Additively manufactured micro-lattice dielectrics for multiaxial capacitive sensors.

Soft sensors that can perceive multiaxial forces, such as normal and shear, are of interest for dexterous robotic manipulation and monitoring of human performance. Typical planar fabrication techniques have substantial design constraints that often prohibit the creation of functionally compelling and complex architectures. Moreover, they often require multiple-step operations for production. Here, we use an additive manufacturing process based on continuous liquid interface production to create high-resolution (30-micrometer) three-dimensional elastomeric polyurethane lattices for use as dielectric layers in capacitive sensors. We show that the capacitive responses and sensitivities are highly tunable through designs of lattice type, thickness, and material-void volume percentage. Microcomputed tomography and finite element simulation are used to elucidate the influence of lattice design on the deformation mechanism and concomitant sensing behavior. The advantage of three-dimensional printing is exhibited with examples of fully printed representative athletic equipment with integrated sensors.

Direct measurement of forces in air-based acoustic levitation systems.

Acoustic levitation is frequently used for non-contact manipulation of objects and to study the impact of microgravity on physical and biological processes. While the force field produced by sound pressure lifts particles against gravity (primary acoustic force), multiple levitating objects in the same acoustic cavity interact via forces that arise from scattered sound (secondary acoustic forces). Current experimental techniques for obtaining these force fields are not well-suited for mapping the primary force field at high spatial resolution and cannot directly measure the secondary scattering force. Here, we introduce a method that can measure both acoustic forces in situ, including secondary forces in the near-field limit between arbitrarily shaped, closely spaced objects. Operating similarly to an atomic force microscope, the method inserts into the acoustic cavity a suitably shaped probe tip at the end of a long, flexible cantilever and optically detects its deflection. This makes it possible to measure forces with a resolution better than 50 nN and also to apply stress or strain in a controlled manner to manipulate levitated objects. We demonstrate this by extracting the acoustic potential present in a levitation cavity, directly measuring the acoustic scattering force between two objects, and applying tension to a levitated granular raft of acoustically bound particles in order to obtain the force-displacement curve for its deformation.

3D-Printed Latticed Microneedle Array Patches for Tunable and Versatile Intradermal Delivery.

Using high-resolution 3D printing, a novel class of microneedle array patches (MAPs) is introduced, called latticed MAPs (L-MAPs). Unlike most MAPs which are composed of either solid structures or hollow needles, L-MAPs incorporate tapered struts that form hollow cells capable of trapping liquid droplets. The lattice structures can also be coated with traditional viscous coating formulations, enabling both liquid- and solid-state cargo delivery, on a single patch. Here, a library of 43 L-MAP designs is generated and in-silico modeling is used to down-select optimal geometries for further characterization. Compared to traditionally molded and solid-coated MAPs, L-MAPs can load more cargo with fewer needles per patch, enhancing cargo loading and drug delivery capabilities. Further, L-MAP cargo release kinetics into the skin can be tuned based on formulation and needle geometry. In this work, the utility of L-MAPs as a platform is demonstrated for the delivery of small molecules, mRNA lipid nanoparticles, and solid-state ovalbumin protein. In addition, the production of programmable L-MAPs is demonstrated with tunable cargo release profiles, enabled by combining needle geometries on a single patch.

High-resolution stereolithography: Negative spaces enabled by control of fluid mechanics.

Stereolithography enables the fabrication of three-dimensional (3D) freeform structures via light-induced polymerization. However, the accumulation of ultraviolet dose within resin trapped in negative spaces, such as microfluidic channels or voids, can result in the unintended closing, referred to as overcuring, of these negative spaces. We report the use of injection continuous liquid interface production to continuously displace resin at risk of overcuring in negative spaces created in previous layers with fresh resin to mitigate the loss of Z-axis resolution. We demonstrate the ability to resolve 50-µm microchannels, breaking the historical relationship between resin properties and negative space resolution. With this approach, we fabricated proof-of-concept 3D free-form microfluidic devices with improved design freedom over device material selection and resulting properties.

High-Risk Histopathological Features of Retinoblastoma following Primary Enucleation: A Global Study of 1426 Patients from 5 Continents.

PURPOSE: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents. METHODS: Retrospective study of 1426 primarily enucleated RB eyes from five continents. RESULTS: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients. CONCLUSION: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

Growing three-dimensional objects with light.

Vat photopolymerization (VP) additive manufacturing enables fabrication of complex 3D objects by using light to selectively cure a liquid resin. Developed in the 1980s, this technique initially had few practical applications due to limitations in print speed and final part material properties. In the four decades since the inception of VP, the field has matured substantially due to simultaneous advances in light delivery, interface design, and materials chemistry. Today, VP materials are used in a variety of practical applications and are produced at industrial scale. In this perspective, we trace the developments that enabled this printing revolution by focusing on the enabling themes of light, interfaces, and materials. We focus on these fundamentals as they relate to continuous liquid interface production (CLIP), but provide context for the broader VP field. We identify the fundamental physics of the printing process and the key breakthroughs that have enabled faster and higher-resolution printing, as well as production of better materials. We show examples of how in situ print process monitoring methods such as optical coherence tomography can drastically improve our understanding of the print process. Finally, we highlight areas of recent development such as multimaterial printing and inorganic material printing that represent the next frontiers in VP methods.

Roll-to-roll, high-resolution 3D printing of shape-specific particles.

Particle fabrication has attracted recent attention owing to its diverse applications in bioengineering1,2, drug and vaccine delivery3-5, microfluidics6,7, granular systems8,9, self-assembly5,10,11, microelectronics12,13 and abrasives14. Herein we introduce a scalable, high-resolution, 3D printing technique for the fabrication of shape-specific particles based on roll-to-roll continuous liquid interface production (r2rCLIP). We demonstrate r2rCLIP using single-digit, micron-resolution optics in combination with a continuous roll of film (in lieu of a static platform), enabling the rapidly permutable fabrication and harvesting of shape-specific particles from a variety of materials and with complex geometries, including geometries not possible to achieve with advanced mould-based techniques. We demonstrate r2rCLIP production of mouldable and non-mouldable shapes with voxel sizes as small as 2.0 × 2.0 µm2 in the print plane and 1.1 ± 0.3 µm unsupported thickness, at speeds of up to 1,000,000 particles per day. Such microscopic particles with permutable, intricate designs enable direct integration within biomedical, analytical and advanced materials applications.

Understanding choroidal nevus risk factors for transformation into melanoma.

A choroidal nevus is a common intraocular tumor in the United States, found in approximately 5% of Caucasian adults. The three main risks of melanocytic choroidal nevus include vision loss from a subfoveal nevus, development of subretinal fluid, and transformation of nevus into melanoma, a malignant counterpart. We explore clinical risk factors that predict benign melanocytic choroidal nevus transformation into a malignant choroidal melanoma. Based on a large analysis of 2,355 cases that were monitored longitudinally using multimodal imaging, the most recent list of clinical features includes tumor Thickness greater than 2 mm on ultrasonography, subretinal Fluid on optical coherence tomography, Symptomatic vision loss 20/50 or worse, Orange pigment on fundus autofluorescence, Melanoma hollow on ultrasonography, and DIaMeter greater than 5 mm on fundus photography. These factors are remembered with a mnemonic of the capital letters TFSOM-DIM for "To Find Small Ocular Melanoma Doing Imaging." Analysis of these factors demonstrated a Kaplan-Meier mean five-year risk of 1% with no risk factors, 11% with any one factor, 22% with any two factors, 34% with any three factors, 51% with any four factors, and 55% with any five factors. There was no patient with six risk factors. Of those with combinations of four risk factors, six of 15 combinations yielded a 70%-100% rate of transformation; of those with combinations of five risk factors, two of five combinations yielded a 70%-100% rate of transformation. Choroidal nevus carries a risk for evolving into melanoma, and understanding of clinical and imaging features predictive of this outcome is highly important.

Effectiveness of treatment for iris melanoma: surgical versus radiotherapeutic approaches.

OBJECTIVE: To evaluate the effectiveness of preventing metastasis for each major treatment modality for iris melanoma. DESIGN: Retrospective case series. PARTICIPANTS: Three hundred consecutive eyes with iris melanoma at a single tertiary referral centre for ocular oncology. METHODS: Retrospective analysis of eyes with iris melanoma, both with (n = 69 eyes) and without (n = 231 eyes) ciliary body extension, was undertaken for metastasis-free survival at 5, 10, and 20 years based on type of treatment, including globe-sparing surgical resection (n = 169 eyes), plaque radiotherapy (n = 74 eyes), or enucleation (n = 57 eyes). RESULTS: For the total population, 5-, 10-, and 20-year metastasis-free survival rates were 95%, 93%, and 87%, respectively, and there was no difference in metastatic rates for tumours with versus without ciliary body extension (p = 0.95). Noninferiority was demonstrated for surgical resection and plaque radiotherapy, with metastasis-free survival rates of 98%, 97%, and 94% for surgical resection and 94%, 94%, and 89% for plaque radiotherapy (p = 0.002). The rates for globe salvage were 94%, 92%, and 90% for surgical resection and 94%, 86%, and 86% for plaque radiotherapy (p = 0.003). However, metastasis-free survival was worse in patients who underwent enucleation (86%, 67%, and NA; p < 0.001). CONCLUSIONS: Metastasis-free survival and globe salvage following plaque radiotherapy and surgical resection are not inferior to either, but eyes undergoing enucleation demonstrated a lower metastasis-free survival, likely because enucleation is performed for larger, more extensive melanomas, often with secondary glaucoma. In this analysis, iris melanoma with ciliary body involvement did not increase the risk of metastasis.

Stretchable, recyclable thermosets via photopolymerization and 3D printing of hemiacetal ester-based resins.

Achieving a circular plastics economy is one of our greatest environmental challenges, yet conventional mechanical recycling remains inadequate for thermoplastics and incompatible with thermosets. The next generation of plastic materials will be designed with the capacity for degradation and recycling at end-of-use. To address this opportunity in the burgeoning technologies of 3D printing and photolithography, we report a modular system for the production of degradable and recyclable thermosets via photopolymerization. The polyurethane backbone imparts robust, elastic, and tunable mechanical properties, while the use of hemiacetal ester linkages allows for facile degradation under mild acid. The synthetic design based on hemiacetal esters enables simple purification to regenerate a functional polyurethane diol.

Conditional Metastasis of Uveal Melanoma in 8091 Patients over Half-Century (51 Years) by Age Group: Assessing the Entire Population and the Extremes of Age.

Purpose: To evaluate cumulative incidence of metastasis at specific timepoints after treatment of uveal melanoma in a large cohort of patients and to provide comparison of conditional outcomes in the youngest and oldest cohorts (extremes of age). Methods: Retrospective analysis of 8091 consecutive patients with uveal melanoma at a single center over a 51-year period. The patients were categorized by age at presentation (0-29 years [n = 348, 4%], 30-59 years [n = 3859, 48%], 60-79 years [n = 3425, 42%], 80 to 99 years [n = 459, 6%]) and evaluated for nonconditional (from presentation date) and conditional (from specific timepoints after presentation) cumulative incidence of metastasis at five, 10, 20, and 30 years. Results: For the entire population of 8091 patients, five-year/10-year/20-year/30-year nonconditional cumulative incidence of metastasis was 15%/23%/32%/36%, and the conditional incidence improved to 6%/15%/25%/30% for patients who did not develop metastasis in the first three years. For the extremes of age (0-29 years and 80-99 years), the nonconditional cumulative incidence of metastasis revealed the younger cohort with superior outcomes at 8%/15%/19%/27% and 21%/29%/29%/29%, respectively (P < 0.001). The conditional incidence (at one-year and two-year timepoints with metastasis-free survival) showed persistent superior younger cohort survival (P < 0.001, P = 0.001), but no further benefit for patients with three-year metastasis-free survival at 4%/12%/16%/24% and 7%/18%/18%/18%, respectively (P = 0.09). Conclusions: Non-conditional metastasis-free survival analysis for patients with uveal melanoma revealed the youngest cohort to have significantly better survival than the oldest cohort, and this persisted into one-year and two-year conditional metastasis-free survival but diminished at the three-year conditional timepoint.

Botfly Myiasis Masquerading as Dacryocystitis.

Cutaneous myiasis is an infection most commonly caused globally by Dermatobia hominus , the human botfly, which is endemic to Central and South America. In North America, the most common cause of cutaneous myiasis is infestation with the larvae of Cuterebra , the North American botfly. The authors describe a 44-year-old man who presented with a 1-month history of intermittent, severe, boring pain along the side of his nose that progressed to swelling and redness along his right inferior orbital rim and lacrimal sac. CT imaging showed a rim-enhancing collection at the right medial canthus with surrounding phlegmonous changes communicating with the skin. Pathologic evaluation revealed curvilinear pigmented material associated with a granulomatous and eosinophil-rich inflammatory infiltrate, consistent with botfly myiasis. This case describes the pathogenesis of the botfly infestation in humans, as well as the clinical, radiographic, and histopathologic features of this rare orbital infection, with an emphasis on its treatment.

Survey of ophthalmic imaging use to assess risk of progression of choroidal nevus to melanoma.

BACKGROUND/OBJECTIVES: The aim of this study was to ascertain the use of ocular imaging and the updated screening criteria in the evaluation of choroidal nevus across the United States. METHODS: Sixty ophthalmologists completed an anonymous 21-question survey addressing their use of the screening criteria for evaluating choroidal nevi, as well as their use of ultrasonography (US), optical coherence tomography (OCT), and autofluorescence (AF) in daily practice. RESULTS: The majority of respondents were from the Northeast (55%), worked in private practice (83%), and practiced general ophthalmology (42%). The 2009 criteria TFSOM-UHHD was used by 39 (65%) respondents, while the 2019 criteria TFSOM-DIM was used by 29 (48%) respondents. Compared to anterior segment ophthalmologists, posterior segment ophthalmologists were more likely to use the TFSOM-UHHD criteria (94% vs. 53%, OR = 13.9, p = 0.014), the TFSOM-DIM criteria (88% vs. 33%, OR = 15.5, p < 0.001), fundus AF (82% vs. 19%, OR = 20.4, p < 0.001), and US (94% vs. 42%, OR = 22.2, p = 0.004) in daily practice. CONCLUSIONS: From the survey of current practice patterns, we learned that there is a general trend of underutilization of the proper imaging modalities - and thus the criteria - in evaluating choroidal nevus. More education about ocular cancer and its screening could improve patient outcomes in the future.

3D-Printed Microarray Patches for Transdermal Applications.

The intradermal (ID) space has been actively explored as a means for drug delivery and diagnostics that is minimally invasive. Microneedles or microneedle patches or microarray patches (MAPs) are comprised of a series of micrometer-sized projections that can painlessly puncture the skin and access the epidermal/dermal layer. MAPs have failed to reach their full potential because many of these platforms rely on dated lithographic manufacturing processes or molding processes that are not easily scalable and hinder innovative designs of MAP geometries that can be achieved. The DeSimone Laboratory has recently developed a high-resolution continuous liquid interface production (CLIP) 3D printing technology. This 3D printer uses light and oxygen to enable a continuous, noncontact polymerization dead zone at the build surface, allowing for rapid production of MAPs with precise and tunable geometries. Using this tool, we are now able to produce new classes of lattice MAPs (L-MAPs) and dynamic MAPs (D-MAPs) that can deliver both solid state and liquid cargos and are also capable of sampling interstitial fluid. Herein, we will explore how additive manufacturing can revolutionize MAP development and open new doors for minimally invasive drug delivery and diagnostic platforms.

Multicenter experience with valve-in-valve transcatheter aortic valve replacement compared with primary, native valve transcatheter aortic valve replacement.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) offers an alternative to reoperative surgical aortic valve replacement. The short- and intermediate-term outcomes after ViV TAVR in the real world are not entirely clear. PATIENTS AND METHODS: A multicenter, retrospective analysis of a consecutive series of 121 ViV TAVR patients and 2200 patients undergoing primary native valve TAVR from 2012 to 2017 at six medical centers. The main outcome measures were in-hospital mortality, 30-day mortality, stroke, myocardial infarction, acute kidney injury, and pacemaker implantation. RESULTS: ViV patients were more likely male, younger, prior coronary artery bypass graft, "hostile chest," and urgent. 30% of the patients had Society of Thoracic Surgeons risk score <4%, 36.3% were 4%-8% and 33.8% were >8%. In both groups many patients had concomitant coronary artery disease. Median time to prosthetic failure was 9.6 years (interquartile range: 5.5-13.5 years). 82% of failed surgical valves were size 21, 23, or 25 mm. Access was 91% femoral. After ViV, 87% had none or trivial aortic regurgitation. Mean gradients were <20 mmHg in 54.6%, 20-29 mmHg in 30.6%, 30-39 mmHg in 8.3% and ≥40 mmHg in 5.87%. Median length of stay was 4 days. In-hospital mortality was 0%. 30-day mortality was 0% in ViV and 3.7% in native TAVR. There was no difference in in-hospital mortality, postprocedure myocardial infarction, stroke, or acute kidney injury. CONCLUSION: Compared to native TAVR, ViV TAVR has similar peri-procedural morbidity with relatively high postprocedure mean gradients. A multidisciplinary approach will help ensure patients receive the ideal therapy in the setting of structural bioprosthetic valve degeneration.

Single-digit-micrometer-resolution continuous liquid interface production.

To date, a compromise between resolution and print speed has rendered most high-resolution additive manufacturing technologies unscalable with limited applications. By combining a reduction lens optics system for single-digit-micrometer resolution, an in-line camera system for contrast-based sharpness optimization, and continuous liquid interface production (CLIP) technology for high scalability, we introduce a single-digit-micrometer-resolution CLIP-based 3D printer that can create millimeter-scale 3D prints with single-digit-micrometer-resolution features in just a few minutes. A simulation model is developed in parallel to probe the fundamental governing principles in optics, chemical kinetics, and mass transport in the 3D printing process. A print strategy with tunable parameters informed by the simulation model is adopted to achieve both the optimal resolution and the maximum print speed. Together, the high-resolution 3D CLIP printer has opened the door to various applications including, but not limited to, biomedical, MEMS, and microelectronics.

Injection continuous liquid interface production of 3D objects.

In additive manufacturing, it is imperative to increase print speeds, use higher-viscosity resins, and print with multiple different resins simultaneously. To this end, we introduce a previously unexplored ultraviolet-based photopolymerization three-dimensional printing process. The method exploits a continuous liquid interface-the dead zone-mechanically fed with resin at elevated pressures through microfluidic channels dynamically created and integral to the growing part. Through this mass transport control, injection continuous liquid interface production, or iCLIP, can accelerate printing speeds to 5- to 10-fold over current methods such as CLIP, can use resins an order of magnitude more viscous than CLIP, and can readily pattern a single heterogeneous object with different resins in all Cartesian coordinates. We characterize the process parameters governing iCLIP and demonstrate use cases for rapidly printing carbon nanotube-filled composites, multimaterial features with length scales spanning several orders of magnitude, and lattices with tunable moduli and energy absorption.

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.

Characterization of a 30 µm pixel size CLIP-based 3D printer and its enhancement through dynamic printing optimization.

Resolving microscopic and complex 3D polymeric structures while maintaining high print speeds in additive manufacturing has been challenging. To achieve print precision at micrometer length scales for polymeric materials, most 3D printing technologies utilize the serial voxel printing approach that has a relatively slow print speed. Here, a 30-µm-resolution continuous liquid interface production (CLIP)-based 3D printing system for printing polymeric microstructures is described. This technology combines the high-resolution from projection microstereolithography and the fast print speed from CLIP, thereby achieving micrometer print resolution at x103 times faster than other high-resolution 3D printing technologies. Print resolutions in both lateral and vertical directions were characterized, and the printability of minimum 30 µm features in 2D and 3D has been demonstrated. Through dynamic printing optimization, a method that varies the print parameters (e.g. exposure time, UV intensity, and dark time) for each print layer, overhanging struts at various thicknesses spanning 1 order of magnitude (25 µm - 200 µm) in a single print are resolvable. Taken together, this work illustrates that the micro-CLIP 3D printing technology, in combination with dynamic printing optimization, has the high resolution needed to enable manufacturing of exquisitely detailed and gradient 3D structures, such as terraced microneedle arrays and micro-lattice structures, while maintaining high print speeds.