Bio


Joseph M. DeSimone is the Sanjiv Sam Gambhir Professor of Translational Medicine and Chemical Engineering at Stanford University. He holds appointments in the Departments of Radiology and Chemical Engineering with courtesy appointments in the Department of Chemistry and in Stanford’s Graduate School of Business.

The DeSimone laboratory's research efforts are focused on developing innovative, interdisciplinary solutions to complex problems centered around advanced polymer 3D fabrication methods. In Chemical Engineering and Materials Science, the lab is pursuing new capabilities in digital 3D printing, as well as the synthesis of new polymers for use in advanced additive technologies. In Translational Medicine, research is focused on exploiting 3D digital fabrication tools to engineer new vaccine platforms, enhanced drug delivery approaches, and improved medical devices for numerous conditions, with a current major focus in pediatrics. Complementing these research areas, the DeSimone group has a third focus in Entrepreneurship, Digital Transformation, and Manufacturing.

Before joining Stanford in 2020, DeSimone was a professor of chemistry at the University of North Carolina at Chapel Hill and of chemical engineering at North Carolina State University. He is also Co-founder, Board Chair, and former CEO (2014 - 2019) of the additive manufacturing company, Carbon. DeSimone is responsible for numerous breakthroughs in his career in areas including green chemistry, medical devices, nanomedicine, and 3D printing. He has published over 350 scientific articles and is a named inventor on over 200 issued patents. Additionally, he has mentored 80 students through Ph.D. completion in his career, half of whom are women and members of underrepresented groups in STEM.

In 2016 DeSimone was recognized by President Barack Obama with the National Medal of Technology and Innovation, the highest U.S. honor for achievement and leadership in advancing technological progress. He has received numerous other major awards in his career, including the U.S. Presidential Green Chemistry Challenge Award (1997); the American Chemical Society Award for Creative Invention (2005); the Lemelson-MIT Prize (2008); the NIH Director’s Pioneer Award (2009); the AAAS Mentor Award (2010); the Heinz Award for Technology, the Economy and Employment (2017); the Wilhelm Exner Medal (2019); the EY Entrepreneur of the Year Award (2019 U.S. Overall National Winner); and the Harvey Prize in Science and Technology (2020). He is one of only 25 individuals elected to all three branches of the U.S. National Academies (Sciences, Medicine, Engineering). DeSimone received his B.S. in Chemistry in 1986 from Ursinus College and his Ph.D. in Chemistry in 1990 from Virginia Tech.

Academic Appointments


2023-24 Courses


Stanford Advisees


All Publications


  • Single-digit-micrometer-resolution continuous liquid interface production. Science advances Hsiao, K., Lee, B. J., Samuelsen, T., Lipkowitz, G., Kronenfeld, J. M., Ilyn, D., Shih, A., Dulay, M. T., Tate, L., Shaqfeh, E. S., DeSimone, J. M. 2022; 8 (46): eabq2846

    Abstract

    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.

    View details for DOI 10.1126/sciadv.abq2846

    View details for PubMedID 36383664

  • 3D-Printed Microarray Patches for Transdermal Applications JACS AU Rajesh, N. U., Coates, I., Driskill, M. M., Dulay, M. T., Hsiao, K., Ilyin, D., Jacobson, G. B., Kwak, J., Lawrence, M., Perry, J., Shea, C. O., Tian, S., DeSimone, J. M. 2022
  • Injection continuous liquid interface production of 3D objects. Science advances Lipkowitz, G., Samuelsen, T., Hsiao, K., Lee, B., Dulay, M. T., Coates, I., Lin, H., Pan, W., Toth, G., Tate, L., Shaqfeh, E. S., DeSimone, J. M. 2022; 8 (39): eabq3917

    Abstract

    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.

    View details for DOI 10.1126/sciadv.abq3917

    View details for PubMedID 36170357

  • Characterization of a 30 m pixel size CLIP-based 3D printer and its enhancement through dynamic printing optimization. Additive manufacturing Lee, B. J., Hsiao, K., Lipkowitz, G., Samuelsen, T., Tate, L., DeSimone, J. M. 2022; 55

    Abstract

    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-m-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 m 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 m - 200 m) 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.

    View details for DOI 10.1016/j.addma.2022.102800

    View details for PubMedID 35602181

  • Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity. Proceedings of the National Academy of Sciences of the United States of America Caudill, C., Perry, J. L., Iliadis, K., Tessema, A. T., Lee, B. J., Mecham, B. S., Tian, S., DeSimone, J. M. 2021; 118 (39)

    Abstract

    Vaccination is an essential public health measure for infectious disease prevention. The exposure of the immune system to vaccine formulations with the appropriate kinetics is critical for inducing protective immunity. In this work, faceted microneedle arrays were designed and fabricated utilizing a three-dimensional (3D)-printing technique called continuous liquid interface production (CLIP). The faceted microneedle design resulted in increased surface area as compared with the smooth square pyramidal design, ultimately leading to enhanced surface coating of model vaccine components (ovalbumin and CpG). Utilizing fluorescent tags and live-animal imaging, we evaluated in vivo cargo retention and bioavailability in mice as a function of route of delivery. Compared with subcutaneous bolus injection of the soluble components, microneedle transdermal delivery not only resulted in enhanced cargo retention in the skin but also improved immune cell activation in the draining lymph nodes. Furthermore, the microneedle vaccine induced a potent humoral immune response, with higher total IgG (Immunoglobulin G) and a more balanced IgG1/IgG2a repertoire and achieved dose sparing. Furthermore, it elicited T cell responses as characterized by functional cytotoxic CD8+ T cells and CD4+ T cells secreting Th1 (T helper type 1)-cytokines. Taken together, CLIP 3D-printed microneedles coated with vaccine components provide a useful platform for a noninvasive, self-applicable vaccination.

    View details for DOI 10.1073/pnas.2102595118

    View details for PubMedID 34551974

  • Methods for modeling and real-time visualization of CLIP and iCLIP-based 3D printing GIANT Lipkowitz, G., Coates, I., Krishna, N., Shaqfeh, E. G., DeSimone, J. M. 2024; 17
  • Stretchable, recyclable thermosets via photopolymerization and 3D printing of hemiacetal ester-based resins. Chemical science Wu, Y. M., Chyr, G., Park, H., Makar-Limanov, A., Shi, Y., DeSimone, J. M., Bao, Z. 2023; 14 (44): 12535-12540

    Abstract

    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.

    View details for DOI 10.1039/d3sc03623e

    View details for PubMedID 38020396

    View details for PubMedCentralID PMC10646930

  • Stretchable, recyclable thermosets <i>via</i> photopolymerization and 3D printing of hemiacetal ester-based resins CHEMICAL SCIENCE Wu, Y., Chyr, G., Park, H., Makar-Limanov, A., Shi, Y., Desimone, J. M., Bao, Z. 2023

    View details for DOI 10.1039/d3sc03623e

    View details for Web of Science ID 001094789200001

  • Palete-PrintAR: an augmented reality fluidic design tool for multicolor resin 3D printing Lipkowitz, G., Shaqfeh, E. G., DeSimone, J. M., ACM ASSOC COMPUTING MACHINERY. 2023
  • Printing atom-efficiently: faster fabrication of farther unsupported overhangs by fluid dynamics simulation Lipkowitz, G., Krishna, N., Coates, I., Shaqfeh, E. G., DeSimone, J. M., Spencer, S. N. ASSOC COMPUTING MACHINERY. 2023
  • Review of high-performance sustainable polymers in additive manufacturing GREEN CHEMISTRY Chyr, G., DeSimone, J. M. 2022

    View details for DOI 10.1039/d2gc03474c

    View details for Web of Science ID 000898743200001

  • 3D-Printed Microarray Patches for Transdermal Applications. JACS Au Rajesh, N. U., Coates, I., Driskill, M. M., Dulay, M. T., Hsiao, K., Ilyin, D., Jacobson, G. B., Kwak, J. W., Lawrence, M., Perry, J., Shea, C. O., Tian, S., DeSimone, J. M. 2022; 2 (11): 2426-2445

    Abstract

    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.

    View details for DOI 10.1021/jacsau.2c00432

    View details for PubMedID 36465529

    View details for PubMedCentralID PMC9709783

  • INNOVATION IN MENTORSHIP ISSUES IN SCIENCE AND TECHNOLOGY Farrell, C. L., Dulay, M. T., DeSimone, J. M. 2022; 39 (1): 10-11
  • 3D Printing Medical Devices AMERICAN SCIENTIST DeSimone, J. 2022; 110 (4): 235-237
  • Continuous Liquid Interface Production of 3D Printed Drug-Loaded Spacers to Improve Prostate Cancer Brachytherapy Treatment. Acta biomaterialia Hagan, C. T., Bloomquist, C., Kim, I., Knape, N. M., Byrne, J. D., Tu, L., Wagner, K., Mecham, S., DeSimone, J., Wang, A. Z. 2022

    Abstract

    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 effecacy 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.

    View details for DOI 10.1016/j.actbio.2022.06.023

    View details for PubMedID 35724920

  • 3D printed drug-loaded implantable devices for intraoperative treatment of cancer. Journal of controlled release : official journal of the Controlled Release Society Tilden Hagan, C. 4., Bloomquist, C., Warner, S., Knape, N. M., Kim, I., Foley, H., Wagner, K., Mecham, S., DeSimone, J., Wang, A. Z. 2022

    Abstract

    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.

    View details for DOI 10.1016/j.jconrel.2022.02.024

    View details for PubMedID 35217100

  • Generative co-design for microfluidics-accelerated 3D printing Lipkowitz, G., Shaqfeh, E. G., DeSimone, J. M., Spencer, S. N. ASSOC COMPUTING MACHINERY. 2022
  • Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Caudill, C., Perry, J. L., Iliadis, K., Tessema, A. T., Lee, B. J., Mecham, B. S., Tian, S., DeSimone, J. M. 2021; 118 (39)
  • Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy (vol 12, pg 877, 2017) NATURE NANOTECHNOLOGY Min, Y., Roche, K. C., Tian, S., Eblan, M. J., McKinnon, K. P., Caster, J. M., Chai, S., Herring, L. E., Zhang, L., Zhang, T., DeSimone, J. M., Tepper, J. E., Vincent, B. G., Serody, J. S., Wang, A. Z. 2021; 16 (6): 743-744

    View details for DOI 10.1038/s41565-021-00864-w

    View details for Web of Science ID 000617405500001

    View details for PubMedID 33580223

    View details for PubMedCentralID PMC9280999

  • Impact of Frictional Interactions on Conductivity, Diffusion, and Transference Number in Ether- and Perfluoroether-Based Electrolytes JOURNAL OF THE ELECTROCHEMICAL SOCIETY Grundy, L. S., Shah, D. B., Nguyen, H. Q., Diederichsen, K. M., Celik, H., DeSimone, J. M., McCloskey, B. D., Balsara, N. P. 2020; 167 (12)
  • Role of Linker Length and Antigen Density in Nanoparticle Peptide Vaccine ACS OMEGA Kapadia, C. H., Tian, S., Perry, J. L., Luft, J., Desimone, J. M. 2019; 4 (3): 5547-5555

    Abstract

    Multiple studies have been published emphasizing the significant role of nanoparticle (NP) carriers in antigenic peptide-based subunit vaccines for the induction of potent humoral and cellular responses. Various design parameters of nanoparticle subunit vaccines such as linker chemistry, the proximity of antigenic peptide to NPs, and the density of antigenic peptides on the surface of NPs play an important role in antigen presentation to dendritic cells (DCs) and in subsequent induction of CD8+ T cell response. In this current study, we evaluated the role of peptide antigen proximity and density on DC uptake, antigen cross-presentation, in vitro T cell proliferation, and in vivo induction of CD8+ T cells. To evaluate the role of antigen proximity, CSIINFEKL peptides were systematically conjugated to poly(ethylene glycol) (PEG) hydrogels through N-hydroxysuccinimide-PEG-maleimide linkers of varying molecular weights: 2k, 5k, and 10k. We observed that the peptides conjugated to NPs via the 2k and 5k PEG linkers resulted in higher uptake in bone marrow-derived DCs (BMDCs) and increased p-MHC-I formation on the surface of bone marrow-derived DCs (BMDCs) as compared to the 10k PEG linker formulation. However, no significant differences in vitro T cell proliferation and induction of in vivo CD8+ T cells were found among linker lengths. To study the effect of antigen density, CSIINFEKL peptides were conjugated to PEG hydrogels via 5k PEG linkers at various densities. We found that high antigen density NPs presented the highest p-MHC-I on the surface of BMDCs and induced higher proliferation of T cells, whereas NPs with low peptide density resulted in higher DC cell uptake and elevated frequency of IFN-γ producing CD8+ T cells in mice as compared to the medium- and high-density formulations. Altogether, findings for these experiments highlighted the importance of linker length and peptide antigen density on DC cell uptake, antigen presentation, and induction of in vivo CD8+ T cell response.

    View details for DOI 10.1021/acsomega.8b03391

    View details for Web of Science ID 000462921900111

    View details for PubMedID 30972374

    View details for PubMedCentralID PMC6450662

  • Formulation of High-Performance Dry Powder Aerosols for Pulmonary Protein Delivery PHARMACEUTICAL RESEARCH Wilson, E. M., Luft, J., DeSimone, J. M. 2018; 35 (10): 195

    Abstract

    Pulmonary delivery of biologics is of great interest, as it can be used for the local treatment of respiratory diseases or as a route to systemic drug delivery. To reach the full potential of inhaled biologics, a formulation platform capable of producing high performance aerosols without altering protein native structure is required.A formulation strategy using Particle Replication in Non-wetting Templates (PRINT) was developed to produce protein dry powders with precisely engineered particle morphology. Stability of the incorporated proteins was characterized and the aerosol properties of the protein dry powders was evaluated in vitro with an Andersen Cascade Impactor (ACI).Model proteins bovine serum albumin (BSA) and lysozyme were micromolded into 1 μm cylinders composed of more than 80% protein, by mass. Extensive characterization of the incorporated proteins found no evidence of alteration of native structures. The BSA formulation produced a mass median aerodynamic diameter (MMAD) of 1.77 μm ± 0.06 and a geometric standard deviation (GSD) of 1.51 ± 0.06 while the lysozyme formulation had an MMAD of 1.83 μm ± 0.12 and a GSD of 1.44 ± 0.03.Protein dry powders manufactured with PRINT could enable high-performance delivery of protein therapeutics to the lungs.

    View details for DOI 10.1007/s11095-018-2452-z

    View details for Web of Science ID 000442609600001

    View details for PubMedID 30141117

  • Use of iontophoresis for the treatment of cancer JOURNAL OF CONTROLLED RELEASE Byrne, J. D., Yeh, J., DeSimone, J. M. 2018; 284: 144-151

    Abstract

    Despite major advancements in cancer treatments, there are still many limitations to therapy including off-target effects, drug resistance, and control of cancer-related symptoms. There are opportunities for local drug delivery devices to intervene at various stages of cancer to provide curative and palliative benefit. Iontophoretic devices that deliver drugs locally to a region of interest have been adapted for the treatment of cancer. These devices have shown promise in pre-clinical and clinical studies for retinoblastoma, skin, bladder, and pancreatic cancers. Herein, we review iontophoretic devices used in the management of cancer.

    View details for DOI 10.1016/j.jconrel.2018.06.020

    View details for Web of Science ID 000441048900013

    View details for PubMedID 29908892

  • Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer CANCER CHEMOTHERAPY AND PHARMACOLOGY Byrne, J. D., Jajja, M. N., O'Neill, A. T., Schorzman, A. N., Keeler, A. W., Luft, J., Zamboni, W. C., DeSimone, J. M., Yeh, J. 2018; 81 (6): 991-998

    Abstract

    Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

    View details for DOI 10.1007/s00280-018-3570-3

    View details for Web of Science ID 000433507600004

    View details for PubMedID 29603014

    View details for PubMedCentralID PMC6753584

  • Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins JOURNAL OF CONTROLLED RELEASE Bloomquist, C. J., Mecham, M. B., Paradzinsky, M. D., Janusziewicz, R., Warner, S. B., Luft, J., Mecham, S. J., Wang, A. Z., DeSimone, J. M. 2018; 278: 9-23

    Abstract

    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.

    View details for DOI 10.1016/j.jconrel.2018.03.026

    View details for Web of Science ID 000432650800002

    View details for PubMedID 29596874

  • Extending antigen release from particulate vaccines results in enhanced antitumor immune response JOURNAL OF CONTROLLED RELEASE Kapadia, C. H., Tian, S., Perry, J. L., Sailer, D., Luft, J., DeSimone, J. M. 2018; 269: 393-404

    Abstract

    Tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) play a critical role in an anti-tumor immune response. However, vaccination intended to elicit a potent CD8+ T cell responses employing tumor-associated peptide antigens, are typically ineffective due to poor immunogenicity. Previously, we engineered a polyethylene glycol (PEG) hydrogel-based subunit vaccine for the delivery of an antigenic peptide and CpG (adjuvant) to elicit potent CTLs. In this study, we further examined the effect of antigen release kinetics on their induced immune responses. A CD8+ T cell epitope peptide from OVA (CSIINFEKL) and CpG were co-conjugated to nanoparticles utilizing either a disulfide or a thioether linkage. Subsequent studies comparing peptide release rates as a function of linker, determined that the thioether linkage provided sustained release of peptide over 72h. Ability to control the release of peptide resulted in both higher and prolonged antigen presentation when compared to disulfide-linked peptide. Both NP vaccine formulations resulted in activation and maturation of bone marrow derived dendritic cells (BMDCs) and induced potent CD8+ T cell responses when compared to soluble antigen and soluble CpG. Immunization with either disulfide or thioether linked vaccine constructs effectively inhibited EG7-OVA tumor growth in mice, however only treatment with the thioether linked vaccine construct resulted in enhanced survival.

    View details for DOI 10.1016/j.jconrel.2017.11.020

    View details for Web of Science ID 000423760400033

    View details for PubMedID 29146244

  • Crosslinked perfluoropolyether solid electrolytes for lithium ion transport SOLID STATE IONICS Devaux, D., Villaluenga, I., Bhatt, M., Shah, D., Chen, X., Thelen, J. L., DeSimone, J. M., Balsara, N. P. 2017; 310: 71-80
  • Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy NATURE NANOTECHNOLOGY Min, Y., Roche, K. C., Tian, S., Eblan, M. J., McKinnon, K. P., Caster, J. M., Chai, S., Herring, L. E., Zhang, L., Zhang, T., DeSimone, J. M., Tepper, J. E., Vincent, B. G., Serody, J. S., Wang, A. Z. 2017; 12 (9): 877-+

    Abstract

    Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology.

    View details for DOI 10.1038/NNANO.2017.113

    View details for Web of Science ID 000409361800013

    View details for PubMedID 28650437

    View details for PubMedCentralID PMC5587366

  • Mechanism of ion transport in perfluoropolyether electrolytes with a lithium salt SOFT MATTER Timachova, K., Chintapalli, M., Olson, K. R., Mecham, S. J., DeSimone, J. M., Balsara, N. P. 2017; 13 (32): 5389-5396

    Abstract

    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, β, 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 β; both parameters vary by four orders of magnitude in our experimental window. Our analysis suggests that transport in electrolytes with low dielectric constants (low β) is dictated by ion hopping between clusters.

    View details for DOI 10.1039/c7sm00794a

    View details for Web of Science ID 000407769800003

    View details for PubMedID 28702622

  • Incipient microphase separation in short chain perfluoropolyether-<i>block</i>-poly(ethylene oxide) copolymers SOFT MATTER Chintapalli, M., Timachova, K., Olson, K. R., Banaszak, M., Thelen, J. L., Mecham, S. J., DeSimone, J. M., Balsara, N. P. 2017; 13 (22): 4047-4056

    Abstract

    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.

    View details for DOI 10.1039/c7sm00738h

    View details for Web of Science ID 000403025900006

    View details for PubMedID 28517013

  • Effect of Anion Size on Conductivity and Transference Number of Perfluoroether Electrolytes with Lithium Salts JOURNAL OF THE ELECTROCHEMICAL SOCIETY Shah, D. B., Olson, K. R., Karny, A., Mecham, S. J., DeSimone, J. M., Balsara, N. P. 2017; 164 (14): A3511-A3517
  • Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer NANO LETTERS Bowerman, C. J., Byrne, J. D., Chu, K. S., Schorzman, A. N., Keeler, A. W., Sherwood, C. A., Perry, J. L., Luft, J. C., Darr, D. B., Deal, A. M., Napier, M. E., Zamboni, W. C., Sharpless, N. E., Perou, C. M., DeSimone, J. M. 2017; 17 (1): 242-248

    Abstract

    Novel treatment strategies, including nanomedicine, are needed for improving management of triple-negative breast cancer. Patients with triple-negative breast cancer, when considered as a group, have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, a finding that reflects the intrinsically adverse prognosis associated with the disease. The aim of this study was to improve the efficacy of docetaxel by incorporation into a novel nanoparticle platform for the treatment of taxane-resistant triple-negative breast cancer. Rod-shaped nanoparticles encapsulating docetaxel were fabricated using an imprint lithography based technique referred to as Particle Replication in Nonwetting Templates (PRINT). These rod-shaped PLGA-docetaxel nanoparticles were tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represents the basal-like subtype of triple-negative breast cancer and is resistant to therapeutics from the taxane family. This GEMM recapitulates the genetics of the human disease and is reflective of patient outcome and, therefore, better represents the clinical impact of new therapeutics. Pharmacokinetic analysis showed that delivery of these PLGA-docetaxel nanoparticles increased docetaxel circulation time and provided similar docetaxel exposure to tumor compared to the clinical formulation of docetaxel, Taxotere. These PLGA-docetaxel nanoparticles improved tumor growth inhibition and significantly increased median survival time. This study demonstrates the potential of nanotechnology to improve the therapeutic index of chemotherapies and rescue therapeutic efficacy to treat nonresponsive cancers.

    View details for DOI 10.1021/acs.nanolett.6b03971

    View details for Web of Science ID 000392036600035

    View details for PubMedID 27966988

    View details for PubMedCentralID PMC5404392

  • Layerless fabrication with continuous liquid interface production PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Janusziewicz, R., Tumbleston, J. R., Quintanilla, A. L., Mecham, S. J., DeSimone, J. M. 2016; 113 (42): 11703-11708

    Abstract

    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.

    View details for DOI 10.1073/pnas.1605271113

    View details for Web of Science ID 000385610400044

    View details for PubMedID 27671641

    View details for PubMedCentralID PMC5081641

  • Liquid perfluoropolyether electrolytes with enhanced ionic conductivity for lithium battery applications POLYMER Olson, K. R., Wong, D. C., Chintapalli, M., Timachova, K., Janusziewicz, R., Daniel, W. M., Mecham, S., Sheiko, S., Balsara, N. P., DeSimone, J. M. 2016; 100: 126-133
  • Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface Production PLOS ONE Johnson, A. R., Caudill, C. L., Tumbleston, J. R., Bloomquist, C. J., Moga, K. A., Ermoshkin, A., Shirvanyants, D., Mecham, S. J., Luft, J., DeSimone, J. M. 2016; 11 (9): e0162518

    Abstract

    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.

    View details for DOI 10.1371/journal.pone.0162518

    View details for Web of Science ID 000383255600054

    View details for PubMedID 27607247

    View details for PubMedCentralID PMC5015976

  • Conductivity of carbonate- and perfluoropolyether-based electrolytes in porous separators JOURNAL OF POWER SOURCES Devaux, D., Chang, Y. H., Villaluenga, I., Chen, X., Chintapalli, M., DeSimone, J. M., Balsara, N. P. 2016; 323: 158-165
  • Pulmonary Delivery of Butyrylcholinesterase as a Model Protein to the Lung MOLECULAR PHARMACEUTICS Rahhal, T. B., Fromen, C. A., Wilson, E. M., Kai, M. P., Shen, T. W., Luft, J., DeSimone, J. M. 2016; 13 (5): 1626-1635

    Abstract

    Pulmonary delivery has great potential for delivering biologics to the lung if the challenges of maintaining activity, stability, and ideal aerosol characteristics can be overcome. To study the interactions of a biologic in the lung, we chose butyrylcholinesterase (BuChE) as our model enzyme, which has application for use as a bioscavenger protecting against organophosphate exposure or for use with pseudocholinesterase deficient patients. In mice, orotracheal administration of free BuChE resulted in 72 h detection in the lungs and 48 h in the broncheoalveolar lavage fluid (BALF). Free BuChE administered to the lung of all mouse backgrounds (Nude, C57BL/6, and BALB/c) showed evidence of an acute cytokine (IL-6, TNF-α, MIP2, and KC) and cellular immune response that subsided within 48 h, indicating relatively safe administration of this non-native biologic. We then developed a formulation of BuChE using Particle Replication in Non-Wetting Templates (PRINT). Aerosol characterization demonstrated biologically active BuChE 1 μm cylindrical particles with a mass median aerodynamic diameter of 2.77 μm, indicative of promising airway deposition via dry powder inhalers (DPI). Furthermore, particulate BuChE delivered via dry powder insufflation showed residence time of 48 h in the lungs and BALF. The in vivo residence time, immune response, and safety of particulate BuChE delivered via a pulmonary route, along with the cascade impaction distribution of dry powder PRINT BuChE, showed promise in the ability to deliver active enzymes with ideal deposition characteristics. These findings provide evidence for the feasibility of optimizing the use of BuChE in the clinic; PRINT BuChE particles can be readily formulated for use in DPIs, providing a convenient and effective treatment option.

    View details for DOI 10.1021/acs.molpharmaceut.6b00066

    View details for Web of Science ID 000375519600019

    View details for PubMedID 27012934

  • Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Fromen, C. A., Rahhal, T. B., Robbins, G. R., Kai, M. P., Shen, T. W., Luft, J., DeSimone, J. M. 2016; 12 (3): 677-687

    Abstract

    Engineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we investigated the cellular response of lung APCs following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10, which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles.Advance in nanotechnology has allowed the production of precise nanoparticles as vaccines. In this regard, pulmonary delivery has the most potential. In this article, the authors investigated the interaction of nanoparticles with various types of lung antigen presenting cells in an attempt to understand the cellular mechanisms. The findings would further help the future design of much improved vaccines for clinical use.

    View details for DOI 10.1016/j.nano.2015.11.002

    View details for Web of Science ID 000373924000011

    View details for PubMedID 26656533

    View details for PubMedCentralID PMC4839472

  • Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Byrne, J. D., Jajja, M. N., Schorzman, A. N., Keeler, A. W., Luft, J., Zamboni, W. C., DeSimone, J. M., Yeh, J. 2016; 113 (8): 2200-2205

    Abstract

    Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

    View details for DOI 10.1073/pnas.1600421113

    View details for Web of Science ID 000370620300069

    View details for PubMedID 26858448

    View details for PubMedCentralID PMC4776454

  • Compliant glass-polymer hybrid single ion-conducting electrolytes for lithium batteries PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Villaluenga, I., Wujcik, K. H., Tong, W., Devaux, D., Wong, D. C., DeSimone, J. M., Balsara, N. P. 2016; 113 (1): 52-57

    Abstract

    Despite high ionic conductivities, current inorganic solid electrolytes cannot be used in lithium batteries because of a lack of compliance and adhesion to active particles in battery electrodes as they are discharged and charged. We have successfully developed a compliant, nonflammable, hybrid single ion-conducting electrolyte comprising inorganic sulfide glass particles covalently bonded to a perfluoropolyether polymer. The hybrid with 23 wt% perfluoropolyether exhibits low shear modulus relative to neat glass electrolytes, ionic conductivity of 10(-4) S/cm at room temperature, a cation transference number close to unity, and an electrochemical stability window up to 5 V relative to Li(+)/Li. X-ray absorption spectroscopy indicates that the hybrid electrolyte limits lithium polysulfide dissolution and is, thus, ideally suited for Li-S cells. Our work opens a previously unidentified route for developing compliant solid electrolytes that will address the challenges of lithium batteries.

    View details for DOI 10.1073/pnas.1520394112

    View details for Web of Science ID 000367520400031

    View details for PubMedID 26699512

    View details for PubMedCentralID PMC4711862

  • Towards programming immune tolerance through geometric manipulation of phosphatidylserine BIOMATERIALS Roberts, R. A., Eitas, T. K., Byrne, J. D., Johnson, B. M., Short, P. J., McKinnon, K. P., Reisdorf, S., Luft, J., DeSimone, J. M., Ting, J. P. 2015; 72: 1-10

    Abstract

    The possibility of engineering the immune system in a targeted fashion using biomaterials such as nanoparticles has made considerable headway in recent years. However, little is known as to how modulating the spatial presentation of a ligand augments downstream immune responses. In this report we show that geometric manipulation of phosphatidylserine (PS) through fabrication on rod-shaped PLGA nanoparticles robustly dampens inflammatory responses from innate immune cells while promoting T regulatory cell abundance by impeding effector T cell expansion. This response depends on the geometry of PS presentation as both PS liposomes and 1 micron cylindrical PS-PLGA particles are less potent signal inducers than 80 × 320 nm rod-shaped PS-PLGA particles for an equivalent dose of PS. We show that this immune tolerizing effect can be co-opted for therapeutic benefit in a mouse model of multiple sclerosis and an assay of organ rejection using a mixed lymphocyte reaction with primary human immune cells. These data provide evidence that geometric manipulation of a ligand via biomaterials may enable more efficient and tunable programming of cellular signaling networks for therapeutic benefit in a variety of disease states, including autoimmunity and organ rejection, and thus should be an active area of further research.

    View details for DOI 10.1016/j.biomaterials.2015.08.040

    View details for Web of Science ID 000362926600001

    View details for PubMedID 26325217

    View details for PubMedCentralID PMC4852957

  • Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery PHARMACEUTICAL RESEARCH Shen, T. W., Fromen, C. A., Kai, M. P., Luft, J., Rahhal, T. B., Robbins, G. R., DeSimone, J. M. 2015; 32 (10): 3248-3260

    Abstract

    We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung.Three sizes of PRINT hydrogel particles (80 × 320 nm, 1.5 and 6 μm donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging.Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80 × 320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles.Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics.

    View details for DOI 10.1007/s11095-015-1701-7

    View details for Web of Science ID 000361720700011

    View details for PubMedID 26002743

    View details for PubMedCentralID PMC4580499

  • Biodistribution and Trafficking of Hydrogel Nanoparticles in Adult Mosquitoes PLOS NEGLECTED TROPICAL DISEASES Paquette, C. H., Phanse, Y., Perry, J. L., Sanchez-Vargas, I., Airs, P. M., Dunphy, B. M., Xu, J., Carlson, J. O., Luft, J., DeSimone, J. M., Bartholomay, L. C., Beaty, B. J. 2015; 9 (5): e0003745

    Abstract

    Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes.PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract.Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector lethal cargoes for mosquito control.

    View details for DOI 10.1371/journal.pntd.0003745

    View details for Web of Science ID 000355303600019

    View details for PubMedID 25996505

    View details for PubMedCentralID PMC4440717

  • Biodistribution and Toxicity Studies of PRINT Hydrogel Nanoparticles in Mosquito Larvae and Cells PLOS NEGLECTED TROPICAL DISEASES Phanse, Y., Dunphy, B. M., Perry, J. L., Airs, P. M., Paquette, C. H., Carlson, J. O., Xu, J., Luft, J., DeSimone, J. M., Beaty, B. J., Bartholomay, L. C. 2015; 9 (5): e0003735

    Abstract

    Mosquito-borne diseases continue to remain major threats to human and animal health and impediments to socioeconomic development. Increasing mosquito resistance to chemical insecticides is a great public health concern, and new strategies/technologies are necessary to develop the next-generation of vector control tools. We propose to develop a novel method for mosquito control that employs nanoparticles (NPs) as a platform for delivery of mosquitocidal dsRNA molecules to silence mosquito genes and cause vector lethality. Identifying optimal NP chemistry and morphology is imperative for efficient mosquitocide delivery. Toward this end, fluorescently labeled polyethylene glycol NPs of specific sizes, shapes (80 nm x 320 nm, 80 nm x 5000 nm, 200 nm x 200 nm, and 1000 nm x 1000 nm) and charges (negative and positive) were fabricated by Particle Replication in Non-Wetting Templates (PRINT) technology. Biodistribution, persistence, and toxicity of PRINT NPs were evaluated in vitro in mosquito cell culture and in vivo in Anopheles gambiae larvae following parenteral and oral challenge. Following parenteral challenge, the biodistribution of the positively and negatively charged NPs of each size and shape was similar; intense fluorescence was observed in thoracic and abdominal regions of the larval body. Positively charged NPs were more associated with the gastric caeca in the gastrointestinal tract. Negatively charged NPs persisted through metamorphosis and were observed in head, body and ovaries of adults. Following oral challenge, NPs were detected in the larval mid- and hindgut. Positively charged NPs were more efficiently internalized in vitro than negatively charged NPs. Positively charged NPs trafficked to the cytosol, but negatively charged NPs co-localized with lysosomes. Following in vitro and in vivo challenge, none of the NPs tested induced any cytotoxic effects.

    View details for DOI 10.1371/journal.pntd.0003735

    View details for Web of Science ID 000355303600016

    View details for PubMedID 25996390

    View details for PubMedCentralID PMC4440723

  • Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle JOURNAL OF CONTROLLED RELEASE Kai, M. P., Keeler, A. W., Perry, J. L., Reuter, K. G., Luft, J., O'Neal, S. K., Zamboni, W. C., DeSimone, J. M. 2015; 204: 70-77

    Abstract

    Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limit its clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, PEGylated, polymeric hydrogels using the Particle Replication In Non-wetting Templates (PRINT®) platform and complexed cisplatin into the particles (PRINT-Platin). Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the best compromise between particle pharmacokinetic (PK) parameters and drug loading (16wt.%). While the PK profile of PEG Brush was superior, the loading was poor (2wt.%). Conversely, the drug loading in non-PEGylated particles was better (20wt.%), but the PK was not desirable. We also showed comparable cytotoxicity to cisplatin in several cancer cell lines (non-small cell lung, A549; ovarian, SKOV-3; breast, MDA-MB-468) and a higher MTD in mice (10mg/kg versus 5mg/kg). The pharmacokinetic profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation, with concurrent renal protection, when cisplatin was formulated in a nanoparticle. PK parameters were markedly improved: a 16.4-times higher area-under-the-curve (AUC), a reduction in clearance (CL) by a factor of 11.2, and a 4.20-times increase in the volume of distribution (Vd). Additionally, non-small cell lung and ovarian tumor AUC was at least twice that of cisplatin in both models. These findings suggest the potential for PRINT-Platin to improve efficacy and reduce toxicity compared to current cisplatin therapies.

    View details for DOI 10.1016/j.jconrel.2015.03.001

    View details for Web of Science ID 000352146500009

    View details for PubMedID 25744827

    View details for PubMedCentralID PMC4413935

  • Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity BIOORGANIC & MEDICINAL CHEMISTRY Sharpe, R. J., Malinowski, J. T., Sorana, F., Luft, J., Bowerman, C. J., DeSimone, J. M., Johnson, J. S. 2015; 23 (8): 1849-1857

    Abstract

    The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation.

    View details for DOI 10.1016/j.bmc.2015.02.022

    View details for Web of Science ID 000351852400018

    View details for PubMedID 25792144

    View details for PubMedCentralID PMC4380168

  • Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Robbins, G. R., Roberts, R. A., Guo, H., Reuter, K., Shen, T., Sempowski, G. D., McKinnon, K. P., Su, L., DeSimone, J. M., Ting, J. 2015; 11 (3): 589-599

    Abstract

    Ideal nanoparticle (NP)-based drug and vaccine delivery vectors should be free of inherent cytotoxic or immunostimulatory properties. Therefore, determining baseline immune responses to nanomaterials is of utmost importance when designing human therapeutics. We characterized the response of human immune cells to hydrogel NPs fabricated using Particle Replication in Non-wetting Templates (PRINT) technology. We found preferential NP uptake by primary CD14(+) monocytes, which was significantly reduced upon PEGylation of the NP surface. Multiplex cytokine analysis of NP treated primary human peripheral blood mononuclear cells suggests that PRINT based hydrogel NPs do not evoke significant inflammatory responses nor induce cytotoxicity or complement activation. We furthered these studies using an in vivo humanized mouse model and similarly found preferential NP uptake by human CD14(+) monocytes without systemic inflammatory cytokine responses. These studies suggest that PRINT hydrogel particles form a desirable platform for vaccine and drug delivery as they neither induce inflammation nor toxicity. From the clinical editor: The authors here fabricated hydrogel nanorods using the PRINT (Particle Replication In Nonwetting Templates) fabrication process. They tested the interaction of human immune cells with these particles and found no immunoreactivity. This finding would suggest that monodisperse PRINT particles of identical shape and size could serve a variety of clinical applications.

    View details for DOI 10.1016/j.nano.2014.11.010

    View details for Web of Science ID 000352081100010

    View details for PubMedID 25596079

    View details for PubMedCentralID PMC4385431

  • Continuous liquid interface production of 3D objects SCIENCE Tumbleston, J. R., Shirvanyants, D., Ermoshkin, N., Janusziewicz, R., Johnson, A. R., Kelly, D., Chen, K., Pinschmidt, R., Rolland, J. P., Ermoshkin, A., Samulski, E. T., DeSimone, J. M. 2015; 347 (6228): 1349-1352

    Abstract

    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.

    View details for DOI 10.1126/science.aaa2397

    View details for Web of Science ID 000351219600038

    View details for PubMedID 25780246

  • Local iontophoretic administration of cytotoxic therapies to solid tumors SCIENCE TRANSLATIONAL MEDICINE Byrne, J. D., Jajja, M. N., O'Neill, A. T., Bickford, L. R., Keeler, A. W., Hyder, N., Wagner, K., Deal, A., Little, R. E., Moffitt, R. A., Stack, C., Nelson, M., Brooks, C. R., Lee, W., Luft, J., Napier, M. E., Darr, D., Anders, C. K., Stack, R., Tepper, J. E., Wang, A. Z., Zamboni, W. C., Yeh, J., DeSimone, J. M. 2015; 7 (273): 273ra14

    Abstract

    Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of -0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.

    View details for DOI 10.1126/scitranslmed.3009951

    View details for Web of Science ID 000349700900003

    View details for PubMedID 25653220

    View details for PubMedCentralID PMC4545246

  • Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fromen, C. A., Robbins, G. R., Shen, T. W., Kai, M. P., Ting, J. Y., DeSimone, J. M. 2015; 112 (2): 488-493

    Abstract

    Pulmonary immunization enhances local humoral and cell-mediated mucosal protection, which are critical for vaccination against lung-specific pathogens such as influenza or tuberculosis. A variety of nanoparticle (NP) formulations have been tested preclinically for pulmonary vaccine development, yet the role of NP surface charge on downstream immune responses remains poorly understood. We used the Particle Replication in Non-Wetting Templates (PRINT) process to synthesize hydrogel NPs that varied only in surface charge and otherwise maintained constant size, shape, and antigen loading. Pulmonary immunization with ovalbumin (OVA)-conjugated cationic NPs led to enhanced systemic and lung antibody titers compared with anionic NPs. Increased antibody production correlated with robust germinal center B-cell expansion and increased activated CD4(+) T-cell populations in lung draining lymph nodes. Ex vivo treatment of dendritic cells (DCs) with OVA-conjugated cationic NPs induced robust antigen-specific T-cell proliferation with ∼ 100-fold more potency than soluble OVA alone. Enhanced T-cell expansion correlated with increased expression of surface MHCII, T-cell coactivating receptors, and key cytokines/chemokine expression by DCs treated with cationic NPs, which were not observed with anionic NPs or soluble OVA. Together, these studies highlight the importance of NP surface charge when designing pulmonary vaccines, and our findings support the notion that cationic NP platforms engender potent humoral and mucosal immune responses.

    View details for DOI 10.1073/pnas.1422923112

    View details for Web of Science ID 000347732300058

    View details for PubMedID 25548169

    View details for PubMedCentralID PMC4299250

  • Calibration-quality cancer nanotherapeutics. Cancer treatment and research Perry, J. L., Kai, M. P., Reuter, K. G., Bowerman, C., Christopher Luft, J., DeSimone, J. M. 2015; 166: 275-91

    Abstract

    Nanoparticle properties such as size, shape, deformability, and surface chemistry all play a role in nanomedicine drug delivery in cancer. While many studies address the behavior of particle systems in a biological setting, revealing how these properties work together presents unique challenges on the nanoscale. "Calibration-quality" control over such properties is needed to draw adequate conclusions that are independent of parameter variability. Furthermore, active targeting and drug loading strategies introduce even greater complexities via their potential to alter particle pharmacokinetics. Ultimately, the investigation and optimization of particle properties should be carried out in the appropriate preclinical tumor model. In doing so, translational efficacy improves as clinical tumor properties increase. Looking forward, the field of nanomedicine will continue to have significant clinical impacts as the capabilities of nanoparticulate drug delivery are further enhanced.

    View details for DOI 10.1007/978-3-319-16555-4_12

    View details for PubMedID 25895873

  • Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT) JOURNAL OF NANOPARTICLE RESEARCH Madden, A. J., Rawal, S., Sandison, K., Schell, R., Schorzman, A., Deal, A., Feng, L., Ma, P., Mumper, R., DeSimone, J., Zamboni, W. C. 2014; 16 (11)

    Abstract

    The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0-last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0-6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

    View details for DOI 10.1007/s11051-014-2662-1

    View details for Web of Science ID 000346696900011

    View details for PubMedID 26392803

    View details for PubMedCentralID PMC4574509

  • Metronomic Docetaxel in PRINT Nanoparticles and EZH2 Silencing Have Synergistic Antitumor Effect in Ovarian Cancer MOLECULAR CANCER THERAPEUTICS Gharpure, K. M., Chu, K. S., Bowerman, C. J., Miyake, T., Pradeep, S., Mangala, S. L., Han, H., Rupaimoole, R., Armaiz-Pena, G. N., Rahhal, T. B., Wu, S. Y., Luft, J., Napier, M. E., Lopez-Berestein, G., DeSimone, J. M., Sood, A. K. 2014; 13 (7): 1750-1757

    Abstract

    The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (P < 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer.

    View details for DOI 10.1158/1535-7163.MCT-13-0930

    View details for Web of Science ID 000338710100007

    View details for PubMedID 24755199

    View details for PubMedCentralID PMC4090269

  • Driving Convergence with Human Diversity SCIENCE TRANSLATIONAL MEDICINE DeSimone, J. M., Farrell, C. L. 2014; 6 (238): 238ed11

    Abstract

    Convergent science will require human diversity-individuals with different backgrounds and life experiences-to drive it forward.

    View details for DOI 10.1126/scitranslmed.3004486

    View details for Web of Science ID 000336668900007

    View details for PubMedID 24871128

  • Nonflammable perfluoropolyether-based electrolytes for lithium batteries PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wong, D. C., Thelen, J. L., Fu, Y., Devaux, D., Pandya, A. A., Battaglia, V. S., Balsara, N. P., DeSimone, J. M. 2014; 111 (9): 3327-3331

    Abstract

    The flammability of conventional alkyl carbonate electrolytes hinders the integration of large-scale lithium-ion batteries in transportation and grid storage applications. In this study, we have prepared a unique nonflammable electrolyte composed of low molecular weight perfluoropolyethers and bis(trifluoromethane)sulfonimide lithium salt. These electrolytes exhibit thermal stability beyond 200 °C and a remarkably high transference number of at least 0.91 (more than double that of conventional electrolytes). Li/LiNi1/3Co1/3Mn1/3O2 cells made with this electrolyte show good performance in galvanostatic cycling, confirming their potential as rechargeable lithium batteries with enhanced safety and longevity.

    View details for DOI 10.1073/pnas.1314615111

    View details for Web of Science ID 000332560300040

    View details for PubMedID 24516123

    View details for PubMedCentralID PMC3948224

  • Particle Replication in Nonwetting Templates Nanoparticles with Tumor Selective Alkyl Silyl Ether Docetaxel Prodrug Reduces Toxicity NANO LETTERS Chu, K. S., Finniss, M. C., Schorzman, A. N., Kuijer, J. L., Luft, J., Bowerman, C. J., Napier, M. E., Haroon, Z. A., Zamboni, W. C., DeSimone, J. M. 2014; 14 (3): 1472-1476

    Abstract

    Delivery systems designed to have triggered release after passively targeting the tumor may improve small molecule chemotherapeutic delivery. Particle replication in nonwetting templates was used to prepare nanoparticles to passively target solid tumors in an A549 subcutaneous xenograft model. An acid labile prodrug was delivered to minimize systemic free docetaxel concentrations and improve tolerability without compromising efficacy.

    View details for DOI 10.1021/nl4046558

    View details for Web of Science ID 000335720300058

    View details for PubMedID 24552251

    View details for PubMedCentralID PMC4157645

  • Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy BIOMATERIALS Chu, K. S., Schorzman, A. N., Finniss, M. C., Bowerman, C. J., Peng, L., Luft, J. C., Madden, A. J., Wang, A. Z., Zamboni, W. C., DeSimone, J. M. 2013; 34 (33): 8424-8429

    Abstract

    Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT(®)), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.

    View details for DOI 10.1016/j.biomaterials.2013.07.038

    View details for Web of Science ID 000324720700042

    View details for PubMedID 23899444

    View details for PubMedCentralID PMC3807740

  • Rapidly-Dissolvable Microneedle Patches Via a Highly Scalable and Reproducible Soft Lithography Approach ADVANCED MATERIALS Moga, K. A., Bickford, L. R., Geil, R. D., Dunn, S. S., Pandya, A. A., Wang, Y., Fain, J. H., Archuleta, C. F., O'Neill, A. T., DeSimone, J. M. 2013; 25 (36): 5060-5066

    Abstract

    Microneedle devices for transdermal drug delivery have recently become an attractive method to overcome the diffusion-limiting epidermis and effectively transport therapeutics to the body. Here, we demonstrate the fabrication of highly reproducible and completely dissolvable polymer microneedles on flexible water-soluble substrates. These biocompatible microneedles (made by using a soft lithography process known as PRINT) showed efficacy in piercing both murine and human skin samples and delivering a fluorescent drug surrogate to the tissue.

    View details for DOI 10.1002/adma.201300526

    View details for Web of Science ID 000327686700008

    View details for PubMedID 23893866

    View details for PubMedCentralID PMC4262250

  • Development of a nanoparticle-based influenza vaccine using the PRINT® technology NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Galloway, A. L., Murphy, A., DeSimone, J. M., Di, J., Herrmann, J. P., Hunter, M. E., Kindig, J. P., Malinoski, F. J., Rumley, M. A., Stoltz, D. M., Templeman, T. S., Hubby, B. 2013; 9 (4): 523-531

    Abstract

    Historically it is known that presentation of vaccine antigens in particulate form, for a wide range of pathogens, has clear advantages over the presentation of soluble antigen alone [J.C. Aguilar, E.G. Rodriguez, Vaccine adjuvants revisited. Vaccine 25 (2007) 3752-3762, M. Singh, D. O'Hagan, Advances in vaccine adjuvants. Nature Biotechnology 17 (1999) 1075-1081]. Herein we describe a novel particle-based approach, which independently controls size, shape, and composition to control the delivery and presentation of vaccine antigen to the immune system. Highly uniform particles were produced using a particle molding technology called PRINT (Particle Replication in Non-wetting Templates) which is an off-shoot of imprint lithography [J Am Chem Soc 127 (2005) 10096-10100, J Am Chem Soc 126 (2004) 2322-2323, Chem Soc Rev 35 (2006) 1095-1104, J Am Chem Soc 130 (2008) 5008-5009, J Am Chem Soc 130 (2008) 5438-5439, Polymer Reviews 47 (2007) 321-327, Acc Chem Res 41 (2008) 1685-1695, Acc Chem Res 44 (10) (2011) 990-998]. Cylindrical (diameter [d]=80 nm, height [h]=320 nm) poly (lactide-co-glycolide) (PLGA) based PRINT particles were designed to electrostatically bind commercial trivalent injectable influenza vaccine. In a variety of blended PLGA formulations, these particles were safe and showed enhanced responses to influenza hemagglutinin in murine models.Shape is one of the determining factors in interactions of nanoparticles with their biologic environment. PRINT technology is able to fabricate nearly uniform nanoparticles and this technology is tested here in murine models to effectively deliver influenza vaccine.

    View details for DOI 10.1016/j.nano.2012.11.001

    View details for Web of Science ID 000318985600010

    View details for PubMedID 23178283

  • Engineering nanomedicines using stimuli-responsive biomaterials ADVANCED DRUG DELIVERY REVIEWS Wang, Y., Byrne, J. D., Napier, M. E., DeSimone, J. M. 2012; 64 (11): 1021-1030

    Abstract

    The ability to engineer particles has the potential to shift the paradigm in the creation of new medicines and diagnostics. Complete control over particle characteristics, such as size, shape, mechanical property, and surface chemistry, can enable rapid translation and facilitate the US Food and Drug Administration (FDA) approval of particle technologies for the treatment of cancer, infectious diseases, diabetes, and a host of other major illnesses. The incorporation of natural and artificial external stimuli to trigger the release of drugs enables exquisite control over the release profiles of drugs in a given environment. In this article, we examine several readily scalable top-down methods for the fabrication of shape-specific particles that utilize stimuli-responsive biomaterials for controlled drug delivery. Special attention is given to Particle Replication In Nonwetting Templates (PRINT®) technology and the application of novel triggered-release synthetic and natural polymers.

    View details for DOI 10.1016/j.addr.2012.01.003

    View details for Web of Science ID 000307689600006

    View details for PubMedID 22266128

    View details for PubMedCentralID PMC3422739

  • Effect of Aspect Ratio and Deformability on Nanoparticle Extravasation through Nanopores LANGMUIR Kersey, F. R., Merkel, T. J., Perry, J. L., Napier, M. E., DeSimone, J. M. 2012; 28 (23): 8773-8781

    Abstract

    We describe the fabrication of filamentous hydrogel nanoparticles using a unique soft lithography based particle molding process referred to as PRINT (particle replication in nonwetting templates). The nanoparticles possess a constant width of 80 nm, and we varied their lengths ranging from 180 to 5000 nm. In addition to varying the aspect ratio of the particles, the deformability of the particles was tuned by varying the cross-link density within the particle matrix. Size characteristics such as hydrodynamic diameter and persistence length of the particles were analyzed using dynamic light scattering and electron microscopy techniques, respectively, while particle deformability was assessed by atomic force microscopy. Additionally, the ability of the particles to pass through membranes containing 0.2 μm pores was assessed by means of a simple filtration technique, and particle recovery was determined using fluorescence spectroscopy. The results show that particle recovery is mostly independent of aspect ratio at all cross-linker concentrations utilized, with the exception of 96 wt % PEG diacrylate 80 × 5000 nm particles, which showed the lowest percent recovery.

    View details for DOI 10.1021/la301279v

    View details for Web of Science ID 000305092700022

    View details for PubMedID 22612428

    View details for PubMedCentralID PMC3374061

  • Tuning Multiphase Amphiphilic Rods to Direct Self-Assembly JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wang, J., Wang, Y., Sheiko, S. S., Betts, D. E., DeSimone, J. M. 2012; 134 (13): 5801-5806

    Abstract

    New methods to direct the self-assembly of particles are highly sought after for multiple applications, including photonics, electronics, and drug delivery. Most techniques, however, are limited to chemical patterning on spherical particles, limiting the range of possible structures. We developed a lithographic technique for fabrication of chemically anisotropic rod-like particles in which we can specify both the size and shape of particles and implement multiple diverse materials to control interfacial interactions. Multiphase rod-like particles, including amphiphilic diblock, triblock, and multiblock were fabricated in the same template mold having a tunable hydrophilic/hydrophobic ratio. Self-assembly of diblock or triblock rods at a water/oil interface led to the formation of bilayer or ribbon-like structures.

    View details for DOI 10.1021/ja2066187

    View details for Web of Science ID 000302490000022

    View details for PubMedID 21988662

  • PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle Theranostics ACCOUNTS OF CHEMICAL RESEARCH Perry, J. L., Herlihy, K. P., Napier, M. E., Desimone, J. M. 2011; 44 (10): 990-998

    Abstract

    Nanotheranostics represents the next generation of medicine, fusing nanotechnology, therapeutics, and diagnostics. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response. This capability could have a profound impact in both the research setting as well as in a clinical setting. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clinical setting, theranostics offers the ability to determine whether patients enrolling in clinical trials are responding, or are expected to respond, to a given therapy based on the hypothesis associated with the biological mechanisms being tested. If not, patients can be more quickly removed from the clinical trial and shifted to other therapeutic options. To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio. There are many biological barriers in the human body that challenge the efficacy of nanoparticle delivery vehicles. These barriers include, but are not limited to, the walls of blood vessels, the physical entrapment of particles in organs, and the removal of particles by phagocytic cells. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chemistry, elasticity, and shape. The effect of particle size and surface chemistry on in vivo biodistribution of nanocarriers has been extensively studied, and general guidelines have been established. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chemistry, and modulus is crucial for designing successful delivery agents. In this Account, we describe the use of particle replication in nonwetting templates (PRINT) to fabricate shape- and size-specific microparticles and nanoparticles. A particular strength of the PRINT method is that it affords precise control over shape, size, surface chemistry, and modulus. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with "stealth" poly(ethylene glycol) chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging. These particles have tremendous potential for applications in nanomedicine and diagnostics.

    View details for DOI 10.1021/ar2000315

    View details for Web of Science ID 000296682400016

    View details for PubMedID 21809808

    View details for PubMedCentralID PMC4157651

  • Amphiphilic Co-networks with Moisture-Induced Surface Segregation for High-Performance Nonfouling Coatings LANGMUIR Wang, Y., Finlay, J. A., Betts, D. E., Merkel, T. J., Luft, J., Callow, M. E., Callow, J. A., DeSimone, J. M. 2011; 27 (17): 10365-10369

    Abstract

    Herein we report the design of a photocurable amphiphilic co-network consisting of perfluoropolyether and poly(ethylene glycol) segments that display outstanding nonfouling characteristics with respect to spores of green fouling alga Ulva when cured under high humidity conditions. The analysis of contact angle hysteresis revealed that the poly(ethylene glycol) density at the surface was enhanced when cured under high humidity. The nonfouling behavior of nonbiocidal surfaces against marine fouling is rare because such surfaces usually reduce the adhesion of organisms rather than inhibit colonization. We propose that the resultant surface segregation of these materials induced by high humidity may be a promising strategy for achieving nonfouling materials, and such an approach is more important than simply concentrating poly(ethylene glycol) moieties at an interface because the low surface energy has been maintained in our work.

    View details for DOI 10.1021/la202427z

    View details for Web of Science ID 000294373300007

    View details for PubMedID 21827199

  • Novel Platforms for Vascular Carriers with Controlled Geometry IUBMB LIFE Pillai, J. D., Dunn, S. S., Napier, M. E., DeSimone, J. M. 2011; 63 (8): 596-606

    Abstract

    The first-generation platforms for vascular drug delivery adopted spherical morphologies. These carriers relied primarily on the size dependence of the enhanced permeability and retention effect to passively target vasculature, resulting in inefficient delivery due to significant variation in endothelial permeability. Enhanced delivery typically requires active targeting via receptor-mediated endocytosis by surface conjugation of targeting ligands. However, vascular carriers (VCs) still face numerous challenges en route to reaching their targets before delivery. The control of carrier shape offers opportunities to overcome in vivo barriers and enhance vascular drug delivery. Geometric features influence the ability of carrier particles to navigate physiological flow patterns, evade biological clearance mechanisms, sustain circulation, adhere to the vascular surface, and finally transport across or internalize into the endothelium. Although previous formulation strategies limited the fabrication of nonspherical carriers, numerous recent advances in both top-down and bottom-up fabrication techniques have enabled shape modulation as a key design element. As part of a series on vascular drug delivery, this review focuses on recent developments in novel vascular platforms with controlled geometry that enhance or modulate delivery functions. Starting with an overview of controlled geometry platforms, we review their shape-dependent functional characteristics for each stage of their vascular journey in vivo. We sequentially explore carrier geometries that evade reticuloendothelial system uptake, display enhanced circulation persistence and margination dynamics in flow, encourage adhesion to the vascular surface or extravasation through endothelium, and impact extravascular transport and cell internalization. The eventual biodistribution of VCs results from the culmination of their successive navigation of all these barriers and is profoundly influenced by their morphology. To enhance delivery efficacy, carrier designs synergistically combining controlled geometry with standard drug delivery strategies such as targeting moieties, surface decorations, and bulk material properties are discussed. Finally, we speculate on possibilities for innovation, harnessing shape as a design parameter for the next generation of vascular drug delivery platforms.

    View details for DOI 10.1002/iub.497

    View details for Web of Science ID 000293742700003

    View details for PubMedID 21721103

  • Generation of a Library of Particles Having Controlled Sizes and Shapes via the Mechanical Elongation of Master Templates LANGMUIR Wang, Y., Merkel, T. J., Chen, K., Fromen, C., Betts, D. E., DeSimone, J. M. 2011; 27 (2): 524-528

    Abstract

    Herein we describe a versatile and readily scalable approach for the fabrication of particles with a variety of shapes and sizes from a single master template by augmenting the particle replication in nonwetting templates (PRINT) method with mechanical elongation. Repetition of the elongation steps in one direction leads to the fabrication of linear particles with high aspect ratio (AR), over 40 times greater than in the original master, while a range of particle shapes can be obtained by repeating the elongation procedure while changing the stretching direction, generating diamond, rectangular, curved parallelogram particles from a single cubic master.

    View details for DOI 10.1021/la1045095

    View details for Web of Science ID 000285990500007

    View details for PubMedID 21166444

  • Investigation of the role of hydrophilic chain length in amphiphilic perfluoropolyether/poly(ethylene glycol) networks: towards high-performance antifouling coatings BIOFOULING Wang, Y., Pitet, L. M., Finlay, J. A., Brewer, L. H., Cone, G., Betts, D. E., Callow, M. E., Callow, J. A., Wendt, D. E., Hillmyer, M. A., DeSimone, J. M. 2011; 27 (10): 1139-1150

    Abstract

    The facile preparation of amphiphilic network coatings having a hydrophobic dimethacryloxy-functionalized perfluoropolyether (PFPE-DMA; M(w) = 1500 g mol(-1)) crosslinked with hydrophilic monomethacryloxy functionalized poly(ethylene glycol) macromonomers (PEG-MA; M(w) = 300, 475, 1100 g mol(-1)), intended as non-toxic high-performance marine coatings exhibiting antifouling characteristics is demonstrated. The PFPE-DMA was found to be miscible with the PEG-MA. Photo-cured blends of these materials containing 10 wt% of PEG-MA oligomers did not swell significantly in water. PFPE-DMA crosslinked with the highest molecular weight PEG oligomer (ie PEG1100) deterred settlement (attachment) of algal cells and cypris larvae of barnacles compared to a PFPE control coating. Dynamic mechanical analysis of these networks revealed a flexible material. Preferential segregation of the PEG segments at the polymer/air interface resulted in enhanced antifouling performance. The cured amphiphilic PFPE/PEG films showed decreased advancing and receding contact angles with increasing PEG chain length. In particular, the PFPE/PEG1100 network had a much lower advancing contact angle than static contact angle, suggesting that the PEG1100 segments diffuse to the polymer/water interface quickly. The preferential interfacial aggregation of the larger PEG segments enables the coating surface to have a substantially enhanced resistance to settlement of spores of the green seaweed Ulva, cells of the diatom Navicula and cypris larvae of the barnacle Balanus amphitrite as well as low adhesion of sporelings (young plants) of Ulva, adhesion being lower than to a polydimethyl elastomer, Silastic T2.

    View details for DOI 10.1080/08927014.2011.629344

    View details for Web of Science ID 000306919100002

    View details for PubMedID 22087876

  • Scalable, Shape-Specific, Top-Down Fabrication Methods for the Synthesis of Engineered Colloidal Particles LANGMUIR Merkel, T. J., Herlihy, K. P., Nunes, J., Orgel, R. M., Rolland, J. P., DeSimone, J. M. 2010; 26 (16): 13086-13096

    Abstract

    The search for a method to fabricate nonspherical colloidal particles from a variety of materials is of growing interest. As the commercialization of nanotechnology continues to expand, the ability to translate particle-fabrication methods from a laboratory to an industrial scale is of increasing significance. In this feature article, we examine several of the most readily scalable top-down methods for the fabrication of such shape-specific particles and compare their capabilities with respect to particle composition, size, shape, and complexity as well as the scalability of the method. We offer an extensive examination of particle replication in nonwetting templates (PRINT) with regard to the versatility and scalability of this technique. We also detail the specific methods used in PRINT particle fabrication, including harvesting, purification, and surface-modification techniques, with an examination of both past and current methods.

    View details for DOI 10.1021/la903890h

    View details for Web of Science ID 000280667900014

    View details for PubMedID 20000620

    View details for PubMedCentralID PMC2891593

  • Challenging nature's monopoly on the creation of well-defined nanoparticles NANOMEDICINE Jeong, W., Napier, M. E., DeSimone, J. M. 2010; 5 (4): 633-639

    Abstract

    Nature has selected and fine-tuned the physical and chemical properties of natural objects, such as size, shape, mechanical properties and surface chemistry, at the molecular level in order to modulate biological functions. A new particle fabrication process, particle replication in nonwetting templates (PRINT), has recently begun to attempt to emulate nature's ability to control those physical and chemical traits. The PRINT technology, which combines modern soft lithography with the unique properties of perfluoropolyether molds, enables the production of nanoparticles with unprecedented control of size, shape, chemical composition, deformability and surface functionality. This scalable 'top-down' fabrication process allows for the generation of well-defined nanostructures without the need for molecular assembly. The ability to flexibly engineer various matrix materials offers unique opportunities for the development of nanomedicines with desired functionality. The strength and versatility of PRINT makes it a powerful platform in nanomedicine for elucidating the role of physical and chemical properties of nanodelivery vehicles on the behavior and fate at the cellular, tissue and whole organism level. Utilizing the PRINT technology, we are generating well-defined nanomedicines with tailored properties for preclinical studies against a variety of human diseases.

    View details for DOI 10.2217/NNM.10.34

    View details for Web of Science ID 000278937100013

    View details for PubMedID 20528457

  • High-Resolution PFPE-based Molding Techniques for Nanofabrication of High-Pattern Density, Sub-20 nm Features: A Fundamental Materials Approach NANO LETTERS Williams, S. S., Retterer, S., Lopez, R., Ruiz, R., Samulski, E. T., DeSimone, J. M. 2010; 10 (4): 1421-1428

    Abstract

    Several perfluoropolyether (PFPE)-based elastomers for high-resolution replica molding applications are explored. The modulus of the elastomeric materials was increased through synthetic and additive approaches while maintaining relatively low surface tension values (<25 mN/m). Using large area (>4 in.(2)) master templates, we experimentally show the relationship between mold resolution and material properties such as modulus and surface tension for materials used in this study. A composite mold approach was used to form flexible molds out of stiff, high modulus materials that allow for replication of sub-20 nm post structures. Sub-100 nm line grating master templates, formed using e-beam lithography, were used to determine the experimental stability of the molding materials. It was observed that as the feature spacing decreased, high modulus PFPE tetramethacrylate (TMA) composite molds were able to effectively replicate the nanograting structures without cracking or tear-out defects that typically occur with high modulus elastomers.

    View details for DOI 10.1021/nl100326q

    View details for Web of Science ID 000276557100058

    View details for PubMedID 20178369

  • Multifunctional Shape and Size Specific Magneto-Polymer Composite Particles NANO LETTERS Nunes, J., Herlihy, K. P., Mair, L., Superfine, R., DeSimone, J. M. 2010; 10 (4): 1113-1119

    Abstract

    Interest in uniform multifunctional magnetic particles is driven by potential applications in biomedical and materials science. Here we demonstrate the fabrication of highly tailored nanoscale and microscale magneto-polymer composite particles using a template based approach. Regiospecific surface functionalization of the particles was performed by chemical grafting and evaporative Pt deposition. Manipulation of the particles by an applied magnetic field was demonstrated in water and hydrogen peroxide.

    View details for DOI 10.1021/nl904152e

    View details for Web of Science ID 000276557100003

    View details for PubMedID 20334397

    View details for PubMedCentralID PMC3357060

  • Direct Patterning of CdSe Quantum Dots into Sub-100 nm Structures LANGMUIR Hampton, M. J., Templeton, J. L., DeSimone, J. M. 2010; 26 (5): 3012-3015

    Abstract

    Ordered, two-dimensional cadmium selenide (CdSe) arrays have been fabricated on indium-doped tin oxide (ITO) electrodes using the pattern replication in nonwetting templates (PRINT) process. CdSe quantum dots (QDs) with an average diameter of 2.7 nm and a pyridine surface ligand were used for patterning. The PRINT technique utilizes a perfluoropolyether (PFPE) elastomeric mold that is tolerant of most organic solvents, thus allowing solutions of CdSe QDs in 4-picoline to be used for patterning without significant deformation of the mold. Nanometer-scale diffraction gratings have been successfully replicated with CdSe QDs.

    View details for DOI 10.1021/la904787k

    View details for Web of Science ID 000274636900009

    View details for PubMedID 20102224

  • Top-down particle fabrication: control of size and shape for diagnostic imaging and drug delivery WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY Canelas, D. A., Herlihy, K. P., DeSimone, J. M. 2009; 1 (4): 391-404

    Abstract

    This review discusses rational design of particles for use as therapeutic vectors and diagnostic imaging agent carriers. The emerging importance of both particle size and shape is considered, and the adaptation and modification of soft lithography methods to produce nanoparticles are highlighted. To this end, studies utilizing particles made via a process called Particle Replication In Non-wetting Templates are discussed. In addition, insights gained into therapeutic cargo and imaging agent delivery from related types of polymer-based carriers are considered.

    View details for DOI 10.1002/wnan.40

    View details for Web of Science ID 000276839700004

    View details for PubMedID 20049805

    View details for PubMedCentralID PMC2804992

  • Photonic Crystal Geometry for Organic Solar Cells NANO LETTERS Ko, D., Tumbleston, J. R., Zhang, L., Williams, S., DeSimone, J. M., Lopez, R., Samulski, E. T. 2009; 9 (7): 2742-2746

    Abstract

    We report organic solar cells with a photonic crystal nanostructure embossed in the photoactive bulk heterojunction layer, a topography that exhibits a 3-fold enhancement of the absorption in specific regions of the solar spectrum in part through multiple excitation resonances. The photonic crystal geometry is fabricated using a materials-agnostic process called PRINT wherein highly ordered arrays of nanoscale features are readily made in a single processing step over wide areas (approximately 4 cm(2)) that is scalable. We show efficiency improvements of approximately 70% that result not only from greater absorption, but also from electrical enhancements. The methodology is generally applicable to organic solar cells and the experimental findings reported in our manuscript corroborate theoretical expectations.

    View details for DOI 10.1021/nl901232p

    View details for Web of Science ID 000268138600041

    View details for PubMedID 19492804

  • The Pursuit of a Scalable Nanofabrication Platform for Use in Material and Life Science Applications ACCOUNTS OF CHEMICAL RESEARCH Gratton, S. A., Williams, S. S., Napier, M. E., Pohlhaus, P. D., Zhou, Z., Wiles, K. B., Maynor, B. W., Shen, C., Olafsen, T., Samulski, E. T., Desimone, J. M. 2008; 41 (12): 1685-1695

    Abstract

    In this Account, we describe the use of perfluoropolyether (PFPE)-based materials that are able to accurately mold and replicate micro- and nanosized features using traditional techniques such as embossing as well as new techniques that we developed to exploit the exceptional surface characteristics of fluorinated substrates. Because of the unique partial wetting and nonwetting characteristics of PFPEs, we were able to go beyond the usual molding and imprint lithography approaches and have created a technique called PRINT (Particle [or Pattern] Replication In Nonwetting Templates). PRINT is a distinctive "top-down" fabrication technique capable of generating isolated particles, arrays of particles, and arrays of patterned features for a plethora of applications in both nanomedicine and materials science. A particular strength of the PRINT technology is the high-resolution molding of well-defined particles with precise control over size, shape, deformability, and surface chemistry. The level of replication obtained showcases some of the unique characteristics of PFPE molding materials. In particular, these materials arise from very low surface energy precursors with positive spreading coefficients, can be photocured at ambient temperature, and are minimally adhesive, nonswelling, and conformable. These distinctive features enable the molding of materials with unique attributes and nanometer resolution that have unprecedented scientific and technological value. For example, in nanomedicine, the use of PFPE materials with the PRINT technique allows us to design particles in which we can tailor key therapeutic parameters such as bioavailability, biodistribution, target-specific cell penetration, and controlled cargo release. Similarly, in materials science, we can fabricate optical films and lens arrays, replicate complex, naturally occurring objects such as adenovirus particles, and create 2D patterned arrays of inorganic oxides.

    View details for DOI 10.1021/ar8000348

    View details for Web of Science ID 000261767600013

    View details for PubMedID 18720952

    View details for PubMedCentralID PMC2645958

  • Microfabricated Particles for Engineered Drug Therapies: Elucidation into the Mechanisms of Cellular Internalization of PRINT Particles PHARMACEUTICAL RESEARCH Gratton, S. A., Napier, M. E., Ropp, P. A., Tian, S., DeSimone, J. M. 2008; 25 (12): 2845-2852

    Abstract

    To investigate the cellular internalization pathways of shape- and size-specific particles as a function of zeta potential in different cell types.A top-down particle fabrication technique called PRINT was utilized to fabricate monodisperse 1 microm cylindrical particles. Cellular internalization of these PRINT particles was monitored using confocal microscopy, flow cytometry, and transmission electron microscopy. The endocytic pathway used by 1 microm cationic PRINT particles was evaluated using different inhibitory strategies. Cytotoxicity assays were used to determine the toxicity of both cationic and anionic PRINT particles in multiple cell types.Particle internalization was confirmed using confocal microscopy, flow cytometry and transmission electron microscopy. The mechanism of internalization of positively charged PRINT particles was found to be predominantly clathrin-mediated endocytosis and macropinocytosis with very few particles utilizing a caveolae-mediated endocytic pathway. The exposed charge on the surface of the particles had a significant effect on the rate of endocytosis in all cell types tested, except for the macrophage cells. No significant cytotoxicity was observed for all PRINT particles used in the present study.Cylindrical 1 microm PRINT particles were readily internalized into HeLa, NIH 3T3, OVCAR-3, MCF-7, and RAW 264.7 cells. Particles with a positive zeta potential exhibited an enhanced rate of endocytosis compared to negatively charged particles with identical sizes and shapes. It was found that PRINT particles with a positive zeta potential were endocytosed into HeLa cells using predominantely clathrin-mediated and macropinocytotic pathways.

    View details for DOI 10.1007/s11095-008-9654-8

    View details for Web of Science ID 000261343500017

    View details for PubMedID 18592353

    View details for PubMedCentralID PMC2593117

  • Molding Block Copolymer Micelles: A Framework for Molding of Discrete Objects on Surfaces LANGMUIR Yu-Su, S. Y., Thomas, D. R., Alford, J. E., LaRue, I., Pitsikalis, M., Hadjichristidis, N., DeSimone, J. M., Dobrynin, A. V., Sheiko, S. S. 2008; 24 (21): 12671-12679

    Abstract

    Soft lithography based on photocurable perfluoropolyether (PFPE) was used to mold and replicate poly(styrene-b-isoprene) block-copolymer micelles within a broad range of shapes and sizes including spheres, cylinders, and torroids. These physically assembled nanoparticles were first formed in a selective solvent for one block then deposited onto substrates having various surface energies in an effort to minimize the deformation of the micelles due to attractive surface forces. The successful molding of these delicate nanoparticles underscores two advantages of PFPE as a molding material. First, it allows one to minimize particle deformation due to adsorption by using low energy substrates. Second, PFPE is not miscible with the organic micelles and thus prevents their dissociation. For spherical PS-b-PI micelles, a threshold value of the substrate surface energy for the mold to lift-off cleanly, that is, the particles remain adhered to the substrate after mold removal was determined to be around gamma congruent with 54 mJ/m2. For substrates with higher surface energies (>54 mJ/m2), the micelles undergo flattening which increase the contact area and thus facilitate molding, although at the expense of particle deformation. The results are consistent with theoretical predictions of a molding range for substrate surface energies, which depends on the size, shape, and mechanical properties of the particles. In a similar fashion, cylindrical PS-b-PI micelles remain on the substrate at surface energies gamma>or=54 mJ/m2 after a mold removal. However, cylindrical micelles behaved differently at lower surface energies. These micelles ruptured due to their inability to slide on the surfaces during mold lift-off. Thus, the successful molding of extended objects is attainable only when the particle is adsorbed on higher energy substrates where deformation can still be kept at a minimum by using stronger materials such as carbon nanotubes for the master.

    View details for DOI 10.1021/la802549s

    View details for Web of Science ID 000260508800083

    View details for PubMedID 18841925

  • Optically Transparent, Amphiphilic Networks Based on Blends of Perfluoropolyethers and Poly(ethylene glycol) JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hu, Z., Chen, L., Betts, D. E., Pandya, A., Hillmyer, M. A., DeSimone, J. M. 2008; 130 (43): 14244-14252

    Abstract

    Amphiphilic networks of perfluoropolyethers (PFPE) and poly(ethylene glycol) (PEG) have been achieved to yield optically transparent, mechanically robust films over a wide range of compositions. Telechelic diols of these oligomers were transformed to a photocurable dimethacryloxy form (DMA) and free radically cured at various composition weight ratios to yield free-standing films. Clear and colorless amphiphilic networks could be achieved when low molar mass versions of both the PFPE-DMA (1 kg/mol) and the PEG-DMA (550 g/mol) were used. The bulk morphologies of the samples were extensively characterized by a variety of techniques including ultraviolet-visible spectroscopy, differential scanning calorimetry, dynamic mechanic thermal analysis, small-angle X-ray scattering, atomic force microscopy, X-ray photoelectron spectroscopy, and optical microscopy, which strongly suggest that nanoscopic to macroscopic phase-separated materials could be achieved. By incorporating a threshold amount of PFPEs into PEG-based hydrogel networks, water swelling could be significantly reduced, which may offer a new strategy for a number of medical device applications. Along these lines, strong inhibition of nonspecific protein adsorption could be achieved with these amphiphilic network materials compared with an oligo(ethylene glycol)-based self-assembled monolayer coated surface.

    View details for DOI 10.1021/ja803991n

    View details for Web of Science ID 000260301700061

    View details for PubMedID 18834196

  • Nanostructured Titania-Polymer Photovoltaic Devices Made Using PFPE-Based Nanomolding Techniques CHEMISTRY OF MATERIALS Williams, S. S., Hampton, M. J., Gowrishankar, V., Ding, I., Templeton, J. L., Samulski, E. T., DeSimone, J. M., McGehee, M. D. 2008; 20 (16): 5229-5234

    View details for DOI 10.1021/cm800729q

    View details for Web of Science ID 000258580500019

  • Electrically driven alignment and crystallization of unique anisotropic polymer particles LANGMUIR Herlihy, K. P., Nunes, J., DeSimone, J. M. 2008; 24 (16): 8421-8426

    Abstract

    Micrometer-sized monodisperse anisotropic polymer particles, with disk, rod, fenestrated hexagon (hexnut), and boomerang shapes, were synthesized using the particle replication in nonwetting templates (PRINT) process, and investigations were conducted on aqueous suspensions of these particles when subjected to alternating electric fields. A coplanar electrode configuration, with 1 to 2 mm electrode gaps (20-50 V ac, 0.5-5.0 kHz) was used, and the experiments were monitored with fluorescence microscopy. For all particle suspensions, the field brought about significant changes in the packing and orientation. Extensive particle chaining and packing were observed for the disk, rod, and hexnut suspensions. Because of the size and geometry of the boomerang particles, limited chaining was observed; however, the field triggered a change from random to a more ordered packing arrangement.

    View details for DOI 10.1021/la801250g

    View details for Web of Science ID 000258377900007

    View details for PubMedID 18646784

  • The patterning of sub-500 nm inorganic oxide structures ADVANCED MATERIALS Hampton, M. J., Williams, S. S., Zhou, Z., Nunes, J., Ko, D., Templeton, J. L., Samulski, E. T., DeSimone, J. M. 2008; 20 (14): 2667-+

    Abstract

    Elastomeric perfluoropolyether molds are applied to pattern arrays of sub-500 nm inorganic oxide features. This versatile soft-lithography technique can be used to pattern a wide range of materials; in this work inorganic oxides including TiO2 , SnO2 , ZnO, ITO, and BaTiO3 are patterned on a variety of substrates with different aspect ratios. An example of TiO2 posts is shown in the figure.

    View details for DOI 10.1002/adma.200702495

    View details for Web of Science ID 000258164800002

    View details for PubMedID 25213887

  • Shape-specific, monodisperse nano-molding of protein particles JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Kelly, J. Y., DeSimone, J. M. 2008; 130 (16): 5438-+

    Abstract

    Herein we report nano-molding proteins for the fabrication of protein PRINT particles of monodisperse size and shape. Lyophilized protein particles are generally highly dispersed in particle size, aggregated, and often made through costly and complicated processes. Attempts to engineer monodisperse, discrete protein particles using wet-milling, spray-freeze-drying, microemulsion, or super critical fluid methods have realized little success. The PRINT technology enables a gentle, facile route to monodisperse particles of 100% protein as small as 200 nm cylinders. Protein PRINT particles of any shape and size are effortlessly achievable. Our research efforts include making PRINT particles composed of albumin and albumin 0.5 wt % siRNA, and Abraxane, the gold standard therapeutic used in metastatic breast cancer.

    View details for DOI 10.1021/ja8014428

    View details for Web of Science ID 000255041400028

    View details for PubMedID 18376832

  • Reductively labile PRINT particles for the delivery of doxorubicin to HeLa cells JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Petros, R. A., Ropp, P. A., DeSimone, J. M. 2008; 130 (15): 5008-+

    Abstract

    A Trojan horse PRINT particle composition was developed that incorporates a reductively labile cross-linker to achieve activated release of doxorubicin in vitro. Particles of discrete size and shape (cube side length = 2 micron) containing 30 wt % of a disulfide-based cross-linker and 2 wt % doxorubicin were synthesized. This PRINT composition was shown to release doxorubicin in response to a reducing environment as measured by flow cytometry and was found to be highly proficient at killing HeLa cells in vitro.

    View details for DOI 10.1021/ja801436j

    View details for Web of Science ID 000254933000004

    View details for PubMedID 18355010

  • A Soft Lithography Route to Nanopatterned Photovoltaic Devices Conference on Nanoscale Photonic and Cell Technologies for Photovoltaics Williams, S. S., Hampton, M. J., Gowrishankar, V., Ding, I., Zhang, L., Ko, D., Templeton, J. L., DeSimone, J. M., McGehee, M. D., Samulski, E. T. SPIE-INT SOC OPTICAL ENGINEERING. 2008

    View details for DOI 10.1117/12.794853

    View details for Web of Science ID 000262507700010

  • The patterning of sub-500 nm inorganic oxide and semiconducting polymeric structures Hampton, M. J., Williams, S. S., Zhou, Z., Nunes, J., Ko, D., Templeton, J. L., DeSimone, J. M., Samulski, E. T., Tsakalakos, L. SPIE-INT SOC OPTICAL ENGINEERING. 2008

    View details for DOI 10.1117/12.794890

    View details for Web of Science ID 000262507700016

  • COLL 177-Nanopatterning TiO2 for photovoltaic applications Williams, S., Earl, M. J., Zhou, Z., Gowrishankar, V., McGehee, M. D., Samulski, E. T., DeSimone, J. M. AMER CHEMICAL SOC. 2007
  • COLL 467-Nanotextured transparent semiconductor oxides for energy conversion Zhou, Z., Ko, D., Earl, M. J., Williams, S., Cheng, B., Gowrishankar, V., McGehee, M. D., DeSimone, J., Samulski, E. T. AMER CHEMICAL SOC. 2007
  • Nanofabricated particles for engineered drug therapies:: A preliminary Biodistribution study of PRINT ™ nanoparticles Gratton, S. A., PohhauS, P. D., Lee, J., Guo, I., Cho, M. J., DeSimone, J. M. ELSEVIER SCIENCE BV. 2007: 10-18

    Abstract

    A novel method for the fabrication of polymeric particles on the order of tens of nanometers to several microns is described. This imprint lithographic technique called PRINT (Particle Replication In Non-wetting Templates), takes advantage of the unique properties of elastomeric molds comprised of a low surface energy perfluoropolyether network, allowing the production of monodisperse, shape-specific nanoparticles from an extensive array of organic precursors. This engineered nature of particle production has a number of advantages over the construction of traditional nanoparticles such as liposomes, dendrimers, and colloidal precipitates. The gentle "top down" approach of PRINT enables the simultaneous and independent control over particle size and shape, composition, and surface functionality, and permits the loading of delicate cargos such as small organic therapeutics and biological macromolecules. Thus, this single tool serves as a comprehensive platform for the rational design and investigation of new nanocarriers in medicine, having applications ranging from therapeutics to advanced diagnostics. Preliminary in vitro and in vivo studies were conducted, demonstrating the future utility of PRINT particles as delivery vectors in nanomedicine. Monodisperse 200 nm poly(ethylene glycol)-based (PEG) particles were fabricated using PRINT methodology and characterized via scanning electron microscopy and dynamic light scattering. Incubation with HeLa cells showed very little cytotoxicity, even at high concentrations. The biodistribution and pharmacokinetics of [(125)I]-labeled particles were studied in healthy mice following bolus tail vein administration. The particles were distributed mainly to the liver and the spleen with an apparent distribution t(1/2) of approximately 17 min followed by slow redistribution with a t(1/2) of 3.3 h. The volume of distribution for the central and peripheral compartments was found to be approximately 3 mL and 5 mL, respectively.

    View details for DOI 10.1016/j.jconrel.2007.05.027

    View details for Web of Science ID 000249079300003

    View details for PubMedID 17643544

    View details for PubMedCentralID PMC1994820

  • Supramolecular nanomimetics: Replication of micelles, viruses, and other naturally occurring nanoscale objects SMALL Maynor, B. W., LaRue, I., Hu, Z., Rolland, J. P., Pandya, A., Fu, Q., Liu, J., Spontak, R. J., Sheiko, S. S., Samulski, R. J., Samulski, E. T., DeSimone, J. M. 2007; 3 (5): 845-849

    View details for DOI 10.1002/smll.200600507

    View details for Web of Science ID 000246557200020

    View details for PubMedID 17393549

  • Nanoparticle drug delivery platform POLYMER REVIEWS Napier, M. E., Desimone, J. M. 2007; 47 (3): 321-327
  • Magneto-polymer composite particles fabricated utilizing patterned perfluoropolyether elastomer molds Herlihy, K. P., DeSimone, J. M., Lercel, M. J. SPIE-INT SOC OPTICAL ENGINEERING. 2007

    View details for DOI 10.1117/12.712058

    View details for Web of Science ID 000246685900099

  • Amorphous linear aliphatic polyesters for the facile preparation of tunable rapidly degrading elastomeric devices and delivery vectors JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Olson, D. A., Gratton, S. A., DeSimone, J. M., Sheares, V. V. 2006; 128 (41): 13625-13633

    Abstract

    A versatile method for preparing amorphous degradable elastomers with tunable properties that can be easily fabricated into a wide variety of shape-specific devices was investigated. Completely amorphous, liquid poly(ester ether) prepolymers with number-average molecular weights between 4 and 6 x 10(3) g/mol were prepared via condensation polymerization. These liquid prepolymers were then thermally cross-linked to form degradable elastomeric structures. The ability to vary the composition of these liquid prepolymers allows for easy control of the mechanical and degradation properties of the resulting elastomeric structures. Materials can be designed to completely degrade in vitro over a range of 30 days to 6 months, while the Young's modulus can be varied over 3 orders of magnitude (G = 0.02-20 MPa). Also, the liquid nature of these prepolymers makes them amenable to a wide variety of fabrication techniques. Using traditional and modified imprint lithography techniques, we have fabricated devices that demonstrate a wide variety of biologically applicable topologies, which could easily be extended to fabricate devices with more complex geometries. Until now, no method has combined this ease and speed of fabrication with the ability to control the mechanical and degradation properties of the resulting elastomers over such a broad range.

    View details for DOI 10.1021/ja063092m

    View details for Web of Science ID 000241157600059

    View details for PubMedID 17031977

  • Molded, high surface area polymer electrolyte membranes from cured liquid precursors JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Zhou, Z., Dominey, R. N., Rolland, J. P., Maynor, B. W., Pandya, A. A., DeSimone, J. M. 2006; 128 (39): 12963-12972

    Abstract

    Polymer electrolyte membranes (PEMs) for fuel cells have been synthesized from easily processable, 100% curable, low molecular weight reactive liquid precursors that are photochemically cured into highly proton conductive solid membranes. The liquid precursors were directly cured into membranes of desired dimensions without the need for further processing steps such as melt extrusion or solvent casting. By employing chemical cross-linking, high proton conductivities can be achieved through the incorporation of significant levels of acidic groups without rendering the material water-soluble, which plagues commonly used non-cross-linked polymers. Fabrication of membrane electrode assemblies (MEAs) from these PEMs resulted in fuel cells that outperformed those based on commercial materials. Moreover, these liquid precursors enabled the formation of three-dimensional, patterned PEMs with high fidelity, micron-scale features by using soft lithographic/micromolding techniques. The patterned membranes provided a larger interfacial area between the membrane and catalyst layer than standard flat PEMs. MEAs composed of the patterned membranes demonstrated higher power densities over that of flat ones without an increase in the macroscopic area of the fuel cells. This can potentially miniaturize fuel cells and promote their application in portable devices.

    View details for DOI 10.1021/ja064391e

    View details for Web of Science ID 000240795000074

    View details for PubMedID 17002393

  • Superhydrophobic behavior of a perfluoropolyether lotus-leaf-like topography LANGMUIR Zhang, L., Zhou, Z., Cheng, B., DeSimone, J. M., Samulski, E. T. 2006; 22 (20): 8576-8580

    Abstract

    We demonstrate the fabrication of 2-D arrays of nanopillars made from perfluoropolyether derivatives using a porous anodic aluminum oxide membrane as a template. Pretexturing the aluminum prior to anodization enables one to engineer multiple morphological length scales and thereby synthesize a lotus-leaf-like topography. Both nanopillars on a flat surface and on a lotus-leaf-like topology exhibit superhydrophobicity, low contact angle hysteresis, and self-cleaning.

    View details for DOI 10.1021/la061400o

    View details for Web of Science ID 000240573200047

    View details for PubMedID 16981778

  • Imparting size, shape, and composition control of materials for nanomedicine CHEMICAL SOCIETY REVIEWS Euliss, L. E., DuPont, J. A., Gratton, S., DeSimone, J. M. 2006; 35 (11): 1095-1104

    Abstract

    This tutorial review presents an overview of strategies for the synthesis and fabrication of organic nanomaterials, specifically those with potential for use in medical applications. Examples include liposomes, micelles, polymer-drug conjugates and dendrimers. Methods of driving shape via"bottom-up" synthetic approaches and thermodynamics and kinetics are discussed. Furthermore, methods of driving shape via"top-down" physical and engineering techniques are also explored. Finally, a novel method (referred to as PRINT) used to produce nanoparticles that are shape-specific, can contain any cargo, and can be easily modified is examined along with its potential future role in nanomedicine.

    View details for DOI 10.1039/b600913c

    View details for Web of Science ID 000241471200007

    View details for PubMedID 17057838

  • Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Rolland, J. P., Maynor, B. W., Euliss, L. E., Exner, A. E., Denison, G. M., DeSimone, J. M. 2005; 127 (28): 10096-10100

    Abstract

    A versatile "top-down" method for the fabrication of particles, Particle Replication In Nonwetting Templates (PRINT), is described which affords absolute control over particle size, shape, and composition. This technique is versatile and general enough to fabricate particles with a variety of chemical structures, yet delicate enough to be compatible with sophisticated biological agents. Using PRINT, we have fabricated monodisperse particles of poly(ethylene glycol diacrylate), triacrylate resin, poly(lactic acid), and poly(pyrrole). Monodisperse particle populations, ranging from sub-200 nm nanoparticles to complex micron-scale objects, have been fabricated and harvested. PRINT uses low-surface energy, chemically resistant fluoropolymers as molding materials, which eliminates the formation of a residual interconnecting film between molded objects. Until now, the presence of this film has largely prevented particle fabrication using soft lithography. Importantly, we have demonstrated that PRINT affords the simple, straightforward encapsulation of a variety of important bioactive agents, including proteins, DNA, and small-molecule therapeutics, which indicates that PRINT can be used to fabricate next-generation particulate drug-delivery agents.

    View details for DOI 10.1021/ja051977c

    View details for Web of Science ID 000230657900048

    View details for PubMedID 16011375

  • Chemical functionalization of silica and alumina particles for dispersion in carbon dioxide LANGMUIR Visintin, P. M., Carbonell, R. G., Schauer, C. K., DeSimone, J. M. 2005; 21 (11): 4816-4823

    Abstract

    The steric stabilization and flocculation of modified silica and alumina particle suspensions in condensed CO(2) were studied. Silica particles (average diameters of 7 and 12 nm) were functionalized using chlorosilanes of the form C(n)F(2n+1)CH(2)CH(2)Si(CH(3))(2)Cl (n = 8, 4, or 1) to give C(n)F(2n+1)-silica. Alumina particles (diameter of 8-14 nm) were grafted with C(8)F(17)CH(2)CH(2)Si(OEt)(3) and chemically modified with perfluorononanoic acid to yield C(8)F(17)-alumina and C(8)F(17)COOH-alumina, respectively. Elemental analysis and thermogravimetric analysis on the derivatized particles were carried out, and surface coverage was calculated. The stabilization of these modified particles in condensed CO(2) was quantified using turbidimetry. Particle stability was found to increase with increasing fluorinated tail length, temperature, and CO(2) density. Unmodified particles and those modified with only -CF(3) tails were unstable in condensed CO(2). Stabilization in supercritical CO(2) is continuous up to 24 h for the C(n)F(2n+1)-silica (n >/= 4) particles and 96 h for the C(8)F(17)-alumina particles. The C(8)F(17)COOH-alumina particles gave a significantly higher graft density than the C(8)F(17)-alumina particles but are not as stable in CO(2). The C(8)F(17)-alumina particles were stable at lower CO(2) densities than the modified silica particles. This stability difference may be attributed to the precursor organosilanes being monofunctional (modified silica) versus trifunctional (modified alumina), producing different structures on the surface.

    View details for DOI 10.1021/la047823c

    View details for Web of Science ID 000229243800013

    View details for PubMedID 15896018

  • Oxidative dissolution of copper and zinc metal in carbon dioxide with <i>tert-</i>butyl peracetate and a β-diketone chelating agent INORGANIC CHEMISTRY Visintin, P. M., Bessel, C. A., White, P. S., Schauer, C. K., DeSimone, J. M. 2005; 44 (2): 316-324

    Abstract

    A series of beta-diketone ligands, R(1)COCH(2)COR(2) [tmhdH (R(1) = R(2) = C(CH(3))(3)); tfacH (R(1) = CF(3); R(2) = CH(3)); hfacH (R(1) = R(2) = CF(3))], in combination with tert-butyl peracetate (t-BuPA), have been investigated as etchant solutions for dissolution of copper metal into carbon dioxide solvent. Copper removal in CO(2) increases in the order tfacH < tmhdH < hfacH. A study of the reactions of the hfacH/t-BuPA etchant solution with metallic copper and zinc was conducted in three solvents: scCO(2) (supercrical CO(2)); hexanes; CD(2)Cl(2). The etchant solution/metallic zinc reaction produced a diamagnetic Zn(II) complex, which allowed NMR identification of the t-BuPA decomposition products as tert-butyl alcohol and acetic acid. Gravimetric analysis of the amount of zinc consumed, together with NMR studies, confirmed the 1:1:2 Zn:t-BuPA:hfacH reaction stoichiometry, showing t-BuPA to be an overall two-electron oxidant for Zn(0). The metal-containing products of the copper and zinc reactions were characterized by elemental analysis, IR spectroscopy, and, as appropriate, NMR spectroscopy and single-crystal X-ray diffraction [trans-M(hfac)(2)(H(2)O)(CH(3)CO(2)H) (1, M = Cu; 2, M = Zn)]. On the basis of the experimental results, a working model of the oxidative dissolution reaction is proposed, which delineates the key chemical variables in the etching reaction. These t-BuPA/hfacH etchant solutions may find application in a CO(2)-based chemical mechanical planarization (CMP) process.

    View details for DOI 10.1021/ic049765o

    View details for Web of Science ID 000226443800025

    View details for PubMedID 15651878

  • Solvent-resistant photocurable liquid fluoropolymers for microfluidic device fabrication [corrected]. Journal of the American Chemical Society Rolland, J. P., van Dam, R. M., Schorzman, D. A., Quake, S. R., DeSimone, J. M. 2004; 126 (8): 2322-2323

    Abstract

    We report the first fabrication of a solvent-compatible microfluidic device based on photocurable "Liquid Teflon" materials. The materials are highly fluorinated functionalized perfluoropolyethers (PFPEs) that have liquidlike viscosities that can be cured into tough, highly durable elastomers that exhibit the remarkable chemical resistance of fluoropolymers such as Teflon. Poly(dimethylsiloxane) (PDMS) elastomers have rapidly become the material of choice for many recent microfluidic device applications. Despite the advantages of PDMS in relation to microfluidics technology, the material suffers from a serious drawback in that it swells in most organic solvents. The swelling of PDMS-based devices in organic solvents greatly disrupts the micrometer-sized features and makes it impossible for fluids to flow inside the channels. Our approach to this problem has been to replace PDMS with photocurable perfluoropolyethers. Device fabrication and valve actuation were accomplished using established procedures for PDMS devices. The additional advantage of photocuring allows fabrication time to be decreased from several hours to a matter of minutes. The PFPE-based device exhibited mechanical properties similar to those of Sylgard 184 before and after curing as well as remarkable resistance to organic solvents. This work has the potential to expand the field of microfluidics to many novel applications.

    View details for PubMedID 14982433

  • Solvent-resistant photocurable "liquid teflon" for microfluidic device fabrication JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Rolland, J. P., van Dam, R. M., Schorzman, D. A., Quake, S. R., DeSimone, J. M. 2004; 126 (8): 2322-2323

    Abstract

    We report the first fabrication of a solvent-compatible microfluidic device based on photocurable "Liquid Teflon" materials. The materials are highly fluorinated functionalized perfluoropolyethers (PFPEs) that have liquidlike viscosities that can be cured into tough, highly durable elastomers that exhibit the remarkable chemical resistance of fluoropolymers such as Teflon. Poly(dimethylsiloxane) (PDMS) elastomers have rapidly become the material of choice for many recent microfluidic device applications. Despite the advantages of PDMS in relation to microfluidics technology, the material suffers from a serious drawback in that it swells in most organic solvents. The swelling of PDMS-based devices in organic solvents greatly disrupts the micrometer-sized features and makes it impossible for fluids to flow inside the channels. Our approach to this problem has been to replace PDMS with photocurable perfluoropolyethers. Device fabrication and valve actuation were accomplished using established procedures for PDMS devices. The additional advantage of photocuring allows fabrication time to be decreased from several hours to a matter of minutes. The PFPE-based device exhibited mechanical properties similar to those of Sylgard 184 before and after curing as well as remarkable resistance to organic solvents. This work has the potential to expand the field of microfluidics to many novel applications.

    View details for DOI 10.1021/ja031657y

    View details for Web of Science ID 000189279700032

  • Self-assembly of phosphate fluorosurfactants in carbon dioxide LANGMUIR Keiper, J. S., Behles, J. A., Bucholz, T. L., Simhan, R., DeSimone, J. M., Lynn, G. W., Wignall, G. D., Melnichenko, Y. B., Frielinghaus, H. 2004; 20 (4): 1065-1072

    Abstract

    Anionic phosphodiester surfactants, possessing either two fluorinated chains (F/F) or one hydrocarbon chain and one fluorinated chain (H/F), were synthesized and evaluated for solubility and self-assembly in liquid and supercritical carbon dioxide. Several surfactants, of both F/F and H/F types and having varied counterions, were found to be capable of solubilizing water-in-CO2 (W/C), via the formation of microemulsions, expanding upon the family of phosphate fluorosurfactants already found to stabilize W/C microemulsions. Small-angle neutron scatteringwas used to directly characterize the microemulsion particles at varied temperatures, pressures, and water loadings, revealing behavior consistent with previous results on W/C microemulsions.

    View details for DOI 10.1021/la034742s

    View details for Web of Science ID 000189013400013

    View details for PubMedID 15803679

  • Etchant solutions for the removal of Cu(0) in a supercritical CO<sub>2</sub>-based "dry" chemical mechanical planarization process for device fabrication JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Bessel, C. A., Denison, G. M., DeSimone, J. M., DeYoung, J., Gross, S., Schauer, C. K., Visintin, P. M. 2003; 125 (17): 4980-4981

    Abstract

    The microelectronics industry is focused on increasing chip complexity, improving the density of electron carriers, and decreasing the dimensions of the interconnects into the sub-0.25 mum regime while maintaining high aspect ratios. Water-based chemical mechanical planarization or polishing (CMP) faces several technical and environmental challenges. Condensed CO2 has significant potential for replacing current CMP solvents as a "dry" etching medium because of its unique properties. In working toward a condensed CO2-based CMP process, we have successfully investigated the oxidation and chelation of solid copper metal in liquid and supercritical CO2 using ethyl peroxydicarbonate and a beta-diketone chelating agent.

    View details for DOI 10.1021/ja034091m

    View details for Web of Science ID 000182491700011

    View details for PubMedID 12708839

  • Polymeric nanogels produced via inverse microemulsion polymerization as potential gene and antisense delivery agents JOURNAL OF THE AMERICAN CHEMICAL SOCIETY McAllister, K., Sazani, P., Adam, M., Cho, M. J., Rubinstein, M., Samulski, R. J., DeSimone, J. M. 2002; 124 (51): 15198-15207

    Abstract

    Polymeric nanogel vectors were developed for cellular gene and antisense delivery. Inverse microemulsion polymerization was utilized to synthesize biocompatible nanogels with controlled size, morphology, and composition. The chemical composition, size, polydispersity, stability, and swelling behavior of the nanogels were investigated by NMR, light scattering, transmission electron microscopy, and atomic force microscopy. The cell viability, uptake, and physical stability of nanogel-DNA complexes were evaluated under physiological conditions. Monodisperse nonionic and cationic nanogels were produced with controllable sizes ranging from 40 to 200 nm in diameter. The nanogels demonstrated extended stability in aqueous media and exhibited low toxicity in cell culture. Cationic nanogels formed monodisperse complexes with oligonucleotides and showed enhanced oligonucleotide uptake in cell culture. The nanogels synthesized in this study demonstrate potential utility as carriers of oligonucleotides and DNA for antisense and gene delivery.

    View details for DOI 10.1021/ja027759q

    View details for Web of Science ID 000180006600027

    View details for PubMedID 12487595

  • Practical approaches to green solvents SCIENCE DeSimone, J. M. 2002; 297 (5582): 799-803

    Abstract

    Solvents are widely used in commercial manufacturing and service industries. Despite abundant precaution, they inevitably contaminate our air, land, and water because they are difficult to contain and recycle. Researchers have therefore focused on reducing solvent use through the development of solvent-free processes and more efficient recycling protocols. However, these approaches have their limitations, necessitating a pollution prevention approach and the search for environmentally benign solvent alternatives. This report highlights opportunities for the practical implementation of such green solvents.

    View details for DOI 10.1126/science.1069622

    View details for Web of Science ID 000177192800039

    View details for PubMedID 12161645

  • CO(2) Technology Platform: An Important Tool for Environmental Problem Solving A list of abbreviations can be found at the end of the article. Angewandte Chemie (International ed. in English) Wells, S. L., DeSimone, J. 2001; 40 (3): 518-527

    Abstract

    CO(2) is a good solvent for many substances when compressed into its liquid or supercritical fluid state. Above the critical temperature and critical pressure (T(c)=31 degrees C, P(c)=73.8 bar, see Figure 1 for the phase diagram for CO(2)), CO(2) has both gaslike viscosities and liquidlike densities. These moderate critical conditions allow CO(2) to be used within safe commercial and laboratory operating conditions. Small changes in temperature and pressure cause dramatic changes in the density, viscosity, and dielectric properties of CO(2), making it a tunable solvent that can be tailored for various applications. Combined, these unique properties make CO(2) a "solvent of choice" for the new millennium.

    View details for PubMedID 11180359

  • CO<sub>2</sub> technology platform:: An important tool for environmental problem solving ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wells, S. L., DeSimone, J. 2001; 40 (3): 519-527

    Abstract

    CO2 is a good solvent for many substances when compressed into its liquid or supercritical fluid state. Above the critical temperature and critical pressure (Tc =31 °C, Pc =73.8 bar, see Figure 1 for the phase diagram for CO2 ), CO2 has both gaslike viscosities and liquidlike densities. These moderate critical conditions allow CO2 to be used within safe commercial and laboratory operating conditions. Small changes in temperature and pressure cause dramatic changes in the density, viscosity, and dielectric properties of CO2 , making it a tunable solvent that can be tailored for various applications. Combined, these unique properties make CO2 a "solvent of choice" for the new millennium.

    View details for Web of Science ID 000166899100002

    View details for PubMedID 29712034

  • Mimicking the antenna-electron transfer properties of photosynthesis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sykora, M., Maxwell, K. A., DeSimone, J. M., Meyer, T. J. 2000; 97 (14): 7687-7691

    Abstract

    A molecular assembly based on derivatized polystyrene is described, which mimics both the light-harvesting and energy-conversion steps of photosynthesis. The system is unique in that the two key parts of a photosynthetic system are incorporated in a functional assembly constructed from polypyridine complexes of Ru(II). This system is truly artificial, as none of the components used in construction of the assembly are present in a natural photosynthetic system. Quantitative evaluation of the energy and electron transfer dynamics after transient irradiation by visible light offers important insights into the mechanisms of energy transport and electron transfer that lead to photosynthetic light-to-chemical energy conversion.

    View details for DOI 10.1073/pnas.97.14.7687

    View details for Web of Science ID 000088048400007

    View details for PubMedID 10884400

    View details for PubMedCentralID PMC16604

  • Polymerizations in supercritical carbon dioxide CHEMICAL REVIEWS Kendall, J. L., Canelas, D. A., Young, J. L., DeSimone, J. M. 1999; 99 (2): 543-563

    View details for DOI 10.1021/cr9700336

    View details for Web of Science ID 000078984700009

    View details for PubMedID 11848992