Office of Technology Transfer – University of Michigan

Poly(lactic-co-glycolic) Acid Additives to Enhance Nitric Oxide Release from Diazeniumdiolate Doped Polymer Coatings

Technology #5436

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Researchers
Mark E. Meyerhoff
Managed By
Tiefei Dong
Senior Licensing Specialist, Life Sciences 734-763-5332
Patent Protection
US Patent 9,566,372

Nitric oxide releasing polymer reduces thrombosis associated with blood-contacting medical devices

Nitric oxide (NO) is an endogenous vasodilator and a natural inhibitor of platelet adhesion, activation and aggregation. One of the key issues with the use of blood-contacting medical devices is their lack of hemo- and biocompatibility which leads to platelet adhesion and thrombosis. Polymers that release or generate NO locally at their surface exhibit greatly enhanced thromboresistivity and have the potential to reduce neointimal hyperplasia caused by device damage to blood vessels. These polymers incorporate NO donor compounds such as diazeniumdiolates and are used to coat the surface of medical devices that come into direct contact with blood.

While diazeniumdiolate is an excellent donor for incorporation into hydrophobic polymers to create NO release coatings, the loss of NO from this molecule leads to a local pH increase that effectively turns off NO release well before the NO reservoir is depleted. Thus, NO release can only be sustained for short periods of time (hours), and is incompatible with most biomedical applications. A modification to the NO releasing matrix that allows for prolonged and consistent NO release (days or weeks) will allow for NO releasing coatings to become useful in a variety of extracorporeal circulation (ECC) machines, implantable catheters and vascular grafts.

New material that enables sustained nitric oxide release

Researchers at the University of Michigan working on extracorporeal circulation without anticoagulation research have created a NO releasing coating that can provide sustained NO release until the NO reservoir is completely depleted. In order to counteract the pH increase that is a byproduct of NO release, they have incorporated poly(lactic-co-glycolic) acid (PLGA) additive that hydrolyzes over time and releases lactic and glycolic acid molecules into the matrix that counteracts the pH increase and allows for continuous NO release. PLGA is a non-toxic polymer that is already FDA approved for numerous products. This new material was tested in vitro and showed sustained NO flux over 14 days that was comparable to that produced by endothelial cells. Researchers also tested this new material in an in vivo rabbit thrombogenicity model where ECC loops were coated with the diazeniumdiolate doped with PLGA. After four hours of blood flow, NO releasing circuits were still patent, while over half of the control ECCs became clotted. NO releasing ECC showed significantly better platelet preservation and reduced thrombus formation. PLGA doped NO releasing ECCs showed ten-fold less adsorption of fibrinogen compared to a tetraphenylborate doped material. Varying the composition of PLGA can change the rate of its hydrolysis, and thus NO release rates can be easily adjusted based on specific needs.

Cardiopulmonary bypass pump (CBP) is used in the majority of open heart surgeries, such as coronary artery bypass graft (CABG) or valve repair/ replacement procedures. To prevent thrombosis, systemic anticoagulants are administered, but improved hemocompatibility of CBP materials can significantly decrease the requirement for anti-platelet therapy. Other ECC machine applications include hemodialysis, hemofiltration, plasmapheresis, apheresis, and extracorporeal membrane oxygenation (ECMO). Implanted devices such as stents and vascular grafts suffer from thrombosis complications as any time a device is implanted, the body attempts to remove it as a foreign object, resulting in blood clot formation. Currently, the majority of surface coatings that aim to prevent thrombosis employ heparin, although several others use hyaluronan or hirudin. Heparin preparations can suffer from impurities and instability (both in shelf life and during use), and NO releasing polymers offer a new effective way to improve performance of all blood-contacting medical devices.

Applications and Advantages

Applications

  • Anti-thrombotic coating to any blood-contacting medical device
  • Extracorporeal circulation machines (CBP, ECMO, hemodialysis)
  • Medical implants (catheters, stents, vascular grafts)

Advantages

  • Enhance hemo- and biocompatibility of medical devices
  • Non-toxic FDA approved additive
  • Reduce need for anticoagulants during heart surgery
  • Reduce cost and time of hospital stays
  • Reduce recovery time
  • Reduce risk of adverse events
  • Reduce platelet damage
  • Decrease inflammation