Growth of High-Quality Oxides on The Inner Surface of ECMO Circuit by Atomic Layer Deposition to Reduce Thrombus Formation
Phase: NA
Conditions: Anticoagulation
Sponsor: National Taiwan University Hospital

20180122 
 
[計畫書] 
Growth of High-Quality Oxides on The Inner Surface of ECMO 
Circuit by Atomic Layer Deposition to Reduce Thrombus 
Formation 
Outline  
I. 
Background 
P2 
II. Specific Aims 
P6 
III. Research Design and Methods 
P7 
IV. Projected Timeline 
P11 
V. Research Personnel 
P12 
VI. Requested Equipment  
P12 
VII. Requested Budget and the Source 
P12 
VIII. Anticipated Outcomes 
P13 
IX. Attribution of Project Achievements 
P14 
X. References 
P14 
 
 

20180122 
 
I. Background 
A. ECMO, as an effective modality for life saving, however, with high risk of complications  
Mechanical circulatory support has evolved markedly over recent years. ECMO (extra corporeal 
membrane oxygenation), essentially a variation of the cardiopulmonary bypass circuit used routinely in 
cardiac surgery, is instituted in an emergency or urgent situation for the management of life-threatening 
pulmonary or cardiac failure (or both) when no other form of treatment has been or is likely to be successful 
[1]. By removing blood from the patient and circulating it through an artificial lung with a pump, ECMO 
can provide pulmonary and cardiac support, depending on the cannula arrangement. Whereas 
cardiopulmonary bypass facilitates open heart surgery for a number of hours, ECMO maintains tissue 
perfusion and oxygenation for days to weeks. It is currently being used worldwide as temporary support, 
usually awaiting recovery of organs, or can be used as a bridge to a more permanent device or cardiac 
transplantation.  
1) 
ECMO-related mortality and morbidity  
Being invasive, complex, resource intensive, and serious related complications, ECMO is restricted 
its use in highly specialized centers and mostly reserved for patients with a high risk of death who have 
failed conventional management and where the underlying respiratory or cardiac disease is reversible [2]. 
Advances in ECMO have made it a more feasible rescue modality compared with early experiences. 
However, the mortality remains high with survival rate of 77% for neonatal respiratory failure, 53% for 
adult respiratory failure, 45% for pediatric cardiac failure, and 32% for adult heart failure. The principal 
causes of ECMO-related mortality and morbidity are bleeding (7-34%) and thrombosis (8-17%) [3].  
2) 
Coagulopathy is the major device-related complications 
ECMO is well known to cause coagulopathy. High extracorporeal blood flow (BF) along with the 
large artificial surfaces of ECMO circuit can trigger serial cascades of inflammatory response including 
coagulation, complement, cytokines and eicosanoid systems with crosstalk among them [4]. The 
continuous activation of the contact and fibrinolytic systems as well as consumption and dilution of factors 
occurs within minutes of initiation of ECMO [5]. Platelets adhere to surface fibrinogen and are activated 
and the resultant platelet aggregation and clumping causes numbers to drop [6]. Correction by platelet 
transfusion produces only a temporary increase in numbers. Prolonged duration of ECMO exacerbates these 

20180122 
 
negative effects rendering the critically ill patients at more potential risks of coagulopathy, either bleeding 
or thrombosis. 
Bleeding can rapidly become life-threatening and appears to be out of proportion to the degree of 
coagulopathy and patient platelet count. Cannulation (7-20%) and surgical site bleeding (6-34%) are 
common. Intracranial bleeding (1-11%), especially in neonates, gastrointestinal haemorrhage (1-4%), and 
pulmonary haemorrhage (4-8%) may also occur [7]. Concurrently, extensive thrombosis will not only 
interferes the blood flow in the ECMO circuit leading to frequent tube changes, but also cause more 
devastating systemic complications, such as disseminated intravascular coagulopathy (DIC), 
cerebrovascular accident, pulmonary embolism, end organ failure, etc. Hemolysis is another well-
recognized complication of ECMO with an incidence of between 5% and 8% and can reciprocally aggravate 
the coagulopathy [8]. The free Hb is monitored as the indicator for screening the microthrombosis in the 
circuit. 
B. 
Current efforts to decrease the coagulopathy 
To prevent clotting of the cannulae, tubing and particularly of the oxygenator, and, moreover, the 
serious systemic thromboembolic events, systemic infusion of unfractionated heparin and heparin-bonded 
circuits are usually needed [6,9]. The thrombus formation is reduced. However, bleeding risk then is 
increased. The balance between hemostasis and thrombosis is critical. To avoid the adverse effects from 
commonly-used pharmacological methods, and since blood-surface interaction is a crucial promoter of the 
subsequent inflammation leading to coagulopathy, it seems more fundamental to treat the major 
complications by modifying the material of ECMO circuit which now is mainly composed of 
polyvinylchloride (PVC) compounds. In most patients, the duration of support required is approximately 1 
week or longer [10]. The biocompatibility is particularly an important issue regarding the extended period 
of ECMO use. 
1) 
Systemic Heparinization and Heparin-Bounded Circuit to Prevent Thromboembolic 
Complications  
Serious coagulopathy has been the major complication during ECMO support, either bleeding or 
thrombosis, leading to high device-related mortality and morbidity. Several efforts have been made 
on this problem, mainly with the pharmacological interventions. To reduce the thromboemolic 

20180122 
 
complications, high doses of heparin is usually needed with its major anticoagulant effect by 
inactivating thrombin and activated factor X (factor Xa) through an antithrombin (AT)-dependent 
mechanism. However, bleeding risk then increases and attempts should be made to avoid or minimize 
all non-urgent invasive procedures. Operative interventions in patients on ECMO can be particularly 
hazardous because of the risk of bleeding and should be avoided if at all possible [11]. Heparin-
bounded circuits were developed recently to reduce the use of systemic heparin and have been reported 
to reduce blood cell trauma [12], complement [13] and granulocyte [14] activation. Nevertheless, 
systemic heparinization is still advisable because of the risk of end organ damage from microthrombus 
and fibrin deposition, although the level of heparinization requito red is still under debate. Regular 
laboratory monitoring with activated partial thromboplastin time (APTT) is required to adjust the 
doses of heparin accordingly and hence makes resource intensive.  
2) 
Anti-Platelet Agents to Treat Coagulopathy 
Anti-platelet agents such as low-dose aspirin (acetylsalicylic acid) and short-acting GP IIb/IIIa 
inhibitors like tirofiban and eptifibatide have all been used to treat the thrombosis-bleeding 
complication by preventing platelets aggregation and possibly reducing inflammation. By using these 
platelet protecting techniques and adding an aprotinin infusion to block excessive fibrinolysis, one 
institution has reported a reduction in bleeding complications from 81% to 9% [15]. However, unlike 
clinical application of APTT to monitor heparin effect, there is no well-established method to guide 
the optimal use of anti-platelet agents in such a complex system.  
C. Improving the biocompatibility of ECMO is a more fundamental approach 
Whereas the pharmacological interventions would bring the critical imbalance between hemostasis 
and thrombosis, efforts to modify the ECMO system may be another essential method to approach the 
problem. Although ECMO remains a short-term support device, the use of such a circuit for extended 
periods (days to weeks) has required some modifications, among which the biocompatibility of the material 
of tubing and circuit system is an important consideration. Biocompatibility is a general term used to 
describe the suitability of a material for exposure to the body or bodily fluids. It is the ability of a material 
to perform with an appropriate response in a specific application. Biocompatibility is vital for medical 
devices. If a material used is not biocompatible, there may be complications such as extended chronic 

20180122 
 
inflammation at the contact point, generation of materials that are toxic to cells (cytotoxicity), cell 
disruption, restenosis after treatment, thrombosis, corrosion of an implant, etc. In the setting of ECMO 
support, using a biocompactible material is thought to minimize the blood-surface interaction, and hence 
give the control of the inflammatory response from the right beginning to prevent the following activation 
of serial cascades. Modification of the ECMO circuit with more biocompatible, especially hemocompatible 
material is reasonably a fundamental way to reduce the potential coagulopathy.  
1) 
Concerns about PVC, the current material of ECMO circuit 
PVC is the currently-used material in the ECMO blood tubing. Although it possesses unique 
physical and chemical properties, PVC was developed primarily for industrial use and later found their 
applications in biomedicine. Thus this synthetic material exhibits the incompatibility with blood and 
tissues. As in direct contact with blood, PVC is still prone to initiate the formation of clots, as the 
platelets and blood coagulation system are activated [16]. Besides, potential health hazards associated 
with the release of the plasticizer di-2(ethylhexyl)phthalate (DEHP) from the (PVC) tubing exist [17]. 
The lipid content of the liquid the PVC is in contact with, the temperature, and the duration of contact 
affects the leaching of DEHP with the greatest concern on the male reproductive system [18]. 
2) 
ZrO2 and Al2O3 are well-known biocompatible and hemocompatible materials 
In this subproject, ZrO2 and Al2O3 are chosen as the thin-film materals deposited on the inner 
surface of ECMO circuit to reduce the thrombus formation because of its excellent biocompatiblility. 
ZrO2 and Al2O3 are well-known biocompatible materials which have been widely utilized in artificial 
implants such as ears, teeth and joints, etc. They exhibit excellent material properties for 
biocompatible coating including good chemical resistance and dimensional stability, high wear 
resistant and hardness, zero water absorption, and noncorrosivity in saline environments. Recent 
researches have reported that ZrO2 can be safely used as an excellent hemocompatible material in the 
right ventricular assist device [19]. Results of coagulation assays and platelet aggregation tests for the 
ZrO2 implants showed no device-induced hemolysis or increase in platelet activation. In addition, 
biological depositions or wear were not observed on the ZrO2 surface, indicating excellent 
biocompatibility and hemocompatibility. These results clearly demonstrate that ZrO2 can be used 
safely and effectively as a blood-contacting tubing surface in ECMO circuit to improve the blood 

20180122 
 
compatibility. However, despite the broad applications of ZrO2 and Al2O3 in artificial implants, 
traditional thin-film coating techniques are unable to deposit these hemocompatible materials on the 
inner surface of the PVC tubes in ECMO circuit. 
D. Atomic layer deposition (ALD) 
ALD is a thin-film deposition process for preparing high-quality oxides with atomic-layer accuracy. 
It offers many benefits including accurate and facile thickness control, excellent step coverage and 
conformality, high uniformity over a large area, low defect density, good reproducibility, and low deposition 
temperature. These features clearly account for the feasibility to deposit high-quality hemocompatible thin 
films on the whole surface of complex 3-D structures, such as the inner surface of PVC tubing in ECMO 
circuit, using the ALD technique. 
II.  Specific Aims 
Surface modification of circuit material to improve the hemocompatibility 
In this project, we will aim at improvement of the biocompatibility of the material used in ECMO circuit 
to reduce the device-induced coagulopathy. A new technique of atomic layer deposition (ALD) will be applied 
to coat biocompatible and hemocompatible zirconium dioxide (ZrO2) and aluminum oxide (Al2O3) 
nanolaminate thin films on the inner (luminal) surface of ECMO circuit. The ALD technique is known to be 
capable of coating high-quality oxide thin films on a variety of complex surfaces. The advantages of ALD lie 
in its capability to produce high-quality and pinhole-free films on the surface of complicated 3-D structures 
with excellent uniformity and conformality as well as accurate thickness and composition control at a single 
atomic layer. Besides the preparation of the hemocompatible thin films on the ECMO tubing surface using 
ALD, surface enhanced Raman spectroscopy (SERS) is another crucial technique utilized in this subproject to 
optically probe the biomedical molecular characterization associated with blood coagulation and platelet 
activation. Moreover, the ALD technique will also be used to provide further enhancement of the 
functionalization, stability and reproducibility of the SERS substrates, so as to push the SERS technique into a 
more practical diagnostic tool in clinical monitoring. The safety and effectiveness of the newly-prepared 
ECMO circuit will be evaluated in the following in vitro and in vivo studies. 
 

20180122 
 
III. Research Design and Methods 
A. Atomic Layer Deposition (ALD) 
ALD is a thin-film deposition technique for preparing high-quality oxides with atomic-layer accuracy. 
The most distinctive feature of ALD is that each precursor is alternately pulsed into the reaction chamber, 
as shown schematically in Fig.5. When the first precursor is introduced into the chamber, the precursor 
molecules absorb upon the substrate surface by chemical absorption, resulting in the saturative absorption 
of one monolayer of precursor on the surface. Between the precursor pulses, the chamber is purged with an 
inert gas to remove all the excess precursors and by-products. As the next precursor is dosed in, it reacts 
with the precursor previously absorbed on the surface, producing one monolayer of solid product and 
gaseous by-products. Contrary to the conventional chemical vapor deposition (CVD), the chemical 
reactions in ALD proceed only at the substrate surface, resulting in self-limiting and layer-by-layer (or 
“digital”) growth. The self-limiting or self-terminating reaction also suggests that precise control of 
precursor homogeneity is not necessary. The only requirement is that sufficient precursor molecules are 
needed to cover the adsorption sites on the surface. In addition, ALD can provide conformal coatings on 
complex 3-D structures due to the diffusion of vapor-phase precursors into porous structures as well as the 
surface-controlled self-limiting growth. 
The advantages of ALD are summarized as follows [20]: 
1. Precise and easy thickness control with one monolayer accuracy. 
2. Accurate composition control and facile doping for achieving high doping concentrations. 
3. Stoichiometric films with low defect densitiy. 
4. High uniformity over a large area, leading to large-area and large-batch capacity. 
5. Excellent conformality and good step coverage. 
6. Low deposition temperature. 
7. Good reproducibility. 

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20180122 
 
addition, the deposition temperature in the PEALD process can be further decreased to be lower than 100◦C, 
which is very substantial for the thermolabile substrates like the PVC tubing in ECMO circuit.   
    One may wonder if ALD is a too slow and expensive process for the biomedical applications.      
Actually, ALD has become a cost-effective thin-film deposition technique due to its large-area and large-
batch capacity. The scale-up of ALD chambers to large batch capacity is facile and straightforward due to 
the self-limiting and layer-by-layer growth, high uniformity, excellent conformality, and good 
reproducibility of ALD. Large batch-type ALD reactors up to 150 wafers are commercially available now 
[21]. For instance, large batch ALD processing has been used to improve the throughput and applied in the 
massive production of solar cells. Another example of commercial application of ALD is the protective 
coating on jewellery. A robust and massive batch processing up to 2000 work pieces (please see Fig.6) has 
made ALD a cost-effective technique. 
  
B. 
Conformal biocompatible coating by ALD at low temperature 
The distinguished benefits of ALD as mentioned above can be further applied in the biomedical 
industry. For example, the ALD technique enables the coating of artificial implants with high-quality 
biocompatible thin films to minimize the impact between the implants and the biological processes inside 
the human body. The benefits of ALD for biocompatible coatings mainly come from the excellent 
conformality and uniformity together with the pinhole-free structure. Biocompatible ALD films can be 
used to reduce diffusion as well as improve corrosion and wear resistance. An ALD thin film only a few 
nanometers thick is flexible enough and thus prevent cracking, formation and spreading of detrimental  
 
 
 
 
Figure 6 A batch ALD reactor with 2000 work pieces being coated 
simultaneously (Copyright Beneq Oy, Finland). 
 
particles. Furthermore, ALD can be used to prepare the surface which resist bacterial growth and 

20180122 
 
accumulation of biological materials. Another advantage of ALD is that the deposition can be performed at 
relatively low temperatures (<150◦C), thereby limiting thermal damage to the thermally fragile and 
temperature-sensitive substrates. 
In this subproject, biocompatible and hemocompatible ZrO2/Al2O3 nanolaminate thin films will be 
coated on the PVC tubing surface of ECMO circuit using ALD to reduce the thrombus formation. It is 
particularly appropriate to prepare high-quality thin films on the whole surface of complicated 3-D 
structures, such as the inner surface of PVC tubes, using ALD due to its high conformality. It may be noted 
that traditional thin-film coating techniques, including physical vapor deposition (PVD) and CVD, are 
unable to deposit these oxides on the inner surface of PVC tubes. The introduction of Al2O3 into the thin 
films will prevent the aging of ZrO2 [22] and improve the adhesion to the PVC tubing surface. Other 
biocompatible materials, such as silicon dioxide (SiO2), titanium dioxide (TiO2), and titanium nitride (TiN), 
will be also prepared and tested to evaluate their hemocompatibility in ECMO circuit in this subproject. 
 
C. Testing of new material  
1) 
Physical characterization 
The thickness and dielectric constant of the ZrO2/Al2O3 nanolaminate thin films will be measured 
using spectroscopic ellipsometry (SE). The structure of ZrO2/Al2O3 nanolaminate thin films will be 
characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-
ray photoelectron spectroscopy (XPS). Atomic force microscopy (AFM) will be used for the analysis of 
surface morphology and roughness. 
2) 
Biological characterization 
Basic biological evaluations following ISO 10993/EN 30993 including chemical, mechanical, 
thermal and aging testing of the ZrO2/Al2O3 nanolaminate thin films are arranged. 
3) Hemocompatibility test 
Healthy non–smoking volunteers are included to donate fresh bloods via venipuncture for in vitro 
hemocompatibility test, while those who are pregnant, with bleeding disorders or taking 
anticoagulants, such as aspirin, NOAC, are excluded. A series of relevant assessments is done as the 
followings:  

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a、 Serum levels of blood platelet-activating-factors  
The blank PVC or PVC with T-ALD/PE-ALD Al2O3 films are planned to be immersed in whole blood 
for 1hr. The bloods are then collected and the sera were separated to determine the levels of blood platelet-
activating-factors including prothrombin, sP-selectin and PAF acetylhydrolase. 
b、 Adhesion and morphology of blood cells 
The blank PVC and Al2O3-coated PVC (T-ALD and PE-ALD) samples are planned to be immersed 
in whole blood and incubated at 37°C for 1 hr under the static condition to check blood-surfaces adhesion,. 
The samples are then washed gently with phosphate buffered saline (PBS), fixed with 2.5% glutaraldehyde 
solution for 2 hr at room temperature, and dehydrated in a gradient of ethanol/distilled water mixtures. 
Finally, the samples are undergone critical-point drying, and subsequently coated with gold ions and then 
inspected using a scanning electron microscopy. 
c、 Inflammatory response 
After 1 hr immersion in whole blood, the inflammatory responses induced by blank PVC or surface-
modified PVC samples are determined. The blood cells are collected, washed, and incubated with 
CD4/CD8, CD42b, CD45, or CD61/CD62P antibodies for 15 minutes on ice, and sorted using a 
fluorescence-activated cell sorter to evaluate the inflammatory responses. 
 
IV. Projected Timeline 
Year 
Development Stage 
1st Year 
2nd Year 
3rd Year 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Synthesis & improvement of 
potential targets 
Design & modification of 
new medical devices 
 
 
 
 
 
 
 
 
 
 
 
 
Optimization of leads & 
device models 
Prototype development 
Pilot-scale manufacturing 
 
 
 
 
 
 
 
 
 
 
 
 
Validation with clinical 
samples 
In vitro efficacy evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 

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VIII. Anticipated Outcomes 
A. Clinical improvement 
(1) Improvement of the device: The coagulopathy which are the major causes of device-related morbidity 
and mortality can be reduced, supporting the ECMO as a safer and more feasible modality for life 
saving. The clinical application of ECMO may be extended. 
(2) Improvement of patients’ outcome: Morbidity and mortality of the critically ill patients on ECMO will 
decrease because of not only avoiding devastating consequences from coagulopathy, but also less 
inflammatory response from the blood-surface interaction. The imbalance of inflammatory system is 
believed to be one of the crucial pathophysiological processes leading to organ failure. 
(3) Improvement of the critical care for patients on ECMO: This approach from the fundamental way of 
material modification instead of pharmacological intervention makes the current complex critical care 
simpler and easier with less complications and treatments. Besides, regular laboratory monitoring to 
guide the dose adjustment of medications is not required. 
(4) Cost & labor reduction: The cost and labor to treat the critically ill patients on ECMO will be reduced 
since the intensity of both treatments and monitoring is reduced for a smoother course. In addition, 
frequent changes of tubing system and oxygenator (around NTD 2,000,000 for one exchange) are 
avoided since there is lower incidence of hemolysis and thromboembolic problems which may lead to 
tube obstruction and plasma leakage. 
B. 
Beneficial impacts on biomedical industry 
(1) The distinguished benefits of ALD have attracted much attention to overcome a variety of technical 
problems, such as in the semiconductor industry in which the complex device structure with nanometer 
scale strongly call for the demand of ALD. However, the ALD applications in the biomedical industry 
still need to be developed. Based on the excellent performance and film quality of the ALD technique, 
this project seeks to explore and discover the potential applications and commercialization of ALD in 
the biomedical industry, including the biocompatible and hemocompatible coatings as well as the 
functionalization and stabilization of SERS substrates. The successful implementation of ALD for 
producing high-quality coatings on biomedical devices is expected as a key manufacturing technique 
in the future biomedical industry. 

20180122 
 
 
IX.  Attribution of Project Achievements 
本計畫為與台灣大學材料系老師合作進行的研究案，其研發成果歸屬台灣大學所有，未來可能將
成果進行技術移轉等運用。 
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