Nitric Oxide-Releasing Metal-Organic Frameworks: Novel Materials for Medical Device

Opportunity

Available for Licensing

IP Status

US Utility Patent US 8771756 B2
US Utility Patent US 9493352 B2
US Utility Patent US 10266408 B2
European Patent Pending: EP2519467 (Recent Notice of Allowance)

Inventors

​Melissa Reynolds
Benjamin Reynolds

At A Glance

Researchers at Colorado State University have developed a new class of nitric oxide-releasing metal-organic frameworks (NOMOFs) through the covalent attachment of nitric oxide-releasing groups directly onto metal-organic framework structures.  These materials can be incorporated into polymers and other media for use in coatings, specifically for medical devices.

Please contact our office directly for more details!

Licensing Director

Jessica Trostel
J.Trostel@colostate.edu
970-491-7100

Reference No.: 10-039

Background

​Each year billions of health care dollars are spent on medical devices that fail in clinical practice (e.g., intravascular and neonatal catheters, coronary artery and vascular stents and grafts, guidewires, extracorporeal membrane oxygenation circuits, heart valves, by-pass circuits, etc.). These device failures are due to the introduction of a foreign material into the body leading to a multitude of serious health risks and undesirable complications including thrombosis, inflammation, cell proliferation, infection, and tissue overgrowth on the surface of the implanted device. Over the last 50 years, much has been learned about these device failures and attempts have been made to prevent failures using (1) alternative systemic drug therapies, (2) surface modifications on the device, or (3) a combination of both approaches.

Despite efforts to improve the efficacy of body-contacting and implantable medical devices, the incompatibility of materials within human blood and tissue still causes serious complications in patients. Thus, systemic or regional drug therapies remain necessary (e.g., use of heparin for short-term anticoagulation applications). Most often, when these drugs are administered, they produce a systemic response in the patient. Systemic responses can mask blood chemistry problems and lead to a greatly increased possibility of complications and morbidity. Research studies examining alternative mechanisms are ongoing, but there is not yet an FDA-approved alternative material that overcomes all the problems associated with body-material interactions and systemic drug therapies. As such, in clinical practice today, all implanted devices eventually fail.

To approach the aforementioned shortcomings, it is worth considering the structure and function of the ideal blood-contacting material. Preferably this material would simultaneously inhibit multiple pathways of device complication (i.e., thrombosis, inflammation, cell proliferation and migration, restenosis as well as infection) but without causing systemic side effects of its own. Such a material strategy requires not only the identification of suitable therapeutic agent(s) with appropriate biological half-lives, but the approach also requires the material’s architecture to be fabricated and tailored specifically to the needs of the clinical application. Thus, the approach to an ideal body-contacting material requires a biomaterial that can be systematically and dramatically tailored for use in a wide variety of devices while promising the simultaneous reduction in complicating factors. Currently, no material substrates exist that can be modified in such diverse ways without significantly altering the chemical, physical, or cytotoxicity properties of the material and, in turn, rendering the material unsuitable for clinical use. A modular biomaterial that can simultaneously reduce or eliminate thrombosis, inflammation, cell proliferation, and infection, and also attenuate normal tissue growth upon exposure to physiological fluid, such as blood, is paramount to improve and advance the efficacy of medical devices.

Benefits
  • Overcomes challenges of biofouling on the surface of synthetic materials
  • Amounts of nitric oxide per gram of material exceed typical nitric oxide materials
  • Can be incorporated in polymer blends to create hybrid materials
  • Remarkable chemical, thermal, and structural stabilities
  • Framework structure allows pore dimensions to be modified for size inclusion/exclusion ability
Applications
  • Biomedical devices and coatings
  • Orthopedic and neurology applications
  • Cancer treatments
  • Wound healing (e.g. bandages)
  • Any polymer coated medical device having complications due to clotting, infection, or tissue overgrowth
Publications 
 

Lutzke, A.; Tapia, J. B.; Neufeld, M. J.; Reynolds, M. M. Sustained Nitric Oxide Release from a Tertiary S-Nitrosothiol-based Polyphosphazene Coating. ACS Appl. Mater. Interfaces. 2017, 9(3), 2104-2113. DOI: 10.1021/acsami.6b12888

Neufeld, M. J.; Ware, B. R.; Lutzke, A.; Khetani, S. R.; Reynolds, M. M. Water-Stable Metal-Organic Framework/Polymer Composites Compatible with Human Hepatocytes. ACS Appl. Mater. Interfaces. 2016, 8, 19343–19352. DOI: 10.1021/acsami.6b05948

Yapor, J. P.; Lutzke, A.; Pegalajar-Jurado, A.; Neufeld, B. H.; Damodaran, V. B.; Reynolds, M. M. Biodegradable Citrate-Based Polyesters with S-Nitrosothiol Functional Groups for Nitric Oxide Release. J. Mater. Chem. B. 2015, 3, 9233-9241. DOI: 10.1039/C5TB01625H

Pegalajar-Jurado, A.; Wold, K. A.; Joslin, J. M.; Neufeld, B. H.; Arabea, K. A.; Suazo, L. A.; McDaniel, S. L.; Bowen, R. A.; Reynolds, M. M. Nitric Oxide Releasing Polysaccharide Derivative Exhibits 8-log Reduction against Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus. J. Controlled Release. 2015, 217, 228 – 234.(Invited). DOI: 10.1016/j.jconrel.2015.09.015

Harding, J. H.; Metz, J. M.; Reynolds, M. M. A Tunable, Stable and Bioactive MOF for Generating a Localized Therapeutic from Endogenous Sources. Adv. Func. Mater. 2014, 24, 7503-7509. DOI: 10.1002/adfm.201402529

Joslin, J. M.; Neufeld, B. H.; Reynolds, M. M. Correlating S-nitrosothiol Decomposition and NO Release for Modified Poly(lactic-co-gycolic acid) Polymer Films. RSC Adv. 2014, 4, 42039-42043. DOI: 10.1039/c4ra04817b

Harding, J. L; Reynolds, M. M. Accurate Nitric Oxide Measurements from Donors in Cell Media: Identification of Scavenging Agents. Anal. Chem. 2014, 86, 2025-2032. DOI: 10.1021/ac403174e

Sylman, J. L., Lantvit, S. M., Reynolds, M. M., Neeves, K. D. Transport Limitations of Nitric Oxide Inhibition of Platelet Aggregation Under Flow. Annals of Biomed. Engr. 2013, 41 (10), 2193-2205. DOI: 10.1007/s10439-013-0803-9

Lantvit, S. L., Barrett, B. J., Reynolds, M. M. Nitric Oxide Releasing Material Adsorbs More Fibrinogen. J. Biomed. Mater. Res. 2013, 101 (11), 3201-3210. DOI: 10.1002/jbm.a.34627

Reynolds, M. M., Witzeling, S. D., Damodaran, V. B, Medeiros, T. N., Edwards, M. A., Lookian, P. P.; Jarigese, D.; Brown, M. A. Application of a Nitric Oxide-Releasing Pro-Drug for Halting Growth of Human Breast and Canine Mammary Carcinoma Cells. J. Vet. Sci. & Med. 2012, 1, 1. DOI: 10.13188/2325-4645.1000002

Damodaran, V. B.; Place, L. W.; Kipper, M. J.; Reynolds, M. M. Enzymatically Degradable Nitric Oxide Releasing Dextran Derivatives for Biomedical Applications. J. Mater. Chem. 2012, 22 (43), 23038-23048. DOI: 10.1039/C2JM34834A

Wold, K. A.; Damodaran, V. B.; Suazo, L. A.; Bowen, R. A.; Reynolds, M. M. Fabrication of biodegradable polymeric nanofibers with covalently attached NO donors. ACS Appl. Mater. Interfaces. 2012, 4, 3022. DOI: 10.1021/am300383w

Damodaran, V. B.; Joslin, J. M.; Wold, K. A.; Lantvit, S. M.; Reynolds, M. M. S-Nitrosated biodegradable polymers for biomedical applications: synthesis, characterization and impact of thiol structure on the physicochemical properties. J. Mater. Chem. 2012, 22, 5990-6001. DOI: 10.1039/C2JM16554F

Harding, J. L. and Reynolds, M. M. Metal Organic Frameworks as Nitric Oxide Catalysts. J. Am. Chem. Soc. 2012, 134, 3330. DOI: 10.1021/ja210771m

Joslin, J. M. and Reynolds, M. M. Kinetics of S-nitrosation Processes in Aqueous Polymer Solution for Controlled Nitric Oxide Loading: Towards Tunable Biomaterials. ACS Appl. Mater. Interfaces 2012, 4, 1126. DOI: 10.1021/am201807c

Damodaran, V. B.; Reynolds, M. M. Biodegradable S-Nitrosothiol Tethered Multiblock Polymer for Nitric Oxide Delivery. J. Mater. Chem. 2011, 21, 5870-5872. DOI: 10.1039/C1JM10315F

Last updated: July 2020

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