Design and Characterization of a Novel Series of Geometrically Complex Intravaginal Rings with Digital Light Synthesis

Abstract

Intravaginal rings (IVRs) represent a sustained-release approach to drug delivery and have long been used and investigated for hormones and microbicides delivery. For decades, IVRs have been manufactured by injection molding and hot-melt extrusion with very limited design and material capabilities. Additive manufacturing (AM), specifically digital light synthesis (DLS), represents an opportunity to harness the freedom of design to expand control and tunability of drug release properties from IVRs. We report a novel approach to IVR design and manufacturing that results in geometrically complex internal architectures through the incorporation of distinct unit cells using computationally-aided design (CAD) software. We developed a systematic approach to design through the generation of an IVR library and investigated the effects of these parameters on ring properties. We demonstrate the ability to precisely and predictably control the compressive properties of the IVR independent of the internal architecture with which control of drug release kinetics can be achieved, thus opening the door for a 'plug-and-play' platform approach to IVR fabrication.

Keywords: 3D printing; Intravaginal rings (IVRs); computationally-aided design (CAD); digital light synthesis; lattice.

Figure 1.. Design and fabrication approach for geometrically complex intravaginal rings.

(A) Design method for geometrically complex IVRs in CAD software. Illustration of template, unit cell and band parameters. The unit cell is arrayed into the template and encased in the band material resulting in the finalized IVR in CAD. (B) Fabrication method of IVRs with DLS with illustration of print orientation and formation of the “dead zone” from oxygen inhibition during part reconstruction. Finalized example ring in silicone-based resin (SIL 30) with stereo microscopy inset illustrating internal architecture.

Figure 2.. Characterization of solid rings as a function of fabrication method and material type.

DLS SIL 30 rings were fabricated to mimic dimensions of placebo Estring (silicone) and NuvaRing (EVA) (A) Dimensional characterization of solid rings by outer and cross-sectional diameter. Average and standard deviations represent n=4 samples per ring type. Italicized percentages represent percent deviation from theoretical values. (B) Shore A hardness testing of materials by sample number (n=4 measurements) and compiled (n=4 samples). (C) Load at 50% compression by solid ring type. Data were assessed via one-way ANOVA for statistical significance. Silicone Estring Placebo and DLS SIL 30: Placebo A were assessed via a two-tailed unpaired t-test where p<0.05 was considered statistically significant (*).

Figure 3.. Fabrication and characterization of IVRs by unit cell design and band presence.

IVRs from group (3) were designed by varying unit cell design, holding unit cell size constant at 3.80 mm with band parameters of 4.0 mm height (H) and 0.6 mm thickness (T). (A) Whole banded DLS fabricated rings are shown in SIL 30 with inlays of internal architecture by CAD, in UMA, and in SIL 30. Fabricated rings were imaged with stereo microscopy. (B) Dimensional analysis of outer diameter, cross-sectional diameter and wall thickness. Outer and cross-sectional diameter measurements represent average and standard deviations of n=4 per ring type. Wall thickness values represent average and standard deviation of n=4 per sample and n=4 per ring type (total of 16). Percent deviation from theoretical values is shown italicized. (C) Load at 50% compression (N) as a function of unit cell type, band presence and force orientation. Values represent average and standard deviation of n=4 per ring type.

Figure 4.. Fabrication and characterization of IVRs by unit cell size and band presence for cylinder and honeycomb unit cells.

IVRs from group (4) were designed by varying unit cell size by integer ratio to the cross-sectional diameter of the template ring. Rings were designed in the absence and presence of a band (4.0 mm H and 0.6 mm T). Whole banded DLS fabricated rings are shown in SIL 30 with inlays of internal architecture by CAD, in UMA, and in SIL 30, by decreasing unit cell size for (A) cylinder and (B) honeycomb. Fabricated rings were imaged with stereo microscopy. (C) Dimensional analysis of outer diameter, cross-sectional diameter and wall thickness. Outer and cross-sectional diameter measurements represent average and standard deviations of n=4 per ring type. Wall thickness values represent average and standard deviation of n=4 per sample and n=4 per ring type (total of 16). Percent deviation from theoretical values is shown italicized. (D) Load at 50% compression (N) as a function of unit cell type, unit cell size and band presence. Values represent average and standard deviation of n=4 per ring type. Data were assessed via one-way ANOVA for statistical significance. The Unbanded Cylinder f(unit cell size) were further assessed via multiple two-tailed unpaired t-tests where p<0.05 was considered statistically significant (*).

Figure 5.. Fabrication and characterization of geometrically complex IVRs as a function of band parameters.

(A) Images of the honeycomb unit cell arrayed at 2.53 mm shown with increasing band height (coverage) from 3.0 to 6.0 mm. Inlays indicate the internal architecture and the increased band height (coverage) observed in CAD, in UMA, and in SIL 30. (B) Confocal dimensional analysis of rings generated as a function of band coverage in SIL 30. Values represent average and standard deviation of n=4 samples for outer and cross-sectional diameters. Values represent average and standard deviation of n=4 measurements of n=4 samples (total of 16) for wall thickness and band height (coverage). Percent deviation from CAD is shown in italics. (C) Dimensional analysis of rings generated as a function of band height (coverage) in SIL 30. Values represent average and standard deviation of n=4 samples for outer and cross-sectional diameters. Values represent average and standard deviation of n=4 measurements of n=4 samples (total of 16) for wall thickness and band height (coverage). Percent deviation from CAD is shown in italics. (D) Load at 50% compression for cylinder rings fabricated with increasing band thickness. Data fitted with log regression with dashed lines indicated 95% confidence intervals. (E) Load at 50% compression for cylinder rings fabricated with increasing band height (coverage). Data fitted with log regression with dashed lines indicated 95% confidence intervals. Values represent average and standard deviation of n=4 samples per ring type.

Figure 6.. Design, fabrication and characterization of geometrically complex IVRs by specific surface area equivalence for allometric scaling to macaque.

(A) Theoretical specific surface area (mm⁻¹) as a function of honeycomb (HC) unit cell size for banded and unbanded macaque-size rings (25 mm outer diameter and 6.0 mm cross sectional diameter). Inlays represent obtained from stereo microscopy of macaque rings fabricated in UMA. Exponential fit for banded rings was used to determine (B) Load at 50% compression for two template ring sizes: 54–7.6 (human) and 25–6.0 (macaque) rings fabricated in SIL 30. Specific surface area equivalence was 5.8 mm⁻¹ yielded unit cell sizes of 1.52 mm (Nodal), 3.80 mm (Cylinder), 3.63 mm (Dode) and 3.12 mm (Honeycomb) for human rings and 2.85 mm (Honeycomb) for macaque rings. Values represent average and standard deviation of n=4 samples per ring type. (C) Compressive load at 50% by ring type for n=4 samples per condition with normalized load relative to the solid template equivalent. Data were assessed via one-way ANOVA for statistical significance. Two groups, the solid human and macaque rings and the honeycomb human and macaque rings were further assessed via two-tailed unpaired t-tests where p<0.05 was considered statistically significant (*).

Figure 7.. Compiled load at 50% compression of IVR library by volume fraction.

Volume fraction for commercially available rings of Estring and NuvaRing placebos is shown as 1. Volume fraction of geometrically complex SIL 30 rings by unit cell type were relative to SIL 30: 54–7.6 solid ring. X-axis error was calculated as compounded error from density and mass measurements. Y-axis error represents standard deviation of n=4 samples per ring type.