Periodic Reporting for period 2 - VasoSurfer (Engineering Interfacial Fluid Trapping for Localized Treatment of Brain Aneurysms)
Período documentado: 2022-10-01 hasta 2024-03-31
Intravascular medical treatments for cardiovascular diseases are progressing to include the ability to navigate to distal disease sites. However, most approaches for localized treatment rely on the use of solid implants, such as stents and metallic coils for embolizing aneurysms, or on direct injection of the therapeutic agent, such as a clot-busting agent, which can further disperse away from the required site of action reducing the therapeutic effect and causing off-target side effects. Thus, there is a need for new approaches to localize treatment that can allow confining a therapeutic agent, such as a potent drug or an injectable biomaterial, to the disease site. The goal of this proposal is to engineer a novel localized intravascular treatment strategy that leverages surface tension to gently isolate and focally treat diseased sites. Fluid confinement and immiscible fluids dynamics have not been explored so far in physiological systems, such as the cardiovascular system. The development of such an approach can be used to locally treat life-threatening conditions such as: clots, plaques, tumors, and aneurysms- blood filled saccular lesions.
Here we develop the proposed strategy while demonstrating it on treatment of brain aneurysms, where current approaches using metallic implants carry a significant risk of procedural morbidity and increased risk of thrombolytic complication. Our treatment modality can naturally and non-mechanically isolate the diseased region, using fluid confinement, as well as allow confined treatment within the defined region. In this research which will advance understanding in fundamental transport phenomena and work towards translation to the clinic, we aim to: 1) Fundamentals: Test and optimize the fluid trapping phenomenon in silico and in vitro in reconstructed models of aneurysms 2) In vitro to in vivo: remotely embolize aneurysms using injectable biomaterials 3) From Bench to Bed: explore a universal surface tension ‘Glider’ for sealing and localized treatment while allowing continuous blood flow. The proposed research will integrate silico multi-physics models, in vitro patient specific reconstructed aneurysm models and in vivo experiments, thus allowing a comprehensive understanding of the proposed mechanism and its therapeutic application.
Here we develop the proposed strategy while demonstrating it on treatment of brain aneurysms, where current approaches using metallic implants carry a significant risk of procedural morbidity and increased risk of thrombolytic complication. Our treatment modality can naturally and non-mechanically isolate the diseased region, using fluid confinement, as well as allow confined treatment within the defined region. In this research which will advance understanding in fundamental transport phenomena and work towards translation to the clinic, we aim to: 1) Fundamentals: Test and optimize the fluid trapping phenomenon in silico and in vitro in reconstructed models of aneurysms 2) In vitro to in vivo: remotely embolize aneurysms using injectable biomaterials 3) From Bench to Bed: explore a universal surface tension ‘Glider’ for sealing and localized treatment while allowing continuous blood flow. The proposed research will integrate silico multi-physics models, in vitro patient specific reconstructed aneurysm models and in vivo experiments, thus allowing a comprehensive understanding of the proposed mechanism and its therapeutic application.
Aim 1: Aim 1 - Test and optimize the fluid trapping phenomenon in silico and in vitro in reconstructed models of aneurysms: We have completed Computational Fluid Mechanics (CFD) simulations to study the physical mechanism of surface tension-based formation of a stable meniscus for isolating and confining aneurysms’ cavities. Our results have shown that without surface tension (zero surface tension) the fluid, as expected, enters the aneurysm’s cavity and as we increase the surface tension of an Immiscible Phase (IMP), a stable and clear meniscus is generated, which isolates the aneurysm. Moreover, we have designed an in vitro experimental system where we tested the stability and robustness of the meniscus with different immiscible phases including fluids (FC-40) and gas (Air) and determined a range of parameters needed for a successful confinement, which includes surface tension, flow rate of the injected phase, size of the aneurysm’s neck and position of the aneurysm. Moreover, to show the efficacy and robustness of the IMP isolation, we successfully showed how we can selectively deliver an agent to endothelial cells inside the aneurysms without affecting the cells in the parent artery. In addition, full embolization of the aneurysm by generating a fibrinogen and thrombin clot was successfully achieved after IMP confinement of patient specific aneurysms.
Aim 2: In vitro to in vivo: remotely embolize aneurysms using injectable biomaterials: We have explored a new hydrogel (osmo-responsive biomimetic GAG analogs based on sulphonate-containing precursor monomers) for the embolization of intracranial aneurysms. Using this hydrogel we also developed an approach for filling the cavity and allowing the hydrogel to swell in the direction of the cavity while selectively hindering its swelling in the directin of the parent artery, via interaction with blood. We have tested in vitro its toxicity with human cells, biocompatibility, and its interaction with blood and it stability as an embolic agent under physiological blood flow conditions. In parallel, we have developed a new approach involving the utilization of gravitational force for the distal filling of cerebral aneurysms. We were able to design a new experimental system and to conduct in vitro experiments to fill and embolize aneurysm models relying on gravity without the use of catheters entering the aneurysm’s cavity. Our results revealed the importance of how to tune different parameters to enable a successful distant filling of the aneurysm. We have shown that the injection flow rate, the properties of the injected fluid and the rotating angle of the aneurysm should be carefully considered, bearing in mind the aneurysm's location and the pathway to efficiently deliver the drug with minimal risks to the patient.
Aim 3: From Bench to Bed: explore a universal surface tension ‘Glider’ for sealing and localized treatment while allowing continuous blood flow: We have performed a proof-of-principle study on a novel localized intravascular treatment strategy by developing a device that allows, through a mechanism of surface tension, to "surf" to the site where treatment is required and to isolate it, while maintaining blood flow through the device during the treatment. We have set a preliminary design of the device which was placed inside our aneurysm model and connected to the perfusion system. We were able to inject an IMP (air) at the annular space between the device and the device outer surface such that the device is hovered on the IMP, and it was possible to move it freely with minimal friction. Then, once the aneurysm was successfully isolated, different fluids were injected to the aneurysm’s cavity. Thus, these results serve as an initial proof-of-principle to our new concept.
Aim 2: In vitro to in vivo: remotely embolize aneurysms using injectable biomaterials: We have explored a new hydrogel (osmo-responsive biomimetic GAG analogs based on sulphonate-containing precursor monomers) for the embolization of intracranial aneurysms. Using this hydrogel we also developed an approach for filling the cavity and allowing the hydrogel to swell in the direction of the cavity while selectively hindering its swelling in the directin of the parent artery, via interaction with blood. We have tested in vitro its toxicity with human cells, biocompatibility, and its interaction with blood and it stability as an embolic agent under physiological blood flow conditions. In parallel, we have developed a new approach involving the utilization of gravitational force for the distal filling of cerebral aneurysms. We were able to design a new experimental system and to conduct in vitro experiments to fill and embolize aneurysm models relying on gravity without the use of catheters entering the aneurysm’s cavity. Our results revealed the importance of how to tune different parameters to enable a successful distant filling of the aneurysm. We have shown that the injection flow rate, the properties of the injected fluid and the rotating angle of the aneurysm should be carefully considered, bearing in mind the aneurysm's location and the pathway to efficiently deliver the drug with minimal risks to the patient.
Aim 3: From Bench to Bed: explore a universal surface tension ‘Glider’ for sealing and localized treatment while allowing continuous blood flow: We have performed a proof-of-principle study on a novel localized intravascular treatment strategy by developing a device that allows, through a mechanism of surface tension, to "surf" to the site where treatment is required and to isolate it, while maintaining blood flow through the device during the treatment. We have set a preliminary design of the device which was placed inside our aneurysm model and connected to the perfusion system. We were able to inject an IMP (air) at the annular space between the device and the device outer surface such that the device is hovered on the IMP, and it was possible to move it freely with minimal friction. Then, once the aneurysm was successfully isolated, different fluids were injected to the aneurysm’s cavity. Thus, these results serve as an initial proof-of-principle to our new concept.
Our new technologies of confined compartmentalization using surface tension-based methods can provide a platform for universal focal treatment of blood vessels, in a variety of cardiovascular diseases. Moreover, the presented work leveraging surface tension phenomena for medical intervention goes beyond any current state of the art approaches. We have already established the physics and governing forces for isolating aneurysm cavities using an immiscible phase. Additionally, we demonstrated that proper design of localized treatment in aneurysm cavities can be performed using an immiscible phase. We plan to further develop fluid-based strategies to remotely embolize distant aneurysms, without direct catheter injection in the cavity. Additionally, we plan to develop novel intravascular ‘surfing’ devices, that are beyond current state-of-the-art devices, that utilize surface tension and allow localized treatments without blocking the flow.