3D Printing of Antibacterial Polymer Devices Based on Nitric Oxide Release from Embedded S-Nitrosothiol Crystals

Abstract

Controlled release of drugs from medical implants is an effective approach to reducing foreign body reactions and infections. We report here on a one-step 3D printing strategy to create drug-eluting polymer devices with a drug-loaded bulk and a drug-free coating. The spontaneously formed drug-free coating dramatically reduces the surface roughness of the implantable devices and serves as a protective layer to suppress the burst release of drugs. A high viscosity liquid silicone that can be extruded based on its shear-thinning property and quickly vulcanize upon exposure to ambient moisture is used as the ink for 3D printing. S-Nitrosothiol type nitric oxide (NO) donors in their crystalline forms are selected as model drugs because of the potent antimicrobial, antithrombotic, and anti-inflammatory properties of NO. Direct ink writing of the homogenized polymer-drug mixtures generates rough and ill-defined device surfaces because of the exposed S-nitrosothiol microparticles. When a low-viscosity silicone (polydimethylsiloxane) is added into the ink, this silicone diffuses outward upon deposition to form a drug-free outermost layer without compromising the integrity of the printed structures. S-Nitrosoglutathione (GSNO) or S-nitroso-N-acetylpenicillamine (SNAP) embedded in the printed silicone matrix releases NO under physiological conditions from days to about one month. The microsized drug crystals are well-preserved in the ink preparation and printing processes, which is one reason for the sustained NO release. Biofilm and cytotoxicity experiments confirmed the antibacterial property and safety of the printed NO-releasing devices. This additive manufacturing platform does not require dissolution of drugs and involves no thermal or UV processes and, therefore, offers unique opportunities to produce drug-eluting silicone devices in a customized manner.

Roles and current applications of S-nitrosoglutathione in anti-infective biomaterials

“… S.aureus/ATCC 29213 K.pneumoniae/ATCC 700603 human foreskin fibroblast cell/HFF-1 P.aeruginosa/ATCC-27853 Yapor, J. P. [ 14 ] 2019 Infection Emulsion containing HA and vitamin E Mixing 1.72 w/w % 46 ​± ​4 ​μmol ​g −1 NA HDFs NA GSNO-containing emulsion was produced and showed no cytotoxicity to HDFs Hopkins, S. P. [ 44 ] 2020 NA Fibers comprising PCL and gelatin Electrospinning 20 ​wt % 3.91 ​± ​0.96 ​× ​10 −10 ​mol ​mg −1 min −1 S.aureus/ATCC 5538 Mouse fibroblast cells/ATCC 1658 NA PCL/gelatin fiber containing GSNO demonstrated antibacterial activity and no cytotoxic response. Li, W. [ 8 ] 2021 Devices-associated inflammation and infection Silicone 3D printing 2 ​wt % >10 ​× ​10 −10 ​mol ​cm −2 min −1 P.mirabilis/ATCC 29906 Murine fibroblast cell/L929 NA GSNO embedded in the printed silicone matrix released NO about one month. Wang, W. [ 87 ] 2022 Cutaneous wound infection CS/GE films Mixing NA NA E.coli NA BALB/c mice CS/GE films containing GSNO functionalized PDA nanoparticles demonstrated antimicrobial efficacy.…”

“…Adapted with permission from Ref. [ 8 ], copyright 2021 American Chemical Society. (e) PVA/PEG films loading GSNO.…”

“…A previous study reported a one-step printing strategy for fabricating NO-eluting devices possessing drug-free coating and drug-loaded substrate, with high-viscosity silicone as the 3D printing ink, crystalline-forms of GSNO as the model drug, and low-viscosity silicone as the outermost layer, and the printed devices had a smooth surface coating because of the low-viscosity silicone diffused outward upon deposition ( Fig. 3 d) [ 8 ]. The GSNO-embedded silicone matrix could release NO for up to one month under physiological conditions showed strong antibacterial performance against P. mirabilis and adequate biosafety for murine fibroblast cells.…”

“…Nitric oxide (NO) is an endogenous gaseous molecule produced from arginine by nitric oxide synthase (eNOS, nNOS, or iNOS) [ 1 ]. NO is involved in multiple physiological processes, including angiogenesis [ 2 ], antiapoptosis, anti-inflammation [ [3] , [4] , [5] ], platelet activation [ 6 , 7 ], antithrombosis [ 8 ], vasodilation [ [9] , [10] , [11] ], and immune response [ [12] , [13] , [14] ]. Additionally, NO exhibits broad-spectrum antibacterial activities via the formation of reactive nitrogen species (RNS), including, but not limited to, peroxynitrile, dinitrogen trioxide, and nitrogen dioxide.…”

PEGDMA-Based Pillar-Shape Nanostructured Antibacterial Films Having Mechanical Robustness

“…Until now, many researchers have suggested antimicrobial and antifouling materials that can effectively suppress biofilm formation and bacterial adhesion. There are representative examples of effective antibacterial activity using microbiocidal substances such as nitric oxide, antibiotics, and silver. − However, these biocidal substances have several intrinsic limitations, such as the proliferation of drug-resistant microorganisms, limited long-term activity, and low biocompatibility. − These limitations can be barriers to their use, where long-term activity and biocompatibility are important, in biomedical applications. Consequently, surface coatings with biocompatible and antifouling materials have emerged as efficient and bio-friendly approaches for controlling biofilm formation without antibiotics or toxic chemicals.…”