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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

Summary

This study investigated the antifouling activity of artificial lung hollow fibers coated by priming the lung device. While this surface modification of fibers approach is practical, the effectiveness of the coating process depends on the graft coverage across fiber mat layers within the bundle.

Abstract

Although the high surface area-to-volume ratio of the artificial lung fiber bundle enhances gas exchange, the large surface area, dense arrangement, and surface chemistries of the fibers are major contributors to thrombosis. To mitigate this, it is essential to uniformly modify the surface chemistries to effectively reduce non-specific protein fouling, which can help limit thrombosis and lower the risk of thromboembolism or bleeding caused by systemic anticoagulants.

In this study, we explored the application and antifouling properties of zwitterionic polymer grafts on polypropylene fiber bundles. The grafting process involved priming the artificial lung device with zwitterionic polysulfobetaine molecules and polydopamine linkers for in situ coating. The antifouling performance was evaluated using standard fibrinogen enzyme-linked immunosorbent assay (ELISA) and platelet lactate dehydrogenase fouling assays. X-ray Photoelectron Spectroscopy confirmed the surface coating, and significant reductions in fouling were observed on coated fibers compared to uncoated ones, demonstrating the utility of the grafting process and the promise of its antifouling effects.

However, differences in the appearance of the coating on fibers within the bundle were noted with the coating by priming process, which could affect the overall antifouling performance. Addressing this issue could further enhance the antifouling efficiency of lung fiber bundles modified through in situ grafting.

Introduction

Artificial lung fibers, also known as hollow fiber membranes, are essential materials for fabricating extracorporeal membrane oxygenation (ECMO) devices that provide respiratory support to critically ill patients. Multiple layers of these fibers make up a dense bundle that serves as the gas exchange unit. The polymeric fiber surface, however, activates the blood coagulation cascade -leading to clot formation (thrombosis). Thrombosis on artificial surfaces is primarily driven by the activation of the coagulation cascade, a complex series of enzymatic reactions that lead to the formation of a blood clot. When blood comes into contact with foreign materials, such as those in medical devices (e.g., artificial lungs, stents, catheters), the coagulation cascade is triggered1,2. This process begins with the exposure of blood to the surfaces of the artificial material, which activates the intrinsic pathway of the cascade. This activation leads to the generation of thrombin, a key enzyme that converts fibrinogen to fibrin, forming the structural basis of a clot. Simultaneously, platelets are activated and aggregate at the site, further reinforcing the clot. The result is thrombosis, which can obstruct blood flow and lead to serious complications such as stroke or myocardial infarction.

To prevent thrombosis on artificial surfaces, traditional anticoagulants, such as heparin, warfarin, and newer direct oral anticoagulants (DOACs), are commonly used3,4. These medications work by interfering with various steps of the coagulation cascade. For example, heparin enhances the activity of antithrombin III, a natural inhibitor of thrombin, while warfarin inhibits the synthesis of vitamin K-dependent clotting factors. However, the use of anticoagulants presents several challenges. First, they increase the risk of bleeding, which can be life-threatening in certain situations. Second, the effectiveness of anticoagulants can be variable, requiring regular monitoring and dose adjustments, particularly with warfarin. Additionally, long-term anticoagulant use is associated with adverse effects such as osteoporosis and skin necrosis. The need for systemic anticoagulation also limits the use of medical devices in patients who are at high risk for bleeding.

Because thrombosis can impede gas exchange across the hollow fiber membrane, antifouling coatings have been applied to the lung fibers using various methods, such as dip coating and electrospinning, to prevent biofouling5,6. Artificial lung manufacturers typically process hollow fibers that are commercially obtained from fiber manufacturers and assemble them into lungs through steps including bundling of the fibers around a solid core, potting (gluing) bundle ends, incorporating potted bundles in a housing capsule featuring gas and blood flow channels, and post assembly cleaning. While the coating of fibers that have not been implanted in the lung can be more flexible, a surface modification at the pre-bundling stage will be subjected to several manufacturing steps that necessitate mechanical and chemical interactions between the surface coating and the downstream process environments, which can lead to denuded fibers in a device where high coating coverage is essential for limiting thrombosis. Alternatively, the coating can be applied to the potted bundle. An advantage of the ability to coat finished lungs is that it is a practical and facile modification approach to surface engineering the artificial lung device and many other devices. But in general, the method of applying coatings, whether through spray or dip coating, is less critical to thrombosis prevention than the effectiveness of the coating itself. For instance, hollow fibers used in medical devices can be dip-coated during extrusion, then knitted into mats, wound into bundles, and incorporated into a finished artificial lung device. Alternatively, coatings can be applied after the device has been manufactured. The key factors, however, are the effective application, durability, and efficacy of the anti-thrombotic coating5. This is because, in the absence of systemic anticoagulation, the function of these coatings is an essential piece of the puzzle for preventing clot formation, necessitating the need for a highly efficient and long-lasting antifouling property to ensure effective thrombosis prevention.

Despite the application of antithrombogenic coatings and the simultaneous low-dose administration of anticoagulants to date, the artificial lung module must be replaced only after a relatively short period of use, ranging from days to 3 weeks7,8, because of thrombosis. The gas exchange efficiency of their fiber membranes deteriorates after a relatively short time because of fouling by a membranous blood clot structure (composed of fibrin, single cells, and cell clusters) that covers large areas of the fibers, increasing their gas diffusion barrier9. In general, the type of coating and application method10,11,12,13,14,15,16,17,18 used depends on the desired properties, such as biocompatibility and durability. Several examples of antifouling coatings have been used on artificial lung fibers. They include silicone which is widely used due to its biocompatibility19, durability, and resistance to biofouling; polyurethane (PU) due to its biocompatibility and resistance to biofouling20; chitosan due to its biocompatible and antimicrobial properties21,22, heparin that inactivates thrombin23,8, and hydrophilic24 polymer-based coatings including poly(ethylene glycol)25,26, poly (2-methoxyethyl acrylate)27, and phosphorylcholine28,29.

Zwitterionic coatings represent a promising strategy for reducing thrombosis on artificial surfaces without the need for systemic anticoagulation5,6. These coatings are composed of molecules with both positive and negative charges, which balance each other out and result in a highly hydrophilic, non-fouling surface. The zwitterionic nature of these coatings reduces protein adsorption and platelet adhesion, both of which are critical steps in the initiation of the coagulation cascade. By preventing the initial interaction between blood proteins and the artificial surface, zwitterionic coatings effectively inhibit the activation of the coagulation cascade and reduce the risk of thrombosis. This approach not only minimizes the need for systemic anticoagulants but also offers a more biocompatible solution for the long-term use of medical devices.

In this study, we evaluated the effectiveness of priming the artificial lung with an ultra-low fouling zwitterionic poly(sulfobetaine methacrylate) (pSBMA) coating combined with a surface adhesive polydopamine (pDOPA) layer. After priming the device, it was positioned side-to-side every 10 min for 2 h during the coating process. To assess potential variations in coating across the fiber bundle, we measured fibrinogen and platelet fouling on fibers located at the surface and within the bundle. Additionally, we analyzed the impact of flow on the antifouling performance by comparing fouling data from lungs before and after exposure to flow. For long-term antibiofouling applications involving complex media flow, zwitterionic coatings must not only inhibit fouling from whole blood -- a challenging task -- but also maintain their effectiveness under hemodynamic stress throughout the application period. These coatings need to provide strong steric repulsion against non-specific protein adsorption and achieve a suitable surface packing density to form a hydration film barrier between the substrate and the complex media. Moreover, they must remain securely attached to the surface without detachment of the linkers anchoring the coating to the substrate30. The protocol described here is designed to ensure the application of coatings that meet these critical requirements for effective and durable surface protection.

Protocol

The protocol follows the guidelines of the human research ethics committee of the University of New Haven.

1. Coating of the artificial lung circuit

NOTE: The artificial lung circuit was coated following a two-step zwitterionic DOPA-SBMA grafting approach. The fiber bundle/oxygenator details are proprietary information. In experiments where the effects of flow on the antifouling activity of coated lung was the focus, the oxygenator and tubing circuit (5/16" Tygon tubing with conjugable polycarbonate connectors) was subjected to a 24 h phosphate-buffered saline (PBS; pH 7.34, temp. ~37 °C) flow limited by our pump's maximum flow rate of 1.22 L/min. For context, the exact flow rates in oxygenators depend on the patient's needs and the specific clinical situation, but they generally range from 2-7 L/min in adult patients. PBS was used in this case to allow for a facile quantification of key blood coagulation marker fouling on coated fibers after flow. Any confounding effects from whole blood fouling, if whole blood flow were used to evaluate the effects of shear rate on the antifouling activity of coated fibers, would be eliminated by using PBS. The following steps were used to coat the artificial lung:

  1. Clean the lung circuit by recirculating 30% methanol in deionized (DI) water for 20 min, followed by recirculating 10% methanol in DI water and DI water for 20 min.
  2. Dry the circuit with filtered house air at low flow for 2 h prior to ultraviolet ozonolysis (UVO) plasma exposure.
  3. Place the cleaned lung circuit into a UVO plasma generator (UVO-Cleaner), close it, and turn on the UVO plasma generator instrument for plasma interaction with the device for 20 min.
  4. After plasma exposure, the device should proceed to the coating step without delay to limit surface chain rearrangement and hiding of reactive sites generated from plasma interaction.
  5. While the surfaces of the device are being modified, prepare a fresh coating solution. In 600 mL of TRIS buffer (pH 8.5), dissolve 1.2 g of Dopamine-HCl followed by dissolving sulfobetaine methacrylate (SBMA) monomer at 1:15 DOPA:SMBA ratio.
  6. Add 5 mM of sodium periodate (20 µL) droplets to the coating solution and mix. Use a glass beaker, a magnetic stir bar, and a stir plate at 150 rpm to aid in mixing.
    NOTE: Add the coating solution to the device no more than 20 min after preparation. Therefore, if multiple lungs are coated, a facile way of priming the devices- for example, the use of pumps for priming- can be helpful.
  7. Prime the lung device with the coating solution using a large volume syringe (60 cc) to draw and fill the circuit. With one end of the circuit clamped, prime it from the other, ensuring that air bubbles can be guided out of the circuit through a circuit access connector.
  8. When fully primed, place the device under a UV light source for 2 h and agitate the solution by re-orienting the ends of the primed device up and down every 10 min.
  9. After the UV light treatment, drain the circuit and gently rinse all samples with deionized (DI) water by priming with a 60 cc syringe and draining repeatedly. When the effluent of the DI rinse is clear, store the device primed with DI water in a 4 °C fridge for autopsy and surface analyses.

2. Lung autopsy

  1. Drain and dry lung circuit with filtered and gentle airflow in a chemical hood.
  2. Perform device autopsy by fixing them in a Bench Vise w/ Swivel Base. Use a bandsaw to section the inlet/outlet connections to the device housing and the front and back face plates of the housing, carefully cutting along their peripheries using an industrial-grade X-acto knife and a hammer.
  3. After removing the face plates, fiber mat layers are accessible. Carefully section across fibers to access fiber matt samples at any location within the bundle (e.g., the surface and within). Handle samples with tweezers at their edges and transfer them into 60 mL tubes filled with deionized water to limit sample contamination.

3. Evaluation of protein fouling on coated lung circuit materials

  1. Fibrinogen adsorption test.
    1. Incubate size (~1 cm x 1 cm) standardized fiber matt samples in 1 mL of 3 mg/mL fibrinogen in well plates for over 90 min at 37 °C with agitation at 60 rpm.
    2. Wash (3x) samples with PBS buffer, transfer them into new wells, and add 1 mL of 1 mg/mL of bovine serum albumin (BSA) to each well. Incubate for another 90 min, then wash again with PBS buffer (3x) and transfer samples into new wells.
    3. In the new wells, add 1 mL of 1:1000 dilution of Horse radish peroxidase (HRP) conjugated fibrinogen antibody in PBS to each well and incubate for 30 min. Then, wash (3x) samples with PBS buffer and transfer them into new wells.
    4. In the new wells, add 500 µL of 1 mg/mL o-Phenylenediamine (OPD) in 0.1 M citrate-phosphate buffer with 0.03% hydrogen peroxide, pH of 5.0 at 30 s intervals and incubate away from light for 30 min.
    5. Halt the peroxidase and OPD reaction by adding 500 µL of 1 N HCL to each well.
    6. Remove and transfer supernatant from each well to a cuvette. Measure the absorbance of supernatant using a UV-visible spectrophotometer at 492 nm.
  2. Platelet adhesion test.
    1. Thaw the lactate dehydrogenase (LDH) assay kit for 20 min.
    2. While the thawing is underway, prepare pooled adult human plasma to obtain platlete rich plasma (PRP).
    3. To prepare PRP, centrifuge thawed human plasma sample tubes at a hard spin at 483 x g to separate the plasma into two regions, in which the lower one-third is PRP and the upper two-thirds of the tube will contain the platelet poor plasma (PPP).
    4. Remove platelet pellets formed at the bottom of the tube as well as the upper two-thirds at the centrifuged blood plasma and disperse the pellet into the upper two-thirds of plasma by gently shaking the tubes.
    5. Add calcium chloride (0.2 M) to the PRP (1:1 v/v) to reverse the effects of citrates before testing.
    6. Incubate the samples (~1 cm x 1 cm) in 500 µL of PRP for 90 min at 37 °C, then rinse three times with PBS buffer, and transfer them into new wells.
    7. Add 300 µL of PBS and 10 µL of 10x lysis buffer and incubate for 45 min.
    8. Add 50 µL of the reaction mix and incubate for 30 min away from light.
    9. Add 50 µL of HCL to stop well reactions.
    10. To detect the LDH activity of lysates from adsorbed platelets, measure the light absorbance by the developed well solutions at 490 nm and 680 nm wavelengths and subtract the 680 nm reading from the 490 nm to analyze platelet adhesion.

4. Flow effects on antifouling activity

  1. Prime the artificial lung circuit with PBS and ensure no leakage. Then, affix the circuit to the roller pump and recirculate the PBS for 24 h.
    NOTE: A flow rate of 1.22 L/min was the highest achievable.
  2. To simulate the normothermic temperature of the blood that would flow through the lung device, incubate the artificial lung in a 37 °C water bath during the recirculation.
  3. Then, perform lung autopsy and protein fouling challenge studies as described above.
    NOTE: One-way analysis of variance was used to determine if there were statistically significant differences among the means of the independent groups, and Tukey's HSD was used to determine which specific groups differed.

Results

A protocol for zwitterionic polymer grafting of artificial lung circuit by priming, disassembly of the device for coated fibers sample collection, and antifouling evaluation of sectioned fibers is presented. In Figure 1, the surface modification of the artificial lung circuit approach is illustrated. Lungs were exposed to UVO plasma for the interaction of radical oxygen singlet with fibers, which was followed by steps of zwitterionic pSBMA coating of the artificial lungs by priming with coat...

Discussion

The PDMS-coated polypropylene (PP) fibers in the artificial lung demonstrated a relationship between ozone exposure and fiber structure, establishing a sensitization limit for ultraviolet ozone plasma. This limit guides the exposure times needed to generate surface radicals for grafting coating materials, specifically polydopamine and polysulfobetaine methacrylate. When the fibers were exposed to ultraviolet ozone plasma for less than 20 min, no significant structural changes were observed. However, exposure times of 30 ...

Disclosures

The authors declare no competing financial interests. Dr. Keith Cook and Dr. David Skoog hold ownership equity in ART LLC.

Acknowledgements

This work was funded in part through a services agreement under NIH 1R01HL140231-01A1.

Materials

NameCompanyCatalog NumberComments
BeakersThermo Fisher Scientifichttps://www.thermofisher.com/search/browse/category/us/en/90094065Used in experiments
Beckman Coulter Allegra X-30R centrifugeBeckman Coulterhttps://www.mybeckman.in/centrifuges/general-purpose/allegra-x-30For centrifugations
Biochemguard BSL2 safety hoodBiochemguardhttps://bakerco.com/images/uploads/assets/BiochemGARD_220v_Web_0.pdfUsed for UV light source in graft coating
Bovine albumin serum (BSA)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/substance/bovineserumalbumin123459048468Fibrinogen assay materials
Citrated pooled male blood plasmaZenBiohttps://www.zen-bio.com/products/serum/human-blood-products.phpUsed for experiments
Citrate-phosphate bufferSigma-Aldrichhttps://www.sigmaaldrich.com/US/en/search/citrate-phosphate-buffer?focus=products&page=1&perpage=30&sort=relevance&term=citrate-phosphate%20buffer&type=productFibrinogen assay materials
Dopamine-hydrochlorideSigma-Aldrichhttps://www.sigmaaldrich.com/US/en/product/aldrich/h60255For coating
Dopamine-hydrochlorideSigma-AldrichN/AFibrinogen assay materials
Fluorescein conjugated Goat Immunoglobulin G (IGG)Sigma Aldrichhttps://www.sigmaaldrich.com/US/en/product/mm/aq303fFor Fluorescence Light Intensity measurements
Horseradish peroxidase-conjugated anti-fibrinogen antibodySigma-Aldrichhttps://www.sigmaaldrich.com/US/en/search/horseradish-peroxidase-conjugated-anti-fibrinogen?focus=products&page=1&perpage=30&sort=relevance&term=horseradish%20peroxidase%20conjugated%20anti-fibrinogen&type=productFibrinogen assay materials
Hot PlateThermo Fisher Scientifichttps://www.thermofisher.com/in/en/home/life-science/lab-equipment/hot-plates-stirrers/lab-hot-plates.htmlUsed in experiments
Human fibrinogen powderSigma-Aldrichhttps://www.sigmaaldrich.com/US/en/search/human-fibrinogen?focus=products&page=1&perpage=30&sort=relevance&term=human%20fibrinogen&type=productFibrinogen assay materials
Jelight UVO-Cleaner model 144AXJelighthttps://www.jelight.com/uvo-cleaner/Used for plasma treatment of medical device materials
LDH assay kitABCAMhttps://www.abcam.com/en-us/products/assay-kits/ldh-assay-kit-lactate-dehydrogenase-assay-kit-colorimetric-ab102526For LDH assay
O-phenylenediamine (OPD)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/product/sigma/p9029Fibrinogen assay materials
PDMS coated polypropylene fibersART LLCN/APart of artificial lung materials
Phosphate buffered saline (PBS)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/product/sigma/p4417Fibrinogen assay materials
Plate Reader (BioTek)BioTekhttps://www.agilent.com/en/product/cell-analysis/real-time-cell-metabolic-analysis/plate-reader-metabolic-assaysFor reading Fluorescence Light Intensity
Polydimethylsiloxane (PDMS)ART LLCN/APart of artificial lung materials
Sodium periodate (NaIO4)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/substance/sodiummetaperiodate213897790285For coating
Stockert Shiley multiflow roller pumpSorin BiomedicalN/AFor flow experiments
Sulfobetaine methacrylate (SBMA)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/search/sulfobetaine-methacrylate-(sbma)For coating
TRIS-buffered saline (pH 8.5)Sigma-Aldrichhttps://www.sigmaaldrich.com/US/en/product/sigma/t8793Prepared in the lab from TRIS sachets
Tygon tubingART LLCN/APart of artificial lung materials

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