Modified poly(4-methyl-1-pentene) membranes by surface segregation for blood oxygenation (2023)

Extracorporeal membrane oxygenation (ECMO) which simulates human natural circulation with extracorporeal circulation to improve oxygenation and remove carbon dioxide (CO₂), facilitates movement and improves physical fitness before transplantation [1], has become the accepted standard for the treatment of advanced acute heart and respiratory failure for adults and pediatrics [2]. ECMO may be appropriate medical support for patients with refractory respiratory failure caused by COVID-19 [3]. Poly-4-methyl-1-pentene (PMP) is an ideal membrane material due to the advantage of high gas permeability (P(O₂)=27 Barrer), good biocompatibility, high thermal stability and high mechanical strength [4]. As a site of indirect contact between venous blood and oxygen [5], PMP hollow fiber membranes (HFM) with a large surface area (~2 m²) show both a microporous main structure for gas transfer and an ultrathin dense epidermal layer to prevent plasma leakage, have become a key part of the modern membrane oxygenator [6,7]. However, those foreign surfaces of PMP HFM would result in the activation of the coagulation cascade and the deposition of platelets when they inevitably come into contact with blood in extracorporeal circuits [8], which leads to reduced gas exchange efficiency, device failure and emboli formation, ultimately remaining unsatisfactory in the long-term operation [[9], [10], [11], [12]]. The clinical routine for reducing thrombus formation is systemic heparinization [13], but it can cause hemorrhagic complications in patients with a high risk of bleeding [14]. Therefore, it is vital for surface modification to achieve the necessary anticoagulation of blood while maintaining an appropriate level of hemostatic activity and to be committed to the development of a safer, more effective, more durable and hemocompatible membrane and membrane oxygenator [15,16].

Much effort has been focused on improving the hemocompatibility of oxygenation membranes, including 1) the construction of surface inertia modification [6,16,17], which concludes hydrophilic modification, superhydrophobic modification, and negatively charged surface modification, which means changing the physicochemical property of the membrane surface to become relatively inert in response to blood [9]. Khorasani et al. [18] found that wettability is an important factor in blood compatibility. Both superhydrophilic and superhydrophobic surfaces show excellent compatibility with blood. 2) achieving a biomimetic surface [5,8,[19], [20], [21]]. Pflaum et al. [20] coated PMP with TiO₂using a pulsed vacuum cathodic arc plasma deposition technique to create a stable interlayer, allowing cell adhesion to the strongly hydrophobic PMP membrane. And adherent endothelial cells (EC) on PMP membranes can form a confluent and non-thrombogenic monolayer, which effectively improves surface hemocompatibility. 3) introduction of bioactive substances [9,13,22,23], Malkin et al. [24] grafted sulfobetaine block copolymers with N-hydroxysuccinimide ester (SBNHS) to amino or hydroxyl functionalization of PMP hollow fiber membranes to form zwitterion-modified PMP surfaces, which showed an 80–95% reduction in platelet deposition from whole blood sheep and uninhibited gas exchange performance. In general, indirectly mediated physical techniques such as etching methods (plasma treatment [5,25], laser [26], flame treatment [27] and corona discharge) [9,28] are used to activate the surface of PMP membranes, followed by after-treatment, however, those after-treatments would affect gas transport to some extent. It is conceivable that the preparation method will be simplified, and a high-efficiency oxygenation membrane can be obtained if it existsin-situmethod for realizing membrane construction and surface modification at the same time.

Surface segregation is a simple and effective method forin-situsurface modification of membranes [29]. In the surface segregation process, amphiphilic polymers are mixed with membrane matrix materials and enriched on the membrane surface by exploiting the differences in thermodynamic properties between the components (ie, hydrophilicity/hydrophobicity) during the membrane formation process [29]. Currently, surface segregation is being investigated for the fabrication of antifouling surfaces, in which surface segregation additives, usually amphiphilic polymers, are mixed with membrane matrix materials and spontaneously enriched on the membrane surface during the membrane formation process, giving the membrane a one-step antifouling property [29] . The hydrophilic chains of the amphiphilic copolymer would detach on the membrane surface to bind water molecules to form a robust hydration shell as a "water barrier" [30] to improve antifouling properties, while the hydrophobic backbone is entangled with the matrix polymer due to the chemical potential difference [29 ]. Therefore, both membrane fabrication and surface modification will be realized if surface segregation can be applied to membrane preparation for oxygenation. Based on the principle of surface segregation, the hemocompatibility of the membrane can be greatly improved by introducing a hydrophilic segment with good hemocompatibility in the segregation agent and which is separated on the membrane surface during the membrane preparation process.

In this study, a hetero-structured membrane with a hemocompatible layer and an asymmetric support layer was prepared in one step through surface segregation for an oxygenation membrane. Pluronic F127, a polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) triblock structure utilizes a high melting point and good temperature stability, which was selected as an ideal surface segregation modifier. The hydrophobic segments of PPO can be anchored in the membrane matrix, and the hydrophilic segments of PEO with good hemocompatibility can easily migrate outside the membrane due to the different hydrophobicity with PMP [31]. Surface topologies and elemental composition were analyzed by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), contact angle (CA) and X-ray photoelectron spectroscopy (XPS). Surface hemocompatibility is characterized by platelet adhesion, hemolysis, coagulation tests. Membrane permeability and in vitro oxygenation tests suggest excellent gas transfer performance. Then we realized the mass product of hollow fiber membranes (HFM), whose structure and elemental composition were analyzed by SEM and XPS, and the assessment of the effect of oxygenation invitroit showed great possibilities of application.