壳聚糖/β-甘油磷酸钠作为液态栓塞材料的可行性分析
摘要
实验目的
体内体外评估温度敏感性壳聚糖/β-甘油磷酸钠水凝胶作为液态栓塞材料的可行性。
实验方法
壳聚糖和β-甘油磷酸钠以7：1比例混合,制作5个样本,观察其在37摄氏度水浴中完全凝胶化所需时间。
配置壳聚糖/β-甘油磷酸钠水凝胶,并加入钽粉,栓塞9只兔子一侧肾动脉。9只兔子依据复查时间分为3组,每组三只兔子。分别为术后1周、4周、8周复查造影。并处死试验动物,取双侧肾脏及肾动脉进行大体观察及病理学分析。
用9只兔子,采用酶消化法,制作动脉瘤模型。模型制作成功后3周,采用双侧股动脉入路,球囊封堵后微导管注射壳聚糖/β-甘油磷酸钠水凝胶栓塞动脉瘤。术后一个月9只兔子复查造影,随后处死兔子,取病理大体观察并做HE染色。
试验结果
1、5个样本在37摄氏度水浴中完全凝胶化需要时间分别为120.11秒、119.93秒、119.85秒、120.08秒、120.04秒,平均值为120秒。我们可以看到壳聚糖/β-甘油磷酸钠在37摄氏度以下为液态,高于此温度时逐渐变为固态。
2、利用1-1.5毫升壳聚糖/β-甘油磷酸钠溶液顺利栓塞一侧肾动脉。材料显影良好,材料推注时间控制在1.8-2分钟。术中无异位栓塞、粘管、导管堵塞等并发症。整个栓塞过程以及术后冲洗导管都顺利进行,没有发现材料导致导管的堵塞现象。术前造影清晰显示肾动脉及其分支,术后立即造影显示肾动脉及其分支完全被栓塞材料封堵。在钽粉的支持下,材料在放射线下清晰可见,并且整个栓塞过程清晰可视。在长达八周的观察期中通过造影复查没有发现肾动脉再通。材料注射到肾动脉后引起血栓以及肉芽组织的增生,从而导致肾动脉的完全阻塞以及肾脏的梗死。术后一周肾动脉病理检查未见严重的内皮细胞损伤以及炎症反应。同时在所有复查点,肾组织病理检查未见严重的炎症反应。术后八周我们可以看到栓塞侧肾脏较对侧明显苍白萎缩,正常肾组织完全被纤维组织所代替。
3、利用酶消化法顺利在9只兔子制作动脉瘤模型,均为囊状,并利用工作站测量其大小。动脉瘤平均宽颈为3.39毫米,平均长径为9.55毫米,平均颈宽为2.63毫米。在球囊封堵辅助下顺利通过微导管栓塞所有动脉瘤,整个栓塞过程顺利,栓塞过程耗时维持在1.8-2分钟。术中无异位栓塞、粘管、导管堵塞等并发症。整个栓塞过程以及术后冲洗导管都顺利进行,没有发现材料导致导管的堵塞现象。术前造影清晰显示动脉瘤,术后立即造影显示动脉瘤被C/GP完全栓塞。在钽粉的支持下,材料在放射线下清晰可见,并且整个栓塞过程清晰可视。一月的观察期中通过造影复查没有发现动脉瘤的再通及复发。材料注射到动脉瘤后引起血栓以及肉芽组织的增生,从而完全封堵动脉瘤的血液供应。病理检查发现动脉瘤壁弹力膜消失,并明显比载瘤动脉壁薄。在动脉瘤附近区域没有发现炎症反应以及异物反应。所有动脉瘤被完全栓塞,没有任何再通的迹象。我们发现动脉瘤颈部被一薄层内膜所覆盖,正是这层内膜导致了动脉瘤的愈合。
结论
壳聚糖/β-甘油磷酸钠水凝胶具有作为新型液态栓塞材料的潜力。
Background
The history of intracranial aneurysm is very long. IN the fourteenth century BC the Egyptians treated intracranial aneurysms by magico-religious therapies, but the nature and site of occurrence of these lesions are not mentioned. Intracranial aneurysm is a very common disease in adult, Autopsy studies have shown that the overall frequency in the general population ranges from 0.2 to 9.9 percent (mean frequency, approximately 5 percent). But most of them are very little and 50-80% of them did not rupture for the life. Kids seldom suffer from this disease, most of the patients are ranging from 40 to 60, and the ratio between men and women is 2:3. In the age distribution of the patients, a low incidence was found in the 30's, a sharp increase took place in the 40's; the peak was reached in the 50's, but stayed high in the 60's. Most intracranial aneurysms locate at the circle of Willis, the internal carotid artery was most frequently involved, followed by the anterior communicating, middle cerebral arteries and vertebrobasilar. Just followed Cerebral thrombosis and Hypertensive intracerebral hemorrhage, intracranial aneurysm is the third factor inducing stroke and 34% of the subarachnoid hemorrhage and 5-15% of the stroke were caused by intracranial aneurysms. Little and unruptured intracranial aneurysms are difficult to find. The symptoms include there aspects they are hemorrhage, Ischemia and compression. CTA (computed tomography ang iography) and MRA (magnetic resonance angiography) were used more and more as to diagnosis this disease, but DSA (Digital subtraction angiography) is still the golden standard. There are there choices to treat intracranial aneurysms medical treatment, clipping and embolizing. In 2002 ISAT (International Subarachnoid Aneurysm Trial) reported that 190 of 801 (23.7%) patients allocated endovascular treatment were dependent or dead at 1 year compared with 243 of 793 (30.6%) allocated neurosurgical treatment (p=0.0019). The relative and absolute risk reductions in dependency or death after allocation to an endovascular versus neurosurgical treatment were 22.6%(95% CI 8.9-34.2) and 6.9%
(2.5-11.3), respectively. They believed that in patients with a ruptured intracranial aneurysm, for which endovascular coiling and neurosurgical clipping are therapeutic options, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling. In 2010 ISAT reported 2143 patients with ruptured intracranial aneurysms were enrolled between 1994 and 2002 at 43 neurosurgical centres and randomly assigned to clipping or coiling,24 rebleeds had occurred more than 1 year after treatment. Of these,13 were from the treated aneurysm (ten in the coiling group and three in the clipping group; log rank p=0·06 by intention-to-treat analysis). There were 8447 person-years of follow-up in the coiling group and 8177 person-years of follow-up in the clipping group. Four rebleeds occurred from a pre-existing aneurysm and six from new aneurysms. At 5 years,11% (112 of 1046) of the patients in the endovascular group and 14%(144 of 1041) of the patients in the neurosurgical group had died (log-rank p=0·03). The risk of death at 5 years was significantly lower in the coiling group than in the clipping group (relative risk 0.77,95% CI 0.61-0.98; p=0·03), but the proportion of survivors at 5 years who were independent did not differ between the two groups:endovascular 83%(626 of 755) and neurosurgical 82%(584 of 713). They believed there was an increased risk of recurrent bleeding from a coiled aneurysm compared with a clipped aneurysm, but the risks were small. The risk of death at 5 years was significantly lower in the coiled group than it was in the clipped group. The standardised mortality rate for patients treated for ruptured aneurysms was increased compared with the general population.
Now embolization was accepted by doctors and patients more and more but at the same time, wide-necked aneurysms are still very difficult to satisfactory treatment. To overcome this difficulties, different kinds of new technology and new embolic agent emerged such as remodeling technique, embolization with the aid of stent, coated coils and liquid embolic agent. They have optimize the outcome of embolization, but it is also not perfect. By now, GDCs (Guglielmi detachable coils) are the best choice on clinical, but even the aneurysm was completely embolized by GDCs, they can only occupy about 20%-30% of the space in aneurysm which could be main factor of recurrence. Because of the good scalability of liquid embolic agent, they can occupy most of the space in aneurysm, so it was believed that liquid embolic agent could be the best choice. NBCA (N-butyl-2 cyanoacrylate) and EVOH (Ethylene vinyl alcohol copolymer) are the leader of liquid embolic agent; They were approved by the FDA for the intravascular treatment of cerebral arteriovenous malformation in 2000 and 2005 respectively. NBCA works instantly, completely occludes vessels, and is permanent. But gluing of the catheter within the vascular pedicle during slow injection period will cause fatal mistake. EVOH is nonadhesive but the solvent dimethyl sulfoxide have the potential risk of excessive inflammatory reaction or vessel damage. Recently, alginate and some thermosensitive polymer have attracted us, in the liquid form they are nontoxic water-based liquid that can flow in the blood, causing no adverse effects, but in the gel form they can quickly occupy the aneurysm. They do not need organic solvents and the viscosity is suitable can not cause "adhesion" effect. Chitosan/β-Glycerophosphate have all the qualities above and they are liquid below 37℃, gelling above 37℃. Based on the thermosensitive quality, we make the feasibility assessment of C/GP as a new liquid embolic agent.
Purpose
We sought to assess the feasibility of thermosensitive Chitosan/β-Glycerophosphate for embolotherapy in vitro and in vivo.
Methods
Firstly, we get 5 samples of C/GP by mixing Chitosan/β-Glycerophosphate at the ratio of 7:1. We record how many minutes they cost between the form transition in the water bath of 37℃.
Secondly, we get 4ml of embolic agent by mixing Chitosan/B-Glycerophosphate/tantalum powder at the ratio of 7:1:3. The renal arteries in nine rabbits were embolized with C/GP. Animals were studied angiographically and sacrificed at 1 week (n=3),4 weeks (n=3). and 8 weeks (n=3) after embolotherapy. Histology was obtained at the same time.
Thirdly, we construct nine aneurysms using an elastase-reduced model in rabbits. Three weeks after the procedure, the aneurysms were embolized using C/GP in combination with an inflated balloon. One month after the embolotherapy, animals were studied angiographically and histological.
Results
Firstly, the five samples cost 120.11s,119.93s,119.85s,120.08s,120.04s separately to fulfill the transition and the average is 120s.
Secondly, The renal artery was successfully embolized with 1-1.5ml of C/GP solution which was injected between 1.8 and 2 minutes, no catheter adhesion was observed in all cases. It was easily handled between the procedures of injection and syringing catheter after injection, no occlusion of the catheter with this material was founded. The angiogram before embolization obviously showed the renal artery and its peripheral branches, the angiogram immediately obtained after embolization showed whole occlusion of the target renal artery in all cases. With the support of tantalum powder, this material was clearly shown in the angiographic images, the renal artery and most of its peripheral branches were embolized with the same gel. During 8 weeks period, there is no recanalization observed and found in the follow-up angiograms.The injection of C/GP into the renal artery aroused the blood clot. The gel combined with thrombus caused the completely occlusion of the renal artery. The endothelium damage and the inflammatory reaction was mild in the renal artery. Then the occlusion led to the infarction of the kidney at the same time we didn't notice any inflammatory reaction in the infarction kidney. Finally, from the observation, it showed that the color of the embolization kidney was pale and the size of it was shrank considerably compared with the control kidney. The normal glomerular were completely replaced by fibrous tissue.
Thirdly, nine elastase-reduced aneurysms in rabbits were successfully constructed. All animals tolerated the induction well. Aneurysm size was measured using a workstation, and the mean height was 3.39 mm, the mean width was 9.55mm, and the mean diameter of the neck of the aneurysm was 2.63 mm.The aneurysms were successfully embolized with C/GP solution which was injected by microcatheter in combination with an inflated balloon between 1.8 and 2 minutes, no catheter adhesion was observed in all cases. It was easily handled between the procedures of injection and syringing catheter after injection, no occlusion of the catheter with this material was founded. The angiogram before embolization obviously showed the aneurysms, the angiogram immediately obtained after embolization showed whole occlusion of the aneurysms in all cases. With the support of tantalum powder, this material was clearly shown in the angiographic images and the process of embolization is clearly visible. During four weeks period, there is no recanalization observed and found in the follow-up angiograms.The injection of C/GP into the renal artery aroused the blood clot then caused granulation tissue formed in the surrounding area, leading to complete occlusion of the aneurysm. Histological evaluation showed that the walls of the aneurysms were thinner than those of the aneurysm-bearing vessels. The elastic lamina had been dissolved as intended. No inflammation or foreign body reaction was observed in the adjacent tissue of the aneurysm. All aneurysms were completely occluded, and there were no signs of recanalization. We found a thin layer of endothelium over the entire neck of all aneurysms which lead to the healing of the aneurysms.
Conclusions
Thermosensitive C/GP have the potential to be a good liquid embolic agent.
体内体外评估温度敏感性壳聚糖/β-甘油磷酸钠水凝胶作为液态栓塞材料的可行性。
实验方法
壳聚糖和β-甘油磷酸钠以7：1比例混合,制作5个样本,观察其在37摄氏度水浴中完全凝胶化所需时间。
配置壳聚糖/β-甘油磷酸钠水凝胶,并加入钽粉,栓塞9只兔子一侧肾动脉。9只兔子依据复查时间分为3组,每组三只兔子。分别为术后1周、4周、8周复查造影。并处死试验动物,取双侧肾脏及肾动脉进行大体观察及病理学分析。
用9只兔子,采用酶消化法,制作动脉瘤模型。模型制作成功后3周,采用双侧股动脉入路,球囊封堵后微导管注射壳聚糖/β-甘油磷酸钠水凝胶栓塞动脉瘤。术后一个月9只兔子复查造影,随后处死兔子,取病理大体观察并做HE染色。
试验结果
1、5个样本在37摄氏度水浴中完全凝胶化需要时间分别为120.11秒、119.93秒、119.85秒、120.08秒、120.04秒,平均值为120秒。我们可以看到壳聚糖/β-甘油磷酸钠在37摄氏度以下为液态,高于此温度时逐渐变为固态。
2、利用1-1.5毫升壳聚糖/β-甘油磷酸钠溶液顺利栓塞一侧肾动脉。材料显影良好,材料推注时间控制在1.8-2分钟。术中无异位栓塞、粘管、导管堵塞等并发症。整个栓塞过程以及术后冲洗导管都顺利进行,没有发现材料导致导管的堵塞现象。术前造影清晰显示肾动脉及其分支,术后立即造影显示肾动脉及其分支完全被栓塞材料封堵。在钽粉的支持下,材料在放射线下清晰可见,并且整个栓塞过程清晰可视。在长达八周的观察期中通过造影复查没有发现肾动脉再通。材料注射到肾动脉后引起血栓以及肉芽组织的增生,从而导致肾动脉的完全阻塞以及肾脏的梗死。术后一周肾动脉病理检查未见严重的内皮细胞损伤以及炎症反应。同时在所有复查点,肾组织病理检查未见严重的炎症反应。术后八周我们可以看到栓塞侧肾脏较对侧明显苍白萎缩,正常肾组织完全被纤维组织所代替。
3、利用酶消化法顺利在9只兔子制作动脉瘤模型,均为囊状,并利用工作站测量其大小。动脉瘤平均宽颈为3.39毫米,平均长径为9.55毫米,平均颈宽为2.63毫米。在球囊封堵辅助下顺利通过微导管栓塞所有动脉瘤,整个栓塞过程顺利,栓塞过程耗时维持在1.8-2分钟。术中无异位栓塞、粘管、导管堵塞等并发症。整个栓塞过程以及术后冲洗导管都顺利进行,没有发现材料导致导管的堵塞现象。术前造影清晰显示动脉瘤,术后立即造影显示动脉瘤被C/GP完全栓塞。在钽粉的支持下,材料在放射线下清晰可见,并且整个栓塞过程清晰可视。一月的观察期中通过造影复查没有发现动脉瘤的再通及复发。材料注射到动脉瘤后引起血栓以及肉芽组织的增生,从而完全封堵动脉瘤的血液供应。病理检查发现动脉瘤壁弹力膜消失,并明显比载瘤动脉壁薄。在动脉瘤附近区域没有发现炎症反应以及异物反应。所有动脉瘤被完全栓塞,没有任何再通的迹象。我们发现动脉瘤颈部被一薄层内膜所覆盖,正是这层内膜导致了动脉瘤的愈合。
结论
壳聚糖/β-甘油磷酸钠水凝胶具有作为新型液态栓塞材料的潜力。
Background
The history of intracranial aneurysm is very long. IN the fourteenth century BC the Egyptians treated intracranial aneurysms by magico-religious therapies, but the nature and site of occurrence of these lesions are not mentioned. Intracranial aneurysm is a very common disease in adult, Autopsy studies have shown that the overall frequency in the general population ranges from 0.2 to 9.9 percent (mean frequency, approximately 5 percent). But most of them are very little and 50-80% of them did not rupture for the life. Kids seldom suffer from this disease, most of the patients are ranging from 40 to 60, and the ratio between men and women is 2:3. In the age distribution of the patients, a low incidence was found in the 30's, a sharp increase took place in the 40's; the peak was reached in the 50's, but stayed high in the 60's. Most intracranial aneurysms locate at the circle of Willis, the internal carotid artery was most frequently involved, followed by the anterior communicating, middle cerebral arteries and vertebrobasilar. Just followed Cerebral thrombosis and Hypertensive intracerebral hemorrhage, intracranial aneurysm is the third factor inducing stroke and 34% of the subarachnoid hemorrhage and 5-15% of the stroke were caused by intracranial aneurysms. Little and unruptured intracranial aneurysms are difficult to find. The symptoms include there aspects they are hemorrhage, Ischemia and compression. CTA (computed tomography ang iography) and MRA (magnetic resonance angiography) were used more and more as to diagnosis this disease, but DSA (Digital subtraction angiography) is still the golden standard. There are there choices to treat intracranial aneurysms medical treatment, clipping and embolizing. In 2002 ISAT (International Subarachnoid Aneurysm Trial) reported that 190 of 801 (23.7%) patients allocated endovascular treatment were dependent or dead at 1 year compared with 243 of 793 (30.6%) allocated neurosurgical treatment (p=0.0019). The relative and absolute risk reductions in dependency or death after allocation to an endovascular versus neurosurgical treatment were 22.6%(95% CI 8.9-34.2) and 6.9%
(2.5-11.3), respectively. They believed that in patients with a ruptured intracranial aneurysm, for which endovascular coiling and neurosurgical clipping are therapeutic options, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling. In 2010 ISAT reported 2143 patients with ruptured intracranial aneurysms were enrolled between 1994 and 2002 at 43 neurosurgical centres and randomly assigned to clipping or coiling,24 rebleeds had occurred more than 1 year after treatment. Of these,13 were from the treated aneurysm (ten in the coiling group and three in the clipping group; log rank p=0·06 by intention-to-treat analysis). There were 8447 person-years of follow-up in the coiling group and 8177 person-years of follow-up in the clipping group. Four rebleeds occurred from a pre-existing aneurysm and six from new aneurysms. At 5 years,11% (112 of 1046) of the patients in the endovascular group and 14%(144 of 1041) of the patients in the neurosurgical group had died (log-rank p=0·03). The risk of death at 5 years was significantly lower in the coiling group than in the clipping group (relative risk 0.77,95% CI 0.61-0.98; p=0·03), but the proportion of survivors at 5 years who were independent did not differ between the two groups:endovascular 83%(626 of 755) and neurosurgical 82%(584 of 713). They believed there was an increased risk of recurrent bleeding from a coiled aneurysm compared with a clipped aneurysm, but the risks were small. The risk of death at 5 years was significantly lower in the coiled group than it was in the clipped group. The standardised mortality rate for patients treated for ruptured aneurysms was increased compared with the general population.
Now embolization was accepted by doctors and patients more and more but at the same time, wide-necked aneurysms are still very difficult to satisfactory treatment. To overcome this difficulties, different kinds of new technology and new embolic agent emerged such as remodeling technique, embolization with the aid of stent, coated coils and liquid embolic agent. They have optimize the outcome of embolization, but it is also not perfect. By now, GDCs (Guglielmi detachable coils) are the best choice on clinical, but even the aneurysm was completely embolized by GDCs, they can only occupy about 20%-30% of the space in aneurysm which could be main factor of recurrence. Because of the good scalability of liquid embolic agent, they can occupy most of the space in aneurysm, so it was believed that liquid embolic agent could be the best choice. NBCA (N-butyl-2 cyanoacrylate) and EVOH (Ethylene vinyl alcohol copolymer) are the leader of liquid embolic agent; They were approved by the FDA for the intravascular treatment of cerebral arteriovenous malformation in 2000 and 2005 respectively. NBCA works instantly, completely occludes vessels, and is permanent. But gluing of the catheter within the vascular pedicle during slow injection period will cause fatal mistake. EVOH is nonadhesive but the solvent dimethyl sulfoxide have the potential risk of excessive inflammatory reaction or vessel damage. Recently, alginate and some thermosensitive polymer have attracted us, in the liquid form they are nontoxic water-based liquid that can flow in the blood, causing no adverse effects, but in the gel form they can quickly occupy the aneurysm. They do not need organic solvents and the viscosity is suitable can not cause "adhesion" effect. Chitosan/β-Glycerophosphate have all the qualities above and they are liquid below 37℃, gelling above 37℃. Based on the thermosensitive quality, we make the feasibility assessment of C/GP as a new liquid embolic agent.
Purpose
We sought to assess the feasibility of thermosensitive Chitosan/β-Glycerophosphate for embolotherapy in vitro and in vivo.
Methods
Firstly, we get 5 samples of C/GP by mixing Chitosan/β-Glycerophosphate at the ratio of 7:1. We record how many minutes they cost between the form transition in the water bath of 37℃.
Secondly, we get 4ml of embolic agent by mixing Chitosan/B-Glycerophosphate/tantalum powder at the ratio of 7:1:3. The renal arteries in nine rabbits were embolized with C/GP. Animals were studied angiographically and sacrificed at 1 week (n=3),4 weeks (n=3). and 8 weeks (n=3) after embolotherapy. Histology was obtained at the same time.
Thirdly, we construct nine aneurysms using an elastase-reduced model in rabbits. Three weeks after the procedure, the aneurysms were embolized using C/GP in combination with an inflated balloon. One month after the embolotherapy, animals were studied angiographically and histological.
Results
Firstly, the five samples cost 120.11s,119.93s,119.85s,120.08s,120.04s separately to fulfill the transition and the average is 120s.
Secondly, The renal artery was successfully embolized with 1-1.5ml of C/GP solution which was injected between 1.8 and 2 minutes, no catheter adhesion was observed in all cases. It was easily handled between the procedures of injection and syringing catheter after injection, no occlusion of the catheter with this material was founded. The angiogram before embolization obviously showed the renal artery and its peripheral branches, the angiogram immediately obtained after embolization showed whole occlusion of the target renal artery in all cases. With the support of tantalum powder, this material was clearly shown in the angiographic images, the renal artery and most of its peripheral branches were embolized with the same gel. During 8 weeks period, there is no recanalization observed and found in the follow-up angiograms.The injection of C/GP into the renal artery aroused the blood clot. The gel combined with thrombus caused the completely occlusion of the renal artery. The endothelium damage and the inflammatory reaction was mild in the renal artery. Then the occlusion led to the infarction of the kidney at the same time we didn't notice any inflammatory reaction in the infarction kidney. Finally, from the observation, it showed that the color of the embolization kidney was pale and the size of it was shrank considerably compared with the control kidney. The normal glomerular were completely replaced by fibrous tissue.
Thirdly, nine elastase-reduced aneurysms in rabbits were successfully constructed. All animals tolerated the induction well. Aneurysm size was measured using a workstation, and the mean height was 3.39 mm, the mean width was 9.55mm, and the mean diameter of the neck of the aneurysm was 2.63 mm.The aneurysms were successfully embolized with C/GP solution which was injected by microcatheter in combination with an inflated balloon between 1.8 and 2 minutes, no catheter adhesion was observed in all cases. It was easily handled between the procedures of injection and syringing catheter after injection, no occlusion of the catheter with this material was founded. The angiogram before embolization obviously showed the aneurysms, the angiogram immediately obtained after embolization showed whole occlusion of the aneurysms in all cases. With the support of tantalum powder, this material was clearly shown in the angiographic images and the process of embolization is clearly visible. During four weeks period, there is no recanalization observed and found in the follow-up angiograms.The injection of C/GP into the renal artery aroused the blood clot then caused granulation tissue formed in the surrounding area, leading to complete occlusion of the aneurysm. Histological evaluation showed that the walls of the aneurysms were thinner than those of the aneurysm-bearing vessels. The elastic lamina had been dissolved as intended. No inflammation or foreign body reaction was observed in the adjacent tissue of the aneurysm. All aneurysms were completely occluded, and there were no signs of recanalization. We found a thin layer of endothelium over the entire neck of all aneurysms which lead to the healing of the aneurysms.
Conclusions
Thermosensitive C/GP have the potential to be a good liquid embolic agent.
引文
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