Abstract
We designed and engineered novel intravaginal ring (IVR) medical devices via fused deposition modeling (FDM) three-dimensional (3D) printing for controlled delivery of hydroxychloroquine, IgG, gp120 fragment (encompassing the CD4 binding site), and coumarin 6 PLGA-PEG nanoparticles (C6NP). The hydrophilic polyurethanes were utilized to 3D-print reservoir-type IVRs containing a tunable release controlling membrane (RCM) with varying thickness and adaptable micro porous structures (by altering the printing patterns and interior fill densities) for controlled sustained drug delivery over 14 days. FDM 3D printing of IVRs were optimized and implemented using a lab-developed Cartesian 3D printer. The structures were investigated by scanning electron microscopy (SEM) imaging and in vitro release was performed using 5 mL of daily-replenished vaginal fluid simulant (pH 4.2). The release kinetics of the IVR segments were tunable with various RCM (outer diameter to inner diameter ratio ranging from 1.12 to 2.61) produced from FDM 3D printing by controlling the printing perimeter to provide daily zero-order release of HCQ ranging from 23.54 ± 3.54 to 261.09 ± 32.49 µg/mL/day. IgG, gp120 fragment, and C6NP release rates demonstrated pattern and in-fill density-dependent characteristics. The current study demonstrated the utility of FDM 3D printing to rapidly fabricate complex micro-structures for tunable and sustained delivery of a variety of compounds including HCQ, IgG, gp120 fragment, and C6NP from IVRs in a controlled manner.Graphical abstract
Highlights
To prevent HIV viral entry and replication, the development of a safe and effective HIV-1 vaccine would undoubtedly be the best solution for the ultimate control of the worldwide AIDS pandemic [1]
A less desired printing result was seen at 25% interior fill (IF) possibly attributed to the rapid XY movement of the print head resulting in insufficient filament extrusion and adherence to the previous layer under such speed
The active pharmaceutical ingredients (APIs) are co-extruded with the selected polymers to form drug-containing filaments and fused deposition modeling (FDM) 3D printing was applied to transform the filaments into solid objects with desired shapes [29,30,31, 33, 35, 40]
Summary
To prevent HIV viral entry and replication, the development of a safe and effective HIV-1 vaccine would undoubtedly be the best solution for the ultimate control of the worldwide AIDS pandemic [1]. Several other strategies attempting to prevent sexual transmission of HIV have been proposed or examined, including the following: (1) pre-exposure prophylaxis (PrEP) via tenofovir disoproxyl fumarate-based regimen as recently recommended by WHO [7]; (2) induction of immune quiescence (IQ) to establish local mucosal resistance to HIV-1 infection by maintaining a low baseline of immune activation and minimizing the HIV-target cells or substrates for productive HIV infection [8,9,10]; (3) direct delivery of potent neutralizing antibodies (NAbs) topically or induce vaginal mucosal immunity by local mucosal immunization via HIV antigens; (4) topical application of antiviral compounds (microbicides) at the genital tract [11]. This provided the rationale of delivering the immunomodulatory compound hydroxychloroquine (HCQ) locally [8] to maintain low baseline of immune activation at the FGT as well as the inhibition in gene expression of host factors related to viral binding/entry including CCR5 and CD4 by nanoparticle-mediated gene knockdown [12,13,14]. We utilized fused deposition modeling (FDM) three-dimensional (3D) printing to develop different reservoir-type intravaginal ring (IVR) devices for controlled and prolonged delivery of HCQ, IgG, gp120 fragment (containing CD4 binding site), and coumarin 6-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles
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