Additive manufacturing processes such as 3D printing use time-consuming, stepwise layer-by-layer approaches to object fabrication. We demonstrate the continuous generation of monolithic polymeric ...parts up to tens of centimeters in size with feature resolution below 100 micrometers. Continuous liquid interface production is achieved with an oxygen-permeable window below the ultraviolet image projection plane, which creates a "dead zone" (persistent liquid interface) where photopolymerization is inhibited between the window and the polymerizing part. We delineate critical control parameters and show that complex solid parts can be drawn out of the resin at rates of hundreds of millimeters per hour. These print speeds allow parts to be produced in minutes instead of hours.
OBJECTIVES/SPECIFIC AIMS: The study aims to develop and test a biocompatible 3D-printed IVRs for the mechanical and release properties of a model drug, β-estradiol, then translate these methods to ...the target drug, progesterone. The goals include demonstrating decoupling of mechanical and release properties of the rings, release profiles driven by geometry and efficacy in sheep animal models to evaluate device safety. METHODS/STUDY POPULATION: A novel 3D-printing platform, continuous liquid interface production (CLIP), pioneered by Carbon, enables the fabrication of complex designs on a timescale that is amenable to manufacturing. The process utilizes computational-aided design (CAD), specifying shape and geometry, which is recreated via a photopolymerization process. IVRs are fabricated with CLIP using a biocompatible resin at a rate of approximately 15 min. per ring. Rings were fabricated and assessed for the release of a model drug, β-estradiol. The process was then translated to the target drug, progesterone. Rings were evaluated for radial compression and in vitro release in simulated vaginal fluid (SVF). RESULTS/ANTICIPATED RESULTS: Intravaginal rings (IVRs) were designed and fabricated to be geometrically complex in an effort to control release. Ring geometry and subsequent pore size was achieved through the use of unit cells. Several design parameters were explored including unit cell type, size, and band presence in two resins of differing mechanical properties. Through design, a wide range of radial compressive properties were achieved which spanned values covered by commercially available rings. The release of β-estradiol in SVF was found to span 57 – 115 days and resulted in near or complete release of the total loaded drug. Changing the internal geometric design of the ring was found to have minimal influence on the compression properties, thus the mechanical and release characteristics of the rings were largely decoupled. DISCUSSION/SIGNIFICANCE OF IMPACT: This is a novel approach to the design and fabrication of intravaginal rings for the treatment of infertility. The use of CAD and the decoupling of release from mechanical properties allows for us to move away from the one-size one-dose fits all approach to IVRs.
Despite the increasing popularity of 3D printing, also known as additive manufacturing (AM), the technique has not developed beyond the realm of rapid prototyping. This confinement of the field can ...be attributed to the inherent flaws of layer-by-layer printing and, in particular, anisotropic mechanical properties that depend on print direction, visible by the staircasing surface finish effect. Continuous liquid interface production (CLIP) is an alternative approach to AM that capitalizes on the fundamental principle of oxygen-inhibited photopolymerization to generate a continual liquid interface of uncured resin between the growing part and the exposure window. This interface eliminates the necessity of an iterative layer-by-layer process, allowing for continuous production. Herein we report the advantages of continuous production, specifically the fabrication of layerless parts. These advantages enable the fabrication of large overhangs without the use of supports, reduction of the staircasing effect without compromising fabrication time, and isotropic mechanical properties. Combined, these advantages result in multiple indicators of layerless and monolithic fabrication using CLIP technology.
Mass customization along with the ability to generate designs using medical imaging data makes 3D printing an attractive method for the fabrication of patient-tailored drug and medical devices. ...Herein we describe the application of Continuous Liquid Interface Production (CLIP) as a method to fabricate biocompatible and drug-loaded devices with controlled release properties, using liquid resins containing active pharmaceutical ingredients (API). In this work, we characterize how the release kinetics of a model small molecule, rhodamine B-base (RhB), are affected by device geometry, network crosslink density, and the polymer composition of polycaprolactone- and poly (ethylene glycol)-based networks. To demonstrate the applicability of using API-loaded liquid resins with CLIP, the UV stability was evaluated for a panel of clinically-relevant small molecule drugs. Finally, select formulations were tested for biocompatibility, degradation and encapsulation of docetaxel (DTXL) and dexamethasone-acetate (DexAc). Formulations were shown to be biocompatible over the course of 175 days of in vitro degradation and the clinically-relevant drugs could be encapsulated and released in a controlled fashion. This study reveals the potential of the CLIP manufacturing platform to serve as a method for the fabrication of patient-specific medical and drug-delivery devices for personalized medicine.
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Globally, there are 20 million adolescent girls and young women living with HIV who have limited access to long-acting, effective, women-controlled preventative methods. Additionally, although there ...are many contraceptive methods available, globally, half of all pregnancies remain unintended. Here we report the first 3D-printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for HIV prevention and contraception. We utilized continuous liquid interface production (CLIP™) to fabricate MPT IVRs in a biocompatible silicone-based resin. Etonogestrel (ENG), ethinyl estradiol (EE), and islatravir (ISL) were loaded into the silicone poly(urethane) IVR in a controlled single step drug loading process driven by absorption. ENG/EE/ISL IVR promoted sustained release of drugs for 150 days in vitro and 14 days in sheep. There were no adverse MPT IVR-related findings of cervicovaginal toxicity or changes in vaginal biopsies or microbiome community profiles evaluated in sheep. Furthermore, ISL IVR in macaques promoted sustained release for 28 days with ISL-triphosphate levels above the established pharmacokinetic benchmark of 50–100 fmol/106 PBMCs. The ISL IVR was found to be safe and well tolerated in the macaques with no observed mucosal cytokine changes or alterations in peripheral CD4 T-cell populations. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls.
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•ENG/EE/ISL were loaded into the IVR in a single step using a controlled solvent-mediated loading process.•ENG/EE/ISL IVRs exhibited sustained release for 150 days in vitro and 14 days in sheep.•ISL IVRs exhibited sustained release in macaques for 28 days above the PK benchmark.•IVRs showed no signs of toxicity in sheep, modeled human vaginal mucosa, and macaques.
Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the ...differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIPLOW for low drug loading and CLIPHIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIPLOW IVRs and NuvaRing. CLIPLOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIPLOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIPHIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIPHIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy.
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Vestibulodynia (VBD), an idiopathic pain disorder characterized by erythema and pain of the vulvar vestibule (the inner ...aspect of the labia minora and vaginal opening), is the most common cause of sexual pain for women of reproductive age. Women also feel discomfort with contact with clothing and tampon use. As most women with this disorder only have pain with provocation of the tissue, topical anesthetics applied to the vestibule are the current first line treatment for temporary pain relief. Treatment options are limited due to anatomical constraints of the vestibular region, poor drug retention time, imprecise dosing, leakage, and overall product messiness. In this study we report a novel approach to treatment of VBD using thin film designed to fit the vulvar vestibule and deliver lidocaine locally. Two use cases for VBD treatment were identified 1) rapid drug release (<5 min), for use prior to intercourse and 2) long-acting release (≥120 min) for prolonged use and relief throughout the day. Cellulose-based mucoadhesive thin films were fabricated using a solvent casting method. Three polymers including hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethycellulose (HMPC), were selected owing to their biocompatibility and ideal properties for film casting. Films casted with HEC, HPC, and HPMC exhibited mucoadhesive properties relative to a control, with the highest mucoadhesive force recorded for films casted with HPC. Effect of media volume, pH, presence of mucin and presence of drug on film dissolution rates were investigated. Dissolution rates were independent of media volume, media pH or drug presence, whereas faster dissolution rates were obtained for all films in presence of mucin. In vitro lidocaine release kinetics were influenced by polymer type, percent drug loading and film casting thickness. Lidocaine release was based on a diffusion mechanism rather than through film dissolution and faster release (∼5 min) was observed for HEC films compared HPC films (∼120 min). Higher drug loading and film thickness resulted in slower and more prolonged release kinetics of lidocaine. All films were biocompatible and exhibited good mechanical properties. Two film formulations (9% w/w HPC with 12% w/w LHC, 5% w/w HEC with 6% w/w LHC) were optimized to meet the two use case scenarios for VBD treatment and moved into in vivo testing. In vivo testing demonstrated the safety of the films in BALB/c mice, and the pharmacokinetic analysis demonstrated the delivery of lidocaine primarily to the vaginal tissue. We demonstrate the ability to develop a mucoadhesive, biodissolvable thin film and fine-tune drug release kinetics to optimize local delivery of lidocaine to the vulva.
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. A novel approach to IVR design and manufacturing is reported that results in geometrically complex internal architectures through the incorporation of distinct unit cells using computationally aided design (CAD) software. A systematic approach is developed to design through the generation of an IVR library and the effects of these parameters are investigated on ring properties. 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 is demonstrated, thus opening the door for a “plug‐and‐play” platform approach to IVR fabrication.
Library of geometrically complex 3D‐printed intravaginal rings (IVRs) with compressible properties independent of internal architecture is presented. IVRs developed with computationally aided design (CAD) software for interchangeable internal architecture fabricated from a silicone‐based resin with digital light synthesis (DLS). Dimensional and mechanical characterization demonstrates controlled diffusion distances and parity with comparable devices, respectively.
Porous structures have long been investigated for advanced material properties however conventional fabrication methods do not have the necessary specificity to dictate void volume size, shape and ...distribution. Additive manufacturing (AM), or more commonly 3D printing, is a rapidly growing field in which material is selectively deposited in a layer wise manner as instructed by a computer-aided design (CAD). Therefore, AM has been seen as an attractive route for fabrication of porous structures. While many AM platforms have been investigated, the overall disadvantage with these processes has been the layer wise assembly method, which yields mechanically weak parts. Additionally, many methods impart an unintentional porosity on the resulting structure that deviates from CAD and aids in the mechanical failure mechanisms. This work sought to investigate and apply a novel AM platform, continuous liquid interface production (CLIP), to the fabrication of porous architected structures. The platform utilizes photopolymerization to reconstruct the CAD in a continuous manner. The platform was investigated for porous structure compatibility through assessment of the fabrication mechanism. It was found that CLIP structures fabricated continuously were layerless, addressing one of the key disadvantages with other platforms. The resolution of CLIP was preliminaryily explored and several contributing factors were identified. The resolution of the CLIP platform was investigated for the fabrication of porous architected structures. Void volumes in the hundreds of microns regime was explored through the fabrication of microlattices. Structures were systematically varied by unit cell type, size, orientation, resin formulation, and CLIP fabrication parameters. The resulting mechanical and physical property space was investigated. The lessons of the importance of low viscosity resin and exposure were carried forward. The tens of micron size range was explored through the fabrication of chromatography columns containg ordered internal architectures with CLIP. Functional resins to enable different separation mechanisms were developed and optimized for CLIP. The pore size of the internal architecture of the column was systematically reduced. The computational limit for CAD generation of complex structures was found and an angular hexagonally packed unit cell designed to facilitate computation as well as mimic monolithic column flow profiles was developed. Columns assembled with CLIP fabricated external housings were assessed for stability. Methods to circumvent computational constraints were developed to allow direct exposure of the light source which enabled the fabrication of smaller pore sizes approaching the theoretical limit of resolution.
We prepared nonflammable liquid polymer electrolytes for lithium-ion batteries by mixing ethoxylated perfluoropolyethers (PFPEs) with LiN(SO2CF3)2 salt. Interestingly, we identified the presence of ...chain coupling in the PFPE polymers and their functionalized derivatives, resulting in a mixture of PFPEs with varying molecular weights. The distribution of molecular weights, along with PFPE's multiple functionalities, allows systematic manipulation of structure to enhance electrochemical and physical properties. Furthermore, the electrolytes exhibited a wide thermal stability window (5% degradation temperature >180 °C). Despite substantial increases in viscosity upon loading the PFPEs with lithium salt, the conductivity (σ ≈ 5 × 10−5 S cm−1 at 28 °C) of the novel electrolytes was about an order of magnitude higher than that of our previously reported PFPE electrolytes. Ethoxylated derivatives of PFPE electrolytes exhibit elevated conductivity compared to non-ethoxylated derivatives, demonstrating our capability to enhance the conductive properties of the PFPE platform by attaching various functional groups to the polymer backbone.
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•Perfluoropolyethers are candidates for nonflammable Li-ion battery electrolytes.•PFPEs interact with the fluorinated anion of lithium salts.•We explored ion transport in a PFPE material with nonfluorinated ether endgroups.•Chain coupling is present in this commercial PFPE product and its derivatives.•Ether groups enhance ion solvation in PFPE electrolytes, boosting conductivity 10×.
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