A Material Conferring Hemocompatibility

Abstract

There is a need for biomimetic materials for use in blood-contacting devices. Blood contacting surfaces maintain their patency through physico-chemical properties of a functional endothelium. A poly(carbonate-urea) urethane (PCU) is used as a base material to examine the feasibility of L-Arginine methyl ester (L-AME) functionalized material for use in implants and coatings. The study hypothesizes that L-AME, incorporated into PCU, functions as a bioactive porogen, releasing upon contact with blood to interact with endothelial nitric oxide synthase (eNOS) present in blood. Endothelial progenitor cells (EPC) were successfully cultured on L-AME functionalized material, indicating that L-AME -increases cell viability. L-AME functionalized material potentially has broad applications in blood-contacting medical devices, as well as various other applications requiring endogenous up-regulation of nitric oxide, such as wound healing. This study presents an in-vitro investigation to demonstrate the novel antithrombogenic properties of L-AME, when in solution and when present within a polyurethane-based polymer.There is a need for biomimetic materials, which can resist thrombosis associated with blood contacting devices which include 1 ; cardiovascular implants, such as vascular bypass grafts, synthetic heart valves, vascular access devices, cardiac patches, coatings for stents, pacemakers as well as implants for wound healing. Several materials currently in clinical use such as polytetrafluoroethylene (ePTFE), polyethylene terephthalate (Dacron ® ) and polyurethane are suboptimal 2 , and often lead to graft failure due to their inherent thrombogenic nature 3 . Ideal materials should possess suitable mechanical properties that provide the required structural support, and mimic the properties of the endothelium; the inner-most blood-contacting tissue in the cardiovascular system. The endothelium, maintains smooth blood flow and nitric oxide (NO) is a key player. NO has the ability to inhibit platelet aggregation and activation, and produce smooth muscle relaxation through activation of the cyclic guanylate monophosphate (cGMP) pathway 4 . It also inhibits smooth muscle cell proliferation. Moreover, NO aids endothelialization, wound healing; although the mechanism in unclear, it has been shown to promote re-epithelialization and collagen formation, as well as angiogenesis 5 . L-Arginine (L-Arg), a commonly occurring amino acid, is an endogenous substrate of nitric oxide synthase (NOS) 6 , a family of enzymes including neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), which all catalyze the formation of NO (along with citrulline) from L-Arg 7 . L-Arg therefore possesses anti-thrombogenic properties. eNOS produces the majority of the NO within the vascular system, and is present in red blood cells, which means that NO can be produced even in the absence of an endothelium 8,9 . Hence, L-Arg is important in cardiovascular physiology, and L-Arg supplementation in individuals with hypercholesterolemia or ath...

Biofunctionalization of biomaterials for nitric oxide delivery: potential applications in regenerative medicine

“…Formation of a porous structure is well recognized with the solvent exchange coagulating process of PCU. 19 Porosity is a significant feature of materials used in surgical implants to confer optimal mechanical properties and to facilitate cell-material interactions. 29 Amphiphiles, such as LCAHs, with the amine groups such as those of OD and DD are expected to form micellar geometries with varying degrees of surface area to volume ratios.…”

“…3 NO has potent antithrombogenic effects and stimulates endothelial cell proliferation, mobilization, and adhesion and inhibits smooth muscle cell proliferation and adhesion. [4][5][6]19 Therefore, NO shows great promise for applications in cardiovascular implants that can address the damage or the absence of an endothelium by restoring cardiovascular homeostasis. 7 Other functions of NO include neurotransmission, antimicrobial, and anticancer properties (Figure 1).…”

“…It has been previously presented that polyhedral oligomeric silsesquioxane poly(carbonate-urea) (PCU) urethane, a relatively hydrophobic polyurethane-based biocompatible polymer scaffold, proved to be effective for the integration of RSNOS, which were passively incorporated and fabricated into bypass grafts. 18,19 This study aimed to exploit the inherent hydrophobic properties of long-chain aliphatic hydrocarbons (LCAHs) for NO delivery. We hypothesized that amine terminated LCAHs, dodecylamine (DD), and/or octadecylamine (OD) would form hydrophobic, spherical structures when conjugated to S-nitro-N-acetylpenicillamine (SNAP), an RSNOS, which has been previously determined to have antithrombogenic properties.…”

Biomimetic heterogenous elastic tissue development

“…We demonstrate a post processing method, which enables surface bio-functionalisation for enhanced cell-adhesion, whilst maintaining bulk mechanical properties and structural integrity of 3D printed constructs. To demonstrate this in-vitro, we have used a solution-based TPU pre-polymer system which we have hybridised with collagen, as an example of extracellular matrix (ECM) component and L-Arginine methyl ester (L-AME) as a porogen 15 (Fig. 2a , Supplementary Figure 7 ).…”

“…Cell-material interactions can be influenced by the presence of bioactive molecules such as those that mimic ECM for cell adhesion, antibacterial molecules to prevent implant associated infection, and antithrombogenic molecules to confer haemocompatibility and mimic the endothelium. 15 , 27 – 29 This surface modification method demonstrated here can serve as an effective platform technology for the integration of a plethora of biomolecules for cell-material interactions. It is also an effective ‘seal’ at the luminal phase to modulate permeability.…”