Bioresorbable poly (L-lactic acid) flow diverter versus cobalt-chromium flow diverter: in vitro and in vivo analysis

概要

Stroke
BASIC AND TRANSITIONAL SCIENCES

Bioresorbable Poly (L-Lactic Acid) Flow Diverter
Versus Cobalt-Chromium Flow Diverter: In Vitro
and In Vivo Analysis
Natsuhi Sasaki , MD; Akira Ishii , MD, PhD; Shinichi Yagi, PhD; Hidehisa Nishi , MD, PhD; Ryo Akiyama , MD;
Masakazu Okawa , MD, PhD; Yu Abekura , MD, PhD; Hirofumi Tsuji , MD; Shinichi Sakurai, PhD; Susumu Miyamoto , MD, PhD
BACKGROUND: Permanent metallic flow diverter (FD) implantation for treatment of intracranial aneurysms requires antiplatelet
therapy for an unclear duration and restricts postprocedural endovascular access. Bioresorbable FDs are being developed
as a solution to these issues, but the biological reactions and phenomena induced by bioresorbable FDs have not been
compared with those of metallic FDs.
METHODS: We have developed a bioresorbable poly (L-lactic acid) FD (PLLA-FD) and compared it with an FD composed of
cobalt-chromium and platinum-tungsten (CoCr-FD). FD mechanical performance and in vitro degradation of the PLLA-FD
were evaluated. For in vivo testing in a rabbit aneurysm model, FDs were implanted at the aneurysm site and the abdominal
aorta in the PLLA-FD group (n=21) and CoCr-FD group (n=15). Aneurysm occlusion rate, branch patency, and thrombus
formation within the FD were evaluated at 3, 6, and 12 months. Local inflammation and neointima structure were also
evaluated.
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RESULTS: Mean strut, porosity, and pore density for the PLLA-FD were 41.7 μm, 60%, and 20 pores per mm2, respectively.
The proportion of aneurysms exhibiting a neck remnant or complete occlusion did not significantly differ between the
groups; however, the complete occlusion rate was significantly higher in the PLLA-FD group (48% versus 13%; P=0.0399).
Branch occlusion and thrombus formation within the FD were not observed in either group. In the PLLA-FD group, CD68
immunoreactivity was significantly higher, but neointimal thickness decreased over time and did not significantly differ from
that of the CoCr-FD at 12 months. Collagen fibers significantly predominated over elastic fibers in the neointima in the
PLLA-FD group. The opposite was observed in the CoCr-FD group.
CONCLUSIONS: The PLLA-FD was as effective as the CoCr-FD in this study and is feasible for aneurysm treatment. No
morphological or pathological problems were observed with PLLA-FD over a 1-year period.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.
Key Words: absorbable implants ◼ animal experiments ◼ intracranial aneurysm ◼ polymers ◼ stent

T

he effectiveness of flow diverter (FD) treatment of
intracranial aneurysms has been demonstrated in
numerous studies.1–4 The complete aneurysm occlusion rate at a 1-year follow-up was 81.9% with Pipeline
(Medtronic) and 95.3% with FRED (Microvention, Aliso
Viejo, CA), which is structurally different from Pipeline.4,5

Diversion of blood flow by FD enables thrombus formation within the aneurysm sac. Moreover, endothelial
cells grow along the FD scaffold. These phenomena can
result in aneurysm occlusion and prevent a recurrence.6
In view of its efficacy and healing mechanism, the braided
stent design with its dense weave and small pores may

 
Correspondence to: Akira Ishii, MD, PhD, Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto
606-8507, Japan. Email ishii@kuhp.kyoto-u.ac.jp
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.042043.
For Sources of Funding and Disclosures, see page 1635.
© 2023 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2023;54:1627–1635. DOI: 10.1161/STROKEAHA.122.042043

June 2023   1627

BASIC AND TRANSITIONAL
SCIENCES

Sasaki et al

Nonstandard Abbreviations and Acronyms
αSMA
alpha-smooth muscle actin
CoCr-FD 
flow diverter composed of cobalt-­
chromium and platinum-tungsten
FD
flow diverter
Mw
weight average molecular weight
OCT
optical coherence tomography
PLLA-FD flow diverter made of poly (L-lactic acid)

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have already reached the expected level of success as a
device concept.
On the contrary, the placement of permanent metallic
FDs is associated with several issues. First, inadequate
duration of antiplatelet medication carries the risk of
ischemic stroke. Second, when an FD-treated aneurysm
recurs, the only endovascular retreatment option is to
place an overlapping FD without changing the strategy.
Third, FD coverage of any branch vessels near the aneurysm makes the approach impossible. Fourth, FDs cause
artifacts on postoperative imaging. These problems could
be solved by devices that bioabsorb after aneurysm
healing.
Bioresorbable polymers have been used to construct
bioresorbable coronary scaffolds with Conformité Européene marking.7,8 Wang et al9 first developed a semibioresorbable polyglycolic acid FD. We first reported
the feasibility of completely bioresorbable poly (L-lactic
acid) FD (PLLA-FD) in a preclinical study.10 Since then,
Jamshidi et al11 have reported preliminary safety data
regarding the implantation of a self-expandable PLLAFD in the rabbit aorta, and the flow diversion behavior of
a novel bioresorbable FD has been reported by Muram et
al.12 However, no study has yet compared bioresorbable
polymer and metallic FDs. Biological reactions associated with the degradation of bioresorbable materials
need to be compared with those of metallic materials.
Since our previous report,10 we have improved the PLLAFD prototype; now, it is structurally similar to commercial metal FD and has self-expanding properties. In this
study, we report its physical properties, bioresorbability,
efficacy, and biological responses and compare it with a
metallic FD composed of cobalt-chromium and platinumtungsten (CoCr-FD) in a rabbit model.

METHODS
The data that support the findings of this study are available
from the corresponding author upon reasonable request.

FD Design and Mechanical Testing
Bioresorbable medical-grade PLLA (BMG, Kyoto, Japan) with a
weight average molecular weight (Mw) of 220 000 g/mol was
used as the PLLA-FD material. PLLA was processed into fine
1628   June 2023

Comparison of Polymer and Metal Flow Diverters

fibers by a melt-spinning method. The PLLA-FD was designed
as a braided structure with 48 PLLA fibers (inner diameter, 4
mm; length, 10–15 mm; Figure 1A). After annealing and cutting, 3 radiopaque gold markers were attached 1 mm inside
each end. The CoCr-FD was braided with 36 cobalt-chromium
and 12 platinum-tungsten wires to have identical inner diameter and length as PLLA-FD (Figure 1B). Mechanical performance testing was conducted on PLLA and CoCr wires to
evaluate tensile strength, tensile modulus, and elongation rate
at break (n=6 per group). Assessments of porosity and pore
density (n=4 per group) were performed (see the Supplemental
Methods for details). Radial force testing was performed on
the PLLA-FD, CoCr-FD, and the initial prototype PLLA-FD we
have reported previously.10

In Vitro Degradation Testing
To determine the status of the PLLA-FD during the period
required for aneurysm healing (real-time degradation test),
samples were assessed on months 3, 6, 9, 12, 15, and 18. Gel
permeation chromatography assessing Mw and number average molecular weight and radial force testing were performed.
To predict when the PLLA-FD bioabsorbes (accelerated degradation test), Gel permeation chromatography was performed on
days 3, 6, 9, 12, 15, and 18. Detailed information is described in
the Supplemental Methods.

In Vivo Animal Experiments
Aneurysm Construction
The animal study protocol was approved by the Institutional
Animal Care Committee of the Kyoto University Graduate
School of Medicine (Med Kyo 20253, 21592). Elastaseinduced aneurysms were created at the origin of the right common carotid artery in 36 female New Zealand white rabbits
(2.6–3 kg; KITAYAMA LABES, Ina, Japan) as described in a
previous study.13 At least 3 weeks were allowed for aneurysm
maturation.

FD Implantation
Oral aspirin (30 mg/day) and clopidogrel (30 mg/day) were initiated 1 week before FD implantation. In each rabbit, the same
type of FD in the preplanned order was implanted into the right
subclavian artery and the abdominal aorta (30 CoCr-FDs in
15 rabbits and 42 PLLA-FDs in 21 rabbits). Detailed information on the procedure of FD implantation is described in the
Supplemental Methods. The FDs were deployed proximal to the
origin of the right vertebral artery to cover the aneurysm neck
and in the abdominal aorta to cover a lumbar artery ostium.
For the CoCr-FD, angioplasty was performed only when FD
malapposition was suspected. Angioplasty was not used with
the PLLA-FD. Aspirin and clopidogrel were continued postoperatively until animal sacrifice.

Specimen Retrieval and Sacrifice
At 3, 6, and 12 months, PLLA-FD rabbits (n=7) and CoCr-FD
rabbits (n=5) were anesthetized to perform DSA and optical coherence tomography (OCT; ILUMIEN OPTIS; Abbott
Vascular, Santa Clara, CA) at the FD implantation site via a
left femoral artery 5F sheath. After evaluation, the rabbits
were euthanized. Detailed information on specimen retrieval is
described in the Supplemental Methods.
Stroke. 2023;54:1627–1635. DOI: 10.1161/STROKEAHA.122.042043

Sasaki et al

Comparison of Polymer and Metal Flow Diverters

BASIC AND TRANSITIONAL
SCIENCES

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Figure 1. Structure of the 2 types of flow diverters and mechanical properties of the constituent wires.
A, Photographs of the poly (L-lactic acid) flow diverter (PLLA-FD) constructed of 48 fine PLLA fibers (top) and scanning electron microscope
(SEM) image of the PLLA-FD showing 60% mean porosity and 20 mean pores per mm2 (bottom). ...

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