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Tissue Engineering\Biomaterials

A Nitric Oxide–Releasing Self-Assembled Peptide Amphiphile Nanomatrix for Improving the Biocompatibility of Microporous Hollow Fibers

El-Ferzli, George T.*†; Andukuri, Adinarayana; Alexander, Grant; Scopel, Michaella; Ambalavanan, Namasivayam*; Patel, Rakesh P.; Jun, Ho-Wook

Author Information
doi: 10.1097/MAT.0000000000000257
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Abstract

Extracorporeal circuits (ECCs) are critical to a number of medical procedures including hemodialysis, heart–lung bypass, and extracorporeal membrane oxygenation.1–4 When blood is exposed to the material of the ECC, platelet activation and adhesion are immediately initiated leading to blood clot formation.5–7 In addition, a systemic inflammatory response syndrome (SIRS) is nearly always present during initiation of extracorporeal life support (ECLS). A crucial factor in triggering the inflammatory response to ECLS is exposure of blood to nonphysiologic surfaces and conditions.

Therefore, elimination of the need for systemic anticoagulation and SIRS is desirable in ECLS. Different approaches have been taken to develop ECC materials that are more biocompatible. One approach is to develop materials that release therapeutics, such as heparin, at the site of blood contact, therefore controlling the initial bioresponse of the material.8 Another approach is the use of coating materials that mimic endothelial cells. In the normal blood vessel, the endothelial lining provides a thromboresistive surface by releasing molecules such as nitric oxide (NO).9,10 Nitric oxide serves as an antiplatelet agent to limit coagulation, reduces adsorption of blood clotting proteins to the material surface, and prevents infection and inflammation.8,11–14 Previous in vitro studies have used polymeric coatings of artificial surfaces that slowly release NO to mimic endothelial NO formation. However, the major drawback of these systems was the prevalence of significant donor leaching from the material into the soaking solution.8,14–19 Despite attempts to coat the ECC with the NO-releasing materials, there have been limited attempts to coat the oxygenator, which is an essential and integral element of the circuit. We have previously developed NO-releasing biomimetic nanomatrix comprising polylysine peptide amphiphiles (PAs). The nanomatrix has been shown to slowly release NO and mediate NO-dependent signaling in endothelial cells, smooth muscle cells, and endothelial progenitor cells, in addition to limiting platelet adhesion.20 In this study, we tested the feasibility of coating microporous hollow fibers with an NO-releasing biomimetic nanomatrix and determined whether this could attenuate platelet adhesion without inhibiting gas exchange.

Materials and Methods

Development of the Biomimetic Nanomatrix

Two PAs were developed: PA-YIGSR [CH3(CH2)14CONH-GTAGLIGQ-YIGSR] and PA-KKKKK [CH3(CH2)14CONH- GTAGLIGQ-KKKKK]. The peptides were synthesized in a solid phase using Fmoc chemistry in an Apex 396 Peptide synthesizer (AAPPTec, Louisville, KY) as described previously.20 The PAs contain enzyme-mediated degradable metalloproteinase (MMP)-2–sensitive sequences along with YIGSR or a polylysine (KKKKK) group to form NO-donating residues. The PA-YKs were designed by mixing 90:10 mol/mol ratios of PA-YIGSR and PA-KKKKK by a water evaporation method. To produce NO-releasing PAs from the biomimetic nanomatrix, PA-YK was reacted with excess NO gas at room temperature for 12 hours, at 5 atm pressure, under anaerobic conditions to form PA-YK-NO and allowed to form a self-assembled coating by water evaporation, which was characterized as described previously.20

Fiber Coating

A sample from a Celgard polypropylene hollow fiber mat (Celgard, LLC, Charlotte, NC) was cut to 2.5 cm × 1.2 cm, mounted by running a steel wire through the pores at the edge of the fibers at two different sites. The steel wire was rotated by a motor as the fibers were immersed in PA solution in an open top container. After coating for 12 hours, the fibers were dried for a further 12 hours at room temperature.

Scanning Electron Microscopy

Morphology of the nanomatrix coated on the hollow fibers was observed under a Philips XL 30 scanning electron microscopy (SEM) 510 (Philips, Andover, MA) at an accelerating voltage of 20 kV at three different magnifications (100×, 400×, and 30,000×). As a control, uncoated fibers were similarly characterized by SEM.

Test Modules

Test modules were constructed from both coated and uncoated control samples of Celgard polypropylene hollow fiber mat (n = 5 modules/group). Each sample was rolled into a bundle, and each end was then potted into male luer connectors using polyurethane potting compound (WC-753, BJB Enterprises, Tustin, CA). The module was then inserted into the test circuit by inserting each end into a female luer.

Test Circuit

A test circuit (Figure 1) was constructed with the test module, connectors, and tubing. The test module was connected to a syringe pump (NE1000 (New Era Pump Systems Inc., Farmingdale, NY)) for precise control of water flow through the device. The outlet of the test module was connected to a syringe for sampling. The test module was attached to 3/8” connector, which was connected to gas flow through a 3/8” Y connector to create 100% O2 environment. The gas circuit consisted of a 100% O2 tank with a pressure regulator and several gas flow controller components. Positioned distal to the tank, a mass flow controller (MFC) valve (Side-Trak 840-M (Sierra Instruments, Monterey, CA)), rated for 20 standard liters per minute (SLM) with air, was installed. The valve was connected through 20-lead ribbon cable to a custom-built MFC Power and Control Unit (Sable Systems International, Las Vegas, NV), which contains a power entry module, a ±15VDC power, as well as valve off and valve purge switches. The MFC valve flow setting was controlled and visualized by a custom Lab VIEW code, and with use of a National Instruments data acquisition hardware (NI cDAQ-9172 chassis and 4 modules: two NI9219 analog input modules, NI9237 bridge module, and NI 9263 analog output module). The gas flow units were SLM (standard conditions defined to be at 21°C and 760 mm Hg; 70 F and 1 atm). The gas flow rate was set at 2 liters per minute (LPM).

Figure 1
Figure 1:
A test circuit was constructed with the test module, connectors, and tubing. The test module was connected to a syringe pump for precise control of the water flow through the device and to another syringe for sampling. The gas circuit consisted of a 100% O2 tank with a pressure regulator. NI, national instruments; I/O, input/output.

Circuit Preparation, Samples, and Gas Transport Measurement

The syringe pump was filled with 5 ml of distilled water. The O2 gas was opened, and the test apparatus was filled with 100% O2. A 1 ml syringe was attached to the outlet of the test module for sample collection. Flow through the syringe pump was initiated. The outlet water was collected in the syringe and immediately analyzed on the blood gas machine. Capillary flow (m/s), partial pressure of O2 (pO2; mm Hg), change in pO2 (ΔpO2; mm Hg), and change in pO2 per surface area of each module (ΔpO2/surface area; mm Hg/m2) were measured at baseline and at water flow rates of 0.1, 0.5, and 1 LPM. All data were recorded manually on designated data sheets. The results from the gas measurements were recorded directly on the individual data sheets and then transcribed on to an Excel spreadsheet for analysis of O2 transfer. The sequence was repeated for each device. Data were collected from three independent experiments on each test module (n = 5 test modules/group).

Nitrite and Nitrate Formation Sample Collection and Measurement

The PA-YK-NO–coated and uncoated 1 cm × 1 cm hollow fiber mats (n = 4/group) were placed individually into a 24-well plate. The mats were covered with 500 μl phosphate-buffered saline (PBS) and incubated at 37°C. At 0, 4, 8, 12 hours, 1 day, 3 days, 5 days, and 7 days, the PBS was removed from each well and frozen in liquid nitrogen. Fresh PBS (500 μl) was added to the wells after each time point. For analysis, nitrite and nitrate levels were measured by the Griess assay coupled with high-performance liquid chromatography detection using the ENO-20 (Eicom, Kyoto, Japan) as described previously.21 Nitrite and nitrate concentrations were determined by comparison with the nitrite and nitrate standard curves.

Platelet Adhesion

Platelet adhesion on the hollow fibers was evaluated by assaying for acid phosphatase22 by incubation of platelet-rich plasma on uncoated and PA-YK-NO-coated hollow fibers. The PA-YK and PA-YK-NO nanofibrous matrix coatings were prepared on Celgard polypropylene hollow fiber surface (1 × 1 cm2). A solution of 2.5 mg/ml collagen I was prepared in 3% glacial acetic acid to serve as a positive control and cast into films. Whole blood from a healthy volunteer was collected in BD Vacutainer Heparin Tubes (BD, Franklin Lakes, NJ) containing 1 ml citrate buffer. This blood was centrifuged at 200g for 20 minutes. The supernatant that contains platelets was collected and used for the experiments. Uncoated hollow fibers and fibers coated with PA-YK, PA-YK-NO and collagen of 1 cm2 were incubated individually with 500 μl supernatant at 37°C for 90 minutes and then rinsed with PBS. Platelet adhesion was evaluated by incubating with acid phosphatase substrate (5 μM p-nitrophenylphosphate, 0.1% Triton X) for 1 hour. The reaction was stopped, color was developed by adding 2M NaOH, and absorbance was read at 410 nm. The protocol used for collecting blood from volunteer was approved by the institutional review board.

Statistical Analysis

All experiments were performed at least three independent times. All data were evaluated using one-way analysis of variance (ANOVA) to evaluate statistical significance between groups using SPSS software (International Business Machines Corp., Armonk, NY). If significant differences were noted by ANOVA, Tukey multiple comparisons test was performed to find significant differences between pairs. A value of p < 0.05 was considered to be statistically significant.

Results

Development of the Biomimetic Matrix and Coating of Hollow Fibers

We first tested the feasibility of coating microporous hollow fibers with PAs. Two PAs, PA-YIGSR and PA-KKKKK, were successfully synthesized and mixed at 90:10 mol/mol ratios of PA-YIGSR to PA-KKKKK to form PA-YK, which was subsequently reacted with NO gas to form PA-YK-NO. The PA-YK-NO self-assembled on the surface of the hollow fibers forming a nanomatrix, which was evaluated by SEM. Scanning electron microscopy at 100× and 400× (Figure 2A) showed the uniform coating of the microporous fibers with the self-assembling nanomatrix compared with uncoated fibers, whereas higher magnification SEM (Figure 2B) showed that the PAs assembled into a porous nanomatrix on the surface of individual fibers.

Figure 2
Figure 2:
A: Scanning electron microscopy of self-assembled nanomatrix over Celgard polypropylene microporous hollow fibers. Magnification: 100× and 400×. B: Scanning electron microscopy of self-assembled nanomatrix over Celgard polypropylene microporous hollow fibers. Magnification: 30,000×.

Gas Exchange

To evaluate the effect of the coating on gas transfer across the microporous hollow fibers, we compared the change of pO2 across fibers between coated and uncoated fiber modules in a test circuit. The change of pO2 was slightly higher, although not statistically significant, across the coated fibers compared with the uncoated fibers at different water velocities (y = −14.9x + 477 for coated fiber modules versus y = −11.3x + 500 for uncoated fiber modules; p > 0.05; Figure 3).

Figure 3
Figure 3:
Oxygen transfer across the Celgard polypropylene microporous hollow fibers (n = 5/group): coated (closed diamond, coated) and uncoated (closed triangle, control). Results are expressed as change in partial pressure of oxygen (pO2) in relation to water velocity through fibers (p > 0.05).

Nitrite and Nitrate Formation

Nitrite and nitrate were measured as an index of NO release. As observed previously, nitrite and nitrate formation were characterized by an initial burst in the first 24 hours followed by sustained release thereafter. Nitrite and nitrate release from the PA-YK-NO–coated fibers was significantly higher than that measured from uncoated fibers (p < 0.005; Figure 4, A and B).

Figure 4
Figure 4:
A: Cumulative nitrite formation from PA-YK-NO–coated (closed square, NO) and uncoated (closed diamond, control) polypropylene microporous hollow fibers over time (n = 4/group). Error bars denote mean ± standard deviation (p < 0.005). B: Cumulative nitrate formation from PA-YK-NO–coated (closed square, NO) and uncoated (closed diamond, control) polypropylene microporous hollow fibers over time (n = 4/group). Error bars denote mean ± standard deviation (p < 0.005). NO, nitric oxide; PA, peptide amphiphile.

Platelet Adhesion

There was no significant difference in platelet adhesion to uncoated fibers compared with collagen controls (Abs/A = 2.75 nm/m2vs. Abs/A = 2.07 nm/m2, respectively; p > 0.05), whereas coating the fibers with PA-YK-NO reduced platelet adhesion by 17-fold (Abs/A = 0.125 nm/m2) compared with the collagen controls (p < 0.05) and 22-fold compared with uncoated fibers (p < 0.05) (Figure 5).

Figure 5
Figure 5:
Platelet adhesion on collagen controls (collagen), uncoated polypropylene microporous hollow fibers (uncoated), and fibers coated with PA-YK-NO (YK-NO). Results are expressed as absorbance per unit area (nm/m2). Data represent the mean of six samples. Error bars represent mean ± standard deviation (*p < 0.05; YK-NO compared with collagen and uncoated). NO, nitric oxide; PA, peptide amphiphile.

Discussion

The overall hypothesis of this study was that coating the microporous hollow fibers with a NO-releasing biomimetic nanomatrix would improve the biocompatibility of the hollow fibers by reducing platelet adhesion without affecting their gas exchange capability. Endothelial cells are known to produce more than 12 different molecules that affect platelet function, the coagulation cascade, or both processes. The major inhibitors of platelet function are NO, prostacyclin, and matrix MMPs.5 This inhibition is transient, so that the platelets resume normal function once they are no longer exposed to these inhibitors. Of these inhibitors, NO has been the agent most often studied for incorporation into polymers, because of its very short half-life, its ability to be present in both liquid and gas states, while it can be incorporated into the sweep gas of gas exchange devices if the biocompatible surface cannot be applied to the surface of these devices without jeopardizing their function.5,15

Previous work by other investigators has mainly focused on material synthesis optimization methods for controlled and sustained NO concentration at the blood–polymer interface. The artificial surfaces were made biocompatible either by entrapping NO donors within their bulk or incorporating catalysts to generate NO from NO donors. Using the first method to improve biocompatibility of pediatric catheters was limited by short NO-release duration, whereas the second method has not been applied to large surface area devices such as oxygenators.23–27

Previously, we showed that NO-releasing polyurethane had great potential for vascular grafts and stents.28–31 However, the use of these materials has so far been limited because of (1) the use of organic solvents causing loss of NO during the reaction and coating processes, (2) inflammation from residual synthetic polymers, (3) difficulty in providing long-term sustained release of NO because of limited diffusion through materials, and (4) delayed or limited endothelialization without endothelial cell–binding moieties. To overcome these problems, we developed a NO-releasing biomimetic nanomatrix by using a bottom-up method to achieve unique synergistic effects from multiple bioactive functions.32,33 The biomimetic nanomatrix has unique features including composition of an exclusively biocompatible peptide–based material that may reduce concerns regarding inflammatory responses and development of a self-assembled coating on the hollow fibers by a water evaporation method without organic solvents. It significantly differs from other NO-releasing materials because NO bound to lysine (K) peptides is entrapped within self-assembled PA-KKKKK nanofibers with uniform diameter between 7 and 8 nm and several microns in length. Therefore, NO can be released by multistage kinetics such as from the top-layered surface of the nanomatrix coating, by diffusion through the several hundred layers of the nanomatrix coating, and from inside each PA-KKKKK nanofiber. These characteristics permit long and sustained release of NO from the biomimetic nanomatrix.20,34

We previously demonstrated that successful NO release occurred as a burst in the first 48 hours, followed by a slower sustained release over a period of 30 days, resulting in a recovery of 90.8% of available NO. The initial burst release is possibly explained by NO release from the surface of PA-YK-NO nanomatrix. The subsequent sustained slower release may be attributed to NO release from the inside of each nanofiber and the bulk of the nanomatrix by diffusion.32 This trend was confirmed in our current study as we showed that there was a sustained formation of nitrite and nitrate over 7 days after an initial burst during the first 24 hours (Figure 4, A and B).

In our previous studies, we calculated that the rate of NO release was of the same order of magnitude as cumulative NO released by endothelial cells at a rate of 1 × 10−10 mol/cm2/min. This flux demonstrates the ability to functionalize polymers to release NO at levels comparable with that produced by the endothelium (0.4–5 × 10−10 mol/cm2/min).8,15,35–38 In our current study, we showed that there was significant decrease in platelet adhesion in the group of fibers coated with the biomimetic nanomatrix compared with the uncoated fibers or collagen controls. These results are in accordance with the studies that showed that surfaces releasing ≥1 × 10−10 mol/cm2/min of NO showed a significant inhibition of clot formation compared with non–NO-releasing controls in in vivo animal studies7,15,39 although other studies showed that platelet consumption was proportional to NO release in the absence of systemic anticoagulation with the optimal level of NO needed to preserve platelet consumption was 13.7 × 10−10 mol/cm2/min in their animal model.5

Although decreases in platelet adhesion and thrombus formation in the presence of NO-releasing polymeric coatings in vitro and in vivo have been observed in several studies, the leaching of potentially harmful amine byproducts from these coatings has also been observed.8,15 The NO-producing materials developed by our group contain covalently bound NO donors, which are derivatives of natural amino acids, and have been shown to decrease platelet adhesion. We have shown previously that the addition of an NO-releasing peptide into the main chain of a polyurethane can improve thromboresistance while retaining the mechanical properties of commercially available vascular graft materials.39 Similarly, we have demonstrated that the PA-YK-NO was stable under physiologic conditions with very little flaking or cracking, even when compared with commercial medical device coatings.40 In this study, we showed that the biomimetic nanomatrix did not affect the gas exchange properties of the microporous hollow fibers in bench-top studies.

Conclusion

Taken together, we have demonstrated the feasibility of coating microporous hollow fibers with a self-assembling NO-releasing biomimetic nanomatrix using a bottom-up methodology. The coating did not affect the gas exchange efficacy of the fibers, whereas it significantly reduced platelet adhesion. Future studies evaluating the effect of shear stress on the release of NO and the stability of the coating as well as the effect of NO on the multitude of biological systems are warranted.

Acknowledgment

The authors thank MC3 Corp (Ann Arbor, MI) for providing them with the hollow fibers and assisting in the benchtop experiments and data analysis.

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Keywords:

nitric oxide; amphiphile; nanomatrix; biocompatibility; oxygenator; hollow fibers

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