Biomimetic modification of poly(vinyl alcohol): Encouraging endothelialization and preventing thrombosis with antiplatelet monotherapy

Abstract

Poly(vinyl alcohol) (PVA) has shown promise as a biomaterial for cardiovascular application. However, its antifouling properties prevent in vivo endothelialization. This work examined the endothelialization and thrombogenicity of modified PVA with different concentrations of proteins and adhesion peptides: collagen, laminin, fibronectin, GFPGER, YIGSR, and cRGD. Material surface properties were quantified, and the endothelialization potential was determined with human endothelial colony forming cells. Additionally, platelet attachment was assessed in vitro with human platelet rich plasma, and promising samples were tested in an ex vivo shunt model. This well-established arteriovenous shunt model was used with and without clinically-relevant antiplatelet therapies, specifically acetylsalicylic acid (ASA) with and without clopidogrel to examine the minimum necessary treatment to prevent thrombosis. Collagen, laminin, and GFPGER biomolecules increased endothelialization, with GFPGER showing the greatest effect at the lowest concentrations. GFPGER-PVA tubes tested under whole blood did exhibit an increase in platelet (but not fibrin) attachment compared to plain PVA and clinical controls. However, application of ASA monotherapy reduced the thrombogenicity of GFPGER-PVA below the clinical control with the ASA. This work is significant in developing cardiovascular biomaterials-increasing endothelialization potential while reducing bleeding side effects by using an antiplatelet monotherapy, typical of clinical patients.

Human Peripheral Blood-Derived Endothelial Colony-Forming Cells Are Highly Similar to Mature Vascular Endothelial Cells yet Demonstrate a Transitional Transcriptomic Signature

“…ECFC represent a cell population that can be differentiated from peripheral blood [12,13,25], umbilical cord blood [25][26][27][28], placenta [29][30][31], bone marrow [32], white adipose tissue [33], peripheral lung tissue [34] and induced pluripotent or embryonic stem cells [35], and is characterized by an endothelial immunophenotype (CD31+vWF+KDR+CD146+CD45-), intracellular CD133 expression, acLDL uptake and UEA binding, considerable tube-forming capacity and high proliferation capability [16,25,28]. The combination of endothelial identity with high proliferative and neovascularization potential suggests ECFC as an efficient tool for regenerative medicine applications including pre-endothelialization [36] and pre-vascularization [27,[37][38][39] of tissue-engineered constructs. However, usefulness of ECFC for indicated tasks depends to a large extent on their similarity to resident EC, such as HCAEC, that are particularly important for pre-seeding of small-diameter vascular grafts, or HUVEC which represent the far most frequently utilized endothelial cell line in biomaterial research [17].…”

Quantifying Physical Thrombus Characteristics on Cardiovascular Biomaterials Using MicroCT

“…The luminal surfaces were then modified using a variety of techniques, including biochemical and topographical modifications, and assessed for thrombogenesis and hemocompatibility in the ex vivo shunt whole blood test. Specific modifications included integration of the peptide sequence Gly-Phe-Pro-Gly-Glu-Arg (GFPGER), plasma modification, addition of gelatin with a carbonyldiimidazole (CDI) covalent linker, and sterilization, and their preparation methods are described in greater detail in previous publications [16][17][18][19]. Samples, which were modified by the integration of GFPGER, a peptide subsequence of type I collagen, had GFPGER mixed with the STMP in the PVA manufacturing process [17].…”

“…Samples were tested in five different animals. For a small subset of samples [17], acetylsalicylic acid (ASA, Bayer Healthcare) or ASA and clopidogrel (Torrent Pharmaceuticals) was given before experimentation to reduce thrombus formation. Specifically, there were six PVA grafts, three ePTFE grafts, and one collagen-coated ePTFE graft treated with ASA; six PVA grafts, three ePTFE grafts, and one collagen-coated ePTFE grafts were treated with ASA and clopidogrel.…”

“…Specifically, ePTFE served as a clinical control; collagen-coated ePTFE acted as a positive, thrombogenic control; and poly(vinyl alcohol) (PVA) served as a preclinical, non-thrombogenic, hydrogel material. Several surface modifications of the PVA, which were previously evaluated for their hemocompatibility and endothelialization potential [16][17][18][19], were used in this work to assess and validate the measurement of the physical properties of the thrombus. Advanced image software analysis was then used to quantify the luminal volume (the inverse of thrombus volume) and the intra-thrombus variability.…”

Challenges for the Implantation of Symbiotic Nanostructured Medical Devices

“…The most promising directions are for the integration of 3D bioelectrodes that utilize some form of cross-linked chitosan to provide the optimal environment for the stabilization of enzymes combined with a protective membrane, such as those formed with PVA as the basis. This type of approach will most likely optimize the design of gel-like polymer membranes to minimize the fibrous encapsulation of implanted enzymatic biofuel cells [41]. Such an approach could include the possibilities of either excluding biofouling with the PVA-based membrane or promoting cell adhesion and hence integration with the body, e.g., by using modified chitosan or polyelectrolyte coatings [42,43].…”