Timothy A. Becker

Calcium alginate gel: A biocompatible and mechanically stable polymer for endovascular embolization

The development and optimization of calcium alginate for potential use in endovascular occlusion was investigated by testing its in vitro and in vivo mechanical stability and biocompatibility. The compressive resistance, rheology, and polymer yield of reacted alginate, and the polymer viscosity of unreacted alginate, were assessed. Biocompatibility was tested by injecting calcium alginate into the kidney capsule of rats. The reactivity of alginates with various structures and levels of purity were compared visually and histologically. Results suggest that calcium alginate is a biocompatible and mechanically stable gel for endovascular applications. Purified alginates exhibited compressive strength of 22 kPa and above at 40% compression, with no significant loss in elasticity. Purified alginate strength was significantly higher than that of crude alginates (p < 0.08). Purified alginates also exhibited significantly lower tissue reaction than crude alginates (p < 0.05). Of the alginates tested, purified high guluronic acid alginates (PHG) exhibited optimal strength and polymer yield, increased biocompatibility, and decreased viscosity. Clinical embolization treatments may be improved with the development of stable and biocompatible polymers such as calcium alginate. Possible uses of improved endovascular polymers include treating arteriovenous malformations (AVMs), aneurysms, blood flow to tumors, and vascular hemorrhaging.

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.

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.

Calcium alginate provides a high degree of embolization in aneurysm models: a specific comparison to coil packing.

OBJECTIVE:Although flexible, current coils do not fill intracranial aneurysms to a high degree, and questions remain regarding their thrombogenic capacity. We evaluated the usefulness of calcium alginate as an embolic material for endovascular embolization in aneurysm models. METHODS:We assessed three endovascular methods of instilling calcium alginate into 10-mm sidewall and 7-mm bifurcation glass aneurysm models using a balloon catheter to seal the aneurysm orifice: 1) instillation of alginate and subsequent instillation of the reactive component calcium chloride (CaCl2) via a single-lumen catheter, 2) simultaneous instillation of alginate and CaCl2 via a side-by-side double-lumen catheter, and 3) instillation of alginate mixed with CaCl2 delivered from a concentric-tube microcatheter. A 13-mm sidewall silicon aneurysm model was used to measure and compare the volume of calcium alginate occupying the aneurysm models. RESULTS:Instillation Method 1 did not achieve optimal filling of the aneurysm with calcium alginate. The percentage volumes of calcium alginate occupying the aneurysm were 69.2 ± 7.7% and 84.6 ± 5.4% for instillation Methods 2 and 3, respectively. In Method 3, calcium alginate began gelation upon leaving the catheter, entered the aneurysms in a strand form, and gelled to a mass that filled the aneurysm while conforming to its inner contour. CONCLUSION:Calcium alginate fills aneurysm models to a significantly higher degree than published results of the space filled by coils. Instillation of calcium alginate, especially in strand form, may produce an embolization that better fills and conforms to the contour of aneurysms compared with coils.

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

OBJECTIVEWe 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. METHODSTen 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. RESULTSAngiography 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. CONCLUSIONCalcium 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.

The use of ALGEL/spl reg/ as an artificial dura for chronic cortical implant neuroprosthetics

Surgical techniques are a critical contributor to the level of success achieved with chronically implanted cortical neuroprosthetic devices. Many different factors contribute to the amount of irritation the tissue is exposed to from the implanted device. Factors include mechanical irritations, infectious pathogens, dural regrowth, etc. In this paper we describe a novel application of the hydrogel polymer, ALGEL/spl reg/ (Neural Intervention Technologies, Ann Arbor, MI), in conjunction with an implanted Michigan probe (CNCT, University of Michigan). This polymer contains many inherent properties that are beneficial to this type of procedure. Properties include: 1) ease of application, 2) biocompatibility, 3) exemplary mechanical properties, and 4) translucent clarity. We believe that ALGEL has been a large contributor to the high level of success achieved with our chronic electrode implantations.

Troubleshooting and hurdles to development of biomaterials

Abstract: This chapter discusses common hurdles to developing a new injectable biomaterial along the path of new medical device creation. The first half of the chapter describes material characterization studies for consideration when attempting to develop a new device. The second half of the chapter describes the process of gaining device approval in the United States, and highlights options for funding a medical device development venture.

Chronic assessment of ALGEL/spl reg/ for endovascular embolization of an arteriovenous malformation model in swine

We sought to assess the stability of ALGEL (Neural Intervention Technologies, Ann Arbor, MI) as an embolic agent in an animal model of a cerebral arteriovenous malformation (AVM). Swine cerebral AVM models were used to test the mechanical stability and biocompatibility of ALGEL as an occlusive agent in a pre-clinical study for up to 6 month survival. The swine cerebral AVM model included a carotid-jugular anastomosis to increase flow to the rete mirabile (RM), thereby simulating the pressure gradient and shunted blood flow of an AVM. ALGEL and the reactive component, calcium chloride, were injected through double-lumen microcatheters to form an RM occlusion in chronic swine models. ALGEL injection 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- and six-month survival results showed that the ALGEL remained a stable occlusive material. Histology results showed a minor bioactive response and encapsulation of ALGEL, thereby increasing the stability and effective occlusion of the embolization material. ALGEL appears to initiate a bioactive response to maintain a stable and long-term endovascular occlusion.

Endovascular embolization of aneurysms with ALGEL/spl reg/: an in vitro study of delivery techniques and resulting gel stability

Continued studies with calcium alginate gel (ALGEL/spl reg/-Neural Intervention Technologies, Ann Arbor, MI) show promise as an aneurysm occlusion material. Controlled ALGEL delivery eliminates flow to aneurysms and, when combined with coils, can eliminate the potential for ALGEL outflow from wide-neck, high flow aneurysms. Several aneurysm sizes were cast in flexible resins to simulate side-wall and bifurcation aneurysms in an in vitro system. First, ALGEL was delivered to small neck aneurysms from a 3F dual-lumen microcatheter. Second, a minimal number of coils were delivered to wide-neck aneurysms to form a matrix structure. ALGEL was then delivered to fill the remaining aneurysm space. ALGEL completely and effectively filled both small-neck aneurysms and, when combined with coils, completely filled wide-neck, high-flow aneurysms and eliminated outflow. Mechanical testing of ALGEL compared shear resistance to estimated shears seen in vivo. The frequency dependence of the complex modulus was determined at multiple % shears. ALGEL exhibits adequate stability to resist typical in vivo blood flow and shear effects subjected on aneurysms. ALGELs mechanical stability and effective occlusion, alone and in combination with coils, makes ALGEL a potentially novel candidate for treating a wide variety of aneurysms and other neurovascular lesions.

ALGEL/sup /spl reg// as a dural sealant, determination of effects on the sensori-motor cortex in rats

ALGEL/sup /spl reg// (Neural Intervention Technologies, Ann Arbor, MI) has shown promise as a biocompatible and mechanically stable material when used as a dural sealant. ALGEL provides a suitable interface between the brain surface and cortical neural implants to help attain long-term neural recordings for over one year in laboratory animals. This paper investigates whether the ALGEL can cause abnormal neural activity or seizures when placed in contact with the motor cortex. Sixteen rats underwent craniotomy procedures and ALGEL and its reactive component, calcium chloride, were placed in contact with the cortex. The response of the animals was evaluated with electroencephalography (EEG) and clinical monitoring of behavior during controlled anesthesia for up to two hours post-application. ALGEL was compared with tranexamic acid (tAMCA), a synthetic fibrinolysis inhibitor that has been shown to cause epileptic seizures. tAMCA, at a dose of 100 mg/ml, showed marked paroxymal brain activity with associated and distinct episodes of jerk-correlated convulsive behaviors. However, various applications of ALGEL on the rat cortex showed no abnormal EEG signals and no episodes of jerk-correlated convulsive behaviors. ALGEL appears to be a safe and effective dural sealant that can be used alone or in combination with neural implants.