Early therapy evaluation of intra-arterial trastuzumab injection in a human breast cancer xenograft model using multiparametric MR imaging.

PURPOSE: To investigate the treatment efficacy of intra-arterial (IA) trastuzumab treatment using multiparametric magnetic resonance imaging (MRI) in a human breast cancer xenograft model. MATERIALS AND METHODS: Human breast cancer cells (BT474) were stereotaxically injected into the brains of nude mice to obtain a xenograft model. The mice were divided into four groups and subjected to different treatments (IA treatment [IA-T], intravenous treatment [IV-T], IA saline injection [IA-S], and the sham control group). MRI was performed before and at 7 and 14 d after treatment to assess the efficacy of the treatment. The tumor volume, apparent diffusion coefficient (ADC), and dynamic contrast-enhanced (DCE) MRI parameters (Ktrans, Kep, Ve, and Vp) were measured. RESULTS: Tumor volumes in the IA-T group at 14 d after treatment were significantly lower than those in the IV-T group (13.1 mm3 [interquartile range 8.48-16.05] vs. 25.69 mm3 [IQR 20.39-30.29], p = 0.005), control group (IA-S, 33.83 mm3 [IQR 32.00-36.30], p<0.01), and sham control (39.71 mm3 [IQR 26.60-48.26], p <0.001). The ADC value in the IA-T group was higher than that in the control groups (IA-T, 7.62 [IQR 7.23-8.20] vs. IA-S, 6.77 [IQR 6.48-6.87], p = 0.044 and vs. sham control, 6.89 [IQR 4.93-7.48], p = 0.004). Ktrans was significantly decreased following the treatment compared to that in the control groups (p = 0.002 and p<0.001 for vs. IA-S and sham control, respectively). Tumor growth was decreased in the IV-T group compared to that in the sham control group (25.69 mm3 [IQR 20.39-30.29] vs. 39.71 mm3 [IQR 26.60-48.26], p = 0.27); there was no significant change in the MRI parameters. CONCLUSION: IA treatment with trastuzumab potentially affects the early response to treatment, including decreased tumor growth and decrease of Ktrans, in a preclinical brain tumor model.

Optimal thrombin injection method for the treatment of femoral artery pseudoaneurysm.

BACKGROUND: Iatrogenic femoral artery pseudoaneurysm (IFP) incidence is increasing with increase in diagnostic and therapeutic angiography, and so, the less invasive percutaneous thrombin injection (PTI) is the most widely used treatment. Moreover, studies that minimize PTI complications and highlight therapeutic effects are lacking. OBJECTIVES: This study performed in vitro thrombosis modeling of pseudoaneurysms and analyzed thrombosis within and thromboembolism outside the sac during thrombin injection. METHODS: We evaluated PTI in terms of thrombin injection location (at the junction of the IFP sac and neck, the center, and the dome, located farthest from the neck of the sac), thrombin injection time (5 and 8 seconds), and blood flow rate (ranging from 210 mL/min to 300 mL/min). Porcine blood was used as the working fluid in this study. RESULTS: Thrombin injection at the junction of the IFP sac and the pseudoaneurysm neck led to less thrombosis within the sac but substantial thrombi consistently outside the sac, whereas thrombin injected at the sac center mostly led to complete thrombosis within the sac, preventing further blood flow into the sac and reducing likelihood of thrombi outside the sac. A longer thrombin injection time enhanced the therapeutic effect and decreased the possibility of thromboembolism. Thromboembolism occurred more frequently at flow rates of >240 mL/min. CONCLUSION: The thrombin injection site in a pseudoaneurysm significantly influences thrombogenesis within and thromboembolism outside the sac. Thus, slow and deliberate injection of thrombin into the center of the sac could potentially reduce complications and enhance treatment efficacy.

Injection of n-Butyl-2-Cyanoacrylate into the Abdominal Aortic Aneurysm Sac during Endovascular Aortic Repair to Prevent Type II Endoleaks Caused by Lumbar Arteries.

PURPOSE: To evaluate midterm results of whether the strategy to occlude target lumbar arteries using n-butyl-2-cyanoacrylate (nBCA) injection during endovascular aneurysm repair (EVAR) reduced the incidence of Type II endoleak (T2EL) after EVAR. MATERIALS AND METHODS: Between 2013 and 2020, 187 patients underwent EVAR; 106 in the treatment group received nBCA injection during EVAR, whereas 81 in the historical control group did not. The incidence of T2EL at 7 days, need for reintervention, and post-EVAR aneurysmal shrinkage were compared between the groups. RESULTS: Between the treatment group and the control group, significant differences were achieved in the incidence of T2EL (2.8% vs 28.4%; P < .0001) and decreased aneurysmal diameter was observed at 1 year after EVAR (-5.2 vs -3.8 mm; P = .034). In multivariate analysis, nBCA injection (odds ratio [OR], 0.04; P = .001) and younger age (OR, 0.92; P = .036) were significantly associated with a reduced incidence of T2EL. As a possible adverse event associated with nBCA injection, 2 cases of transient lower-limb motor dysfunction (1.9%) were observed. Propensity score analysis revealed that the treatment group had a significantly lower incidence of T2EL than that in the control group (P = .0002) even though there was no difference in the incidence of inferior mesenteric artery coil embolization between the groups. The survival rate without aneurysm sac enlargement (100.0% vs 69.8%; P = .014) and the reintervention-free rate (100.0% vs 63.1%; P = .034) in the treatment group were significantly higher than those in the control group. CONCLUSIONS: Concomitant nBCA injection can provide durable EVAR without T2EL, as supported by the avoidance of reintervention associated with aneurysm sac enlargement.

In vivo study of the utility of selective intra-arterial injection of thiopental for neuroprotection in reversible cerebral ischemia.

BACKGROUND: Neuroprotective agents are needed to reduce cerebral damage during surgical or neurointerventional procedures including stroke patients. PURPOSE: To evaluate if thiopental can be used as a neuroprotective agent when injected intra-arterially in a transient ischemia model. MATERIAL AND METHODS: In total, 24 rabbits were studied as four groups of six animals. Group 1 served as the control group. In group 2, transient ischemia was obtained by intracarotid administration of degradable starch microspheres (DSM). Group 3 was administered thiopental intra-arterially via the carotid artery. Group 4 (experimental group) received both thiopental and DSM intra-arterially. DSM and thiopental were administered through a microcatheter placed into the common carotid artery via the central ear artery access. After sacrifice, apoptotic cells in the cerebral tissues of the animals were evaluated in H&E and TUNEL stained slides. RESULTS: There was a significant increase in the number of apoptotic glial or neuronal cells in group 2 compared to the control group and group 3. The mean number of both the apoptotic neuronal cells (6.8 ± 2.1 vs. 2.5 ± 1.3, P < 0.001) and the apoptotic glial cells (9.4 ± 3.1 vs. 4.6 ± 1.6, P < 0.001) were higher in group 2 compared to group 4. In addition, a higher level of neurological improvement was observed in group 4 compared to group 2 based on neurological assessment score. CONCLUSION: The intra-arterial administration of thiopental has a protective effect on both glial and neuronal cells during temporary cerebral ischemia in low doses.

Accidental Intraarterial Placement of a Venous Cannula: When In Doubt Take It Out!-A Case Report.

An artery may be entered on the dorsum of the hand with the mistaken belief that it is a vein. Intraarterial injection of drugs is one of the dreadful consequences of accidental intraarterial cannulation. In this case of a 3-month-old infant, we emphasize the fact that careful observation can prevent unintentional intraarterial drug injection via an 'assumed intravenous' cannula and prevent the associated morbidity. When there is a suspicion of an intraarterial placement of venous cannula, it is of paramount significance to confirm before the injection of medications. Aberrant arterial anatomy should be kept in mind, particularly in children on the dorsum of the hand, where placement of an intravenous cannula is usually considered safe.

Advances in Regional Vascular Injection Techniques for the Delivery of Stem Cells to Musculoskeletal Injury Sites.

Vascular injections of stem cells are a pertinent alternative to direct intralesional injections when treating multiple or extensive lesions or with lesions impossible to reach directly. Extensive research using stem cell tracking has shown that intra-arterial injections without the use of a tourniquet should be preferred over venous or arterial regional limb perfusion techniques using a tourniquet. The median artery is used for the front limbs and the cranial tibial artery for the hind limbs. Proper efficacy studies are still lacking but early clinical work seems promising.

Intra-Arterial Injection of Temporary Embolic Material Through a Needle Inserted into the Radial or Ulnar Artery for Distal and Proximal Interphalangeal Joint Osteoarthritis: A Retrospective Study of 92 Patients.

PURPOSE: To assess the efficacy and safety of intra-arterial injection of imipenem/cilastatin sodium (IPM/CS) via a needle placed into the radial artery or ulnar artery (RA/UA) for distal interphalangeal and proximal interphalangeal joint osteoarthritis (DIP/PIP-OA). MATERIALS AND METHODS: This is a retrospective single-arm cohort study. Ninety-two patients [92% women, mean (SD) age 55(8.3) years] with a primary DIP/PIP-OA meet the American College of Rheumatology criteria for hand osteoarthritis with pain ≥ 4 on the 0-10 numeric rating scale (NRS) were enrolled. All procedures were performed by injecting IPM/CS through a 24-gauge needle percutaneously inserted into the RA/UA. Two procedures were planned; the second procedure was scheduled 1-2 months after the first. NRS, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, Patient Global Impression of Change (PGIC) scale, and procedure-related adverse events were evaluated. RESULTS: Technical success, defined as injection of IPM/CS into the RA/UA, was achieved in all patients. Clinical success, defined as a reduction of 2 points or more in the NRS at 12 months, was 77% (95% confidence interval 68-85%). The NRS improved from the baseline to 3, 6, and 12 months (7.8 ± 1.6 vs. 3.8 ± 2.6, 3.9 ± 2.7, and 4.0 ± 2.8, respectively, all p < 0.001). The QuickDASH score improved from the baseline to 12 months (27 ± 15 vs. 19 ± 17, p < 0.001) respectively. No major adverse events were observed. CONCLUSIONS: Intra-arterial injection of IPM/CS is a feasible treatment option for DIP/PIP-OA.

Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection.

Purpose: Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle. This study investigated a new approach of local delivery of polymeric nanoparticles (NPs) via intra-arterial injection for targeted local gene delivery to HCC tumors in an orthotopic rat liver tumor model. Methods: Poly(beta-amino ester) (PBAE) nanoparticles were formulated and assessed for GFP transfection in N1-S1 rat HCC cells in vitro. Optimized PBAE NPs were next administered to rats via intra-arterial injection with and without orthotopic HCC tumors, and both biodistribution and transfection were assessed. Results: In vitro transfection of PBAE NPs led to >50% transfected cells in adherent and suspension culture at a variety of doses and weight ratios. Administration of NPs via intra-arterial or intravenous injection demonstrated no transfection of healthy liver, while intra-arterial NP injection led to transfection of tumors in an orthotopic rat HCC model. Conclusion: Hepatic artery injection is a promising delivery approach for PBAE NPs and demonstrates increased targeted transfection of HCC tumors compared to intravenous administration, and offers a potential alternative to standard chemotherapies and TACE. This work demonstrates proof of concept for administration of polymeric PBAE nanoparticles via intra-arterial injection for gene delivery in rats.

Analysis of vascular perfusion territory using selective intraarterial injection CT angiography before and after revascularization surgery in patients with moyamoya disease.

OBJECTIVE: In moyamoya disease (MMD), blood flow to the internal carotid artery (ICA) system is supplied via the basal fine vascular network, leptomeningeal anastomoses, and transdural collateral vessels from the external carotid artery (ECA). After revascularization, there is a dramatic change in cerebral perfusion to the ECA system. Understanding this shift in blood supply is important for evaluating treatment efficacy and elucidating the postoperative pathophysiology. However, anatomical and quantitative methods for doing so have not yet been established. In the present study, selective intraarterial injection CT angiography (iaCTA) was performed in patients with MMD, and blood supply changes in each arterial system before and after revascularization surgery were evaluated. METHODS: This study included 10 hemispheres in 10 patients who underwent combined revascularization surgery for adult MMD. Digital subtraction angiography was performed before and 3 months after surgery, and selective iaCTA was performed from the ICA, ECA, and vertebral artery (VA) at the same times in a hybrid CT/digital subtraction angiography suite. The anatomical distribution of each vessel was determined and perfusion volume was measured quantitatively on contrast-enhanced axial CT images. RESULTS: Selective iaCTA clearly depicted the anatomical distribution of perfusion for each vessel. Conversion of blood supply from the ICA and VA to the ECA system was observed in the cerebral cortices and insulae but not in the basal ganglia. The mean volume of perfusion territories of the ECA (preoperative 0.9 cm3, postoperative 98.8 cm3); ICA (preoperative 225.7 cm3, postoperative 159.3 cm3); and VA (preoperative 244.0 cm3, postoperative 163.6 cm3) in the cerebral hemispheres changed significantly after revascularization. There was a correlation between increase in the ECA territory volume and decrease in the VA territory volume due to revascularization (R = -0.84, p < 0.005). CONCLUSIONS: Selective iaCTA enabled clear visualization of anatomical changes in each vascular perfusion territory and quantitative measurement of each perfusion volume. Perfusion conversion to the ECA system after bypass surgery was observed in the cortical regions and in the insulae on the bypass operation sides, but not in the basal ganglia. Combined revascularization promoted the development of ECA-perfused territory, which correlated with a decrease in hemodynamic burden of the posterior cerebral artery.

Mental Nerves in the Lower Lip: Anatomical Basis for the Recovery of Sensation following Inferior Alveolar Nerve Damage.

BACKGROUND: Inferior alveolar nerve damage is one of the most common complications of surgery on the lower third of the face. It can have a significant psychological and social impact, and its evolution varies in terms of the duration and degree of recovery. In the literature, few studies adequately explain this phenomenon. The author therefore aims to establish the anatomical basis of recovery and its variability. METHODS: The author studied 60 mental nerves on 30 lips. A total of 25 lips were studied in situ, including five receiving an intraarterial injection of latex, whereas five lips were removed and dissected under transillumination. RESULTS: The author identified three types of intralabial distribution of the mental nerves: type I, absence of connections; type II, connections on the upper third of the lower lip; and type III, connections on the upper, middle, and lower thirds of the lower lip. Some cases also had a dominant side with more numerous fibers and a larger diameter than the contralateral side. CONCLUSIONS: Rapid or total recovery after inferior alveolar nerve damage is well known. The author's study showed the nerve map to repair nerve damage, and for the first time, to the author's knowledge, it highlighted the connections between the mental nerves in the lip. Types II and III allow the recovery of labiomental sensation.

Unintentional Intra-arterial Injection of 177Lu-PSMA-1 in a Patient With a Peritoneal Carcinosis Secondary to a Metastatic Prostate Cancer.

ABSTRACT: We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.

Intra-arterial injection of particulate corticosteroids: mechanism of injury.

Mechanism of neurologic complications after epidural spinal injections (ESI) of particulate steroids at the cervical spine include intrathecal injection, epidural hematoma, direct spinal cord injury, and brain stem or cord infarction due to an arterial spasm or inadvertent intra-arterial injection of particulate steroids. At the lumbar spine, there is evidence that a spinal cord infarction secondary to an inadvertent intra-arterial injection of particulate steroids through a transforaminal approach is the leading mechanism.Variations in the arterial supply of the spinal cord help to understand how a lumbar ESI may lead to a spinal cord infarction at the thoracic level. A radiculomedullary artery arising from the lumbar or sacral spine may participate to the supply of the spinal cord. All radicular and radiculomedullary arteries penetrate the spinal canal through the intervertebral foramen. Therefore, its catheterization carries a risk of inadvertent intraarterial injection. An ex vivo animal study has shown that particulate steroids injected in the blood stream produce an immediate and unexpected change of red blood cells into spiculated cells which aggregate and cause arterioles obstruction, while no particulate steroid macroaggregates or vascular spasm were observed. Rare instances of neurologic complications also occurred after ESI performed through a posterior approach. All occurred in previously operated on patients suggesting a pathologic role for the epidural scar.

Prophylactic intra-arterial injection of lidocaine: a novel strategy to prevent endovascular embolization-induced trigeminocardiac reflex.

BACKGROUND: Trigeminocardiac reflex (TCR) is a brainstem reflex that can lead to hemodynamic instability manifested as bradycardia, decrease/increase of mean arterial pressure (MAP) and, in the worst case scenario, asystole during surgery. The effective intraoperative management of recurrent and profound TCR has yet to be established. This randomized paired study was performed to identify the effect of a prophylactic intra-arterial injection of lidocaine to prevent TCR caused by Onyx embolization during cerebrovascular intervention surgery. METHODS: A total of 136 patients who received Onyx embolization under general anesthesia were assigned to a control group pretreated with intra-arterial saline injection or a lidocaine group pretreated with an intra-arterial injection of 20 mg lidocaine. Heart rate (HR) and MAP were closely monitored during the embolization procedures and the incidence of TCR, mainly characterized by a decrease in HR of ≥20%, and perioperative adverse events was recorded. RESULTS: During dimethyl sulfoxide (DMSO)/Onyx injection, HR was much slower in the control group than in the lidocaine group (p<0.05). TCR occurred in 12 patients (17.6%) in the control group (cardiac arrest in 3 patients) with decreased (7 cases) or increased (5 cases) MAP, whereas no TCR was observed in the lidocaine group. Notably, most TCR episodes occurred in patients with dural arteriovenous fistula and middle meningeal artery being affected. The composite adverse events were significantly higher in the control group than in the lidocaine group (p<0.05). CONCLUSION: This prospective study shows that a prophylactic intra-arterial injection of 20 mg lidocaine could be recommended as a novel strategy to effectively and safely prevent TCR during endovascular embolization.

In vivo restoration of dystrophin expression in mdx mice using intra-muscular and intra-arterial injections of hydrogel microsphere carriers of exon skipping antisense oligonucleotides.

Duchenne muscular dystrophy (DMD) is a genetic disease caused by a mutation in the X-linked Dytrophin gene preventing the expression of the functional protein. Exon skipping therapy using antisense oligonucleotides (AONs) is a promising therapeutic strategy for DMD. While benefits of AON therapy have been demonstrated, some challenges remain before this strategy can be applied more comprehensively to DMD patients. These include instability of AONs due to low nuclease resistance and poor tissue uptake. Delivery systems have been examined to improve the availability and stability of oligonucleotide drugs, including polymeric carriers. Previously, we showed the potential of a hydrogel-based polymeric carrier in the form of injectable PEG-fibrinogen (PF) microspheres for delivery of chemically modified 2'-O-methyl phosphorothioate (2OMePs) AONs. The PF microspheres proved to be cytocompatible and provided sustained release of the AONs for several weeks, causing increased cellular uptake in mdx dystrophic mouse cells. Here, we further investigated this delivery strategy by examining in vivo efficacy of this approach. The 2OMePS/PEI polyplexes loaded in PF microspheres were delivered by intramuscular (IM) or intra-femoral (IF) injections. We examined the carrier biodegradation profiles, AON uptake efficiency, dystrophin restoration, and muscle histopathology. Both administration routes enhanced dystrophin restoration and improved the histopathology of the mdx mice muscles. The IF administration of the microspheres improved the efficacy of the 2OMePS AONs over the IM administration. This was demonstrated by a higher exon skipping percentage and a smaller percentage of centered nucleus fibers (CNF) found in H&E-stained muscles. The restoration of dystrophin expression found for both IM and IF treatments revealed a reduced dystrophic phenotype of the treated muscles. The study concludes that injectable PF microspheres can be used as a carrier system to improve the overall therapeutic outcomes of exon skipping-based therapy for treating DMD.

Exogenous Amylase Reverses Cerebral Ischemia Induced by Selective Intraarterial Injection of Degradable Starch Microspheres: An Angiographic and Histological Study in a Novel in Vivo Animal Model.

AIM: To validate a new particulate embolization method using degradable starch microspheres (DSM) and intraarterial exogenous amylase administration, which allow for regulated temporary cerebral arterial embolization without compromising tissue perfusion. MATERIAL AND METHODS: Twenty-four male New Zealand rabbits were randomly divided into three groups. All animals underwent routine angiography. The control group received no additional intervention. In the ischemia group, 0.2ml DSM was administered to the animals via the right carotid artery with pulsed, gentle injections to induce ischemia in the cerebral microcirculation. Animals in the reperfusion group received 0.05 ml of exogenous amylase along with DSM administration. Six hours after the procedure, the animals were sacrificed and histopathological analysis was performed. RESULTS: The ischemia group was the most adversely affected group by embolization, with the highest number of pyknotic neurons. The reperfusion group, which received exogenous amylase, had lower pyknotic neurons than the ischemia group. The pyknotic neuron count was similar in some regions between reperfusion and control groups. CONCLUSION: Exogenous amylase can rapidly attenuate cerebral ischemia caused by microembolization with DSM.

Significant Vision Recovery from Filler-Induced Complete Blindness with Combined Intra-Arterial Injection of Hyaluronidase and Thrombolytic Agents.

With the increase of cosmetic injectable hyaluronic acid (HA), there have been more cases with serious complications, including skin necrosis, blindness, and cerebral embolism. Patients who have recovered from HA filler-induced total vision loss are extremely rare. We report a case of a 27-year-old female who developed severe ocular pain on the right side and total vision loss following a 1.0 ml HA filler injection in the nasal dorsum. She arrived at our hospital 4 hours later. Her visual acuity was no light perception (NLP), and she exhibited eyelid ptosis, ophthalmoplegia, and frontal and nasal ecchymosis. She was promptly treated with subcutaneous and retrobulbar hyaluronidase injections, as well as intra-arterial 1500 IU hyaluronidase injections into the right ophthalmic artery with DSA assistance. Her vision improved from NLP to counting fingers at 1.0 meters. Unfortunately, 13 hours later, she felt an intense headache, and her vision again decreased to NLP. We immediately performed an injection of 1500 IU hyaluronidase combined with 8 mg alteplase for intra-arterial thrombolysis (IAT) into the right ophthalmic artery. Her vision improved immediately afterward. After 3 months, her visual acuity had significantly recovered from NLP (admission vision status) to 20/50 (Snellen chart with glasses). Similarly, skin, conjunctival, eye movement, and ptosis symptoms completely recovered. This case demonstrates that reversal of complete blindness due to embolism of the ophthalmic and central retinal arteries could be accomplished through multidisciplinary therapies, especially IAT using fibrinolytic agents combined with hyaluronidase followed by an anticoagulant regimen.Level of evidence VThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

Standardized approach to treatment of retinal artery occlusion after intraarterial injection of soft tissue fillers: EYE-CODE.

BACKGROUND: Inadvertent intraarterial injection of soft tissue fillers during facial aesthetic procedures can result in serious adverse events including visual impairment and blindness. Once the retinal artery has been occluded, only a short window of opportunity exists before blindness becomes irreversible. All physicians should be prepared for the eventuality of intraarterial injection, despite its rarity. OBJECTIVE: The aim of this document is to provide a simple and evidence-based protocol using the easy to remember acronym EYE-CODE: EYE (I call retinal referral center), C (check vision), O (optic nerve function), D (decrease intraocular pressure), and E (erase filler). METHODS: The EYE-CODE acronym incorporates 2 key components: (1) a systematic office-based protocol to first determine whether vision loss is present and to what extent and (2) a treatment strategy that can be started in the acute office setting and continued by an emergency ophthalmologist. RESULTS: The protocol incorporates a crash kit of treatments readily available to an aesthetic physician combining measures to rapidly reduce intraocular pressure to allow the emboli to dislodge downstream with measures to improve retinal perfusion. CONCLUSION: EYE-CODE provides an up-to-date, one-stop reference for appropriate management of retinal artery occlusion induced by injection of soft tissue fillers.

Hyperosmolar blood-brain barrier opening using intra-arterial injection of hyperosmotic mannitol in mice under real-time MRI guidance.

The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable. We demonstrated that this variability could be highly reduced or eliminated when the procedure of osmotic BBB opening is performed under the guidance of interventional MRI. Studies have reported the utility and applicability of this technique in several species. Here we describe a protocol to open the BBB by IA injection of hyperosmotic mannitol under the guidance of MRI in mice. The procedures (from preoperative preparation to postoperative care) can be completed within ~1.5 h, and the skill level required is on par with the induction of middle cerebral artery occlusion in small animals. This MRI-guided BBB opening technique in mice can be utilized to study the biology of the BBB and improve the delivery of various therapeutic agents to the brain.