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Original research
First-in-human experience of sirolimus coated balloon for symptomatic intracranial artery stenosis
  1. Jichang Luo1,2,
  2. Renjie Yang1,2,
  3. Tao Wang1,2,
  4. Jian Chen1,2,
  5. Xia Lu1,2,
  6. Bin Yang1,2,
  7. Peng Gao1,2,3,
  8. Yabing Wang1,2,
  9. Yanfei Chen1,2,
  10. Adam A Dmytriw4,5,
  11. Jiamin Zheng4,
  12. Robert W Regenhardt5,
  13. Zheng Li6,
  14. Han Xu7,
  15. Yan Ma1,2,
  16. Jonathon Zhao6,
  17. Liqun Jiao1,2
  1. 1Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China
  2. 2China International Neuroscience Institute (China-INI), Beijing, China
  3. 3Interventional Neuroradiology, Xuanwu Hospital Capital Medical University, Beijing, China
  4. 4Neurointerventional Program, Departments of Medical Imaging & Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Ontario, Canada
  5. 5Neuroendovascular Program, Massachusetts General Hospital & Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Zylox-Tonbridge Medical Technology, HangZhou, ZheJiang, China
  7. 7R&D Center, Zylox-Tonbridge Medical Technology, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Liqun Jiao, Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China; liqunjiao{at}; Jonathon Zhao, Zylox-Tonbridge Medical Technology, Inc. No. 270, Shuyun Road, Hangzhou, Zhejiang, 311121, China; Jon.zhao{at}


Background The drug coated balloon is a promising endovascular therapy for intracranial atherosclerosis (ICAS), potentially combining the advantages of primary angioplasty and antiproliferative drugs. Previous studies have focused on the paclitaxel coated balloon, revealing promising outcomes in the treatment of ICAS, while concerns about the neurotoxicity of paclitaxel were reported. Sirolimus was shown to have less neurotoxicity in the canine cerebral vasculature. The feasibility and safety of a sirolimus coated balloon (SCB) for ICAS have never been evaluated in humans. We assessed the first-in-human feasibility and safety of SCBs for treating symptomatic patients with severe ICAS.

Methods This prospective, open label, single arm cohort study was designed to enroll patients with transient ischemic attacks or non-disabling, non-perforator territory ischemic stroke caused by severe ICAS (70–99%) and following at least 3 weeks after the onset of ischemic symptoms. The primary outcome was stroke or death within 30 days. All patients were followed up to detect restenosis at 6 months.

Results A total of 60 eligible patients were enrolled with an average age of 59.4±10.8 years. The technical success rate of SCBs for ICAS was 100%. Seven patients (11.7%) required stenting because of flow limited dissections or elastic retraction. Three patients (5.0%) had 30 day strokes, including two ischemic strokes and one hemorrhagic stroke. An additional three patients had recurrent stroke or death during follow-up. Ten patients had restenosis but only two had symptoms.

Conclusions SCBs may be feasible and safe in selected patients with symptomatic ICAS, with high grade stenosis (70–99%). Further studies are warranted.

  • Intracranial atherosclerosis
  • Drug-coated balloon
  • Sirolimus
  • Stroke
  • Severe stenosis

Data availability statement

Data are available upon reasonable request.

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  • Endovascular treatment is an effective alternative treatment for intracranial atherosclerosis (ICAS).

  • However, high perioperative complications and long term restenosis are associated with endovascular treatment with traditional stents and balloons.

  • To overcome these limitations, drug coated balloon has been introduced, which have been recommended as firstline devices in percutaneous coronary intervention.

  • Recently, paclitaxel coated balloons have been applied to the treatment of ICAS with promising short term and long term outcomes.

  • However, several studies have revealed the high neurotoxicity of paclitaxel and less neurotoxicity of sirolimus but the feasibility and safety of sirolimus coated balloons (SCBs) for ICAS have never been evaluated in humans.


  • SCBs were used in the human intracranial vasculature for the first time.

  • SCB treatment appeared to be feasible and safe for select patients with symptomatic ICAS with high grade stenosis (70–99%).


  • This preliminary study demonstrated the first-in-human promising short term outcomes of SCBs for ICAS, providing a new device to treat ICAS.

  • Further studies are warranted to validate the findings of this study.


Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of stroke worldwide, particularly in Asia, accounting for 30–50% of all ischemic stroke.1 Endovascular treatment is an efficient alternative to medical treatment in carefully selected cases.2 Several studies have suggested that the recurrent risk of stroke in critical stenosis beyond 30 days may be as high as three times greater in the medical group compared with the stenting group (6.6% vs 2.2%), and patients with hemodynamic dysfunction had a 37% risk of 1 year stroke recurrence.3 4 The Wingspan Stent System Post Market Surveillance (WEAVE) trial and the Wingspan One-year Vascular Events and Neurologic Outcomes (WOVEN) trial revealed that under strict control of indications, endovascular treatment was associated with a 2.6% perioperative risk and 8.5% 1 year risk of stroke or death.5 6 Nevertheless, endovascular treatment for ICAS is challenging due to the relatively high risk of perioperative complications and long term restenosis.7 8 Several studies have reported 14.7% rates for perioperative complications and 29.8% rates for in-stent restenosis.8 9

To overcome these issues, drug coated balloons (DCBs) have been introduced for ICAS, which combine the advantages of primary angioplasty and antiproliferative drugs. In percutaneous coronary intervention, DCBs have been verified to be superior to traditional balloons or stents, and are recommended as a firstline device.10 11 DCBs are suitable for tortuous vasculature owing to greater flexibility and compliance compared with stents. Additionally, treatment with DCBs without permanent implantation reduces the inflammatory response of the intima and shortens the necessary course of dual antiplatelet therapy.12

To date, several studies have reported preliminary experience of DCBs for symptomatic ICAS with promising short term and long term outcomes.13 However, most DCBs for ICAS are coated with paclitaxel, and experience with sirolimus coated balloons (SCBs) for ICAS has not been reported. Increasing evidence from preclinical studies has demonstrated that high dose paclitaxel was found to cause plaque vulnerability due to increased apoptosis in the vessel wall, while sirolimus was not neurotoxic.14 15 Meanwhile, sirolimus inhibits the DNA synthesis of vascular smooth muscle cells and may have stronger antiproliferation effects than paclitaxel.16 The Resolute Onyx stent eluting with a sirolimus-like drug (zotarolimus) has shown excellent clinical outcomes in coronary artery studies and several intracranial artery studies, which was approved as a next generation stent in coronary intervention by the US Food and Drug Administration.17 In the current study, we report the first-in-human experience of SCB in the treatment of symptomatic ICAS. We aimed to evaluate the feasibility and safety of SCBs for this indication.

Material and methods

Study design

This prospective, open label, single arm cohort study was conducted at a high volume tertiary stroke center. Consecutive patients were enrolled between September 2021 and March 2022. This cohort was drawn from a single arm trial evaluating a drug eluting balloon dilatation catheter for the treatment of symptomatic intracranial atherosclerosis (NCT04949880). Our study was reported in line with the STROCSS (Strengthening the Reporting of Cohort Studies in Surgery) criteria.18

An interdisciplinary team of neurosurgeons and neuroradiologists evaluated each case for this indication before enrollment, and written informed consent was obtained from each patient. Symptomatic patients with severe ICAS stenosis were enrolled according to these criteria: (1) aged 18–80 years; (2) patients with transient ischemic attacks or non-disabling, non-perforator territory ischemic stroke for more than 3 weeks; (3) symptomatic intracranial atherosclerosis located within an intracranial segment of the vertebral artery (V4), internal carotid artery (ICA), first segment of the middle cerebral artery (M1), or basilar artery; (4) degree of artery stenosis of 70–99% diagnosed by angiography; (5) modified Rankin Scale (mRS) score of <2 before enrollment; (6) diameter of target vessel of 2.00–4.50 mm and length of target lesion <14 mm. Patients who had a new cerebral ischemic event within 3 weeks were excluded from this study. Other exclusion criteria were history of stent intervention within the target vessel, hypertension uncontrolled by medicine (systolic pressure ≥180 mm Hg or diastolic pressure 110 mm Hg continuously), and non-atherosclerotic disease, such as arterial dissection, arteritis, thrombosis, intracranial arteriovenous malformation, and aneurysms. A detailed description of the inclusion and exclusion criteria for the study is presented in online supplemental file 1.

Supplemental material

Endpoint assessment

Technical outcomes were considered to assess feasibility, including technical success rate, degree of stenosis after the procedure, risk of arterial dissection, and remedial stenting. Technical success was defined as successful delivery and expansion of SCBs at the target lesion, as well as smooth withdrawal of the SCB without rupture. Arterial dissection was assessed by angiography and defined by vessel irregularity not consistent with residual atherosclerosis and with evidence of floating intima suggestive of injury.19 Remedial stenting was performed if there was elastic retraction or vessel dissection with a degree of stenosis >50%.

Safety and efficacy assessments were according to clinical outcomes. The primary outcome of this study was stroke or death within 30 days. Secondary endpoints were: 30 day ischemic stroke after the procedure; 30 day hemorrhagic stroke after the procedure; death within 30 days of the procedure; and National Institutes of Health Stroke Scale (NIHSS) score and mRS score at the 30 day follow-up. Other endpoints included the 6 month incidence of stroke or death, ischemic stroke, hemorrhagic stroke, or death after the procedure, and restenosis, and NIHSS and mRS scores at the 6 month follow-up.

Ischemic stroke was defined as sudden onset of new neurological deficits, such as hemiplegia, hemianopia, aphasia, dysphagia, sensory impairment, or confusion, which persisted for >24 hours, with new cerebral infarction detected with diffusion weighted MRI or CT. Hemorrhagic stroke was described as the sudden onset of neurological deficits caused by parenchymal, subarachnoid, or intraventricular hemorrhage detected by CT or MRI.20 Restenosis was defined as >50% stenosis within the target lesion and >20% absolute luminal loss during follow-up.

Study procedure

Each patient was treated by a team of neurosurgeons and neuroradiologists with >15 years of experience in endovascular treatment. Aspirin (100 mg daily) and clopidogrel (75 mg daily) were given to all patients 5 days before the intervention. The procedure was performed under general anesthesia using a biplane angiography system. Intravenously administered heparin was dosed at 83 units/kg of body weight to prevent systemic coagulation. One hour later, another half dose of heparin was administered.

Using a shuttle sheath of 8 F, right femoral access was used to navigate into the target artery. A 6 F guiding catheter (5 F is the minimum requirement) (NeuronTMMax; Penumbra, Alameda, California, USA) and a 5 F intermedial catheter (AXS Catalyst 6; Stryker Neurovascular, Fremont, California, USA) were used for the delivery and support of the balloon. Under roadmap guidance, a microguidewire (Transend; Stryker Neurovascular) was placed to cross the stenosis, followed by a microcatheter (Excelsior SL-10; Stryker Neurovascular) to ensure access to the true lumen of the target vessel. The distal tip of the wire was still positioned adjacent to the lesion after withdrawing the microcatheter. Over-the-wire balloons were positioned across the stenosis and slowly inflated (median 6 atm, IQR 4–8) for 30 s. According to the submaximal angioplasty technique, balloon size was selected according to the reference diameter of the target vessel (0.8 diameter to reference vessel). This balloon was selected in such a manner as to at least cover the plaque. A same sized SCB was then inflated for 60 s to facilitate drug delivery. After deflation and withdrawal of the SCB, post-interventional angiograms were performed to evaluate the effect of the treatment and rule out perforations, dissections, or emboli. Diffusion weighted MRI was performed within 24 hours following the intervention to identify ischemic or hemorrhagic lesions (figure 1).

Figure 1

A adult patient with hypertension and diabetes presented with recurrent transient attacks of vertigo for 1 month. It was evident from preoperative diffusion-weighted imaging (A) and apparent diffusion coefficient (B) that there was no cerebral infarction. Plaque assessment was based on cross-sectional T1-weighted images obtained at the sites of maximal lumen narrowing (MLN) (C) and reference (REF) (D). The vessel area (VA) and lumen area (LA) were manually measured at the MLN (C, VA=0.118 cm2, LA=0.003 cm2) or REF (D, VA=0.216 cm2, LA=0.045 cm2) sites. There was a concentric plaque with negative remodeling. (E) Preoperative digital subtraction angiography showed 93.7% degree of stenosis and 4.9 mm length of lesion at the basilar artery. Micro-guidewires crossed the lesion (F), and pre-dilation by a traditional submaximal balloon (G) was performed to facilitate sirolimus-coated balloon delivery and treatment (H). Neither diffusion-weighted imaging (I) nor apparent diffusion coefficient imaging (J) identified a new cerebral infarction after intervention.

During the course of 3 months after the intervention, aspirin (100 mg daily) and clopidogrel (75 mg daily) were administered as dual antiplatelet therapy. The dual antiplatelet therapy was reduced to a single antiplatelet therapy after 3 months. In addition, all patients received lipid lowering medication, and cerebrovascular risk factors were controlled and managed medically. CT angiography or DSA was performed 6 months after the procedure to detect restenosis.

Imaging protocol and analysis

DSA and high resolution MRI (HR-MRI) were used to assess lesion characteristics. Before the intervention, HR-MRI was performed using a 3.0 T magnetic resonance scanner (Magnetom Spectra; Siemens) equipped with an eight channel head coil. A description of the parameters of the sequences was provided in a previous study.21 DSA was performed during the procedure to assess the degree of stenosis before and after the intervention.

An evaluation of lumen diameter, vessel area (VA), and lumen area (LA) was required at the maximum lumen narrowing (MLN) or reference site. We established a reference site based on WASID (Warfarin vs Aspirin for Symptomatic Intracranial Disease) criteria.22 Based on DSA and HR-MRI imaging, the following vessel characteristics were observed:

  • The degree of stenosis was calculated from DSA as (1-lunar diameter at MLN/luminal diameter at reference site).

  • Three types of Mori lesions were recognized: Mori A is a short and concentric lesion (5 mm); Mori B is a tubular or extreme eccentric lesion with an intermediate length (between 5 and 10 mm); and Mori C is a diffuse lesion with a long length (>10 mm).23

  • Eccentric plaque was defined as >0.5 eccentricity index, and concentric plaque as <0.5 eccentricity index. Eccentricity index was calculated by dividing maximum wall thickness by minimum wall thickness.24

  • Plaque enhancement was defined as a higher enhancement than the reference wall.25

  • Remodeling index (RI) was calculated as VA MLN/VA reference. Positive remodeling was defined as RI ≥1.05, negative remodeling as ≤0.95, and intermediate remodeling as 0.95–1.05.26

Each image was reviewed by the IsCore image corelab ( Raters were blinded to the clinical data of the patients and were not involved in the statistical analysis. Before the formal assessment, 5% of the data from the cohort analyzed were used to train the raters. Once a high level of agreement between two raters was achieved (reliability >0.9), a formal evaluation of the imaging data was conducted.

Statistical analysis

A wide range of variables, including demographic data, cerebrovascular events, lesion characteristics, and laboratory examination results, were anonymized and analyzed. Descriptive statistics were conducted using SPSS software, V.26.0 (IBM, Chicago, Illinois, USA). Variables with a normal distribution were expressed as mean±SD, while variables with a non-normal distribution were expressed as median (IQR). Numbers and percentages were used to describe categorical variables. To identify relevant risk factors for 30 day stroke or death, univariate and multivariate analyses by logistic regression were performed. Multivariate regression analysis was conducted for variables with P<0.20 from univariate analysis. P<0.05 was considered statistically significant.


Baseline and lesion characteristics

A total of 165 patients were screened, and 60 eligible patients were enrolled in our center and treated with an SCB. A summary of the baseline characteristics is presented in table 1. Mean age of the patients was 59.4±10.8 years and most (70%) were men. All patients presented with symptomatic ischemic events at the time of admission, with more than half (63.3%) of cases being ischemic strokes. Most patients had at least one vascular risk factor, including hypertension, dyslipidemia, and diabetes. Approximately 42% of the target lesions were in the middle cerebral artery. Pre-interventional stenosis was 78.5±7.2% with a mean length of 7.0±3.3 mm. Most of the lesions were Mori A, with eccentric plaque, negative remodeling, and plaque enhancement.

Table 1

Baseline and lesion characteristics of patients with symptomatic intracranial artery stenosis

Clinical and technical outcomes

SCB treatment was successfully performed in all patients with 100% technical success rate. The average degree of stenosis after SCB was 31.7±18.2%, which was less than that before dilatation. Seven patients (11.7%) required stenting because of flow limited artery dissections following angioplasty (four cases) or elastic retraction of vessels (three cases). These patients were implanted with Wingspan or Appolo stents. Twelve patients were found to have artery dissections after DCB, of which four received remedial treatment (table 2figure 2). Additional technical parameters during the procedure are presented in online supplemental file 1.

Table 2

Technical and clinical outcomes

Figure 2

A adult patient with hyperlipidemia presented with sudden language dysfunction for 22 months. It was evident from preoperative diffusion-weighted imaging (A) and apparent diffusion coefficient (B) that there was no cerebral infarction. Plaque assessment was based on cross-sectional T1-weighted images obtained at the sites of maximal lumen narrowing (MLN) (C) and reference (REF) (D). The vessel area (VA) and lumen area (LA) were manually measured at the MLN (C, VA=0.096 cm2, LA=0.008 cm2) or REF (D, VA=0.114 cm2, LA=0.048 cm2) sites. There was an eccentric plaque with negative remodeling. (E) Preoperative digital subtraction angiography showed 81.4% degree of stenosis and 5.9 mm length of lesion at the first segment of right middle cerebral artery. Micro-guidewires crossed the lesion (F), and pre-dilation by a traditional submaximal balloon (G) was performed to facilitate sirolimus-coated balloon delivery and treatment. Postoperative angiography revealed non-flow-limiting dissection with signs of vascular enlargement in the target vessel (H). However, there was no new cerebral infarction detected by diffusion-weighted imaging (I) and apparent diffusion coefficient imaging (J) and no clinical symptoms.

The overall clinical outcome was favorable, with a median NIHSS score of 0 (IQR 0–0.8) and a median mRS of 0 (0–0.75) at the 30 day follow-up. Thirty-four patients (56.7%) had new cerebral infarctions on postoperative MRI. Of these patients, only three were symptomatic. Most of the new cerebral infarctions were caused by artery–artery emboli (82.4%). Three patients (5.0%) had 30 day stroke or death, including two ischemic strokes and one hemorrhagic stroke. Ischemic strokes were caused by lesions located at M1 and the basilar artery. Hemorrhagic stroke with mild subarachnoid hemorrhage was caused by guidewire vessel perforation (table 2).

Outcomes at the 6 month follow-up demonstrated that an additional three patients had stroke or death. Two patients had recurrent ischemic stroke due to restenosis of a target lesion, and one patient died because of traumatic fractures. Ten patients (16.7%) had restenosis, and only two had recurrent ischemic symptoms and additional intervention performed (table 2).


Our study is the first to demonstrate that in-human use of SCBs may be feasible and safe in select patients with symptomatic ICAS with high grade stenosis (70–99%). There was 100% rate of technical success of SCB; 57% of patients had a new high signal on diffusion weighted imaging after the procedure, but most were asymptomatic. This study also reported a 5% risk of 30 day stroke or death, a 10% risk of 6 month stroke or death, and a 16.7% risk of restenosis of SCB.

Recently, growing experience has demonstrated that DCBs and drug eluting stents (DESs) were superior to the traditional instruments in the treatment of ICAS. Jia et al reported a multicenter randomized clinical trial suggesting that DESs were superior to bare metal stents for symptomatic high grade ICAS with a low risk of ischemic stroke recurrence (1% vs 9%, P=0.03) and in-stent restenosis (10% vs 32%, P<0.001).27 DCBs have further advantages compared with DESs. The procedure of DCB has a higher success rate given the enhanced flexibility and compliance of balloons, especially in tortuous intracranial arteries.28 In this study, 100% rate of operation success was achieved, demonstrating the flexibility of DCBs. Pre-dilation with a flexible, small diameter conventional balloon to facilitate DCB advancement and intermediate catheters to provide proximal support are other approaches to improve the success rate. Furthermore, the DCB inhibits intima hyperplasia and excessive proliferation of smooth muscle cells by localizing antiproliferative agents to the arterial wall without permanent implantation of polymer matrix and metal mesh.12 This may reduce the inflammatory response of the intima and the risk of thrombosis, as well as shorten the course of dual antiplatelet therapy. The short term use of double antiplatelet therapy for 1–3 months may reduce the bleeding risk, avoid delayed endothelialization, and reduce the risk of thrombosis compared with stent implantation.29

To date, several types of DCBs, such as SeQuent Please (B Braun), DIOR (Eurocor), and Neuro Elutax SV (Aachen Resonance, Aachen, Germany) have been used for the treatment of ICAS.13 Most of the available DCBs are coated with paclitaxel, while SCBs have less intracranial data available and no in-human experience, to our knowledge, before this study. As previously reported, DCBs were used to treat intracranial stenosis with rates of perioperative complications of 2.5–10.3%.30 This is consistent with our findings of 5% for short term complications. The long term complications in this study were 10%, which was also similar to previous DCB studies.29 However, there was a higher rate of iatrogenic arterial dissection (20.0%) in this study, which may account for pre-dilatation and dilatation of the DCB. Pre-dilatation was hypothesized to be required for the facilitation of drug transport through the intima and media due to the creation of microdissections. Furthermore, pre-dilation was believed to facilitate lesion crossing with the bulkier DCB, compared with a traditional balloon, and to prevent potential scrape-off of the drug.31 Due to the limited arterial dissections and elastic retraction of vessels, 11.7% of cases received remedial stenting, which corresponds to rates reported in previous studies ranging from 0% to 23.8%.30 Thus SCBs may be feasible and safe for ICAS since our results are equivalent to the results of studies evaluating the paclitaxel-coated balloon.

Importantly, accumulating evidence had demonstrated that sirolimus is an antiproliferation drug that does not cause neurotoxicity in the intracranial vasculature, while paclitaxel is a cytotoxic agent that may cause some degree of neurotoxicity.32 33 In addition, preclinical studies have shown that paclitaxel’s antiproliferation ability is significantly weaker than that of sirolimus under hypoxic conditions, with the potential mechanism being related to inhibiting HIF-1α expression and glycolysis.34 Despite the 16.7% restenosis rate at the 6 month follow-up in this study, only 3.3% of patients had recurrent ischemic symptoms. It was believed that the relatively high restenosis rate was caused by the high residual stenosis after dilatation with a small sized balloon, in conjunction with elastic retraction of the target vessel. However, DCBs have been reported with persistent luminal gain due to the antiproliferation effect.35 Therefore, it is anticipated that long term stenosis will be detected during ongoing follow-up.

Study limitations

This study had some limitations. First, the study was the first-in-human experience of SCBs for ICAS with a small sample size. Our results warrant further study with larger sample sizes and preferably in a multicenter setting. Second, this study only reported the 6 month follow-up outcomes to evaluate the feasibility and safety of SCBs; long term outcomes to assess SCBs for ICAS are expectant.


These data present the first in-human use of SCBs within the intracranial vasculature. SCBs appear to be feasible and safe for the treatment of ICAS. Our results warrant further investigation in larger multicenter studies.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the ethics committee of Xuanwu Hospital of Capital Medical University ([2021]008), and was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and the applicable laws. Participants gave informed consent to participate in the study before taking part.


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


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  • JL and RY contributed equally.

  • Contributors Concept and design: LJ and YM. Drafting of the manuscript: JL, RY, and TW. Critical revision of the manuscript for important intellectual content: XL and AAD. Statistical analysis: RWR and JZ. Obtained funding: JZ, ZL, and HX. Supervision: JC, BY, PG, YW, and YC. Responsible for the overall content: LJ and JZ

  • Funding This work was funded by Zylox-Tonbridge Medical Technology. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of manuscript; and decision to submit the manuscript for publication.

  • Competing interests JZ is the funder and significant shareholder of Z-T Medical Technology. ZL and HX are product engineers at Z-T Medical Technology and served on advisory boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.