Xtrace: Novel Bioresorbable Device for Patent Foramen Ovale

Closure

Sara Abu Ajamieh

, Diana Mindroc-Filimon

, Irene Mozo

and Isabel Rocha

Karolinska Institutet, Stockholm, Sweden

German Cancer Research Center, Heidelberg, Germany

Faculty of Physics, University of Barcelona, Barcelona, Spain

Santa Maria Hospital, Lisbon, Portugal

Keywords: Patent Foramen Ovale, Cryptogenic Stroke, PFO Closure, Bioabsorbable Occluder.

Abstract: Patent foramen ovale (PFO) is a congenital cardiac lesion, affecting about 25% to 30% of the adult

population. It is associated with several serious complications, including cryptogenic strokes, transient

ischemic attacks, and migraine. The prevalence of PFO has significantly increased in patients with

cryptogenic stroke; up to 40% of ischemic strokes with an unknown cause have a PFO. Recently, technical

advancements in medical engineering have made the percutaneous transcatheter closure of PFO a feasible

treatment option. However, current PFO closure devices may lead to complications such as the need for

replacing the device after several years, sudden migration of the implant, erosion, infection, or arrhythmias.

Attempts are needed to produce a safer and more effective closure devices. Here, we propose an innovative

medical device called Xtrace. It consists of a biodegradable material that will be partially degraded by the

host body while substituted by autologous host tissue. This innovative device will potentially fulfill the

essential unmet clinical need, as well as provide a safe and effective delivery of therapy for the general

population.

1 INTRODUCTION

The foramen ovale is a compulsory channel between

the two atria during fetal development. It provides

placental oxygenated blood to reach the arterial

circulation of the fetus. Naturally, the hole is

completely sealed at birth, as it can be seen in Figure

1. However, closure does not occur for approximately

a quarter of the general population (Hagen, 1984).

This is due to a defect in the postnatal fusion of the

septum primum and secundum, forming tunnel-like

gap called patent foramen ovale (PFO). Although the

reason behind PFO is unknown, studies suggest that

it may be genetic. PFO has been implicated in several

serious complications, including cryptogenic strokes,

transient ischemic attacks, and migraine. The primary

cause of stroke is still unknown in about 40% of

patients with a stroke diagnosis (Giblett, 2019). The

occurrence of a PFO with either transient or

continuous right to left shunt can potentially lead to

paradoxical embolism (Belkin, 1990). Over the past

three decades, technical advancements in medical

engineering have made the percutaneous

transcatheter closure of PFO a feasible treatment

option. Several percutaneous PFO closure devices

have various advantages and are expected to work

equally well if placed in their most suitable anatomy

(Ko, 2010). However, PFO closure devices may lead

to some complications such as the need for replacing

the device after several years, sudden migration of the

implant, erosion, infection, thrombogenicity, or

arrhythmias. Attempts to produce safer and more

effective closure devices are underway.

Figure 1: Representation image of a human heart. (A)

Normal heart with a closed foramen ovale. (B) Heart with

an open foramen ovale.

344

Ajamieh, S., Mindroc-Filimon, D., Mozo, I. and Rocha, I.

Xtrace: Novel Bioresorbable Device for Patent Foramen Ovale Closure.

DOI: 10.5220/0009374603440349

In Proceedings of the 13th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2020) - Volume 1: BIODEVICES, pages 344-349

ISBN: 978-989-758-398-8; ISSN: 2184-4305

2 STATE OF THE ART

Currently, there are different varieties of therapeutic

approaches that can be adopted for the treatment of PFO.

2.1 Pharmacological Treatment

Anticoagulant or antiplatelet therapies can be used to

treat PFO. However, drug treatment is only

symptomatic, and may be contraindicated in some

cases and requires life lasting engagement. Cross-

sectional multicenter studies have shown that PFO

closure is associated with a significant risk reduction

when compared with pharmacological treatment

(Saver, 2017).

2.2 Implantation of Occluders

Percutaneous PFO closure procedures have been

originated from well-established atrial septal defect

(ASD) closure techniques. In experienced centers,

this is a very low-risk procedure that can be carried

out in a short time (Meier, 2005). Therefore,

catheterization laboratories worldwide have seen a

substantial rise in the number of trans-catheter PFO

closures being performed (Opotowsky, 2008). In

some practices, a submissive sizing balloon together

with periprocedural echocardiographic guidance

(either trans-esophageal or intra- cardiac) is used in

patients during PFO device closure (Ko, 2010). From

the design features perspective, several types of

devices can be distinguished:

Self Expanding Double Disk Occluders: These

devices consist of commonly used PFO closure

devices; they include two metallic opposing discs

covered by fabric and attached by a thin waist. A

combination of oppositional mechanical forces

formed by the 2 opposing discs and fibrous tissue

encapsulation seal the PFO. The GORE

CARDIOFORM Septal Occluder and the Abbott

Amplatzer

PFO Occluder, both using a nitinol

framework, are the only devices of this nature

currently permitted by the US Food and Drug

Administration (FDA) for PFO closure in the United

States.

Occluders with PFO Tunnel: These devices are

placed on the PFO tunnel and stabilized by adjustable

atrial anchors. This technique brings the septum

primum and secundum in close apposition, reducing

the amount of material exposed to blood circulation.

The Coherex FlatStent

occluder (Coherex Medical,

Inc) is the most popular device of this family.

Figure 2: Amplatzer device and respective intervention.

(Amplatzer, 2019).

Bioabsorbable PFO Occluders: Bioabsorbable

occluders follow the same deploying technique as

metallic occluders. However, they substitute the

metallic material constituting the disk with resorbable

polymers, which are expected to be replaced by native

tissue upon reabsorption. The risk of thrombosis is

reduced, as well as arrhythmia and device migration.

However, bioabsorbable devices are still ongoing

clinical evaluation phases

HeartStitch

Occluder (Sutura, Inc): The

HeartStitch occluder utilizes complex suture

technology to seal the septum primum and secundum.

However, this technique requires greater surgeon

proficiency and is still not available for clinical use.

The current solutions present a series of

disadvantages. The pharmacological treatment

represents just a symptomatic solution and does not

actually solve the problem. On the other hand, the

metallic disk occluders can be refused by the patient’s

body, cause inflammation, migrate from the foramen

ovale or require a replacement after a specific time.

Plus, these devices are composed of metallic

materials, and can cause long term inflammatory

response as well as magnetic resonance artifacts. The

bioabsorbable occluders are not available anymore,

since a higher risk of shunts was associated to their

use. Moreover, the available devices were still

leaving a metallic framework behind in the body

(Meier, 2005).

3 PROPOSAL OF THE PRODUCT

3.1 Design of the X-trace Device

The proposed device will be composed by two

opposed disks of an acellular porcine collagen type I

matrix, each of which will be supported by two arms

of the biodegradable JDBM-2 Mg alloy (Mao, 2017).

Each of the arms will account with 3 interposed

spring hinges that will serve to attach the device to the

host tissue.

Xtrace: Novel Bioresorbable Device for Patent Foramen Ovale Closure

345

3.1.1 Disks Design

The disks will be composed of porcine collagen type

I matrix. This material offers full guarantees as it has

already been used in PFO closure procedures

(Morgan, 2010). Full growth of autologous tissue has

been shown six months after implantation of this type

of collagen matrix. This suggests that the material

induces a sufficient host tissue response to repair the

size of the defect.

3.1.2 Framework Design

The framework will be composed by a Mg alloy, Mg-

2.2Nd-0.1Zn-0.4Zr, denoted JDBM-2, that has

already shown promising results upon application on

vascular stents (Morgan, 2010). Magnesium is one of

the most promising metals used on bioabsorbable

devices, as the corrosion products of Mg alloys can

be absorbed or excreted by the human metabolic

system (Staiger, 2006). Mg alloys also show excellent

anti-platelet deposition (Gu, 2009) and low

thrombogenicity (Staiger, 2006). After being exposed

to a double extrusion procedure, the JDBM-2 alloy

shows excellent mechanical properties (YS = 66 +- 3

Mpa, UTS = 181 +- 5 MPa, elongation = 10.2 +-

1.3%), which makes it a promising candidate for

cardiovascular intervention. Moreover, the treatment

applied to the JDBM-2 alloy implies a great

improvement of its corrosion properties, which are

often a problem in Mg alloys.

Classically, the galvanic corrosion rates of Mg

alloys are too high compared with those of other

metals, which derives on device failure between the

tissue has completely healed. However, the JDBM-2

alloy corrosion properties (0.37 mm/year) make it

suitable for this kind of applications, as complete

structural and mechanical integrity of stents

manufactured with this alloy has been shown after 6

months of implantation (Mao, 2017).

3.2 Delivery System and Deployment of

the Device

The delivery and deployment of the device will be

done following the same techniques and principles

used on metallic devices implantation. As usual, the

whole process will be guided through fluoroscopy

and intracardiac echocardiography (ICE), and

patients will be under general sedation. The delivery

system, based on the AMPLATZER Delivery system,

will be composed of:

Loader: Used to introduce the device intro the

catheter

Hemostasis Valve: This part accounts with an

extension tube and stopcock that controls bleeding

Delivery Sheat: Used to deliver the device itself

Dilator: Used to allow tissue penetration

Delivery Cable: This cable is used for delivery of the

device, which is screwed to the distal tip of the cable.

To hydrate the collagen disks, the device will have to

be exposed to a soaked saline solution during

approximately 5 minutes. The device will be then

collapsed and loaded into the delivery system thanks

to the loader cable. The device will be administered

together with heparin and antibiotics to prevent

coagulation and infections.

3.3 Follow-up

The follow up of the procedure will consist of

periodic transthoracic echocardiography and chest

RX at 24 hours, three months, six months, and one

year after implantation, as done with similar devices.

It is also important to perform blood marker control

in order to check for any possible complications such

as coagulation and infections.

3.4 Benefit and Concerns

The use of 100% bioabsorbable materials translate

into multiple potential benefits of our device, X-

Trace. Those include decreased long-term

thrombogenicity, lower inflammatory response,

lower erosion potential and reduced

arrhythmogenicity. Plus, as the device will be

substituted by fibrous endothelialized tissue, the risks

of lifespan and chronic mechanical stress are almost

avoided. Moreover, the X-Trace device will increase

eligibility for PFO closure treatment: until now, all

the devices being used contain metallic materials that

have a long life inside the body which are not

compatible with the treatment of atrial fibrillation

(echocardiographic ablation). The proposed device,

which does not leave any metallic residues behind,

will enhance a better treatment of comorbidities. The

most significant concern is resorption or mechanical

failure of the device before its replacement by

autologous endocardial tissue, which could lead to a

recurrent device over it.

4 RISK ANALYSIS AND

ESSENTIAL REQUIREMENTS

According to 21 CFR 860, our product classifies as

Class III Medical Product. This translates into a high

ClinMed 2020 - Special Session on Designing Future Health Innovations as Needed

346

Table 1: Risk Assessment.

Hazardous situation Hazard Initial risk level Safety control measures

Final risk

level

Wrong insertion of

catheter

Bruising, damage to

artery

Acceptable

Experienced medical staff,

trainings

Acceptable

Forgetting to

assembly parts of the

intervention set

Incomplete intervention

set, necessity of removal

and reinsertion

Unacceptable

Trainings, intuitive design of

the product, warnings, clear

instructions of use

Acceptable

Use of contrast agent

for imaging

Allergic reaction Acceptable

Thorough pre-examination

of the patient record

Acceptable

Misplacement of the

product in situ

Migration of the device,

incomplete closure

Unacceptable Training, accurate imaging Acceptable

Device does not open

in situ

Tissue harm by removal

and reinsertion

Unacceptable

Testing, training, clear

instructions of use

Acceptable

Shape of collagen

matrix is

compromise

Tissue harm by removal

and reinsertion

Unacceptable

Testing, training, clear

instructions of use

Acceptable

Different

absorption rate of

the materials

Incomplete closure of

the ovale

Unacceptable

Thorough preclinical and

clinical trials

Acceptable

Migration of the

device

Artery, blockage,

tissue har

Unacceptable

Thorough preclinical and

clinical trials

Acceptable

risk medical device, which poses numerous risks and

its design requires a thorough risk analysis .Our work

follows the requirements from 21 CFR 820 in terms

of this risk analysis. Some of the identified risks are

presented in Table 1.

5 DEVELOPMENT PLAN

5.1 Timeline

The development plan will include the following

steps:

1. Initiation opportunity and risk analysis: During this

phase, the minimum requirements in terms of

mechanical properties, performance and

bioabsorbability for the device will be assessed

through literature review and advice from

professionals and key opinion leaders (KOL).

Moreover, basic financial, regulatory and legal

aspects will be evaluated, in conjunction with early

risk assessment and regulatory and clinical path.

Furthermore, a market and competence analysis will

be performed. Funding opportunities will be assessed.

2. Formulation of concept and feasibility: The initial

project plan will be elaborated and responsibilities

will be allocated to individual team members. Plus,

considering the needs and problem specification –

mechanical properties, self-deployability,

bioabsorbability, etc- and the professional’s opinion,

an early prototype will be selected. The extended risk

analysis will be initiated; all the possible risks, as well

as alternatives to avoid and minimize them, will be

listed. The preliminary economic, financial and

regulatory strategies will be further defined. Pre-

clinical studies to prove the non-toxicity and to

characterize the mechanical properties of the

materials to be used will be also performed.

Moreover, basic prototypes to sustain proof of

concept will be elaborated.

3. Design and development: At this phase, the product

design will be implemented and evaluated, ensuring

that the basic essential requirements are satisfied.

Moreover, the risk management, in which design, use

and process will have to be considered, and regulatory

Xtrace: Novel Bioresorbable Device for Patent Foramen Ovale Closure

347

strategies will be defined and implemented,

considering the specific device design. Furthermore,

the clinical validation plan will be designed

considering the applicable legislation as well as the

particularities of the designed device.

4. Final validation and product launch preparation: At

this phase, approval from the competent authorities

(in this case, FDA) will be required to commercialize

the product. Hence, all the applicable documentation

(clinical studies, safety, etc) will have to be presented.

Moreover, a market launch plan must be prepared:

direct contact with professionals and health provider

must be made to make them aware of our product.

5. Product launch and post-launch assessment:

During this phase, physicians must be trained in the

use of our product and sales strategies must be set in

practice. Moreover, to ensure safety, post-market

surveillance and follow up studies must be done.

Follow up is fundamental to identify and correct any

potential mistakes appearing on the process.

5.2 Tests and Experiments

During the product development phase, a series of

tests and studies is necessary in order to be able to

finally access the market. These tests are the

recommended endpoints by ISO 10993-1:2009 and

FDA. Firstly, cytotoxicity and cytocompatibility in-

vitro tests will have to be performed to evaluate the

toxic potential of the materials used in our product

and their biological acceptance by human tissue.

Permanent lineage cells will be used to classify the

modifications from non-cytotoxic to severe

cytotoxicity, while human differentiated cells will be

used to evaluate the cytocompatibility. For both tests,

it is afterwards intended to use small animal models

as rats for initial in-vivo testing of the bioresorbable

materials. A mechanical analysis in silico would be

necessary to test the material properties.

Secondly, a large animal model as a sheep is

necessary to validate in vivo biocompatibility and the

whole intervention process. Preferably, interventional

cardiologists would perform PFO closure on created

defects in the atrial septum of 10-20 animals.

Irritation, acute systemic toxicity, genotoxicity,

implantation and hemocompatibility can be evaluated

through these experiments. The collected data will be

used for further modifications of the device.

After successful experiments on animal models, a

pilot clinical study with 5-10 patients would have to

be performed to evaluate the device in terms of

biological reaction and the intervention process in

humans. This study will be a long term study with

follow-up of the patients to assess the degradation

rate of the materials, potential inflammations or other

complications. The collected data will be used for

further modifications of the device. The following

trials would be clinical trials on a bigger number of

patients to collect the necessary data for clinical

approval. Inclusion criteria, the choice of the

comparator, blinding, the duration of the study and

follow-up are all matters which will be taken into

consideration when creating the protocol. After

successful entry on the market, post-market follow-

up studies will have to be performed to collect

complaints and mitigate emerging risks.

6 DISCUSSION

Previous studies have tried to develop effective

solutions that prevent the adverse side effects and

complications of the current FDA approved PFO

occluders but without a successful outcome (Giblett,

2019 and Schwerzmann, 2005). The use of metallics

materials (mainly nitinol) can lead to late erosion.

Moreover, the bioabsorbable occluders are not

available in clinic due to higher risk of shunts.

Evidence suggests that the closure of PFO using the

bioabsorbable device is correlated with a low

complication rate and a low recurrence rate of

embolic events. Nevertheless, a high percentage of

mild or moderate residual shunting is present in the

following 6-months after the procedure. We analysed

previous clinical studies (Van den Branden, 2010),

performed literature review, as well as gained

feedback from professionals and key opinion leaders

(KOL) on designing the novel medical device in order

to solve these complications.

In order not to leave any foreign material behind,

the used material must be bioabsorbable, i.e., capable

of being absorbed into living tissue. To prevent

complete failure of the device before complete tissue

replacement, the service lifetime of the device must

be between 6 and 12 months. As the material will be

in direct contact with living tissue, it must be bio- and

hemocompatible. The used material must prevent

platelet aggregation and thrombogenesis. Moreover,

it must not cause excessive tissue inflammation.

Therefore, it is essential to assess the mechanical

properties, performance and bio-absorbability of our

proposed device to achieve a safe treatment. We find

ourselves in the very early stages of the project at the

moment of this communication, therefore the

majority of the research has been done only at a

theoretical level.

ClinMed 2020 - Special Session on Designing Future Health Innovations as Needed

348

7 CONCLUSION

Although our aim is initially to target the adult

population who suffer from cryptogenic strokes and

other complications, our prospects do include

expanding our target audience and tacking pediatric

treatment too. Moreover, skills are certainly needed

to be learned for the PFO closure procedure with the

help of an experienced interventional cardiologist

performing interventions with our device. The

availability of the product for different categories of

patients will fulfill the essential unmet clinical need,

as well as provide a safe and effective delivery of

therapy for the whole population. On the technical

side, there is the possibility to include a bioactive

coating capable of releasing anticoagulant drugs

directly into the framework of the device, thus

removing the necessity of administering the drugs

after the intervention separately.

ACKNOWLEDGEMENTS

We want to give a special thanks to the organisers of

EIT Health Clinmed 2019 summer school, as well as

the mentors for giving us advice and feedback on our

project during the workshop days. We also thank the

Faculty of Medicine of the University of Lisbon and

the Cardiology Imaging Unit at the Santa Maria

Hospital (Lisbon, Portugal) for arranging the

immersive experience.

REFERENCES

AMPLATZER PFO Occluder: PFO Closure Device.

Retrieved from https://www.cardiovascular.abbott/us/

en/hcp/products/structural-heart/amplatzer-pfo.html

Belkin, R. N., & Kisslo, J. (1990). Atrial septal aneurysm:

Recognition and clinical relevance. American Heart

Journal, 120(4), 948–957. doi: 10.1016/0002-

8703(90)90214-i

Branden, B. J. V. D., Post, M. C., Plokker, H. W., Berg, J.

M. T., & Suttorp, M. J. (2010). Patent Foramen Ovale

Closure Using a Bioabsorbable Closure Device. JACC:

Cardiovascular Interventions, 3(9), 968–973. doi:

10.1016/j.jcin.2010.06.012

Collado, F. M. S., Poulin, M. F., Murphy, J. J., Jneid, H., &

Kavinsky, C. J. (2018). Patent Foramen Ovale Closure

for Stroke Prevention and Other Disorders. Journal of

the American Heart Association, 7(12). doi:

10.1161/jaha.117.007146

Giblett, J. P., Abdul-Samad, O., Shapiro, L. M., Rana, B.

S., & Calvert, P. A. (2019). Patent Foramen Ovale

Closure in 2019. Interventional cardiology (London,

England), 14(1), 34–41. doi:10.15420/icr.2018.33.2

Gu, X., Zheng, Y., Cheng, Y., Zhong, S., & Xi, T. (2009).

In vitro corrosion and biocompatibility of binary

magnesium alloys. Biomaterials, 30(4), 484–498.

https://doi.org/10.1016/j.biomaterials.2008.10.021

Hagen, P. T., Scholz, D. G., & Edwards, W. D. (1984).

Incidence and Size of Patent Foramen Ovale During the

First 10 Decades of Life: An Autopsy Study of 965

Normal Hearts. Mayo Clinic Proceedings, 59(1), 17–

20. doi: 10.1016/s0025-6196(12)60336-x

Ko, R., Walker, N. E., & Mullen, M. J. (2010). Different

patent foramen ovale closure techniques in varying

anatomies. Interventional Cardiology, 2(1), 85–95. doi:

10.2217/ica.09.36

Mao, L., Shen, L., Chen, J., Zhang, X., Kwak, M., Wu, Y.,

Ding, W. (2017). A promising biodegradable

magnesium alloy suitable for clinical vascular stent

application. Scientific Reports, 7(1). doi:

10.1038/srep46343

Meier, B. (2005). Closure of patent foramen ovale:

technique, pitfalls, complications, and follow up. Heart,

91(4), 444–448. doi: 10.1136/hrt.2004.052258

Morgan, G., Lee, K.-J., Chaturvedi, R., & Benson, L.

(2010). A biodegradable device (BioSTAR™) for atrial

septal defect closure in children. Catheterization and

Cardiovascular Interventions, 76(2), 241–245. doi:

10.1002/ccd.22517

Opotowsky, A.R., Landzberg, M.J., Kimmel, S.E., Webb,

G.D., Trends in the Use of Percutaneous Closure of

Patent Foramen Ovale and Atrial Septal Defect in

Adults, 1998-2004. (2008). JAMA, 299(5), 521–522.

https://doi.org/10.1001/jama.299.5.521

Rhodes, J. (2008) PFO Closure for Prevention of Recurrent

Cryptogenic Stroke. Cardiac Interventions Today, 72.

Saver, J. L., Carroll, J. D., Thaler, D. E., Smalling, R. W.,

MacDonald, L. A., Marks, D. S., & Tirschwell, D. L.

(2017). Long-Term Outcomes of Patent Foramen Ovale

Closure or Medical Therapy after Stroke. The New

England Journal of Medicine, 377(11), 1022–1032.

https://doi.org/10.1056/NEJMoa1610057

Schwerzmann, M., & Salehian, O. (2005). Hazards of

percutaneous PFO closure. European Journal of

Echocardiography : the Journal of the Working Group

on Echocardiography of the European Society of

Cardiology, 6(6), 393–395. https://doi.org/10.1016/j.

euje.2005.09.007

Staiger, M. P., Pietak, A. M., Huadmai, J., & Dias, G.

(2006). Magnesium and its alloys as orthopedic

biomaterials: A review. Biomaterials, 27(9), 1728–

1734. doi: 10.1016/j.biomaterials.2005.10.003

Xtrace: Novel Bioresorbable Device for Patent Foramen Ovale Closure

349