Continuous liquid interface production of 3D printed drug-loaded spacers to improve prostate cancer brachytherapy treatment.

Brachytherapy, which is the placement of radioactive seeds directly into tissue such as the prostate, is an important curative treatment for prostate cancer. By delivering a high dose of radiation from within the prostate gland, brachytherapy is an effective method of killing prostate cancer cells while limiting radiation dose to normal tissue. The main shortcomings of this treatment are: less efficacy against high grade tumor cells, acute urinary retention, and sub-acute urinary frequency and urgency. One strategy to improve brachytherapy is to incorporate therapeutics into brachytherapy. Drugs, such as docetaxel, can improve therapeutic efficacy, and dexamethasone is known to decrease urinary side effects. However, both therapeutics have high systemic side effects. To overcome this challenge, we hypothesized that we can incorporate therapeutics into the inert polymer spacers that are used to correctly space brachytherapy seeds during brachytherapy to enable local drug delivery. To accomplish this, we engineered 3D printed drug-loaded brachytherapy spacers using continuous liquid interface production (CLIP) with different surface patterns to control drug release. These devices have the same physical size as existing spacers, allowing them to easily replace commercial spacers. We examined these drug-loaded spacers using docetaxel and dexamethasone as model drugs in a murine model of prostate cancer. We found that drug-loaded spacers led to higher therapeutic efficacy for brachytherapy, and there was no discernable systemic toxicity from the drug-loaded spacers. STATEMENT OF SIGNIFICANCE: There has been high interest in the application of 3D printing to engineer novel medical devices. However, such efforts have been limited by the lack of technologies that can fabricate devices suitable for real world medical applications. In this study, we demonstrate a unique application for 3D printing to enhance brachytherapy for cancer treatment. We engineered drug-loaded brachytherapy spacers that can be fabricated using Continuous Liquid Interface Production (CLIP) 3D printing, allowing tunable printing of drug-loaded devices, and implanted intraoperatively with brachytherapy seeds. In combined chemotherapy and brachytherapy we are able to achieve greater therapeutic efficacy through local drug delivery and without systemic toxicities. We believe our work will facilitate further investigation in medical applications of 3D printing.

3D printed drug-loaded implantable devices for intraoperative treatment of cancer.

Surgery is an important treatment for cancer; however, local recurrence following macroscopically-complete resection is common and a significant cause of morbidity and mortality. Systemic chemotherapy is often employed as an adjuvant therapy to prevent recurrence of residual disease, but has limited efficacy due to poor penetration and dose-limiting off-target toxicities. Selective delivery of chemotherapeutics to the surgical bed may eliminate residual tumor cells while avoiding systemic toxicity. While this is challenging for traditional drug delivery technologies, we utilized advances in 3D printing and drug delivery science to engineer a drug-loaded arrowhead array device (AAD) to overcome these challenges. We demonstrated that such a device can be designed, fabricated, and implanted intraoperatively and provide extended release of chemotherapeutics directly to the resection area. Using paclitaxel and cisplatin as model drugs and murine models of cancer, we showed AADs significantly decreased local recurrence post-surgery and improved survival. We further demonstrated the potential for fabricating personalized AADs for intraoperative application in the clinical setting.

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

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.

Difference between approximate and rigorously measured transference numbers in fluorinated electrolytes.

The performance of binary electrolytes is governed by three transport properties: conductivity, salt diffusion coefficient, and transference number. Rigorous methods for measuring conductivity and the salt diffusion coefficient are well established and used routinely in the literature. The commonly used methods for measuring transference number are the steady-state current method, t+,id, and pulsed field gradient NMR, t+,NMR. These methods yield the transference number only if the electrolyte is ideal, i.e., the salt dissociates completely into non-interacting anions and cations. In this work, we present a complete set of ion transport properties for mixtures of a functionalized perfluoroether, dimethyl carbonate terminated perfluorinated tetraethylene ether, and lithium bis(fluorosulfonyl)imide (LiFSI). The equations used to determine these properties from experimental data are based on Newman's concentrated solution theory. The concentrated-solution-theory-based transference number, t, is negative across all salt concentrations, and it increases with increasing salt concentration. In contrast, the ideal transference number, t+,id, is positive across all salt concentrations and it decreases with salt concentration. The NMR-based transference number, t+,NMR, is approximately 0.5, independent of salt concentration. The disparity between the three transference numbers, which indicates the dominance of ion clustering, is resolved by the use of Newman's concentrated solution theory.

Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins.

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.

Mechanism of ion transport in perfluoropolyether electrolytes with a lithium salt.

Perfluoropolyethers (PFPEs) are polymer electrolytes with fluorinated carbon backbones that have high flash points and have been shown to exhibit moderate conductivities and high cation transference numbers when mixed with lithium salts. Ion transport in four PFPE electrolytes with different endgroups was characterized by differential scanning calorimetry (DSC), ac impedance, and pulsed-field gradient NMR (PFG-NMR) as a function of salt concentration and temperature. In spite of the chemical similarity of the electrolytes, salt diffusion coefficients measured by PFG-NMR and the glass transition temperature measured by DSC appear to be uncorrelated to ionic conductivity measured by ac impedance. We calculate a non-dimensional parameter, ß, that depends on the salt diffusion coefficients and ionic conductivity. We also use the Vogel-Tammann-Fulcher relationship to fit the temperature dependence of conductivity. We present a linear relationship between the prefactor in the VTF fit and ß; both parameters vary by four orders of magnitude in our experimental window. Our analysis suggests that transport in electrolytes with low dielectric constants (low ß) is dictated by ion hopping between clusters.

Incipient microphase separation in short chain perfluoropolyether-block-poly(ethylene oxide) copolymers.

Incipient microphase separation is observed by wide angle X-ray scattering (WAXS) in short chain multiblock copolymers consisting of perfluoropolyether (PFPE) and poly(ethylene oxide) (PEO) segments. Two PFPE-PEO block copolymers were studied; one with dihydroxyl end groups and one with dimethyl carbonate end groups. Despite having a low degree of polymerization (N ∼ 10), these materials exhibited significant scattering intensity, due to disordered concentration fluctuations between their PFPE-rich and PEO-rich domains. The disordered scattering intensity was fit to a model based on a multicomponent random phase approximation to determine the value of the interaction parameter, χ, and the radius of gyration, Rg. Over the temperature range 30-90 °C, the values of χ were determined to be very large (∼2-2.5), indicating a high degree of immiscibility between the PFPE and PEO blocks. In PFPE-PEO, due to the large electron density contrast between the fluorinated and non-fluorinated block and the high value of χ, disordered scattering was detected at intermediate scattering angles, (q ∼ 2 nm-1) for relatively small polymer chains. Our ability to detect concentration fluctuations was enabled by both a relatively large value of χ and significant scattering contrast.

Organic Polymer Chemistry in the Context of Novel Processes.

This article was written to shed light on a series of what some have stated are not so obvious connections that link polymer synthesis in supercritical CO2 to cancer treatment and vaccines, nonflammable polymer electrolytes for lithium ion batteries, and 3D printing. In telling this story, we also attempt to show the value of versatility in applying one's primary area of expertise to address pertinent questions in science and in society. In this Outlook, we attempted to identify key factors to enable a versatile and nimble research effort to take shape in an effort to influence diverse fields and have a tangible impact in the private sector through the translation of discoveries into the marketplace.

Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface Production.

Microneedles, arrays of micron-sized needles that painlessly puncture the skin, enable transdermal delivery of medications that are difficult to deliver using more traditional routes. Many important design parameters, such as microneedle size, shape, spacing, and composition, are known to influence efficacy, but are notoriously difficult to alter due to the complex nature of microfabrication techniques. Herein, we utilize a novel additive manufacturing ("3D printing") technique called Continuous Liquid Interface Production (CLIP) to rapidly prototype sharp microneedles with tuneable geometries (size, shape, aspect ratio, spacing). This technology allows for mold-independent, one-step manufacturing of microneedle arrays of virtually any design in less than 10 minutes per patch. Square pyramidal CLIP microneedles composed of trimethylolpropane triacrylate, polyacrylic acid and photopolymerizable derivatives of polyethylene glycol and polycaprolactone were fabricated to demonstrate the range of materials that can be utilized within this platform for encapsulating and controlling the release of therapeutics. These CLIP microneedles effectively pierced murine skin ex vivo and released the fluorescent drug surrogate rhodamine.

Layerless fabrication with continuous liquid interface production.

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.