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. 2025 Oct 17;15:36365. doi: 10.1038/s41598-025-20287-0

Earlier and greater vascular endothelial cell proliferation on hydrocoils compared to bare platinum coils: an in vitro study

Xiaojie Ding 1, Minglei Wang 1,✉, Chao Zhang 2,✉
PMCID: PMC12534521  PMID: 41107335

Abstract

The HydroCoil Embolic System (HES) has shown promise in improving aneurysm treatment by enhancing aneurysm filling and reducing recurrence. This study investigated the differences in endothelial cell adhesion between HydroCoils and bare platinum coils using bEnd.3 mouse cerebrovascular endothelial cells. Cells were detached from the coils and quantified at various time points (D0, D1, D3, D7, D14, and D21). Growth curves of cells on bare platinum coils and HydroCoils are described and statistically analyzed. Fluorescent staining for cell death and PECAM-1 were also performed. Growth curves revealed a Day 3 proliferation peak on HydroCoils, stabilizing by Day 7, while bare platinum coils peaked later on Day 14 with lower cell numbers. Live/Dead cell staining revealed adhesion to bare platinum coils but not HydroCoils. PECAM-1 expression of vascular endothelial cells on HydroCoil was markedly weaker than those on bare platinum coil. These results indicate that HydroCoils support faster endothelial proliferation and higher cell numbers compared to bare platinum coils, but also followed by an earlier apoptotic phase.

Keywords: Intracranial aneurysm, Hydrocoil embolic system, Endothelial cell adhesion, Vascular proliferation

Subject terms: Cerebrovascular disorders, Neurovascular disorders

Introduction

Subarachnoid hemorrhage is a form of hemorrhagic stroke with severe morbidity and mortality that results from rupture of an intracranial aneurysm1. There currently exist two primary modalities of treatment for intracranial aneurysms: microsurgical and endovascular. As endovascular technology and techniques have expanded, the standard of care for aneurysm treatment has leaned in favor of endovascular therapies2. Within the endovascular realm, placement of detachable coils with or without stent placement has been the most common form of treatment. However, endovascular treatment has not been as durable as microsurgical clipping due to a higher risk of subarachnoid hemorrhage from a previously coiled aneurysm as well as aneurysm recurrence requiring repeat treatment3. This has led to significant interest regarding the process of aneurysm remodeling following coiling, particularly of the inflammatory reaction generated and the rate of thrombosis4,5.

Volumetric studies have shown that following coiling, 15–40% of the aneurysm is packed with coils while the remainder of the aneurysm volume is filled with thrombus6. Numerous studies have shown that low packing density leads to a higher risk of aneurysmal recurrence7,8. Histopathology from patients treated with coils shows that the aneurysm contains thrombus during the first month following treatment, but then, this develops into an acellular fibrous matrix9. At the 3-month timepoint, endothelial proliferation begins to take place and at one year after coil placement, the coils are embedded in fibrous tissue with evidence of endothelialization at the aneurysm neck10,11. Aneurysm recurrence is thought to ensue due to the final step of aneurysm neck endothelialization not occurring and therefore, eventual coil compaction and thrombus dissolution from the pulsatile nature of blood flow. Therefore, this raises the question of whether there are certain coil characteristics that will lead to a more robust cellular reaction and therefore, higher likelihood of aneurysm obliteration.

The HydroCoil Embolic System (HES) was designed to improve volumetric filling of the aneurysm by coating platinum coils with an expansile hydrogel that fills more of the aneurysm lumen than standard bare platinum coils (BPCs). This additional coating is thought to potentially provide a better scaffold for neointima formation and healing. The HydroCoil Endovascular Aneurysm Occlusion and Packing Study (HELPS) trial showed that there was a statistically significant decrease in risk of aneurysm recurrence with the HydroCoil technology over platinum coils for various types of aneurysms12,13. Our previous study with the rat external carotid artery (ECA) sidewall aneurysm model has shown that hydrogel-coated coils cause more tissue reaction compared to bare platinum coils14. To further investigate the underlying cellular mechanisms that lead to such a reaction, we carried out an in vitro study investigating the growth of a mouse cerebral microvascular endothelial cell line on HydroCoil vs. platinum coils.

Materials and methods

Cell culture

The bEnd.3 cell line (a mouse cerebral microvascular endothelial cell line), provided by ATCC (No. CRL-2299), was cultured on tissue culture flasks under sterile conditions at 37 °C in Dulbecco’s Modified Eagle’s Medium (DMEM) (Thermo Fisher Scientific, 11965) supplemented with 10% fetal bovine serum (FBS) (GIBCO, 10082147) in a humidified incubator under 5% CO2 and 95% air. The medium was replaced every two days. After 2 weeks of proliferation, cells were trypsinized and washed in phosphate-buffered saline and diluted to 1,000,000 cells/ml for plating.

Cell seeding on coils

Two types of coils, the bare platinum coil and the HydroCoil (MicroVention Manufacturers), were used. Each coil was cut into 5 mm long segments and weighed using an analytical balance. For each time point, a total of 4–5 segments of each coil type were used, of which 1–2 segments were used for imaging and 3 coil segments for cell counting. All coil segments were placed in a 48-well plate and sterilized under ultraviolet light for 12 h prior to cell seeding. Following trypsinization and dilution to 1 × 106 cells/ml, 500 µl of the cell suspension was seeded onto each coil segment and incubated at 37 °C for 6 hours. Coils segments were then removed, washed with 1×PBS, and placed in a new 48-well plate with 500 µl of medium (DMEM with 10% FBS). Coil segments were then removed for imaging, cell counting, as well as live-dead analysis at various time points.

Cell counting

For cell counting, bEnd.3 cells on the coil segments were detached using 200 µl of 0.25% trypsin. Before and after trypsinization, the coil segments were examined under the microscope to verify successful cell detachment. 10 µl of the detached cell suspension and 10 µl of Trypan blue were mixed and placed on the Invitrogen™ Countess automated cell counter. Cell counting was performed twice for each coil segment and average values are reported. These time points for each analysis were Day 0 (D0), 1 (D1), 3 (D3), 7 (D7), 14 (D14) and 21 (D21).

Imaging of cells on coil

Invitrogen™ Live/Dead (L/D) Cytotoxicity kit was used for staining of living vs. dead cells. This kit consists of two reagents: A (a membrane-permanent calcein AM cleaved by esterases in live cells to yield cytoplasmic green fluorescence) and reagent B (membrane-impermeant ethidium homodimer-1 that labels nucleic acids of membrane-compromised cells with red fluorescence). A solution of 10 ml of 1×PBS, 5 ml of reagent A, and 20 ml of reagent B was used to prepare the cells. At each time point, 100 µl of the pre-mixed L/D reagent was added to wells containing 100 µl of medium and the coil segment. The coils were then incubated for 1 h at 37 °C. A control coil was created performing a similar procedure but without any cell seeding. Imaging was performed under fluorescence microscopy with green fluorescence (live cells) and red fluorescence (dead cells).

Immunofluorescent staining

On Day 7, the platelet endothelial cell adhesion molecule-1 (PECAM-1) immunofluorescent staining was carried out in standard fashion. Briefly, a coil segment was placed in 4% paraformaldehyde for 30 min for cell fixation. After 1% PBST (Triton in phosphate buffer solution) wash x 3, the segment was placed in 5% BSA (bovine serum albumin in PBST) solution for 1 h at room temperature. The segment was then incubated with primary antibody (goat anti-mouse, 1:200) over night at 4 °C, washed 3x with 1% PBST, and then incubated with fluorescein-conjugated secondary antibody for 1 h at 37 °C in the dark. The coil segment was then washed with 1% PBST, stained with 0.5 µg/ml DAPI for 10 min and imaged using fluorescence microscopy.

Statistical analysis

Cell counting data was analyzed using GraphPad Prism 9.0. The results are presented as mean ± standard deviation (SD). Comparison of mean values was conducted using two-tailed Mann-Whitney U-test and significance levels were measured at p < 0.05.

Results

Following cell seeding on coils and incubation, coils were examined under the microscope before and after trypsinization to determine whether the cellular detachment process was effective. The images in Fig. 1 indicate that the majority of cells were removed from the coil after trypsinization, leading to reliable cell counting. When depicted along a growth curve, bEnd.3 cells reached a peak cell quantity on Day 14 with bare coils compared to Day 3 with HydroCoils (Fig. 2A, B).

Fig. 1.

Fig. 1

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Cellular detachment following trypsinization. This figure shows bEnd.3 cell attachment to the bare coil and HydroCoil before trypsinization that was not present following trypsin administration.

Fig. 2.

Fig. 2

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bEnd3 cell growth on bare coil and hydrocoil. (A) The growth curve of the bEnd3 cells on bare coil from Day 0 to Day 21. (B) The growth curve of the bEnd3 cells on Hydrocoil from Day 0 to Day 21. (C) Quantification of bEnd3 cell numbers per milligram of bare coil and HydroCoil at all time points (mean cell number with standard error of the mean, n = 3 per group per time point).

The growth curves of bEnd.3 cells cultured on bare platinum coils and HydroCoils over a 21-day period revealed distinct patterns of proliferation and adhesion. Cells on HydroCoils exhibited a rapid increase in quantity, peaking on Day 3 (mean 1079.07 ± 427.50) before noticeable declining and stabilizing by Day 7 (mean 714.53 ± 206.49). In contrast, cells on bare platinum coils showed a slower rate of proliferation, reaching their peak on Day 14 (mean 871.80 ± 117.51) and maintaining a relatively stable quantity through Day 21 (mean 736.10 ± 221.51). During the early phase (Day 1), the number of cells on HydroCoils was greater than that on bare platinum coils (p = 0.1), suggesting superior early adhesion and proliferation. However, the rapid decline in cell numbers after Day 3 on HydroCoils indicated a transition to apoptosis or detachment, in contrast to the sustained cell growth observed on bare coils. These differences highlight the distinct temporal dynamics of cellular responses to the two coil materials.

On Day 1, the mean cell number on HydroCoils was 859.03 ± 202.68, while on bare coil it was 233.63 ± 60.85 (p = 0.1). Similarly, on Day 3, HydroCoils exhibited a tendency of higher cell count (mean 1079.07 ± 427.50 vs. 688.63 ± 124.67 on bare coils, p = 0.4, Fig. 2C). These results reinforce the notion of enhanced early cell proliferation on HydroCoils. However, by Day 7 and beyond, the differences in cell quantity diminished, with HydroCoils showing stabilization and bare coils reaching their peak proliferation by Day 14 (mean 871.80 ± 117.51 for bare coils vs. 655.03 ± 121.70 for HydroCoils at Day 14). By Day 21, both groups displayed comparable cell quantities (mean 796.93 ± 69.25 for HydroCoils and 736.10 ± 221.51 for bare coils, p = 0.7), suggesting distinct temporal patterns in cellular adhesion and growth dynamics between the two coil types.

Live/Dead cell staining corroborated results in Figs. 2 and showed that live cells on the bare coil were most numerous on Day 14 with rare adherent dead cells (Fig. 3). On the HydroCoil, live cells were most numerous on Day 3 but interestingly, there was almost no evidence of adherent dead cells (Fig. 4). Based on immunofluorescence staining carried out on Day 7, when the cell quantities were similar between the bare coils and Hydrocoils, PECAM-1 expression of bEnd.3 cells on HydroCoil were markedly weaker than on bare platinum coil (Fig. 5).

Fig. 3.

Fig. 3

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Live/Dead immunofluorescent staining of bEnd3 cells on bare coil. These images show immunofluorescence of living cells emitting green fluorescence and dead cells emitting red fluorescence at all time points on bare coil.

Fig. 4.

Fig. 4

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Live/Dead immunofluorescent staining of bEnd3 cells on hydrocoil. These images show immunofluorescence of living cells emitting green fluorescence and dead cells emitting red fluorescence at all time points on HydroCoil.

Fig. 5.

Fig. 5

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PECAM-1 immunofluroescence on day 7 after cell seeding. PECAM-1 immunofluorescent staining of bEnd3 cells on bare coil and hydrocoil on day 7.

Discussion

Based on the above results, HydroCoils appear to have earlier cellular proliferation, greater peak live cell quantity, and reduced PECAM-1 expression compared to the bare platinum coils. These findings indicate that the HydroCoil leads to more rapid and extensive cellular proliferation, likely independent of PECAM-1 expression.

Aneurysm recurrence, need for re-treatment and risk of subarachnoid hemorrhage continue to be important long-term outcomes assessed with both microsurgical and endovascular treatment of aneurysms. However, since endovascular treatment has been associated with an increased risk of aneurysm recurrence and the need for re-treatment, investigation into coil features that reduce this risk has garnered significant interest. Specifically, the HydroCoil, an expandable hydrogel polymer-coated platinum coil, has been shown to reduce the risk of aneurysm recurrence clinically compared to BPCs15,16.

The microenvironment within the aneurysm generated by coil embolization is essential to understanding the pathogenesis of aneurysm recurrence and for further device development. It has been shown that strong cellular adhesion on the surface of endovascular devices improves outcomes17 and ways to augment this adhesion process have been investigated, including ion implantation18. Similarly, the inflammatory reaction leading to granulation tissue formation that is elicited by coil placement has also been shown to possibly play a role in improving long-term anatomical outcomes19. To facilitate this reaction, one group created a coil with a fibroblast growth factor (FGF) core and was able to show that animal aneurysms treated with FGF-core coils had greater fibrotic changes on histology20. Fibrosis at the aneurysm dome and deposition of collagen matrix have been shown to be essential to the aneurysm healing process21.

At a cellular level, the histopathological hallmark of ruptured intracranial aneurysms is mural cell loss22. These cells, the mural smooth muscle cells (SMCs), promote aneurysm healing post-coiling and have been shown to be involved in thrombus formation23. A prior study revealed that HydroCoils lead to more robust infiltration of α-smooth muscle actin positive cells, which are presumed to represent vascular smooth muscle cells, when compared to bare platinum coils14. In this study, the HydroCoil led to earlier as well as quantitatively greater endothelial cellular proliferation compared to the BPCs. This observation may be, in part, responsible for the improved outcomes seen with the HES compared to BPCs, and the subsequent reduction in endothelial cells after Day 3 in the HydroCoil group suggests an early apoptotic phase. Such apoptosis, although observed in vitro, may correlate with endothelial turnover and remodeling processes in vivo, potentially influencing aneurysm wall healing, neointima formation, and stabilization. Prior studies have highlighted that apoptosis is an integral step of aneurysm remodeling, and our findings extend this concept by suggesting that HydroCoils may accelerate this cellular sequence24.

Interestingly, apoptosis is a known mechanism of aneurysm healing and occurs at 3–4 weeks post-coil embolization, primarily at the aneurysm dome25. There is speculation that this apoptosis may be the result of a lack of physiologic stimulation from pulsatile flow secondary to stasis induced by aneurysm coils21. In this study, after peak cell quantity was achieved on Day 3 in the HydroCoil group, there was a reduction in the number of cells from Day 3 to Day 7 to match levels seen in the BPC group. When Live/Dead staining was performed, there were rare dead cells adherent to the BPCs but not to the Hydrocoils. This reduction may suggest, but does not confirm, the occurrence of an apoptotic phase, as no specific staining for apoptotic markers was performed in this study. It also suggests that the HydroCoil does not present an optimal surface for cell adherence following apoptosis. Thus, we speculate that after HydroCoil is implanted into the aneurysm, vascular endothelial cells rapidly proliferate in a short period; but as time goes on, the growth of endothelial cells whose contact with hydrogel is inhibited, cell apoptosis occurs, the intimal layer is destroyed and no dead cells adhere. However, the subsequent reduction in cell number is hypothesized to involve apoptosis based on morphological changes rather than direct evidence, and this possibility warrants further investigation with specific apoptotic markers. The expanded hydrogel contacts with the elastic lamina, lead to tissue reaction of aneurysmal wall observed in the former experiment.

PECAM-1 (CD31) is a member of the immunoglobulin cellular adhesive molecular superfamily, which is expressed largely on the surface of endothelial cells in addition to platelets, monocytes, neutrophils, and lymphocytes26. As a trans-membrane protein, PECAM-1 not only plays a role in signal transduction but also plays an important role in regulating the body’s inflammatory response26,27. In this study, on Day 7, when the cell quantities were similar between the bare coils and Hydrocoils, bEnd.3 cellular expression of PECAM-1 on HydroCoil was markedly weaker than on bare platinum coil. This may be a potential explanation for why endothelial cells on bare platinum coils are more likely to inhibit a healing inflammatory response by promoting platelet adhesion and thrombosis by PECAM-1. It is also plausible that the hydrogel coating of HydroCoils modifies surface bioactivity or mechanical cues, thereby influencing endothelial cell junction formation and maturation and ultimately contributing to the downregulation of PECAM-1 expression. Nevertheless, this potential mechanism requires further investigation to be confirmed.

The HydroCoil Embolic System and bare platinum coils are commercially available for the treatment of intracranial aneurysms. Though the HydroCoil has been shown to improve aneurysm filling and reduce rates of recanalization, there do not exist any studies investigating the in vitro differences between the two types of coils. Current literature shows that the majority of the healing following aneurysm embolization occurs within the first month after treatment21. Based on this study, the HydroCoil Embolic System may accelerate the timeframe of that healing by allowing early rapid cell proliferation. However, continued research is necessary to further refine the current technology and allow for better endothelialization at the aneurysm neck, which would likely reduce the likelihood of aneurysm recurrence.

While our findings demonstrate accelerated endothelial proliferation and subsequent apoptosis on HydroCoils in vitro, it is important to interpret these results within the limitations of a static experimental model. The lack of physiological flow dynamics and inflammatory cell interactions in our model warrants caution, and the relatively small sample size further limits the statistical power and generalizability of our findings. Future studies with larger sample sizes and in vivo models are needed to confirm whether these cellular responses translate into improved clinical outcomes.

Conclusion

In this in vitro model utilizing a mouse endothelial cell line, HydroCoils induce a more rapid and intensive cellular proliferation phase compared to bare platinum coils that may be followed by an apoptotic phase. Such a quick response may be an explanation for the reduced rates of recurrence seen with the HydroCoil Embolic System.

Author contributions

X.D. and C.Z. wrote the main manuscript text. X.D. prepared Figs. 1 and 2. C.Z. prepared Figs. 3, 4 and 5. M.W. revised the manuscript. All authors reviewed the manuscript.

Data availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Minglei Wang, Email: wangzhuzi@tongji.edu.cn.

Chao Zhang, Email: zhangchao_neurosurgery@huashan.org.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets analysed during the current study are available from the corresponding author on reasonable request.

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