Annick Metcalfe

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 CHEMs unique physical properties.

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.

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 T0 (P = 0.015). Median angiographic and neointimal scores were significantly better at 12 weeks with endothelial denudation (P = 0.011 and 0.026, respectively). Conclusion— Endothelial denudation can prevent recanalization after coil embolization.

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 &mgr;Ci) showed absent recanalization but delayed organization of the clot at 3 months compared with low-activity or nonradioactive coils (P<0.05). Conclusions— β-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.

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.

Endovascular Treatment with Platinum Coils. Recanalization is Associated with Early Increased von Willebrand Factor mRNA.

Recanalization after coil occlusion is a concern for long-term results of endovascular treatment. Knowledge of molecular events following coil occlusion and recanalization could help design specific strategies to promote permanent occlusion. Platinum coils were implanted into canine maxillary, vertebral or lingual arteries. Coil occlusion (treatment 1), routinely followed by recanalization was compared with two strategies to prevent recanalization: beta radiation using 32P coils (treatment 2) and endothelial denudation, using an endovascular device, followed by coil occlusion (treatment 3). The evolution of initial complete occlusions was followed by angiography and pathology at three months. Levels of messenger RNA of vWF (von Willebrand factor), SMA (smooth muscle actin), CD14, CD31 (or PECAM-1: Platelet Endothelial Cell Adhesion Molecule-1), PDGFBB (platelet-derived growth factor), TGF-b1 (transforming growth factor), MCP-1 (macrophage chemoattractant protein), Angiopoietins, Metalloproteinases-9, 14 and inhibitors (TIMP-2, 4) were followed by Reverse Transcription and Polymerase Chain Reaction (RT-PCR). Analyses were performed one, four, seven and 14 days after coiling, and levels of expression after the three treatments were compared using ANOVA s. Intact arteries treated with platinum coils routinely recanalize (100%), but arteries treated by denudation and coiling or with radioactive coils recanalize in only 17% and 4% respectively (P<.001). Recanalization was associated with increased levels of vWF mRNA at seven days, a finding that was not observed with denudation or radiation (P=.015). There was no other significant difference. Recanalization is associated with early vWF expression, perhaps reflecting the development of endothelialized channels through thrombus formed after coil occlusion.

In vivo thrombogenicity of embolic protection systems for angioplasty and stenting.

Despite the increasing use of embolic protection systems (EPS) for carotid stenting, their intrinsic in vivo thrombogenicity remains unknown. We studied three different types of EPS (n = 24) deployed in the carotid arteries of pigs in which pools of platelets and fibrinogen were labelled with 111In and 125I. The amount of clot deposition seen on photography was also scored using a qualitative scale. EPS made of fabric nets under normal flow conditions were 5–6 and 15–16 times more thrombogenic (for both platelet (P=.04) and fibrin (P=.007)) than Nitinol mesh nets. Clot deposition on Nitinol mesh nets was more abundant under flow arrest than under normal flow conditions (P=.018). EPS differ in intrinsic thrombogenicity, a characteristic of the material that could be investigated in pre-clinical studies designed to optimize devices.

Radioactive coil embolisation of intracranial aneurysms. Experimental and preliminary clinical data.

Coil embolisation of intracranial aneurysms can improve the outcome of patients treated after subarachnoid haemorrage as compared to surgical clipping 1. Unfortunately, angiographic recurrences are not infrequent and although their clinical significance remains to be determined, they may be responsible for future ruptures2. In situ beta radiation, using coils ion-implanted with 32P, may prevent recanalization and thus improve long-term results of endovascular treatment. The present article will review the experimental data as well as present the clinical feasibility of radioactive coil embolisation of intracranial aneurysms.