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Perfluorohexyloctane ophthalmic solution (Miebo ® ) is a single-entity, water-, steroid- and preservative-free, first-in-class semifluorinated alkane that is approved in the USA for the treatment of the signs and symptoms of dry eye disease (DED). DED is often linked with meibomian gland dysfunction (MGD), which causes an excessive evaporation of tears. Perfluorohexyloctane ophthalmic solution stabilizes the lipid layer of the tear film and inhibits tear evaporation by forming a monolayer at the air-liquid interface. In the phase III GOBI and MOJAVE trials in adults with DED associated with MGD, one drop of perfluorohexyloctane ophthalmic solution instilled in each eye four times daily over 8 weeks resulted in statistically significant and clinically meaningful improvements in the signs and symptoms of DED compared with hypotonic saline (0.6%). The agent was generally well tolerated, with most ocular adverse events being mild or moderate in severity. The efficacy and tolerability of perfluorohexyloctane ophthalmic solution was sustained for up to 52 weeks in an extension study (KALAHARI). As the first and currently the only prescription treatment approved in the USA directly addressing the pathophysiology of excessive tear evaporation, perfluorohexyloctane ophthalmic solution is a valuable emerging option for the management of DED., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In comparison to other stroke types, subarachnoid hemorrhage (SAH) is characterized by an early age of onset and often results in poor prognosis. The inadequate blood flow at the site of the lesion leads to localized oxygen deprivation, increased level of hypoxia-inducible factor-1α (HIF-1α), and triggers inflammatory responses and oxidative stress, ultimately causing hypoxic brain damage. Despite the potential benefits of oxygen (O 2 ) administration, there is currently a lack of efficient focal site O 2 delivery following SAH. Conventional clinical O 2 supply methods, such as transnasal oxygenation and hyperbaric oxygen therapy, do not show the ideal therapeutic effect in severe SAH patients. The perfluorocarbon oxygen carrier (PFOC) demonstrates efficacy in transporting O 2 and responding to elevated levels of CO 2 at the lesion site. Through cellular experiments, we determined that PFOC oxygenation serves as an effective therapeutic approach in inhibiting hypoxia. Furthermore, our animal experiments showed that PFOC oxygenation outperforms O 2 breathing, leading to microglia phenotypic switching and the suppression of inflammatory response via the inhibition of HIF-1α. Therefore, as a new type of O 2 therapy after SAH, PFOC oxygenation can effectively reduce hypoxic brain injury and improve neurological function., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ischemic stroke primarily leads to insufficient oxygen delivery in ischemic area. Prompt reperfusion treatment for restoration of oxygen is clinically suggested but mediates more surging reactive oxygen species (ROS) generation and oxidative damage, known as ischemia-reperfusion injury (IRI). Therefore, the regulation of oxygen content is a critical point to prevent cerebral ischemia induced pathological responses and simultaneously alleviate IRI triggered by the sudden oxygen restoration. In this work, we constructed a perfluorocarbon (PFC)-based artificial oxygen nanocarrier (PFTBA-L@GB), using an ultrasound-assisted emulsification method, alleviates the intracerebral hypoxic state in ischemia stage and IRI after reperfusion. The high oxygen solubility of PFC allows high oxygen efficacy. Furthermore, PFC has the adhesion affinity to platelets and prevents the overactivation of platelet. The encapsulated payload, ginkgolide B (GB) exerts its anti-thrombosis by antagonism on platelet activating factor and antioxidant effect by upregulation of antioxidant molecular pathway. The versatility of the present strategy provides a practical approach to build a simple, safe, and relatively effective oxygen delivery agent to alleviate hypoxia, promote intracerebral oxygenation, anti-inflammatory, reduce intracerebral oxidative stress damage and thrombosis and caused by stroke., (© 2023 Wiley-VCH GmbH.)

The article is devoted to historiography of perfluorocarbons, as well as discoverers of perftorane and their discoveries. There would be no national priority in transfusiology without these discoveries. Perftorane is the only one of the world series of perfluorocarbon emulsion drugs that has passed all phases of clinical trials. Perftorane has been used in clinical medicine for 30 years.

Background: No studies have been retrieved comparing perfluorobutane with sulfur hexafluoride for microwave ablation (MWA) in small hepatocellular carcinoma(sHCC)., Objective: To retrospective investigate the value of perfluorobutane ultrasonography contrast agent in ultrasonography (US)-guided MWA of sHCC., Methods: We conducted a retrospective clinical controlled study about US-guided percutaneous MWA in patients with sHCC, and in patients undergoing intra-operative treatment with perfluorobutane or sulfur hexafluoride. In both groups, a contrast agent was injected to clear the tumor and then a needle was inserted. A 5-point needle prick difficulty score was developed to compare needle prick difficulty in the two groups of cases., Results: A total of 67 patients were included: 25 patients in group perfluorobutane, aged 41-82 (60.64±9.46), tumor size 1.1-2.8 (1.78±0.45) cm. 42 patients in group sulfur hexafluoride, aged 38-78 (62.26±9.27), with tumor size of 1.1-3.0 (1.89±0.49) cm. There was no significant difference in age or tumor size in both groups (P > 0.05). Puncture difficulty score (5-point): 2.0-2.7 (2.28±0.29) in group perfluorobutane, and 2.0-4.7 (2.95±0.85) in group sulfur hexafluoride, and the difference between the two groups was statistically significant (P < 0.05). Enhanced imaging results within 3 months after surgery: complete ablation rate was 100% (25/25) in the group perfluorobutane, 95.2% (40/42 in the group sulfur hexafluoride), with no significant difference between the two groups (P > 0.05)., Conclusion: Perfluorobutane kupffer phase can make the operator accurately deploy the ablation needle and reduce the difficulty of operation.

Hydrogen gas is recently proven to have anti-oxidative and anti-inflammation effects on ischemia-reperfusion injury. However, the efficacy of hydrogen therapy is limited by the efficiency of hydrogen storage, targeted delivery, and controlled release. In this study, H 2 -PFOB nanoemulsions (NEs) is developed with high hydrogen loading capacity for targeted ischemic myocardium precision therapy. The hydrogen-carrying capacity of H 2 -PFOB NEs is determined by gas chromatography and microelectrode methods. Positive uptake of H 2 -PFOB NEs in ischemia-reperfusion myocardium and the influence of hydrogen on 19 F-MR signal are quantitatively visualized using a 9.4T MR imaging system. The biological therapeutic effects of H 2 -PFOB NEs are examined on a myocardial ischemia-reperfusion injury mouse model. The results illustrated that the developed H 2 -PFOB NEs can efficaciously achieve specific infiltration into ischemic myocardium and exhibit excellent antioxidant and anti-inflammatory properties on myocardial ischemia-reperfusion injury, which can be dynamically visualized by 19 F-MR imaging system. Moreover, hydrogen burst release induced by low-intensity focused ultrasound (LIFU) irradiation further promotes the therapeutic effect of H 2 -PFOB NEs with a favorable biosafety profile. In this study, the potential therapeutic effects of H 2 -PFOB NEs is fully unfolded, which may hold great potential for future hydrogen-based precision therapeutic applications tailored to ischemia-reperfusion injury., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Perfluorohexyloctane (F6H8), a physically and chemically inert synthetic compound, has recently emerged as a promising candidate for the treatment of DED due to its unique properties. A systematic review that only include full-length randomized controlled studies (RCTs), reporting the effects of F6H8 in three databases, PubMed, Scopus and Web of Science, was performed according to the PRISMA statement. The search period was performed between June 1, 2023, and June 21, 2023. The Cochrane risk of bias tool was used to analyze the quality of the studies selected. A total of six RCTs were included in this systematic review. F6H8 tear substitutes treatment achieved a higher improvement than control group interventions in most of the reported variables. The mean differences between both groups were in favor of F6H8 and were as follow: eye dryness score (EDS) base on a visual analogue scale (VAS) of -6.12 ± 4.3 points, ocular surface disease index (OSDI) questionnaire score of -2.8 ± 2.3 points, lipid layer thickness (LLT) of 11.4 ± 10.4 μm, total corneal fluorescein staining (tCFS) of -0.8 ± 0.3 points and ocular treatment-emergent adverse events (TEAEs) of -0.66 ± 1.7. Tear film break-up time (TBUT) was the only variable in favor of control group with a mean of -0.5 ± 0.4 s. Patient satisfaction after F6H8 tear substitutes treatment was high. Therefore, F6H8 tear substitutes improve dry eye symptoms and signs with a satisfactory tolerability and could be recommended in patients with DED., Competing Interests: Declaration of competing interest The authors have no financial/non-financial competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Ventriculoperitoneal shunting, the most common treatment for the neurological disorder hydrocephalus, has a failure rate of up to 98% within 10 years of placement, mainly because of proximal obstruction of the ventricular catheter (VC). The authors developed a new VC design modified with tethered liquid perfluorocarbon (TLP) and tested it in a porcine model of hydrocephalus. In this study, they aimed to determine if their TLP VC design reduced cell surface attachment and consequent shunt obstruction in the pig model., Methods: TLP VCs were designed to reduce drainage hole obstruction using modified TLP and slightly enlarged draining holes, but their number and placement remained very similar to standard VCs. First, the authors tested the device in nonhydrocephalic rats to assess biocompatibility. After confirming safety, they implanted the VCs in hydrocephalic pigs. Hydrocephalus was induced by intracisternal kaolin injections in 30-day-old domestic juvenile pigs. Surgical implantation of the ventriculoperitoneal shunt (clinical control or TLP) was performed 10-14 days postinduction and maintained up to 30 days posttreatment. MRI was performed to measure ventricular volume before treatment and 10 and 30 days after treatment. Histological and immunohistochemical analyses of brain tissue and explanted VCs, intracranial pressure measurement, and clinical scoring were performed when the animals were euthanized., Results: TLP VCs showed a similar surgical feel, kink resistance, and stiffness to control VCs. In rats (biocompatibility assessment), TLP VCs did not show brain inflammatory reactions after 30 or 60 days of implantation. In pigs, TLP VCs demonstrated increased survival time, improved clinical outcome scores, and significantly reduced total attached cells on the VCs compared with standard clinical control VCs. TLP VCs exhibited similar, but not worse, results related to ventriculomegaly, intracranial pressure, and the local tissue response around the cortical shunt track in pigs., Conclusions: TLP VCs may be a strong candidate to reduce proximal VC obstruction and improve hydrocephalus treatment.

Purpose: To prospectively assess the effect of a single and regular application of either a cationic nanoemulsion of mineral oil (CN) or perfluorohexyloctane (F6H8) on the lipid layer of the tear film and higher order aberrations (HOA) in patients with Dry Eye Disease (DED)., Methods: Fifty-seven patients with a lipid layer thickness (LLT) ≤ 75 interferometric colour units (ICU) were included in the study. In group A (20 patients) the effect of a single drop of F6H8 or CN on HOA and LLT was assessed immediately after application and up to two hours later. For long term effects (Group B) 37 patients applied CN or F6H8 five times a day for 12 weeks. Measurement of LLT, HOA, non-invasive-tear-break-up-time (NIBUT) and meibography were assessed prior to as well as at 4 weeks and 12 weeks after initiation of treatment. Our study is registered in the "German Clinical Trials Register" under the trial number: DRKS00028696., Results: CN led to an increase of the LLT from 46.8 ± 16.9 ICU to 76.3 ± 23.5 ICU (p = 0.021) and to an increase of HOA from 0.43 ± 0.06 μm to 0.48 ± 0.08 μm immediately after application (p = 0.027). There was no correlation between the increase of LLT and HOA (r = -0.04; p = 0.90). In group B an increase of LLT was observed in the F6H8 group from 45.8 ± 8.8 ICU at baseline to 66.7 ± 19.5 ICU at 12 weeks (p = 0.002). No changes of HOA were measured throughout the observation period in group B. After 12 weeks CN increased NIBUT from 9.9 ± 5.3 seconds to 15.5 ± 5.6 seconds (p = 0.04). F6H8 increased NIBUT from 12.4 ± 5.9 seconds to 16.9 ± 4.7 seconds (p = 0.02) after 12 weeks., Conclusion: CN leads to a short-term increase in LLT and HOA, but only immediately after application. In contrast F6H8 does lead to an increase of LLT after regular long-term use but has no effect on HOA. The regular application of lipid-based products does not seem to decrease the quality of vision as measured in HOA. Instead, CN and F6H8, both are able to stabilize the tear film after regular application., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Habbe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Low accumulation of anticancer drugs in tumors and serious systemic toxicity remain the main challenges to the clinical efficiency of pharmaceuticals. Pulmonary delivery of nanoscale-based drug delivery systems offered a strategy to increase antitumor activity with minimal adverse exposure. Herein, we report an osimertinib-loaded perfluoro-15-crown-5-ether (AZD9291-PFCE) nanoemulsion, through intratracheal and intravenous delivery, synergizes with 19 F magnetic resonance imaging ( 19 F MRI)-guided low-intensity focused ultrasound (LIFU) for lung cancer therapy. Pulmonary delivery of AZD9291-PFCE nanoemulsion in orthotopic lung carcinoma models achieves quick distribution of the nanoemulsion in lung tissues and tumors without short-term and long-term toxic effects. Furthermore, LIFU can trigger drug release from the AZD9291-PFCE nanoemulsion and specifically increases tumor vascular and tumor tissue permeability. 19 F MRI was applied to quantify nanoemulsion accumulation in tumors in real time after LIFU irradiation. We validate the treatment effect of AZD9291-PFCE nanoemulsion in resected human lung cancer tissues, proving the translational potential to enhance clinical outcomes of lung cancer therapy. Thus, this work presents a promising pulmonary nanoemulsion delivery system of osimertinib (AZD9291) for targeted therapy of lung cancer without severe side effects.

PRECLINICAL STUDIES: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) STUDY OBJECTIVES: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer RESULTS: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination CONCLUSIONS: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED., Methods: SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment., Results: The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID (P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes., Conclusions: The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease., Competing Interests: J. Tauber, D. L. Wirta, and K. Sall all received research grants for the study. D. Willen and S. Krösser are employees of Novaliq. The other author has no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), and IL-6 which are key elements of cytokine storm are by nuclear factor κβ (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Developing biocompatible, synthetic oxygen carriers is a consistently challenging task that researchers have been pursuing for decades. Perfluorocarbons (PFC) are fascinating compounds with a huge capacity to dissolve gases, where the respiratory gases are of special interest for current investigations. Although largely chemically and biologically inert, pure PFCs are not suitable for injection into the vascular system. Extensive research created stable PFC nano-emulsions that avoid (i) fast clearance from the blood and (ii) long organ retention time, which leads to undesired transient side effects. PFC-based oxygen carriers (PFOCs) show a variety of application fields, which are worthwhile to investigate. To understand the difficulties that challenge researchers in creating formulations for clinical applications, this review provides the physical background of PFCs' properties and then illuminates the reasons for instabilities of PFC emulsions. By linking the unique properties of PFCs and PFOCs to physiology, it elaborates on the response, processing and dysregulation, which the body experiences through intravascular PFOCs. Thereby the reader will receive a scientific and easily comprehensible overview why PFOCs are precious tools for so many diverse application areas from cancer therapeutics to blood substitutes up to organ preservation and diving disease.

Breast cancer is a major threat to health and lives of females. Biomimetic nanotechnology brought brighter hope for early diagnosis and treatment of breast cancer. Here, we proposed a platelet (PLT) membrane-derived strategy for enhanced photoacoustic (PA)/ultrasonic (US)/fluorescence (FL) multimodal imaging and augmented synergistic photothermal/chemotherapeutic efficacy in tumor cells. A PA imaging contrast and photothermal agent, nanocarbons (CNs), a chemotherapeutic and FL material, doxorubicin (DOX), and perfluoropentane (PFP) were coencapsulated into the poly(lactic- co -glycolic) acid (PLGA) skeletons. Then, the PLT membranes were coated onto the PLGA NPs, which were named as "nanoplatelets" (DOX-PFP-CNs@PLGA/PM NPs). The "nanoplatelets", which conserved the structural advantages and inherent properties of PLTs, could not only escape from phagocytosis of macrophages but also actively targeted tumor cells by the way of antigen-antibody interactions between P-selectin on the PM and CD44 receptors of the tumor cells. With CNs and DOX loaded in, these "nanoplatelets" could serve as an excellent contrast agent for PA/FL imaging. Under laser irradiation, the "nanoplatelets" could turn light energy into heat energy. The laser-triggered photothermal effect, on the one hand, could ablate the tumor cells immediately, and on the other hand, could initiate the optical droplet vaporization of PFP, which subsequently enhanced US imaging and promoted the discharge of encapsulated DOX from the "nanoplatelets" for remarkably strengthening photothermal therapeutic power in turn. In this work, as compared with the bare drug-loaded nanoparticles, the "nanoplatelets" exhibited much more accumulation in the tumor cells, demonstrating superior multimodal imaging capability and preferable synergistic therapeutic performance. In conclusion, the "nanoplatelets" could serve as contrast agents for US imaging and PA imaging to guide the therapy. What is more, the bioinspired PLT-derived, targeted, and nontoxic "nanoplatelets", which were exploited for multimodal PA/US/FL imaging-guided synergistic photothermal/chemo therapy, will be of great value to breast cancer theranostics in the days to come.

With an estimated failure rate of about 90%, immunotherapies that are intended for the treatment of solid tumors have caused an anomalous rise in the mortality rate over the past decades. It is apparent that resistance towards such therapies primarily occurs due to elevated levels of HIF-1 (Hypoxia-induced factor) in tumor cells, which are caused by disrupted microcirculation and diffusion mechanisms. With the advent of nanotechnology, several innovative advances were brought to the fore; and, one such promising direction is the use of perfluorocarbon nanoparticles in the management of solid tumors. Perfluorocarbon nanoparticles enhance the response of hypoxia-based agents (HBAs) within the tumor cells and have been found to augment the entry of HBAs into the tumor micro-environment. The heightened penetration of HBAs causes chronic hypoxia, thus aiding in the process of cell quiescence. In addition, this technology has also been applied in photodynamic therapy, where oxygen self-enriched photosensitizers loaded perfluorocarbon nanoparticles are employed. The resulting processes initiate a cascade, depleting tumour oxygen and turning it into a reactive oxygen species eventually to destroy the tumour cell. This review elaborates on the multiple applications of nanotechnology based perfluorocarbon formulations that are being currently employed in the treatment of tumour hypoxia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The treatment of decompression sickness (DCS) with hyperbaric oxygen (HBO2) serves to decrease intravascular bubble size, increase oxygen (O2) delivery to tissue and enhance the elimination of inert gas. Emulsified perfluorocarbons (PFC) combined with breathing O2 have been shown to have similar effects animal models. We studied an ovine model of severe DCS treated with the intravenous PFC Oxycyte™ while breathing O2 compared to saline control also breathing O2., Methods: Juvenile male sheep (N=67; weight 24.4±2.10kg) were compressed to 257 feet of sea water (fsw) in our multiple large-animal chamber where they remained under pressure for 31 minutes. Animals then were decompressed to surface pressure and randomized to receive either Oxycyte at 5mL/kg intravenously (IV) or 5mL/kg saline IV (both receiving 100% O2) 10 minutes after reaching surface pressure. Mortality was recorded at two hours, four hours, and 24 hours after receiving the study drug. Surviving animals underwent perfusion fixation and harvesting of the spinal cord at 24 hours. Spinal cord sections were assessed for volume of lesion area and compared., Results: There was no significant difference in survival at two hours (p=0.2737), four hours (p=0.2101), or 24 hours (p=0.3171). Paralysis at 24 hours was not significantly different. However, spinal cord lesion area was significantly smaller in the Oxycyte group as compared to the saline group, with median spinal cord lesion areas 0.65% vs. 0.94% (p=0.0107)., Conclusion: In this ovine model of severe DCS the intravenous PFC Oxycyte did not reduce mortality but did ameliorate spinal cord injury when used after the onset of DCS., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Our exploration of multimodal nanoprobes aims to combine photoacoustic (PA) imaging, 19 F magnetic resonance (MR), and fluorescence (FL) imaging, which offers complementary advantages such as high spatial resolution, unlimited penetration, and high sensitivity to enable more refined images for accurate tumor diagnoses. In this research, perfluorocarbons (PFCs) and indocyanine green (ICG) are encapsulated by poly(lactic- co -glycolic acid) (PLGA) for intravital 19 F MR/FL/PA tri-modal imaging-guided photothermal therapy. Then, it is coated with an A549 cancer cell membrane (AM) to fabricate versatile theranostic nanoprobes (AM-PP@ICGNPs). After systemic administration, FLI reveals time-dependent tumor homing of NPs with high sensitivity, 19 F MRI provides tumor localization of NPs without background signal interference, and PAI illustrates the detailed distribution of NPs inside the tumor with high spatial resolution. What is more, AM-PP@ICGNPs accumulated in the tumor area exhibit a prominent photothermal effect (48.4 °C) under near infrared (NIR) laser irradiation and realize an enhanced antitumor response in vivo. These benefits, in combination with the excellent biocompatibility, make AM-PP@ICGNPs a potential theranostic nanoagent for accurate tumor localization and ultimately achieve superior cancer therapy.

Purpose: We investigated risk factors for breakthrough vitreous hemorrhage (VH) after an intravitreal tissue plasminogen activator (tPA) and gas injection in patients with submacular hemorrhage (SMH) associated with age-related macular degeneration (AMD)., Methods: The medical records of patients diagnosed with SMH associated with AMD who received an intravitreal tPA (50 μg/0.05 mL) and perfluoropropane gas (0.3 mL) injection were reviewed retrospectively. We analyzed the associations of breakthrough VH with age, sex, best-corrected visual acuity, intraocular pressure, AMD subtype, accompanying sub-retinal pigment epithelium (RPE) hemorrhage, history of cataract surgery, history of hypertension and diabetes mellitus, history of drinking and smoking, and history of antiplatelet or anticoagulant medication. We also examined the relationships between various parameters, including the area ratio of the SMH to the optic disc (AHD) and the height of the SMH obtained from optical coherence tomography., Results: In total, 52 eyes from 52 patients were enrolled in this study; 16 eyes (30%) showed breakthrough VH. The proportions of patients with a current smoking history were 75.0% in the VH group and 22.2% in the non-VH group (p = 0.010). Other factors did not differ significantly between the two groups. The proportion of cases with accompanying sub-RPE hemorrhage was 50.0% and 58.3% in the VH and non-VH groups, respectively (p = 0.763). The AHD (p = 0.001) and SMH height (p < 0.001) were significantly greater in the VH group. In a receiver operating characteristic curve analysis, the cut-off values of AHD and SMH height were 20.1 and 1208 μm, respectively. According to logistic regression analysis, when the AHD and SMH height were greater than the individual cut-off values, the odds ratio of VH increased by 10.286 fold (95% confidence interval [CI], 2.452-43.148; p = 0.001) and 75.400 fold (95% CI, 7.991-711.441; p < 0.001), respectively, with respect to their respective reference groups (less than the cut-off value). Among the significant factors associated with VH occurrence, including current smoking, AHD, and SMH height, only current smoking and SMH height were found to be significant in multiple regression analysis (p = 0.040, 0.016)., Conclusions: The incidence of breakthrough VH was significantly higher in those with current smoking status and for SMH with a larger AHD and greater height. The height of the SMH was more predictable of the possibility of VH than AHD., Competing Interests: The authors have declared that no competing interests exist.

Fluorine-19 ( 19 F) magnetic resonance (MR) molecular imaging is a promising noninvasive and quantitative molecular imaging approach with intensive research due to the high sensitivity and low endogenous background signal of the 19 F atom in vivo. Perfluorocarbons (PFCs) have been used as blood substitutes since 1970s. More recently, a variety of PFC nanoparticles have been designed for the detection and imaging of physiological and pathological changes. These molecular imaging probes have been developed to label cells, target specific epitopes in tumors, monitor the prognosis and therapy efficacy and quantitate characterization of tumors and changes in tumor microenvironment noninvasively, therefore, significantly improving the prognosis and therapy efficacy. Herein, we discuss the recent development and applications of 19 F MR techniques with PFC nanoparticles in biomedicine, with particular emphasis on ligand-targeted and quantitative 19 F MR imaging approaches for tumor detection, oxygenation measurement, smart stimulus response and therapy efficacy monitoring, et al., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Wu et al.)

Photodynamic therapy (PDT) is a method for killing cancer cells by employing reactive singlet oxygen ( 1 O 2 ). However, the inherent hypoxia and oxygen consumption in tumors during PDT lead to a deficient oxygen supply, which in turn hinder the photodynamic efficacy. To overcome this issue, fluorinated-functionalized polysaccharide-based nanocomplexes were prepared by anchoring perfluorocarbons (PFCs) and pyropheophorbide a (Ppa) onto the polymer chains of hyaluronic acid (HA) to deliver O 2 in hypoxia area. These amphiphilic conjugates can self-assemble into micelles and its application in PDT is evaluated. Due to the high oxygen affinity of perfluorocarbon segments, and the tumor-targeting nature of HA, the photodynamic effect of the oxygen self-carrying micelles is remarkably enhanced, which is confirmed by increased generation of 1 O 2 and elevated phototoxicity in vitro and in vivo. These results emphasize the promising potential of polysaccharide-based nanocomplexes for enhanced PDT of Ocular Choroidal Melanoma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Initial reports from the 1960s describing the observations of ultrasound contrast enhancement by tiny gaseous bubbles during echocardiographic examinations prompted the development of the first ultrasound contrast agent in the 1980s. Current commercial contrast agents for echography, such as Definity, Optison, Sonazoid and SonoVue, have proven to be successful in a variety of on- and off-label clinical indications. Whereas contrast-specific technology has seen dramatic progress after the introduction of the first approved agents in the 1990s, successful clinical translation of new developments has been limited during the same period, while understanding of microbubble physical, chemical and biologic behavior has improved substantially. It is expected that for a successful development of future opportunities, such as ultrasound molecular imaging and therapeutic applications using microbubbles, new creative developments in microbubble engineering and production dedicated to further optimizing microbubble performance are required, and that they cannot rely on bubble technology developed more than 3 decades ago., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this mechanistic clinical study was to explore the effect of water-free perfluorohexyloctane eye drops on tear film thickness (TFT) in patients with dry eye disease (DED). Methods: Forty-eight patients with mild to moderate DED participated in this randomized, single-masked, observer-blinded parallel group study in a 1:1 ratio to receive either perfluorohexyloctane or unpreserved 0.9% saline solution (Hydrabak ® , Thea, France) eye drops 4 times daily in both eyes for 4 weeks. A custom-built ultrahigh-resolution optical coherence tomography system was used to measure TFT. Furthermore, evaluation of lipid layer thickness (LLT) and noninvasive tear film breakup time, as well as standard clinical tests for signs and symptoms of DED were performed. Results: Mean TFT and LLT at baseline were comparable between the 2 treatment groups. After a single drop instillation, perfluorohexyloctane eye drops temporarily increased TFT immediately. After multiple dosing, perfluorohexyloctane eye drops gradually increased TFT over time with a maximum effect at the end of the study (least square mean difference: 6.42%; P  = 0.0142 at week 4). LLT values measured before drop instillation showed a more prominent increase in LLT for perfluorohexyloctane eye drops (13.36% ± 26.33% vs. 3.21% ± 28.65%). All other parameters got better in both treatment groups with no statistical difference between groups. Conclusions: These results demonstrate that perfluorohexyloctane eye drops increase TFT as well as LLT over time. These tear film reestablishing attributes are in line with the mode of action of perfluorohexyloctane eye drops to avoid evaporation through stabilization of the lipid layer.

Blast lung injury is associated with high morbidity and mortality. Vaporized perfluorocarbon (PFC) inhalation has been reported to attenuate acute respiratory distress syndrome in humans and animal models. However, the effect of vaporized PFC on blast lung injury is still unknown. In this study, we investigated the protective effects and potential underlying mechanisms of action of vaporized PFC on blast lung injury in a canine model. This was a prospective, controlled, animal study in adult male hybrid dogs randomized to sham, blast (B), blast plus mechanical ventilation (B + M), and blast plus PFC (B + P) groups. All groups except for the sham were exposed to blast wave. The B + P group was treated with vaporized PFC for 1.5 h followed by 5.5 h mechanical ventilation. B + M group received 7.5 h mechanical ventilation and B group was observed for 7.5 h. Blast lung injury was induced using a shock tube. Blood gas, inflammatory cytokines, and oxidative stress were measured. Expression of nuclear factor (NF)-κB activation, mitogen-activated protein kinase (MAPK) and nuclear factor, erythroid 2 like 2 (Nrf2) were measured using western blot. Lung injury observed after blast exposure was marked by increased histopathological scores, ratio of lung wet to dry weight. PFC treatment attenuated blast lung injury as indicated by histopathological scores and ratio of lung wet to dry weight. PFC treatment downregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malondialdehyde (MDA), and upregulated superoxide dismutase (SOD) activity. PFC also suppressed expression of MAPK/NF-κB and Nrf2 protein levels. Our results suggest that PFC attenuated blast-induced acute lung injury by inhibiting MAPK/NF-κB activation and inducing Nrf2 expression in dogs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The excessive production of inflammatory mediators by inflammatory cells contributes to the pathogenesis of rheumatoid arthritis. Tenascin-C (TN-C) is expressed in rheumatoid joint, and is associated with levels of inflammatory mediators. FC-99 (N1-[(4-methoxy)methyl]-4-methyl-1,2-Benzenediamine), a novel 1,2-benzenediamine derivative, was previously reported to block the prolonged expression of key rheumatoid arthritis inflammatory cytokines and relieve zymosan-induced joint inflammation. However, the specific mechanism is unknown. This study aimed to examine the effects of FC-99 on TN-C expression and inflammation and investigate its possible molecular mechanism. The results showed that FC-99 treatment reduced the high expression of TN-C in ankle joints of arthritis mice. Besides, FC-99 reduced the increased number of macrophages in arthritis mice, while did not change the number of synovioblasts. Concomitantly, expression of TN-C in synovial fibroblasts exhibited no difference between control and ZIA groups, and was not apparently altered following FC-99 treatment, while FC-99 decreased TN-C expression in macrophages both in vivo and in vitro. Meanwhile, TargetScan and luciferase assays indicated that TN-C was negatively regulated by miR-494. Transfection assay further demonstrated that FC-99 inhibited TN-C by targeting miR-494. Furthermore, the reduction of miR-494 mimic on expression of TN-C was associated with NF-κB pathway. Similarly, the down-regulation of FC-99 on TN-C was considerably decreased when NF-κB pathway was inhibited. These results indicated that FC-99 relieved macrophages inflammation via the miR-494/TN-C/NF-κB pathway, finally leading to the relief of inflammation in arthritis. The findings suggested that FC-99 might be a potential therapeutic candidate for the treatment of rheumatoid arthritis., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: This study evaluated the usefulness of intraprocedural contrast-enhanced ultrasound (CEUS)/ultrasound (US) fusion imaging using a perflubutane-based contrast agent combined with preprocedural auto sweep three-dimensional US to obtain volume data for guidance and evaluation of the therapeutic efficacy of radiofrequency ablation (RFA). Methods: This uncontrolled clinical trial included 50 hepatocellular carcinomas (HCCs) with a mean diameter of 15.3 mm that had been treated by RFA. The efficacy of RFA was evaluated by CEUS/US fusion imaging during the procedure. If the ablation was deemed to be inadequate, further ablation was performed until adequate ablation was achieved. Contrast-enhanced computed tomography (CECT) or contrast-enhanced magnetic resonance imaging (CEMRI) was performed a month after RFA, and the images obtained using each modality were reviewed to evaluate the efficacy of RFA. Results: Thirty-three of the 50 lesions were evaluated by CEUS/US fusion imaging as having been adequately ablated after the first RFA procedure. The ablation was evaluated as inadequate in the remaining 17 lesions, for which additional ablation was performed. Ninety-eight (49/50) of all HCCs were evaluated as having been eventually adequately ablated on intraprocedural CEUS/US fusion imaging. The concordance rate for evaluations between intraprocedural CEUS/US fusion imaging and CECT/CEMRI performed 1 month after RFA was 88% (44/50). The kappa value for agreement between the two methods of evaluation was 0.792. Conclusion: Intraprocedural fusion imaging combining CEUS and auto sweep three-dimensional US appears to be a useful modality for RFA guidance and evaluation of therapeutic efficacy of RFA in patients with HCC.

Purpose: Ocular graft-versus-host disease (oGvHD) following allogeneic hematopoietic stem cell transplantation develops as severe dry eye disease (DED) and is initially treated with lubricants, although no clinical trials are available using artificial tears in oGvHD. This trial was set up to test perfluorohexyloctane (NovaTears®) as nonpreserved layer-forming agent for the treatment of DED in oGvHD., Methods: 25 patients with severe DED due to oGvHD received 1 drop perfluorohexyloctane 4 times daily during a prospective, multicenter, observational 12-week study on top of established topical therapy. Clinical parameters included Schirmer test, tear film breakup time, corneal staining, meibum secretion and ocular surface disease index. Adverse events, visual acuity and intraocular pressure were key safety parameters., Results: From 25 patients recruited, 23 presented for the second visit. Perfluorohexyloctane treatment did not lead to any changes in clinical or safety parameters but led to fast relief in symptoms in 57% of the patients. One adverse reaction occurred., Conclusions: This study showed no change in clinical signs in severe DED due to oGvHD, which was not unexpected due to the underlying pathomechanisms. However, the study showed improvement of symptoms in individual patients allowing application of perfluorohexyloctane as an additional symptomatic therapy in oGvHD., (© 2019 S. Karger AG, Basel.)

Decompression illness (DCI) is a complex clinical syndrome caused by supersaturation of respiratory gases in blood and tissues after abrupt reduction in ambient pressure. The resulting formation of gas bubbles combined with pulmonary barotrauma leads to venous and arterial gas embolism. Severity of DCI depends on the degree of direct tissue damage caused by growing bubbles or indirect cell injury by impaired oxygen transport, coagulopathy, endothelial dysfunction, and subsequent inflammatory processes. The standard therapy of DCI requires expensive and not ubiquitously accessible hyperbaric chambers, so there is an ongoing search for alternatives. In theory, perfluorocarbons (PFC) are ideal non-recompressive therapeutics, characterized by high solubility of gases. A dual mechanism allows capturing of excess nitrogen and delivery of additional oxygen. Since the 1980s, numerous animal studies have proven significant benefits concerning survival and reduction in DCI symptoms by intravenous application of emulsion-based PFC preparations. However, limited shelf-life, extended organ retention and severe side effects have prevented approval for human usage by regulatory authorities. These negative characteristics are mainly due to emulsifiers, which provide compatibility of PFC to the aqueous medium blood. The encapsulation of PFC with amphiphilic biopolymers, such as albumin, offers a new option to achieve the required biocompatibility avoiding toxic emulsifiers. Recent studies with PFC nanocapsules, which can also be used as artificial oxygen carriers, show promising results. This review summarizes the current state of research concerning DCI pathology and the therapeutic use of PFC including the new generation of non-emulsified formulations based on nanocapsules.

Perftoran, which has been rebranded as Vidaphor for marketing in North America, is an emulsion of perfluorocarbons in a surfactant and electrolyte mixture. It was developed in Russia as an oxygen-carrying intravenous plasma additive for hemorrhagic anemia and ischemic conditions from various etiologies. It was approved for clinical use in Russia in 1996 and used by the Russian Armed Forces and in civilian medical care. It was also approved in Mexico from 2005 to 2010. It has been reportedly administered to over 35,000 patients with significant evidence of benefit and relatively mild and manageable adverse effects. It may have significant potential for use in hemorrhagic shock if human red blood cells are not available, and for several other applications including treatment of vascular gas embolism, cerebral or spinal trauma, and regional ischemia. It is different from other perfluorocarbon preparations under development in the United States in that it uses a different primary perfluorocarbon (perfluorodecalin) and a surfactant (Proxanol 268) instead of egg-yok phospholipid as the emulsion vehicle. Perftoran has a much smaller particle size resulting in milder adverse effects. It has been safely administered to more patients than any oxygen carrier currently under development. A newly formed United States Corporation (FluorO2 Therapeutics, Inc.) intends to manufacture the product in the United States under GMP standards and make it available for clinical use in Mexico and Latin America and pursue research to support eventual approval in the United States for human and veterinary use. This article will briefly review key information about this product and provide references for the interested reader.

Purpose: To accelerate 19 F-MR imaging of inhaled perfluoropropane using compressed sensing methods, and to optimize critical scan acquisition parameters for assessment of lung ventilation properties., Methods: Simulations were performed to determine optimal acquisition parameters for maximal perfluoropropane signal-to-noise ratio (SNR) in human lungs for a spoiled gradient echo sequence. Optimized parameters were subsequently employed for 19 F-MRI of inhaled perfluoropropane in a cohort of 11 healthy participants using a 3.0 T scanner. The impact of 1.8×, 2.4×, and 3.0× undersampling ratios on 19 F-MRI acquisitions was evaluated, using both retrospective and prospective compressed sensing methods., Results: 3D spoiled gradient echo 19 F-MR ventilation images were acquired at 1-cm isotropic resolution within a single breath hold. Mean SNR was 11.7 ± 4.1 for scans acquired within a single breath hold (duration = 18 s). Acquisition of 19 F-MRI scans at shorter scan durations (4.5 s) was also demonstrated as feasible. Application of both retrospective (n = 8) and prospective (n = 3) compressed sensing methods demonstrated that 1.8× acceleration had negligible impact on qualitative image appearance, with no statistically significant change in measured lung ventilated volume. Acceleration factors of 2.4× and 3.0× resulted in increasing differences between fully sampled and undersampled datasets., Conclusion: This study demonstrates methods for determining optimal acquisition parameters for 19 F-MRI of inhaled perfluoropropane and shows significant reduction in scan acquisition times (and thus participant breath hold duration) by use of compressed sensing., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Perfluorocarbons (PFCs) have been investigated as oxygen carriers for several decades in varied biomedical applications. PFCs are chemically and biologically inert, temperature and storage stable, pose low to no infectious risk, can be commercially manufactured, and have well established gas transport properties. In this review, we highlight design and development strategies for their successful application in regenerative medicine, transplantation and organ preservation. Effective tissue preservation strategies are key to improving outcomes of extremity salvage and organ transplantation. Maintaining tissue integrity requires adequate oxygenation to support aerobic metabolism. The use of whole blood for oxygen delivery is fraught with limitations of poor shelf stability, infectious risk, religious exclusions and product shortages. Other agents also face clinical challenges in their implementation. As a solution, we discuss new ways of designing and developing PFC-based artificial oxygen carriers by implementing modern pharmaceutical quality by design and scale up manufacturing methodologies.

Dodecafluoropentane emulsion (DDFPe) is a novel nanotechnology for oxygen delivery with therapeutic potential for hemorrhagic shock and/or traumatic brain injury (TBI). DDFPe demonstrates efficacy at smaller doses than previously tested perfluorocarbon oxygen therapeutics. This smaller dose potentially eliminates toxicities exhibited by previous oxygen therapeutics, whereas anti-inflammatory properties of DDFPe may alleviate damage from ischemia reperfusion injury. This minireview summarizes our progress in developing a battlefield-ready product to prevent combat death due to hemorrhagic shock and/or TBI. Preclinical studies, for both indications, show promising effects of DDFPe as a resuscitation fluid. DDFPe may become a part of the toolkit for tactical healthcare professionals in battlefield and domestic emergency medicine.

Hypoxia plays vital roles in the development of tumor resistance against typical anticancer therapies and local reoxygenation has proved effective to overcome the hypoxia-induced chemoresistance. Perfluorocarbon (PFC) is an FDA approved oxygen carrier and currently vigorously investigated for oxygen delivery to tumors. This study reports a perfluorocarbon and etoposide (EP) loaded porous hollow Fe 3 O 4 -based theranostic nanoplatform capable of delivering oxygen to solid tumors to enhance their susceptibility against EP. Results show that oxygen could be released at a moderate rate from the porous hollow magnetic Fe 3 O 4 nanoparticles (PHMNPs) over an extended period of time, therefore effectively reducing the hypoxia-induced EP resistance of tumor cells. Moreover, the surface of PHMNPs was modified with lactobionic acid (LA)-containing amphiphilic polymers via hydrophobic interaction, which could provide targeting effect against certain types of tumors. The hydrophilic moiety would be subsequently shed by the intratumoral GSH after cellular internalization and result in the agglomeration of nanocarriers inside tumor cells, consequently impeding the nanoparticle exocytosis to enhance their intracellular retention. The enhanced retention could elevate the intracellular EP level and effectively boost the tumor cell killing effect. In addition to the therapeutic benefits, the Fe 3 O 4 nanocage could also be used for the magnetic resonance imaging of the tumor area. The assorted benefits of the composite nanosystem are anticipated to be advantageous for the treatment of drug-resistant hypoxic tumors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Idiopathic macular holes (IMH) are common and affect central vision. We demonstrate the effectiveness of 0.2 ml intravitreal perfluoropropane (C3F8) in Stage-2 IMH., Case: A 61-year-old woman presented with blurred vision OD. Best-corrected visual acuity (BCVA) was 20/125 OD and 20/20 OS. Biomicroscopy of OD evidenced a Stage-2 IMH. Intravitreal C3F8 was injected and postural measures prescribed. Optical coherence tomography 1 week after revealed posterior vitreous detachment and vitreomacular traction resolution. Full anatomical and functional recovery was achieved at week 4 and remained stable during a 6-month follow-up (BCVA 20/20 OD)., Conclusion: Intravitreal C3F8 as initial therapy for Stage 2 IMH represents a good alternative to vitrectomy for patients with IMH., (Copyright: © 2019 Permanyer.)

Objective: Subarachnoid hemorrhage (SAH) frequently results in severe morbidity, even mortality. Hypothermia is known to have a neuroprotective effect in ischemic injuries. The aim of this study was to determine whether nasopharyngeal (NP) perfluorochemical (PFC) cooling could be used in a rat model of SAH model for neuroprotection., Methods: SAH was induced in 16 male Sprague-Dawley rats by cisterna magna injection of 0.3 mL autologous blood. Vital signs, temperatures, cerebral blood flow (CBF), and brain histology were assessed. Brain cooling was performed on the treatment group using the NP-PFC method starting from 20 minutes after SAH., Results: No SAH-related deaths were observed in either group. SAH caused an immediate decrease in mean arterial pressure (17.0% ± 4.90% below baseline values). SAH induction caused a significant and rapid decrease in CBF from baseline (approximately -65%, ranging from -32% to -85%) in both hemispheres. In the left hemisphere, cooling facilitated the return of CBF to baseline values within 20 minutes of treatment with further increase in CBF that stabilized by the 2 hours after injury time point. Quantitative immunohistochemistry showed that there were significantly more NeuN-positive cells in the cortex and significantly fewer IBA-1-positive microglia and glial fibrillary acidic protein-positive astrocytes cells in both cortex and hippocampus in the animals that received NP-PFC cooling compared with no treatment, reflecting preserved neuronal integrity and reduced inflammation., Conclusions: The data from this study indicate that local hypothermia by NP-PFC cooling supports return of CBF and neuronal integrity and suppresses the inflammatory response in SAH, suggestive of a promising neuroprotective approach in management of SAH., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Artificial blood is an innovative concept of transfusion medicine where specifically designed compounds perform the task of transport and delivery of oxygen in the body to replace this function of allogenic human blood transfusion. Several molecules have been developed in the past few decades to achieve this objective and continous refinements are being continuously made in the quest of the ideal blood substitute. Currently, available technology manufactures artificial blood from haemoglobin obtained from outdated human/bovine blood (Haemoglobin Based Oxygen Carriers) or utilizing Perfluorocarbons. These synthetic blood substitutes are advantageous in that they do not require compatibility testing, are free from blood borne infections, have prolonged shelf life and do not require refrigeration. Artificial blood is projected to have a significant impact on the development of medical care in the future. It can complement the current blood products for transfusion and create a stable supply of safe and effective products. It is likely to reduce the requirements of blood transfusions drastically especially in settings of trauma and surgery thereby reducing the reliance on banked donated blood., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nanoparticles are submicrometer in size and are used in a variety of ways in the biomedical field. They can carry therapeutic drugs, either in the particle core or surface to target cancer sites in the body. Additionally they can contain imaging agents to diagnose and monitor the tumor size using different imaging modalities, such as fluorescence and nuclear magnetic resonance imaging. Novel theranostic nanoparticle agents, called perfluorohexane nanoemulsions (PFH-NEs) were synthesized whose intrinsic properties could be used for both imaging (ultrasound and photoacoustic) and therapy. Compared to other theranostic agents, our PFH-NEs can absorb sufficient near-infrared light to enhance contrast and provide deeper penetration imaging at laser fluences causing minimal damage to healthy tissue. One contrast mechanism (optical absorption/photoacoustics) allows us to validate localization of the agent and another (acoustic impedance/ultrasound) allows the imaging of therapeutic delivery after particle activation. In this work, we show the potential of these PFH-NEs to be used as multimodal imaging agents and for therapy.

Chemotherapy and photo-sonodynamic therapy (PSDT) can be combined through drug delivery nano-platforms to enhance the anti-tumor efficacy, however, which is limited by hypoxia in tumor, thereby causing chemotherapy resistance. Perfluoropentane (PFP) has the ability to carry oxygen and to enhance ultrasound or photoacoustic imaging after vaporization. Herein, we constructed a kind of nanoparticles (PTX/ICG and oxygen loaded PLGA nanoparticles (PIO&#95;NPs)), which had PFP core carrying oxygen and PLGA shell loaded indocyanine green (ICG) and paclitaxel (PTX). PIO&#95;NPs harbored good optical stability and the ability to transit phase. Moreover, it could rapidly release PTX and generate ROS under the mediation by near-infrared laser and low-intensity ultrasound. The PIO&#95;NPs enhanced contrast of the ultrasound and PA imaging. In particular, PIO&#95;NPs may be used to monitor and guide treatment for the accumulation of PIO&#95;NPs at tumor site can be observed by PA imaging. Compared with PTX or other nanoparticles, PIO&#95;NPs combined with laser and ultrasound (L.U) significantly induced apoptosis of SKOV3 cells and inhibited SKOV3 tumor growth. Therefore, PIO&#95;NPs are of great potential in cancer imaging and therapy.

Near-Infrared (NIR) dyes, with improved tissue penetration, minimal invasiveness and high specificity, have gained great interests in diagnosing and treating tumors. However, the poor solubility in aqueous medium and low 1O2 quantum yields of NIR dyes restrict their application in PDT (photodynamic therapy) research. Herein, a novel nanosystem with modifying the NIR dyes and encapsulating perfluorocarbon is reported for improving the PDT effectiveness of NIR dyes. By adding the PEG2000-SH and the C13 carbon chain to a NIR representative dye IR780, the new formed material PEG-IR780-C13 shows good solubility in water. Then PFTBA was encapsulated into PEG-IR780-C13 to form a nanosystem (PFTBA@PEG-IR780-C13). When exposed to laser irradiation, the nanosystem showed enhanced production of 1O2 and significantly increased PDT both in vivo and in vitro. Therefore, this work provides an approach for design and application of NIR dyes.

Objective: The aim of this study was to assess, in two experiments, the safety and efficacy of the PFC emulsion Oxycyte as an oxygen therapeutic for TBI to test the hypothesis that early administration of this oxygen-carrying fluid post-TBI would improve brain tissue oxygenation (P bt O 2 )., Methods: The first experiment assessed the effects of Oxycyte on cerebral vasoactivity in healthy, uninjured rats using intravital microscopy. The second experiment investigated the effect of Oxycyte on cerebral P bt O 2 using the PQM in TBI model. Animals in the Oxycyte group received a single injection of Oxycyte (6 mL/kg) shortly after TBI, while NON animals received no treatment., Results: Oxycyte did not cause vasoconstriction in small- (<50 μm) or medium- (50-100 μm) sized pial arterioles nor did it cause a significant change in blood pressure. Treatment with Oxycyte while breathing 100% O 2 did not improve P bt O 2 . However, in rats ventilated with ~40% O 2 , P bt O 2 improved to near pre-TBI values within 105 minutes after Oxycyte injection., Conclusions: Although Oxycyte did not cause cerebral vasoconstriction, its use at the dose tested while breathing 100% O 2 did not improve P bt O 2 following TBI. However, Oxycyte treatment while breathing a lower enriched oxygen concentration may improve P bt O 2 after TBI., (© 2018 John Wiley & Sons Ltd.)

Respiratory distress syndrome (RDS) represents one of the major causes of mortality among preterm infants, and the best approach to treat it is an open research issue. The use of perfluorocarbons (PFC) along with non-invasive respiratory support techniques has proven the usefulness of PFC as a complementary substance to achieve a more homogeneous surfactant distribution. The aim of this work was to study the inhaled particles generated by means of an intracorporeal inhalation catheter, evaluating the size and mass distribution of different PFC aerosols. In this article, we discuss different experiments with the PFC perfluorodecalin (PFD) and FC75 with a driving pressure of 4-5 bar, evaluating properties such as the aerodynamic diameter (D a ), since its value is directly linked to particle deposition in the lung. Furthermore, we develop a numerical model with computational fluid dynamics (CFD) techniques. The computational results showed an accurate prediction of the airflow axial velocity at different downstream positions when compared with the data gathered from the real experiments. The numerical validation of the cumulative mass distribution for PFD particles also confirmed a closer match with the experimental data measured at the optimal distance of 60 mm from the catheter tip. In the case of FC75, the cumulative mass fraction for particles above 10 µm was considerable higher with a driving pressure of 5 bar. These numerical models could be a helpful tool to assist parametric studies of new non-invasive devices for the treatment of RDS in preterm infants., Competing Interests: The authors declare no conflict of interest.

Alleviation of tumor hypoxia has been the premise for improving the effectiveness of radiotherapy, which hinges upon the advanced delivery and rapid release of oxygen within the tumor region. Herein, we propose a "bubble-enhanced oxygen diffusion" strategy to achieve whole tumor oxygenation for significant radiation enhancement based on the "bystander effect". Toward this end, sub-50 nm CuS-modified and 64 Cu-labeled hollow mesoporous organosilica nanoparticles were constructed for tumor-specific delivery of O 2 -saturated perfluoropentane (PFP). Through the aid of PFP gasification arising from NIR laser-triggered mild hyperthermia, simultaneous PET/PA/US multimodality imaging and rapid oxygen diffusion across the tumor can be achieved for remarkable hypoxic radiosensitization. Furthermore, the multifunctional oxygen-carrying nanotheranostics also allow for other oxygen-dependent treatments, thus greatly advancing the development of bubble-enhanced synergistic therapy platforms.

Introduction: Perfluorocarbons (PFC) are fluorinated hydrocarbons that dissolve gases to a much greater degree than plasma and hold promise in treating decompression sickness (DCS). The efficacy of PFC in a mixed gender model of DCS and safety in recompression therapy has not been previously explored., Methods: Swine (25 kg; N = 104; 51 male and 53 female) were randomized into normal saline solution (NSS) or PFC emulsion treatment groups and subjected to compression on air in a hyperbaric chamber at 200 fsw for 31 min. Then the animals were decompressed and observed for signs of DCS. Afterwards, they were treated with oxygen and either PFC (4 cc · kg-1) or NSS (4 cc · kg-1). Surviving animals were observed for 4 h, at which time they underwent recompression therapy using a standard Navy Treatment Table 6. After 24 h the animals were assessed and then euthanized., Results: Survival rates were not significantly different between NSS (74.04%) and PFC (66.67%) treatment groups. All swine that received recompression treatment survived to the end of the study and no seizures were observed in either PFC or NSS animals. Within the saline treated swine group there were no significant differences in DCS survival between male (75.00%, N = 24) and female (73.08%, N = 26) swine. Within the PFC treated swine, survival of females (51.85%, N = 27) was significantly lower than males (81.48%, N = 27)., Discussion: In this large animal mixed gender efficacy study in DCS, PFC did not improve mortality or spinal cord injury, but appears safe during recompressive therapy. Gender differences in DCS treatment with PFC will need further study.Cronin WA, Hall AA, Auker CR, Mahon RT. Perfluorocarbon in delayed recompression with a mixed gender swine model of decompression sickness. Aerosp Med Hum Perform. 2018; 89(1):14-18.

Goal: Recent preclinical studies have shown that therapeutic hypothermia induced in less than 30 min by total liquid ventilation (TLV) strongly improves the survival rate after cardiac arrest. When the lung is ventilated with a breathable perfluorocarbon liquid, the inspired perfluorocarbon allows us to control efficiently the cooling process of the organs. While TLV can rapidly cool animals, the cooling speed in humans remains unknown. The objective is to predict the efficiency and safety of ultrafast cooling by TLV in adult humans., Methods: It is based on a previously published thermal model of ovines in TLV and the design of a direct optimal controller to compute the inspired perfluorocarbon temperature profile. The experimental results in an adult sheep are presented. The thermal model of sheep is subsequently projected to a human model to simulate the optimal hypothermia induction and its sensitivity to physiological parameter uncertainties., Results: The results in the sheep showed that the computed inspired perfluorocarbon temperature command can avoid arterial temperature undershoot. The projection to humans revealed that mild hypothermia should be ultrafast (reached in fewer than 3 min (-72 °C/h) for the brain and 20 min (-10 °C/h) for the entire body)., Conclusion: The projection to human model allows concluding that therapeutic hypothermia induction by TLV can be ultrafast and safe., Significance: This study is the first to simulate ultrafast cooling by TLV in a human model and is a strong motivation to translate TLV to humans to improve the quality of life of postcardiac arrest patients.

Purpose: Meibomian gland disease is generally accepted as the leading cause for evaporative dry eye disease (DED). In a previous study, perfluorohexyloctane, a semifluorinated alkane, has been demonstrated to significantly increase tear film breakup time and to reduce corneal fluorescein staining in patients with evaporative DED, thereby vastly reducing dry eye-related symptoms. This study was set up to evaluate perfluorohexyloctane in a larger population of patients with Meibomian gland dysfunction., Methods: Seventy-two patients with Meibomian gland disease and associated dry eye received 1 drop of perfluorohexyloctane 4 times daily during an observational, prospective, multicenter, 6-8-week study. Clinical assessment included best-corrected visual acuity, intraocular pressure, Schirmer test I, tear film breakup time, anterior and posterior blepharitis assessment, number of expressible Meibomian glands, meibum quality and quantity, ocular surface fluorescein staining, lid margin and symptom assessment, and Ocular Surface Disease Index (OSDI © )., Results: From the 72 patients recruited, 61 completed the trial per protocol. Nine patients did not apply the medication as recommended and 2 patients were lost to follow-up. Tear film breakup time, corneal and conjunctival fluorescein staining, number of expressible Meibomian glands, and severity of anterior and posterior blepharitis significantly improved after 6-8 weeks of perfluorohexyloctane application. In addition, symptoms improved as demonstrated by a significant decrease of OSDI-values from 37 (±13) to 26 (±16)., Conclusions: In concordance with previous findings, 6-8 weeks of topical application of perfluorohexyloctane significantly improves clinical signs of Meibomian gland disease and associated mild to moderate DED.

We study the influence of ultrasound on paclitaxel-loaded nanocapsules in vitro and in vivo. These nanocapsules possess a shell of poly(dl-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) and a liquid core of perfluorooctyl bromide (PFOB). In vitro experiments show that mechanical effects such as cavitation are negligible for nanocapsules due to their small size and thick and rigid shell. As the mechanical effects were unable to increase paclitaxel delivery, we focused on the thermal effects of ultrasound in the in vivo studies. A focused ultrasound sequence was therefore optimized in vivo under magnetic resonance imaging guidance to obtain localized mild hyperthermia with high acoustic pressure. Ultrasound-induced mild hyperthermia (41-43°C) was then tested in vivo in a subcutaneous CT-26 colon cancer murine model. As hyperthermia is applied, an inhibition of tumor growth for both paclitaxel-loaded nanocapsules and the commercial formulation of paclitaxel, namely Taxol® have been observed (p<0.05). Ultrasound-induced mild hyperthermia at high acoustic pressure appears as an interesting strategy to enhance cytotoxic efficacy locally., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy., Aim: To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2)., Results: PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone., Conclusion: IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.

Context Incontinence-associated dermatitis (IAD) is a type of moisture-associated dermatitis caused by repeated skin exposure to urine or stool. A product that could mitigate such symptoms would have a significant impact on cost of care and patients' quality of life. Objective This study compared the clinical efficacy of RD1433 and a comparator product (Vaseline®) in preventing and treating experimental IAD skin lesions. Materials and methods For the "prevention" part of the study, skin sites in eight human volunteers were treated daily for 5 d with either RD1433 or Vaseline® immediately prior to synthetic urine exposure. In the "treatment" part, exposure to synthetic urine was substituted for Vaseline® or RD1433 application on the first 2 d to promote the development of skin lesions prior to the application of the products from day three. Product efficacy was quantified by visual scoring and an array of biophysical instruments. Results Both RD1433 and Vaseline® significantly reduced lesion progression when applied as a prophylactic. When applied as a treatment (following establishment of skin lesions), RD1433 demonstrated a statistically significant improvement in several measures of skin function whereas there was no statistically significant improvement following treatment with Vaseline®. Conclusions The findings of this study suggest that RD1433 may be superior to Vaseline® in the prevention and treatment of experimental IAD lesions. Clearly, further work is required to establish the efficacy of RD1433 with patients in a clinical environment.