Large, Wide-Neck, Side-Wall Aneurysm Treatment in Canines Using NeuroCURE: A Novel Liquid Embolic.

BACKGROUND: Untreated intracranial aneurysms can rupture and result in high rates of morbidity and mortality. Although there are numerous approved endovascular aneurysm treatment devices, most require dual anti-platelet therapy, are minimally biocompatible, or are prone to recanalization. Neurovascular Controlled Uniform Rapid Embolic (NeuroCURE) is an innovative polymer gel material with long-term stability, biocompatibility, and hemocompatibility developed for the treatment of large, wide-neck aneurysms. METHODS: Sidewall aneurysms were surgically created in 10 canines and NeuroCURE was injected through a 0.025 microcatheter under a single balloon inflation period. Aneurysm treatment was angiographically assessed post-embolization and pre-term with Raymond-Roy occlusion classification and a qualitative flow grade scale. Aneurysm neck stability and biocompatibility was histologically assessed to grade platelet/fibrin thrombus, percent endothelialization, and neointimal formation. Aneurysm sac stability was assessed by NeuroCURE sac content, inflammation, and neo-angiogenesis scales. RESULTS: Explanted aneurysms exhibited a smooth surface at the aneurysm neck with nearly complete neointimal coverage at 3-months. By 6-months, neck endothelialization was 100% in all animals (average Raymond-Roy occlusion classification of 1.2), with no instances of aneurysm recanalization or parent vessel flow compromise. Biocompatibility assessments verified a lack of inflammatory response, neo-angiogenesis, and platelet/fibrin thrombus formation. CONCLUSION: The NeuroCURE material promotes progressive occlusion of wide-necked side wall aneurysms over time without the need for dual antiplatelet agents. NeuroCURE also promotes neointimal tissue infill without dependence on thrombus formation and thus resists aneurysm recanalization. NeuroCURE remains a compelling investigational device for the treatment of intracranial aneurysms.

Application of nondestructive mechanical characterization testing for creating in vitro vessel models with material properties similar to human neurovasculature.

Vessel models are a first step in developing endovascular medical devices. However, these models, often made from glass or silicone, do not accurately represent the mechanical properties of human vascular tissue, limiting their use to basic training and proof-of-concept testing. This study outlines methods to quantify human vascular tissue mechanical properties and synthetic biomaterials for creating representative vessel models. Human vascular tissue was assessed and compared to silicone and new UV-cured polymers (VC-A30) using the following eight mechanical tests: compressive, shear, tensile dynamic elastic modulus, Poisson's ratio, hardness, radial force, compliance, and lubricity. Half of these testing methods were nondestructive, allowing for multiple mechanical and histological characterizations of the same human tissue sample. Histological evaluation of the cellular and extracellular matrix of the human vessels verified that the dynamic moduli and Poison's ratio tests were nondestructive. Fluid absorption by VC-A30 showed statistically significant softening of mechanical properties, stabilizing after 4 days in phosphate-buffered saline (PBS). Human vasculature exhibited notably similar results to VC-A30 in five of eight mechanical tests (≤30% difference) versus two of eight for standard silicone (≤38% difference). Results show that VC-A30 provides a new option for 3D-printing translucent in vitro vascular models with anatomically relevant mechanical properties. These new vessel analogs may simulate patient-specific vessel disease states, improve surgical training models, accelerate new endovascular device developments, and ultimately reduce the need for animal models.

Quantifying the mechanical and histological properties of thrombus analog made from human blood for the creation of synthetic thrombus for thrombectomy device testing.

BACKGROUND: Untreated ischemic stroke can lead to severe morbidity and death, and as such, there are numerous endovascular blood-clot removal (thrombectomy) devices approved for human use. Human thrombi types are highly variable and are typically classified in qualitative terms - 'soft/red,' 'hard/white,' or 'aged/calcified.' Quantifying human thrombus properties can accelerate the development of thrombus analogs for the study of thrombectomy outcomes, which are often inconsistent among treated patients. METHODS: 'Soft'human thrombi were created from blood samples ex vivo (ie, human blood clotted in sample vials) and tested for mechanical properties using a hybrid rheometer material testing system. Synthetic thrombus materials were also mechanically tested and compared with the 'soft' human blood clots. RESULTS: Mechanical testing quantified the shear modulus and dynamic (elastic) modulus of volunteer human thrombus samples. This data was used to formulate a synthetic blood clot made from a composite polymer hydrogel of polyacrylamide and alginate (PAAM-Alg). The PAAM-Alg interpenetrating network of covalently and ionically cross-linked polymers had tunable elastic and shear moduli properties and shape memory characteristics. CONCLUSIONS: Due to its adjustable properties, PAAM-Alg can be modified to mimic various thrombi classifications. Future studies will include obtaining and quantitatively classifying patient thrombectomy samples and altering the PAAM-Alg to mimic the results for use with in vitro thrombectomy studies.

In vivo embolization of lateral wall aneurysms in canines using the liquid-to-solid gelling PPODA-QT polymer system: 6-month pilot study.

OBJECT: Over the past 20 years, endovascular embolization has become the preferred method of treating cerebral aneurysms. While there are many embolic devices on the market, none is ideal. In this study the authors investigated the use of a liquid-to-solid gelling polymer system-that is, poly(propylene glycol) diacrylate and pentaerythritol tetrakis (3-mercaptopropionate) (PPODA-QT)-to embolize in vivo aneurysms over a 6-month period. METHODS: Experimental aneurysms were created in the carotid arteries of 9 canines. Aneurysms were embolized with the polymer only (PPODA-QT, 3 dogs), filled with PPODA-QT after placement of a "framing" platinum coil (coil+PPODA-QT, 3 dogs), or packed with platinum coils (coils only, 3 dogs). Aneurysm occlusion was angiographically monitored immediately and 6 months after embolization. After 6 months, the ostial regions of explanted aneurysms were assessed macroscopically and histologically. RESULTS: All aneurysms showed 100% angiographic occlusion at 6 months, but turbulent blood flow was observed in 1 coils-only sample. Ostial regions of explanted coils-only aneurysms showed neointimal tissue surrounding individual coils but no continuous tissue layer over the aneurysm neck. All PPODA-QT aneurysms displayed smooth ostial surfaces, but 2 of 3 coil+PPODA-QT aneurysms showed polymer (unassociated with the coil) protruding into the vessel lumen, contributing to rough ostial surfaces. Neointimal tissue was present in PPODA-QT and coil+PPODA-QT aneurysms and covered smooth ostial surfaces more completely than in coils-only aneurysms. CONCLUSIONS: This study compared neointimal tissue overgrowth in the ostium of experimental aneurysms embolized with PPODA-QT, PPODA-QT plus a framing coil, or coils alone. The coils-only and coil+PPODA-QT groups showed rough and discontinuous ostial surfaces, which hindered neointimal tissue coverage. The PPODA-QT aneurysms consistently produced smooth ostial surfaces that facilitated more complete neointimal tissue coverage over aneurysm necks.

Preliminary investigation of calcium alginate gel as a biocompatible material for endovascular aneurysm embolization in vivo.

OBJECTIVE: We sought to expand our assessment of calcium alginate as an embolic agent in an aneurysm model in swine that survived from 30 to 90 days. The objective of this study was to assess the biocompatibility and stability of calcium alginate in aneurysms in vivo. METHODS: Ten models were created from a venous pouch sutured to the carotid artery, simulating flow to a side-wall aneurysm. Eight swine received complete embolizations, and two were less than 50% embolized to be used as controls. Alginate and calcium chloride were injected from concentric-tube microcatheters to form a mass that filled the aneurysm pouch. RESULTS: Angiography and histology verified complete aneurysm occlusion and neck healing up to 90 days in eight swine. Both control animal aneurysms ruptured within 8 days. No animals showed evidence of downstream calcium alginate gel propagation. A minor bioactive response to the alginate gel was noted at 30 days, and fibrous tissue grew over the aneurysm orifice, sealing off the defect. No degenerative or inflammatory response was observed. At 90 days, moderate fibrous tissue surrounded the alginate. Tissue growth across the aneurysm neck remained complete and stable with no signs of neointimal growth into the parent vessel. CONCLUSION: Calcium alginate was an effective endovascular occlusion material that filled the aneurysm and provided an effective template for tissue growth across the aneurysm neck after 30 days and up to 90 days. Complete filling of the aneurysm with calcium alginate ensures stability, biocompatibility, and optimal healing for up to 90 days in swine.

Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response.

Members of the carbonic anhydrase (CA) family play an important role in the regulation of pH, CO(2), ion, and water transport. CA IV and CA XIV are membrane-bound isozymes expressed in the eye. CA IV immunostaining is limited to the choriocapillaris overlying the retina, whereas CA XIV is expressed within the retina in Müller glial cells and retinal pigment epithelium. Here, we have characterized the physiological and morphological phenotype of the CA IV-null, CA XIV-null, and CA IV/CA XIV-double-null mouse retinas. Flash electroretinograms performed at 2, 7, and 10 months of age showed that the rod/cone a-wave, b-wave, and cone b-wave were significantly reduced (26-45%) in the CA XIV-null mice compared with wild-type littermates. Reductions in the dark-adapted response were not progressive between 2 and 10 months, and no differences in retinal morphology were observed between wild-type and CA XIV-null mice. Müller cells and rod bipolar cells had a normal appearance. Retinas of CA IV-null mice showed no functional or morphological differences compared with normal littermates. However, CA IV/CA XIV double mutants showed a greater deficit in light response than the CA XIV-null retina. Our results indicate that CA XIV, which regulates extracellular pH and pCO(2), plays an important part in producing a normal retinal light response. A larger functional deficit in the CA IV/CA XIV double mutants suggests that CA IV can also contribute to pH regulation, at least in the absence of CA XIV.

Calcium alginate gel as a biocompatible material for endovascular arteriovenous malformation embolization: six-month results in an animal model.

OBJECTIVE: We sought to expand our assessment of calcium alginate as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). The objective of this study was to assess the long-term biocompatibility and stability of calcium alginate in AVM swine models that survived from 1 to 6 months. METHODS: The swine model included a carotid-jugular anastomosis to redirect flow to the rete mirabile (RM), thereby simulating flow to an AVM. Alginate and the reactive component, calcium chloride, were injected from double-lumen or concentric-tube microcatheters to form an occlusion of the RM feeding vessel and the inferior portion of the RM. RESULTS: Angiography and histology verified complete occlusion of the RM feeding vessel for up to 6 months in eight of nine swine. Blood flow remained open to the superior portion of the RM and the circle of Willis. No evidence of downstream calcium alginate gel was seen in the follow-up angiograms or the histological preparations of the circle of Willis. A minor bioactive response to the alginate gel was noted at 1 month, yet no degenerative or inflammatory response was seen. At 6 months, there was moderate fibrous tissue around the alginate, which further sealed off flow to the embolized areas of the RM. CONCLUSION: Over a period of 6 months, calcium alginate was an effective endovascular occlusion material that blocked blood flow to the inferior portion of the RM. The chronic AVM model verified the long-term stability and biocompatibility of calcium alginate.

In vivo assessment of calcium alginate gel for endovascular embolization of a cerebral arteriovenous malformation model using the Swine rete mirabile.

OBJECTIVE: We sought to assess the stability of calcium alginate as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). Swine cerebral AVM models were used to test the injectability, radiographic visualization, mechanical stability, and biocompatibility of calcium alginate as an occlusive agent. METHODS: The swine cerebral AVM model included a carotid-to-jugular anastomosis to increase flow to the rete mirabile (RM), thereby simulating the pressure gradient and shunted blood flow of an AVM. Alginate and the reactive component, calcium chloride, were injected from double-lumen microcatheters to form a complete RM occlusion in the "acute swine" AVM model and a partial occlusion in a "survival swine" model. RESULTS: Angiographic and histological results verified complete occlusion of the left RM in acute animals when alginate was injected in stages. Partial RM occlusion in the survival animals blocked blood flow to the inferior portion of the RM but left flow open to the superior portion of the RM and the circle of Willis. One-week survival results showed that the alginate remained a stable occlusive material. Histological results showed a minor bioactive response and encapsulation of the alginate polymer, thereby increasing the stability and effective occlusion of the embolization material. CONCLUSION: Calcium alginate proved to be an effective endovascular occlusion material that blocked blood flow to the swine RM. The swine AVM models provided assessment of alginate injectability and effective occlusion and provided initial in vivo characteristics of alginate stability and biocompatibility.

Flow properties of liquid calcium alginate polymer injected through medical microcatheters for endovascular embolization.

The flow properties of liquid calcium alginate injections were investigated for application in endovascular embolization. Alginate shear properties were assessed with a rheometer and a controlled injection system. The experimental results were used to model the flow properties and predict alginate's flow characteristics within various medical microcatheter delivery systems. The results suggest that alginates undergo shear-thinning effects with increasing shear. A flow comparison of 2.0 wt % alginate and a Newtonian fluid (82 cP) injected from the same microcatheter had similar flow rates at low injection pressure (100 kPa). However, at high injection pressure (2100 kPa), the alginate was injectable at a flow rate 100% higher than was the Newtonian fluid. Further analysis of injections through microcatheters resulted in a flow model for predicting viscosity changes, flow rates, and injection pressures of liquid alginate at medium-to-high shear rates. The predicted injection pressures and flow rates had an average variance of less than 15% from that of the experimental flow data. This study indicates that calcium alginate has the requisite flow properties for successful delivery to vascular lesions via endovascular injection. Possible uses of alginates include treating arteriovenous malformations (AVMs), aneurysms, blood flow to tumors, and vascular hemorrhages.