Medical applications of shape memory polymers.

Shape memory polymers (SMP) are lightweight, have a high strain/shape recovery ability, are easy to process, and required properties can be tailored for variety of applications. Recently a number of medical applications have been considered and investigated, especially for polyurethane-based SMP. SMP materials were found to be biocompatible, non-toxic and non-mutagenic. The glass transition temperature (T(g)) can be tailored for shape restoration/self-deployment of clinical devices when inserted in the human body. Newly developed SMP foams, together with cold hibernated elastic memory (CHEM) processing, further broaden their potential biomedical applications. Polyurethane-based SMP are described here and major advantages are identified over other medical materials. Some SMP applications are already used in a clinical setting, whereas others are still in development. Lately, several important applications are being considered for CHEM foams as self-deployable vascular and coronary devices. One example is the endovascular treatment of aneurysms.

Endoluminal cryotherapy to prevent recanalization after endovascular occlusion with platinum coils.

PURPOSE: Endovascular embolization with platinum coils is sometimes followed by recanalization. The present study was undertaken to assess whether cryoablation of the endothelial lining could prevent recanalization after coil occlusion. MATERIALS AND METHODS: Recanalization rates of canine maxillary and vertebral arteries (n = 20) occluded with platinum coils with or without previous cryoablation (with temperatures of -40 degrees C to -45 degrees C for 90 seconds) were analyzed by angiography immediately and at 1 and 3 months in five animals. Pathologic recanalization and fibrosis was assessed at 3 months with use of a qualitative scoring system. Findings were compared with Mann-Whitney tests. RESULTS: Recanalization after coil occlusion occurred in 50% and 60% of cases with cryoablation at 1 and 3 months, respectively, compared with 100% without ablation (P = .012 and P= .029). There was no significant difference in pathologic scores (P = .348). The brachial plexus in the vicinity of vertebral arteries was injured by cryotherapy in three animals in which an ipsilateral neurologic deficit developed. CONCLUSIONS: Cryotherapy was moderately effective in the prevention of recanalization after coil occlusion. Deep nerve injury was excessive with the protocol used in the present study.

Safety and effectiveness of radioactive coil embolization of aneurysms: effects of radiation on recanalization, clot organization, neointima formation, and surrounding nerves in experimental models.

BACKGROUND AND PURPOSE: Recanalization after coil embolization can be prevented by radiation emitted from 32P coils. We wanted to determine the upper limits of 32P activities that could be implanted onto coils with respect to the potential injury to nearby nerves, delay in organization of the clot, and effects on neointima formation and recanalization. METHODS: We studied the effects of various 32P activities on recanalization and organization of thrombus after coil occlusion of canine arteries and on neointima formation at the neck of canine carotid bifurcation aneurysms. We also tested potential injury to nerves in the vicinity of radioactive or nonradioactive coils in 3 models: the brachial plexus (near proximal vertebral arteries) and the lingual nerve in a lingual artery bifurcation aneurysm model, both models being treated by radioactive or standard coil occlusion. Finally, we wrapped lingual nerves with nonradioactive or high-activity coils and studied their effects on lingual nerves and tongues. Results were assessed with a pathological scoring system and compared with Mann-Whitney and Kruskal-Wallis tests. RESULTS: No deleterious effect of radiation on nerves could be detected. Neointima formation was not hampered, scores of aneurysms treated with 32P-coils being significantly better when compared with treatments with standard coils (P=0.002). Arteries treated with high-activity coils (>3.39 microCi) showed absent recanalization but delayed organization of the clot at 3 months compared with low-activity or nonradioactive coils (P<0.05). CONCLUSIONS: beta-Radiation can prevent recanalization after coil occlusion. We could not demonstrate any deleterious effects of radioactivity on nervous structure or on neointima formation. Delayed organization of thrombus provides a rational basis to establish an upper limit for 32P activities to be implanted onto coils.

Production of radioactive particles for endovascular therapeutic interventions.

Recanalization is a common phenomenon that decreases the efficacy of embolization procedures. It can be inhibited by beta-radiation. Two novel ways of producing radioactive particles are described, by neutron beam irradiation of gold-containing microspheres, or by using the 32P binding capacity of zirconium-containing microspheres. Particles were tested in vivo, to assess their ability to deliver radioactivity locally, using canine renal artery, porcine rete mirabile, and rabbit ear embolization models. Both radioactive microspheres (198Au and 32P) showed no detectable activity outside the target territory. 32P microspheres demonstrated typical radiation changes in a porcine rete mirabile arteriovenous malformation model.

Endovascular treatment of aneurysms: gene expression of neointimal cells recruited on the embolic agent and evolution with recurrence in an experimental model.

PURPOSE: The authors attempted to identify genes associated with healing or recurrence after embolization in an aneurysm model in which neointima formation at the neck varies according to flow zones. A better understanding of the relationship between blood flow, molecular events, and healing or recurrence may provide future avenues to improve results of endovascular treatment of aneurysms. METHODS: Bilateral carotid venous pouch aneurysms were constructed in 36 dogs and embolized with gelatin sponges. Angiography and pathological studies were performed at T0 and/or 3 weeks (n=22). Angiographic results and neointima formation were scored using a qualitative index applied to the distal (inflow) and proximal (outflow) zones of the neck. In 14 animals, mRNA expression 1 to 14 days after embolization at the proximal or distal segment of the sponge was analyzed by RT-PCR, attempting to correlate flow zones, gene expression, and neointima formation. RESULTS: Aneurysms recurred at 3 weeks, as shown by significantly worse angiographic scores as compared to T0 (P<.01). Neointimal scores differed at pathology, with a more complete neointima at the proximal as compared to the distal aspect of the sponge at 3 weeks (P=.027). Embolization was followed by migration of CD31+, CD14+, smooth muscle alpha-actin+ (SMA+) cells that progressively expressed metalloproteinases (MMP-9,-12,-14), but stable or lesser, retarded expression of inhibitors (TIMP1-4). Growth factors (PDGF-BB, TGF-beta1, TNF-alpha, MCP-1 and Ang-1) were expressed at increasing levels, maximal at 7 to 14 days. Differences between distal and proximal zones were limited to increased expression of MMP-2 proximally (P<.035). CONCLUSION: Gene expression after embolization is compatible with patterns associated with neointima formation. The authors have not identified key factors involved in recurrence.

Recanalization of arterial thrombus, and inhibition with beta-radiation in a new murine carotid occlusion model: MRNA expression of angiopoietins, metalloproteinases, and their inhibitors.

BACKGROUND: Recanalization is an important physiologic phenomenon because it can efficiently reestablish circulation after thrombosis. We attempted to characterize molecular events related to recanalization or organization of arterial thrombus in a new murine model by studying genes reported to be involved in angiogenesis or neointima formation. METHODS: Platinum coils, radioactive phosphorus 32 coils or not, were implanted in the carotid artery in mice to cause thrombotic occlusion. The outcome of the occlusion was followed up with transmyocardial angiography and pathologic analysis at 2, 6, or 15 days. Angiographic results were compared with the Pearson chi2 test. Messenger RNA expression of von Willebrand factor (vWF); smooth muscle alpha-actin (SMA+); platelet endothelial cell adhesion molecule-1 (PECAM-1); vascular endothelium cadherin (VE-Cad); endothelial nitric oxide synthase (eNOS); vascular cell adhesion molecule-1 (VCAM-1); tumor necrosis factor alpha (TNF-alpha); matrix metalloproteinase (MMP-9, MMP-12, and MMP-14), and tissue inhibitors of MMPs (TIMPs: TIMP-1, TIMP-2, TIMP-3, TIMP-4); angiopoietins (Ang-1, Ang-2); and receptors Tie-1 and Tie-2, were analyzed with reverse transcriptase polymerase chain reaction 2, 6, and 15 days after surgery. Levels of mRNA expression were compared with analysis of variance and the Student t test. RESULTS: Carotid arteries implanted with nonradioactive 0.015-caliber coils were occluded in 84% of arteries on day 2, but in only 57% of arteries on day 15, which confirms that recanalization occurred in this model. Arteries implanted with 0.015-caliber 32P coils did not become recanalized, and 100% were occluded on day 15 (n = 13; P = .006). Recanalization was associated with endothelial-like cell-lined channels, whereas persistent occlusion was caused by complete filling of the lumen with conjunctive tissue. Coil occlusion, with or without recanalization, was followed by decreased expression of vWf, VE-Cad, eNOS, VCAM-1, MMP-2, TIMP-1, and TIMP-2; stable expression of PECAM-1, SMA+, and TIMP-3; and overexpression of Ang-1 and Ang-2, MMP-9, MMP-14, and TIMP-4. Statistically significant differences when arteries were implanted with 32P coils included decreased expression of TIMP-4 (P = .011) and increased expression of MMP-9 (P = .02). CONCLUSION: Recanalization and organization of arterial thrombus is associated with expression of genes involved in angiogenesis and neointima formation. Recanalization can be prevented with beta-radiation, but molecular mechanisms remain to be refined. CLINICAL RELEVANCE: A better understanding of molecular mechanisms involved in angiogenesis has permitted its regulation as a new option in treatment of various diseases. Inhibition of angiogenesis may help control diseases such as cancer, arthritis, or diabetes retinopathy. On the other hand, stimulation of angiogenesis may palliate conditions associated with insufficient blood supply, such as ischemic heart disease or critical limb ischemia. Yet little is known regarding recanalization (to be differentiated from thrombolysis), a cellular process that occurs concurrently with thrombus "organization." Recanalization is an important physiologic phenomenon because it can efficiently reestablish antegrade circulation after thrombosis both in veins and in arteries, and could be modulated for therapeutic purposes. Thus our efforts at better understanding of mechanisms involved in recanalization could be used, in addition to its promotion to recover flow after thrombotic occlusions, to prevent its occurrence after endovascular interventions designed to permanently occlude aneurysms.

Lingual artery bifurcation aneurysms for training and evaluation of neurovascular devices.

We present a canine lingual artery bifurcation aneurysm and assess its value for training in endovascular techniques and testing new embolic agents. The experimental aneurysm described herein mirrors human bifurcation aneurysms, and with this model, we sought to reproduce endovascular technical difficulties. However, the lesions created in this canine model did not show angiographic or histologic evidence of aneurysmal recurrence. We conclude that this model may be useful for training in endovascular techniques, but because of the lack of sufficient aneurysmal recurrence, it is not suitable for evaluating new embolic agents.

Role of the endothelial lining in recurrences after coil embolization: prevention of recanalization by endothelial denudation.

BACKGROUND AND PURPOSE: Endovascular treatment can improve the outcome of patients treated for ruptured intracranial aneurysms as compared with surgical clipping, but angiographic recurrences are frequent. Endothelial denudation before coil embolization may prevent recanalization and improve results of endovascular treatment. METHODS: We compared angiographic and pathological results 3 months after coil occlusion of paired canine arteries (n=16), with or without previous denudation of the endothelial lining using an endovascular device. The technique was then used to denude the neck of carotid venous pouch bifurcation aneurysms before coil embolization in 8 dogs, and the angiographic evolution at 12 weeks was compared with 7 control aneurysms treated by coiling only. Qualitative scoring systems were used to compare angiographic results with time and neointimal coverage at the neck of aneurysm after necropsy. The evolution of angiographic scores was analyzed using Wilcoxon signed rank tests whereas angiographic and neointimal scores of the 2 groups were compared using the Mann-Whitney test. RESULTS: All arteries embolized with platinum coils recanalized, whereas most arteries (12/16 or 75%) denuded before coil embolization remained occluded at 3 and 12 weeks (P<0.001). Aneurysms treated with coils without previous denudation tended to recur, with angiographic scores significantly worse at 12 weeks as compared with T(0) (P=0.015). Median angiographic and neointimal scores were significantly better at 12 weeks with endothelial denudation (P=0.011 and 0.026, respectively). CONCLUSIONS: Endothelial denudation can prevent recanalization after coil embolization.

Transcatheter embolization using degradable crosslinked hydrogels.

Therapeutic embolization is the selective transcatheter blockage of blood vessels or diseased vascular structures. The majority of current embolization materials in clinical use are permanent. There are clinical situations however, in which temporary embolization is desired. Degradable hydroxyethyl acrylate (HEA) microspheres have been synthesized. Canine renal arteries and rabbit central auricular arteries were embolized with HEA microspheres, and compared with degradable human serum albumin (HSA) microspheres, and permanent microspheres. HSA and HEA microspheres both achieved temporary occlusions. HSA and HEA microspheres were recanalizated at 1 and 3 weeks, respectively, while arteries occluded with permanent microspheres did not recanalize. All embolic microspheres led to tissue infarction, with the short-term HSA microspheres providing the least damage, and the permanent microspheres leading to extensive damage. Advantages of temporary embolization were not convincingly demonstrated since temporary occlusions still led to tissue infarction.

Temporary vascular occlusion with poloxamer 407.

There is a need for safe and reversible occlusions during percutaneous endovascular procedures. Poloxamer 407 is a non-ionic surfactant with rapid reversible sol-gel transition behaviour. The safety and efficacy of this polymer as a temporary embolic agent was investigated. First, dissolution time after gelation of poloxamer was determined in an in vitro model. Then, transient poloxamer occlusion of renal and pulmonary arteries of seven dogs was followed by serial angiograms. Macroscopic and pathological changes were studied 1 week later. This experiment was repeated in similar arteries in one pig, and in auricular arteries of two rabbits. Poloxamer dissolution after in vitro polymerization was completed within 1-20 h, depending on concentrations. In vivo poloxamer 22% injections led to complete occlusion, followed by full recanalization within 10-90 min without complication. The only biochemical effect of poloxamer occlusions was transient elevation of triglyceride levels. There were no pathological abnormalities at 1 week. Poloxamer 407 could be used as an embolic material for temporary occlusions.

High-concentration ethylene-vinyl alcohol copolymer and endovascular treatment of experimental aneurysms: feasibility of embolization without protection devices at the neck.

BACKGROUND AND PURPOSE: Coiling of intracranial aneurysms is both safe and effective but may be followed by recurrences. The purpose of this study was to assess the feasibility of endovascular treatment of aneurysms with high-concentration ethylene-vinyl alcohol copolymer (HCEVOH), without the use of protection devices at the neck. METHODS: Wide-necked bifurcation aneurysms with a high propensity for recurrences were constructed in 22 dogs. HCEVOH embolization was performed with a dedicated high-pressure microcatheter in 12 animals. Angiographic results at 3 and 12 weeks and pathologic results at 12 weeks were compared with those of a separate group of 10 animals treated with platinum coils. We used a qualitative scoring system to grade angiographic results, neointima formation, and recanalization at the neck. RESULTS: Intraaneurysmal HCEVOH injections could be performed without carotid emboli and without a protection device in 11 of 12 animals. Fragments detached upon traction of the microcatheters at the end of the procedure on two occasions. Immediate and late angiographic results were not significantly different between the two groups (P =.807), with a tendency for angiographic recurrences at 3 months (angiographic scores were significantly worse in both groups at 12 weeks as compared with T0 [P <.02]). A complete occlusion, including the neck, even at the cost of protrusion of material at the level of the branches, is necessary to decrease risks of recurrences. Neointima formation at the surface of the embolic agent was complete at the neck of aneurysms treated with HCEVOH. The neointimal score was significantly improved with HCEVOH as compared with coil embolization (P =.03). CONCLUSION: HCEVOH embolization of aneurysms without neck protection is feasible. It does not, however, eliminate recurrences in an experimental wide-necked aneurysm model.

Alginate for endovascular treatment of aneurysms and local growth factor delivery.

BACKGROUND AND PURPOSE: Coil embolization is safe and effective but may be followed by aneurysm recurrence. Our purpose was to explore the use of alginate as a new embolic agent that could deliver growth factors and improve results of endovascular treatment of aneurysms. METHODS: We first assessed the potential of alginate as a vector for growth factor delivery by using in vitro binding and elution studies. Lateral wall (n = 68) and bifurcation (n = 4) aneurysms were then constructed in six pigs and 36 dogs. We explored iodine-125 transforming growth factor-beta(1) in vivo alginate delivery in 16 canine aneurysms. We next assessed the effects of adding alginate to gelatin sponges on angiographic and pathologic results at 3 weeks (n = 4 each) in an established model used for the study of recanalization and recurrence. We then explored techniques to control endovascular alginate delivery without protection (n = 4), with the protection of a balloon (n = 4), and with the protection of a single coil (n = 12) at the aneurysm neck in 12 porcine aneurysms, four canine lateral wall aneurysms, and four canine bifurcation aneurysms. The stability of cross-linked alginate was studied after intraoperative injections in eight aneurysms. Finally, to determine the value of the material with or without growth factor in promoting aneurysm healing, we compared angiographic results and neointima formation 3 weeks after intraoperative embolization of canine lateral wall aneurysms with alginate blocks with or without platelet-derived growth factor-BB or transforming growth factor-beta(1) (n = 5 each). RESULTS: Growth factors rapidly eluted from alginate in vitro and in vivo. Alginate coating of sponges led to improved angiographic results and thick neointima formation. Intraoperative alginate block embolization did not lead to recurrence, and growth factors delivered with alginate did not show added benefits. Endovascular alginate embolization was complicated by carotid emboli, and the polymer was unstable once injected, causing delayed neurologic deficits. CONCLUSION: Growth factor delivery can be performed with alginate, but formulation changes and improved endovascular control are necessary before contemplating its use in intracranial aneurysms.

Cold hibernated elastic memory foams for endovascular interventions.

Cold hibernated elastic memory (CHEM) polyurethane-based foam is a new shape memory polymeric self-deployable structure. Standard cytotoxicity and mutagenicity tests were conducted on CHEM in vitro, to ensure biocompatibility before studying potential medical applications. In vivo, lateral wall aneurysms were constructed on both carotid arteries of eight dogs. Aneurysms were occluded per-operatively with CHEM blocks. In two dogs, CHEM embolization was compared with gelatin sponge fragment embolization. Internal maxillary arteries (Imax) were also occluded with CHEM using a 6F transcatheter technique. Angiography and pathology were used to study the evolution of aneurysms and Imax at 3 and 12 weeks. Imax embolized with CHEM foam remained occluded at 3 weeks. Most aneurysms embolized with CHEM showed a small residual crescent of opacification at initial angiography, but angiographic scores were significantly better at 3 weeks. Thick neointima formation over the CHEM at the neck of aneurysms was demonstrated at pathology. The foamy nature of CHEM favours the ingrowth of cells involved in neointima formation. New devices for endovascular interventions could be designed using CHEM's unique physical properties.