores the need for rigorous preoperative evaluation of AKA origin and anastomoses in patients undergoing spinal embolization for bone metastases. Given the significant presence of AKA and related anastomoses, especially with renal extra-compartmental tumors, caution is advised to reduce complications and optimize patient outcomes. Further research is required for best practice guidelines involving bone metastases and AKA.

Efficacy of Embolization in Acquired Uterine Vascular Malformations: An Experience in Tertiary Care Centre in India.

OBJECTIVE: To determine the efficacy of Uterine Artery Embolization in patients with bleeding acquired uterine arteriovenous malformations (AVMs). METHODS: A prospective review of all patients who underwent Uterine Artery Embolization at our institution between July 2015 and April 2022 was performed. 225 patients were diagnosed with a uterine vascular malformation on doppler and corresponding MRI imaging. All patients underwent transcatheter embolization of the uterine arteries. Embolic agents in the 375 procedures included Histoacryl glue only (n = 326), polyvinyl alcohol (PVA) particles and Histoacryl glue (n = 29), PVA particles (n = 5), Gelfoam (n = 5), coils (n = 4), PVA particles and coils (n = 3), Histoacryl glue and Gelfoam (n = 2), and Histoacryl glue and coils (n = 1). RESULTS: A total of 375 embolization procedures were performed in 225 patients. 90 patients required repeat embolization for recurrence of bleeding. The technical success rate of embolization was 100%. The clinical success rate was 92%: bleeding was controlled in 222 of 225 patients and three patients underwent a hysterectomy. 60 of the 225 patients had uneventful intrauterine pregnancies carried to term. The 210 patients who underwent successful embolization had no recurrence of bleeding at a median follow-up of 53 months (range, 5-122 months) after treatment. 15 patients were eventually lost to follow-up. One minor complication (0.4%) of non-flow-limiting dissection of the internal iliac artery occurred. CONCLUSION: Uterine Artery Embolization is a safe, effective, minimally invasive method to treat uterine AVMs with long-term efficacy, which can provide the preservation of fertility.

Initial experience of coaxial percutaneous liver biopsy with tract embolization using N-Butyl cyanoacrylate.

OBJECTIVE: Bleeding occurs after liver biopsy in up to 10.9% cases, and patients with impaired hemostasis or ascites are considered to have absolute or relative contraindications. N-butyl cyanoacrylate enables immediate hemostasis, even in lethal situations. Therefore, percutaneous liver biopsy combined with tract embolization using N-butyl cyanoacrylate is expected to enable safe biopsy, even in patients for whom conventional biopsy is contraindicated. Here we describe our initial experience with coaxial percutaneous biopsy with tract embolization using N-butyl cyanoacrylate. MATERIALS AND METHODS: Eighty-six patients who underwent tract embolization using N-butyl cyanoacrylate between October 2014 and July 2020, including 21 patients who had absolute or relative contraindications for liver biopsy, were retrospectively analyzed. Tract embolization using N-butyl cyanoacrylate comprised two steps: (1) liver biopsy with a biopsy needle inserted via a coaxial introducer needle and (2) embolization of the puncture route by injecting N-butyl cyanoacrylate via the coaxial needle. RESULTS: No complications occurred in any patient. The mean number of biopsies per patient was 3.30 (range, 1-7). Histologically adequate samples were acquired in all cases, and pathological diagnoses were obtained. The mean time required for tract embolization was 52.8 s (range, 6-132 s). The mean peak skin dose was 9.97 mGy (range, 2-68 mGy), which is far below the 3-Gy threshold dose for temporary erythema. CONCLUSIONS: This proposed technique may be a promising and straightforward alternative to improve the management of patients with severe liver disease by allowing safer biopsy, including patients for whom conventional liver biopsy is contraindicated.