Mimicking the Endothelium: Dual Action Heparinized Nitric Oxide Releasing Surface

Abstract

The management of thrombosis and bacterial infection is critical to ensure the functionality of medical devices. While administration of anticoagulants is the current antithrombotic clinical practice, a variety of complications, such as uncontrolled hemorrhages or heparin-induced thrombocytopenia, can occur. Additionally, infection rates remain a costly and deadly complication associated with use of these medical devices. It has been hypothesized that if a synthetic surface could mimic the biochemical mechanisms of the endothelium of blood vessels, thrombosis could be reduced, anticoagulant use could be avoided, and infection could be prevented. Herein, the interfacial biochemical effects of the endothelium were mimicked by altering the surface of medical grade silicone rubber (SR). Surface modification was accomplished via heparin surface immobilization (Hep) and the inclusion of a nitric oxide (NO) donor into the SR polymeric matrix to achieve synergistic effects (Hep-NO-SR). An in vitro bacteria adhesion study revealed that Hep-NO-SR exhibited a 99.46 ± 0.17% reduction in viable bacteria adhesion compared to SR. An in vitro platelet study revealed Hep-NO-SR reduced platelet adhesion by 84.12 ± 6.19% compared to SR, while not generating a cytotoxic response against fibroblast cells. In a 4 h extracorporeal circuit model without systemic anticoagulation, all Hep-NO-SR samples were able to maintain baseline platelet count and device patency; whereas 66% of SR samples clotted within the first 2 h of study. Results indicate that Hep-NO-SR creates a more hemocompatible and antibacterial surface by mimicking two key biochemical functions of the native endothelium.

Nitric Oxide Release for Enhanced Biocompatibility and Analytical Performance of Implantable Electrochemical Sensors

“…Given the inevitable decrease of NO fluxes over time, it will be appealing to explore a dynamic, multifaceted strategy that combines a number of agents/materials, to possibly mimic the non‐thrombogenic surface of vascular endothelium and complement NO eluting sensor devices. In fact, considerable research efforts have been devoted to dual‐/multi‐functional polymeric coatings that combine NO release functionality with other active agents for increased efficacies, including anticoagulants (e. g., heparin) [166–168], direct thrombin inhibitors [169], antimicrobial metal ions [170], quaternary ammonium compounds [171], PEG [172], zwitterionic polymers [173], antibiotics [174], CD47 peptide [112], and nonsteroidal anti‐inflammatory drugs (NSAIDs) [175]. However, in spite of the preliminary evidence that supports simultaneous use of complementary antithrombotic/anti‐inflammatory methods, the development of such multi‐functional approaches still has to be studied to ensure that there are no negative effects on detection mechanism for implantable NO releasing sensors, and that reliable long‐term output signals can be truly realized in vivo .…”

Tissue‐Engineered Vascular Grafts: Emerging Trends and Technologies

“…[ 6 ] In order to produce highly effective antithrombotic surfaces, co‐immobilization of heparin and NO is envisioned to closely mimic the biochemical effects exerted by the endothelium at the interface of blood and vessel wall. [ 53 ] To create a biochemical analog of natural endothelium, coating glycocalyx‐like hydrogel comprising of hyaluronic acid onto decellularized TEVGs has shown protective effects against thrombus formation. This novel methodology shields the underlying collagen layer, thereby preventing platelet adhesion and activation.…”

Reply to the “Comment on ‘A Pumpless Microfluidic Neonatal Lung Assist Device for Support of Preterm Neonates in Respiratory Distress’” by Li Wang, Fang Li, Zhichun Feng, Yuan Shi

“…However, this development is still challenged by maintaining the inbuilt hemocompatibility by surface coating and prevention of blood clotting in the oxygenator units. [7,8]…”