Eric Appel

All Publications

• Wildfire prevention through prophylactic treatment of high-risk landscapes using viscoelastic retardant fluids. Proceedings of the National Academy of Sciences of the United States of America Yu, A. C., Lopez Hernandez, H., Kim, A. H., Stapleton, L. M., Brand, R. J., Mellor, E. T., Bauer, C. P., McCurdy, G. D., Wolff, A. J., Chan, D., Criddle, C. S., Acosta, J. D., Appel, E. A. 2019

  Abstract

  Polyphosphate fire retardants are a critical tactical resource for fighting fires in the wildland and in the wildland-urban interface. Yet, application of these retardants is limited to emergency suppression strategies because current formulations cannot retain fire retardants on target vegetation for extended periods of time through environmental exposure and weathering. New retardant formulations with persistent retention to target vegetation throughout the peak fire season would enable methodical, prophylactic treatment strategies of landscapes at high risk of wildfires through prolonged prevention of ignition and continual impediment to active flaming fronts. Here we develop a sprayable, environmentally benign viscoelastic fluid comprising biopolymers and colloidal silica to enhance adherence and retention of polyphosphate retardants on common wildfire-prone vegetation. These viscoelastic fluids exhibit appropriate wetting and rheological responses to enable robust retardant adherence to vegetation following spray application. Further, laboratory and pilot-scale burn studies establish that these materials drastically reduce ignition probability before and after simulated weathering events. Overall, these studies demonstrate how these materials actualize opportunities to shift the approach of retardant-based wildfire management from reactive suppression to proactive prevention at the source of ignitions.

  View details for DOI 10.1073/pnas.1907855116

  View details for PubMedID 31570592

• Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier. Nature biomedical engineering Stapleton, L. M., Steele, A. N., Wang, H., Lopez Hernandez, H., Yu, A. C., Paulsen, M. J., Smith, A. A., Roth, G. A., Thakore, A. D., Lucian, H. J., Totherow, K. P., Baker, S. W., Tada, Y., Farry, J. M., Eskandari, A., Hironaka, C. E., Jaatinen, K. J., Williams, K. M., Bergamasco, H., Marschel, C., Chadwick, B., Grady, F., Ma, M., Appel, E. A., Woo, Y. J. 2019; 3 (8): 611–20

  Abstract

  Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.

  View details for DOI 10.1038/s41551-019-0442-z

  View details for PubMedID 31391596

• Supramolecular polymeric biomaterials. Biomaterials science Mann, J. L., Yu, A. C., Agmon, G., Appel, E. A. 2017

  Abstract

  Polymeric chains crosslinked through supramolecular interactions-directional and reversible non-covalent interactions-compose an emerging class of modular and tunable biomaterials. The choice of chemical moiety utilized in the crosslink affords different thermodynamic and kinetic parameters of association, which in turn illustrate the connectivity and dynamics of the system. These parameters, coupled with the choice of polymeric architecture, can then be engineered to control environmental responsiveness, viscoelasticity, and cargo diffusion profiles, yielding advanced biomaterials which demonstrate rapid shear-thinning, self-healing, and extended release. In this review we examine the relationship between supramolecular crosslink chemistry and biomedically relevant macroscopic properties. We then describe how these properties are currently leveraged in the development of materials for drug delivery, immunology, regenerative medicine, and 3D-bioprinting (253 references).

  View details for PubMedID 29164196

• A Multiscale Model for Solute Diffusion in Hydrogels. Macromolecules Axpe, E., Chan, D., Offeddu, G. S., Chang, Y., Merida, D., Hernandez, H. L., Appel, E. A. 2019; 52 (18): 6889–97

  Abstract

  The number of biomedical applications of hydrogels is increasing rapidly on account of their unique physical, structural, and mechanical properties. The utility of hydrogels as drug delivery systems or tissue engineering scaffolds critically depends on the control of diffusion of solutes through the hydrogel matrix. Predicting or even modeling this diffusion is challenging due to the complex structure of hydrogels. Currently, the diffusivity of solutes in hydrogels is typically modeled by one of three main theories proceeding from distinct diffusion mechanisms: (i) hydrodynamic, (ii) free volume, and (iii) obstruction theory. Yet, a comprehensive predictive model is lacking. Thus, time and capital-intensive trial-and-error procedures are used to test the viability of hydrogel applications. In this work, we have developed a model for the diffusivity of solutes in hydrogels combining the three main theoretical frameworks, which we call the multiscale diffusion model (MSDM). We verified the MSDM by analyzing the diffusivity of dextran of different sizes in a series of poly(ethylene glycol) (PEG) hydrogels with distinct mesh sizes. We measured the subnanoscopic free volume by positron annihilation lifetime spectroscopy (PALS) to characterize the physical hierarchy of these materials. In addition, we performed a meta-analysis of literature data from previous studies on the diffusion of solutes in hydrogels. The model presented outperforms traditional models in predicting solute diffusivity in hydrogels and provides a practical approach to predicting the transport properties of solutes such as drugs through hydrogels used in many biomedical applications.

  View details for DOI 10.1021/acs.macromol.9b00753

  View details for PubMedID 31579160

• Block copolymer composition drives function of self-assembled nanoparticles for delivery of small-molecule cargo JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY Maikawa, C. L., Sevit, A., Lin, B., Wallstrom, R. J., Mann, J. L., Yu, A. C., Waymouth, R. M., Appel, E. A. 2019; 57 (12): 1322–32

  View details for DOI 10.1002/pola.29393

  View details for Web of Science ID 000469938700008

• A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering ADVANCED HEALTHCARE MATERIALS Steele, A. N., Stapleton, L. M., Farry, J. M., Lucian, H. J., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Thakore, A. D., Wang, H., Yu, A. C., Chan, D., Appel, E. A., Woo, Y. 2019; 8 (5)

  View details for DOI 10.1002/adhm.201801147

  View details for Web of Science ID 000461575200003

• A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering. Advanced healthcare materials Steele, A. N., Stapleton, L. M., Farry, J. M., Lucian, H. J., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Thakore, A. D., Wang, H., Yu, A. C., Chan, D., Appel, E. A., Woo, Y. J. 2019: e1801147

  Abstract

  Hydrogels have emerged as a diverse class of biomaterials offering a broad range of biomedical applications. Specifically, injectable hydrogels are advantageous for minimally invasive delivery of various therapeutics and have great potential to treat a number of diseases. However, most current injectable hydrogels are limited by difficult and time-consuming fabrication techniques and are unable to be delivered through long, narrow catheters, preventing extensive clinical translation. Here, the development of an easily-scaled, catheter-injectable hydrogel utilizing a polymer-nanoparticle crosslinking mechanism is reported, which exhibits notable shear-thinning and self-healing behavior. Gelation of the hydrogel occurs immediately upon mixing the biochemically modified hyaluronic acid polymer with biodegradable nanoparticles and can be easily injected through a high-gauge syringe due to the dynamic nature of the strong, yet reversible crosslinks. Furthermore, the ability to deliver this novel hydrogel through a long, narrow, physiologically-relevant catheter affixed with a 28-G needle is highlighted, with hydrogel mechanics unchanged after delivery. Due to the composition of the gel, it is demonstrated that therapeutics can be differentially released with distinct elution profiles, allowing precise control over drug delivery. Finally, the cell-signaling and biocompatibility properties of this innovative hydrogel are demonstrated, revealing its wide range of therapeutic applications.

  View details for PubMedID 30714355

• Non-Newtonian Polymer-Nanoparticle Hydrogels Enhance Cell Viability during Injection MACROMOLECULAR BIOSCIENCE Hernandez, H., Grosskopf, A. K., Stapleton, L. M., Agmon, G., Appel, E. A. 2019; 19 (1)

  View details for DOI 10.1002/mabi.201800275

  View details for Web of Science ID 000458817700008

• Non-Newtonian Polymer-Nanoparticle Hydrogels Enhance Cell Viability during Injection. Macromolecular bioscience Lopez Hernandez, H., Grosskopf, A. K., Stapleton, L. M., Agmon, G., Appel, E. A. 2018: e1800275

  Abstract

  Drug delivery and cell transplantation require minimally invasive deployment strategies such as injection through clinically relevant high-gauge needles. Supramolecular hydrogels comprising dodecyl-modified hydroxypropylmethylcellulose and poly(ethylene glycol)-block-poly(lactic acid) have been previously demonstrated for the delivery of drugs and proteins. Here, it is demonstrated that the rheological properties of these hydrogels allow for facile injectability, an increase of cell viability after injection when compared to cell viabilities of cells injected in phosphate-buffered saline, and homogeneous cell suspensions that do not settle. These hydrogels are injected at 1mL min-1 with pressures less than 400kPa, despite the solid-like properties of the gel when at rest. The cell viabilities immediately after injection are greater than 86% for adult human dermal fibroblasts, human umbilical vein cells, smooth muscle cells, and human mesenchymal stem cells. Cells are shown to remain suspended and proliferate in the hydrogel at the same rate as observed in cell media. The work expands on the versatility of these hydrogels and lays a foundation for the codelivery of drugs, proteins, and cells.

  View details for PubMedID 30369048

• Self-assembled biomaterials using host-guest interactions SELF-ASSEMBLING BIOMATERIALS: MOLECULAR DESIGN, CHARACTERIZATION AND APPLICATION IN BIOLOGY AND MEDICINE Yu, A. C., Stapleton, L. M., Mann, J. L., Appel, E. A., Azevedo, H. S., DaSilva, R. M. 2018: 205–31

  View details for DOI 10.1016/B978-0-08-102015-9.00010-1

  View details for Web of Science ID 000462711900010

• Engineering the Mechanical Properties of Polymer Networks with Precise Doping of Primary Defects. ACS applied materials & interfaces Chan, D., Ding, Y., Dauskardt, R. H., Appel, E. A. 2017

  Abstract

  Polymer networks are extensively utilized across numerous applications ranging from commodity superabsorbent polymers and coatings to high-performance microelectronics and biomaterials. For many applications, desirable properties are known; however, achieving them has been challenging. Additionally, the accurate prediction of elastic modulus has been a long-standing difficulty owing to the presence of loops. By tuning the prepolymer formulation through precise doping of monomers, specific primary network defects can be programmed into an elastomeric scaffold, without alteration of their resulting chemistry. The addition of these monomers that respond mechanically as primary defects is used both to understand their impact on the resulting mechanical properties of the materials and as a method to engineer the mechanical properties. Indeed, these materials exhibit identical bulk and surface chemistry, yet vastly different mechanical properties. Further, we have adapted the real elastic network theory (RENT) to the case of primary defects in the absence of loops, thus providing new insights into the mechanism for material strength and failure in polymer networks arising from primary network defects, and to accurately predict the elastic modulus of the polymer system. The versatility of the approach we describe and the fundamental knowledge gained from this study can lead to new advancements in the development of novel materials with precisely defined and predictable chemical, physical, and mechanical properties.

  View details for PubMedID 29135222

• Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Appel, E. A., Biedermann, F., Hoogland, D., del Barrio, J., Driscoll, M. D., Hay, S., Wales, D. J., Scherman, O. A. 2017; 139 (37): 12985–93

  Abstract

  Kinetics and thermodynamics in supramolecular systems are intimately linked, yet both are independently important for application in sensing assays and stimuli-responsive switching/self-healing of materials. Host-guest interactions are of particular interest in many water-based materials, sensing, and drug delivery applications. Herein we investigate the binding dynamics of a variety of electron-rich aromatic moieties forming hetero-ternary complexes with the macrocycle cucurbit[8]uril (CB[8]) and an auxiliary guest, dimethyl viologen, with high selectivity and equilibrium binding constants (Keq up to 1014 M-2). Using stopped-flow spectrofluorimetry, association rate constants were observed to approach the diffusion limit and were found to be insensitive to the structure of the guest. Conversely, the dissociation rate constants of the ternary complexes varied dramatically with the guest structure and were correlated with the thermodynamic binding selectivity. Hence differing molecular features were found to contribute to the associative and dissociative processes, mimicking naturally occurring reactions and giving rise to a decoupling of these kinetic parameters. Moreover, we demonstrate the ability to exploit these phenomena and selectively perturb the associative process with external stimuli (e.g., viscosity and pressure). Significantly, these complexes exhibit increased binding equilibria with increasing pressure, with important implications for the application of the CB[8] ternary complex for the formation of hydrogels, as these gels exhibit unprecedented pressure-insensitive rheological properties. A high degree of flexibility therefore exists in the design of host-guest systems with tunable kinetic and thermodynamic parameters for tailor-made applications across a broad range of fields.

  View details for PubMedID 28661667

• Mixed Reversible Covalent Crosslink Kinetics Enable Precise, Hierarchical Mechanical Tuning of Hydrogel Networks ADVANCED MATERIALS Yesilyurt, V., Ayoob, A. M., Appel, E. A., Borenstein, J. T., Langer, R., Anderson, D. G. 2017; 29 (19)

  Abstract

  Hydrogels play a central role in a number of medical applications and new research aims to engineer their mechanical properties to improve their capacity to mimic the functional dynamics of native tissues. This study shows hierarchical mechanical tuning of hydrogel networks by utilizing mixtures of kinetically distinct reversible covalent crosslinks. A methodology is described to precisely tune stress relaxation in PEG networks formed from mixtures of two different phenylboronic acid derivatives with unique diol complexation rates, 4-carboxyphenylboronic acid, and o-aminomethylphenylboronic acid. Gel relaxation time and the mechanical response to dynamic shear are exquisitely controlled by the relative concentrations of the phenylboronic acid derivatives. The differences observed in the crossover frequencies corresponding to pKa differences in the phenylboronic acid derivatives directly connect the molecular kinetics of the reversible crosslinks to the macroscopic dynamic mechanical behavior. Mechanical tuning by mixing reversible covalent crosslinking kinetics is found to be independent of other attributes of network architecture, such as molecular weight between crosslinks.

  View details for DOI 10.1002/adma.201605947

  View details for Web of Science ID 000401170600014

  View details for PubMedID 28295624

• Single-Chain Polymeric Nanocarriers: A Platform for Determining Structure-Function Correlations in the Delivery of Molecular Cargo BIOMACROMOLECULES Chan, D., Yu, A. C., Appel, E. A. 2017; 18 (4): 1434-1439

  Abstract

  There has been growing interest in producing stable, biocompatible nanocarriers for the controlled delivery of therapeutics. With micelles, it remains a challenge to predict a priori the size, aggregation number, and functionality of the self-assembled aggregates. Utilizing controlled radical polymerization techniques, we have prepared tunable high molecular weight amphiphilic comb copolymers that self-assemble into unimolecular "micelle-like" nanocarriers of predictable size and functionality. Excellent control over self-assembly behavior and structure allows for systematic determination of the role of important polymeric material properties (i.e., glass transition) on the release of model therapeutics while simultaneously controlling for size, dispersity, structural, and functionality effects. Moreover, these single-chain polymeric nanocarriers represent a class of drug delivery systems allowing for interrogation of the limitations of standard methods for characterization of micellar aggregates.

  View details for DOI 10.1021/acs.biomac.7b00249

  View details for Web of Science ID 000399061100040

  View details for PubMedID 28263572

• Engineering the Mechanical Properties of Polymer Networks with Precise Doping of Primary Defects ACS Applied Materials and Interfaces Chan, D., Ding, Y., Dauskardt, R., Appel, E. A. 2017; 9: 42217-42224
• Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nature communications Bertrand, N., Grenier, P., Mahmoudi, M., Lima, E. M., Appel, E. A., Dormont, F., Lim, J. M., Karnik, R., Langer, R., Farokhzad, O. C. 2017; 8 (1): 777

  Abstract

  In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm2 prolong circulation times, irrespective of size. In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection. Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles. In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times. In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density. These results further our understanding of nanopharmacology.Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.

  View details for PubMedID 28974673

  View details for PubMedCentralID PMC5626760

• Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes Advanced Materials Fenton, O. S., et al 2017; 29: e1606944
• Distinguishing the Respective Mechanical Contributions of Polymer and Supramolecular Dynamics in Transiently Crosslinked Polymeric Networks Polymer Chemistry Tan, C. S., Agmon, G., Hoogland, D., Janecek, E., Toprakcioglu, C., Appel, E. A., Scherman, O. A. 2017; 8: 5336-5343
• Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes Journal of the American Chemical Society Appel, E. A., Biedermann, F., Driscoll, M. D., Hay, S., Wales, D. J., Scherman, O. A. 2017; 139: 12985-12993
• Supramolecular Polymeric Biomaterials Biomaterials Science Mann, J. L., Yu, A. C., Agmon, G., Appel, E. A. 2017; 6: 10-37
• Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics Nature Communication Bertrand, N., et al 2017; 8: e777
• Supramolecular PEGylation of biopharmaceuticals PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Webber, M. J., Appel, E. A., Vinciguerra, B., Cortinas, A. B., Thapa, L. S., Jhunjhunwala, S., Isaacs, L., Langer, R., Anderson, D. G. 2016; 113 (50): 14189-14194

  Abstract

  The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host-guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])-PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.

  View details for DOI 10.1073/pnas.1616639113

  View details for Web of Science ID 000389696700033

  View details for PubMedID 27911829

• Scalable manufacturing of biomimetic moldable hydrogels for industrial applications PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yu, A. C., Chen, H., Chan, D., Agmon, G., Stapleton, L. M., Sevit, A. M., Tibbitt, M. W., Acosta, J. D., Zhang, T., Franzia, P. W., Langer, R., Appel, E. A. 2016; 113 (50): 14255-14260

  Abstract

  Hydrogels are a class of soft material that is exploited in many, often completely disparate, industrial applications, on account of their unique and tunable properties. Advances in soft material design are yielding next-generation moldable hydrogels that address engineering criteria in several industrial settings such as complex viscosity modifiers, hydraulic or injection fluids, and sprayable carriers. Industrial implementation of these viscoelastic materials requires extreme volumes of material, upwards of several hundred million gallons per year. Here, we demonstrate a paradigm for the scalable fabrication of self-assembled moldable hydrogels using rationally engineered, biomimetic polymer-nanoparticle interactions. Cellulose derivatives are linked together by selective adsorption to silica nanoparticles via dynamic and multivalent interactions. We show that the self-assembly process for gel formation is easily scaled in a linear fashion from 0.5 mL to over 15 L without alteration of the mechanical properties of the resultant materials. The facile and scalable preparation of these materials leveraging self-assembly of inexpensive, renewable, and environmentally benign starting materials, coupled with the tunability of their properties, make them amenable to a range of industrial applications. In particular, we demonstrate their utility as injectable materials for pipeline maintenance and product recovery in industrial food manufacturing as well as their use as sprayable carriers for robust application of fire retardants in preventing wildland fires.

  View details for DOI 10.1073/pnas.1618156113

  View details for Web of Science ID 000389696700044

  View details for PubMedID 27911849

  View details for PubMedCentralID PMC5167152

• Injectable and Glucose-Responsive Hydrogels Based on Boronic Acid-Glucose Complexation LANGMUIR Dong, Y., Wang, W., Veiseh, O., Appel, E. A., Xue, K., Webber, M. J., Tang, B. C., Yang, X., Weir, G. C., Langer, R., Anderson, D. G. 2016; 32 (34): 8743-8747

  Abstract

  Injectable hydrogels have been widely used for a number of biomedical applications. Here, we report a new strategy to form an injectable and glucose-responsive hydrogel using the boronic acid-glucose complexation. The ratio of boronic acid and glucose functional groups is critical for hydrogel formation. In our system, polymers with 10-60% boronic acid, with the balance being glucose-modified, are favorable to form hydrogels. These hydrogels are shear-thinning and self-healing, recovering from shear-induced flow to a gel state within seconds. More importantly, these polymers displayed glucose-responsive release of an encapsulated model drug. The hydrogel reported here is an injectable and glucose-responsive hydrogel constructed from the complexation of boronic acid and glucose within a single component polymeric material.

  View details for DOI 10.1021/acs.langmuir.5b04755

  View details for Web of Science ID 000382513900022

  View details for PubMedID 27455412

  View details for PubMedCentralID PMC5242094

• Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery ADVANCED MATERIALS Fenton, O. S., Kauffman, K. J., McClellan, R. L., Appel, E. A., Dorkin, J. R., Tibbitt, M. W., Heartlein, M. W., DeRosa, F., Langer, R., Anderson, D. G. 2016; 28 (15): 2939-2943

  Abstract

  Thousands of human diseases could be treated by selectively controlling the expression of specific proteins in vivo. A new series of alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable of delivering human mRNA with unprecedented levels of in vivo efficacy is demonstrated. This study highlights the importance of utilizing synthesis tools in tandem with biological inspiration to understand and improve nucleic acid delivery in vivo.

  View details for DOI 10.1002/adma.201505822

  View details for Web of Science ID 000374336700011

  View details for PubMedID 26889757

  View details for PubMedCentralID PMC5245883

• Supramolecular biomaterials NATURE MATERIALS Webber, M. J., Appel, E. A., Meijer, E. W., Langer, R. 2016; 15 (1): 13-26

  View details for DOI 10.1038/NMAT4474

  View details for Web of Science ID 000366690600014

• Injectable Self-Healing Glucose Responsive Hydrogels with pH-Regulated Mechanical Properties Advanced Materials Yesilyurt, V., Webber, M. J., Appel, E. A., Godwin, C., Langer, R., Anderson, D. G. 2016; 28: 86-91
• Water soluble, biodegradable amphiphilic polymeric nanoparticles and the molecular environment of hydrophobic encapsulates: Consistency between simulation and experiment POLYMER Miller, R. D., Yusoff, R. M., Swope, W. C., Rice, J. E., Carr, A. C., Parker, A. J., Sly, J., Appel, E. A., Nguyen, T., Piunova, V. 2015; 79: 255-261

  View details for DOI 10.1016/j.polymer.2015.10.008

  View details for Web of Science ID 000365042500028

• Formation of Cucurbit[8]uril-Based Supramolecular Hydrogel Beads Using Droplet-Based Microfluidics BIOMACROMOLECULES Xu, X., Appel, E. A., Liu, X., Parker, R. M., Scherman, O. A., Abell, C. 2015; 16 (9): 2743-2749

  Abstract

  Herein we describe the use of microdroplets as templates for the fabrication of uniform-sized supramolecular hydrogel beads, assembled by supramolecular cross-linking of functional biopolymers with the macrocyclic host molecule, cucurbit[8]uril (CB[8]). The microdroplets were formed containing diluted hydrogel precursors in solution, including the functional polymers and CB[8], in a microfluidic device. Subsequent evaporation of water from collected microdroplets concentrated the contents, driving the formation of the CB[8]-mediated host-guest ternary complex interactions and leading to the assembly of condensed three-dimensional polymeric scaffolds. Rehydration of the dried particles gave monodisperse hydrogel beads. Their equilibrium size was shown to be dependent on both the quantity of material loaded and the dimensions of the microfluidic flow focus. Fluorescein-labeled dextran was used to evaluate the efficacy of the hydrogel beads as a vector for controlled cargo release. Both passive, sustained release (hours) and triggered, fast release (minutes) of the FITC-dextran was observed, with the rate of sustained release dependent on the formulation. The kinetics of release was fitted to the Ritger-Peppas controlled release equation and shown to follow an anomalous (non-Fickian) transport mechanism.

  View details for DOI 10.1021/acs.biomac.5b01048

  View details for Web of Science ID 000361341700020

  View details for PubMedID 26256409

• Exploiting Electrostatic Interactions in Polymer-Nanoparticle Hydrogels ACS MACRO LETTERS Appel, E. A., Tibbitt, M. W., Greer, J. M., Fenton, O. S., Kreuels, K., Anderson, D. G., Langer, R. 2015; 4 (8): 848-852

  View details for DOI 10.1021/acsmacrolett.5b00416

  View details for Web of Science ID 000359891200009

• A Facile Method for the Stain-Free Visualization of Hierarchical Structures with Electron Microscopy JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY Williams, P. E., Appel, E. A., Jones, S. T., del Barrio, J., Lan, Y., Scherman, O. A. 2015; 53 (7): 842-845

  View details for DOI 10.1002/pola.27517

  View details for Web of Science ID 000350278400002

• Non-Cell-Adhesive Substrates for Printing of Arrayed Biomaterials ADVANCED HEALTHCARE MATERIALS Appel, E. A., Larson, B. L., Luly, K. M., Kim, J. D., Langer, R. 2015; 4 (4): 501-505

  Abstract

  Cellular microarrays have become extremely useful in expediting the investigation of large libraries of (bio)materials for both in vitro and in vivo biomedical applications. An exceedingly simple strategy is developed for the fabrication of non-cell-adhesive substrates supporting the immobilization of diverse (bio)material features, including both monomeric and polymeric adhesion molecules (e.g., RGD and polylysine), hydrogels, and polymers.

  View details for DOI 10.1002/adhm.201400594

  View details for Web of Science ID 000351225700002

  View details for PubMedID 25430948

  View details for PubMedCentralID PMC4447497

• Self-Assembled Hydrogels Utilising Polymer-Nanoparticle Interactions Nature Communications Appel, E. A., Tibbitt, M. W., Webber, M. J., Mattix, B. A., Veiseh, O., Langer, R. 2015; 6: e6295
• The control of cargo release from physically crosslinked hydrogels by crosslink dynamics BIOMATERIALS Appel, E. A., Forster, R. A., Rowland, M. J., Scherman, O. A. 2014; 35 (37): 9897-9903

  Abstract

  Controlled release of drugs and other cargo from hydrogels has been an important target for the development of next generation therapies. Despite the increasingly strong focus in this area of research, very little of the published literature has sought to develop a fundamental understanding of the role of molecular parameters in determining the mechanism and rate of cargo release. Herein, a series of physically crosslinked hydrogels have been prepared utilizing host-guest binding interactions of cucurbit[8]uril that are identical in strength (plateau modulus), concentration and structure, yet exhibit varying network dynamics on account of the use of different guests for supramolecular crosslinking. The diffusion of molecular cargo through the hydrogel matrix and the release characteristics from these hydrogels were investigated. It was determined that the release processes of the hydrogels could be directly correlated with the dynamics of the physical interactions responsible for crosslinking and corresponding time-dependent mesh size. These observations highlight that network dynamics play an indispensable role in determining the release mechanism of therapeutic cargo from a hydrogel, identifying that fine-tuning of the release characteristics can be gained through rational design of the molecular processes responsible for crosslinking in the carrier hydrogels.

  View details for DOI 10.1016/j.biomaterials.2014.08.001

  View details for Web of Science ID 000343639700015

  View details for PubMedID 25239043

• GLUING GELS A nanoparticle solution NATURE MATERIALS Appel, E. A., Scherman, O. A. 2014; 13 (3): 231-232

  View details for DOI 10.1038/nmat3893

  View details for Web of Science ID 000331945200014

  View details for PubMedID 24553651

• Activation Energies Control Macroscopic Properties of Supramolecular Crosslinked Materials Angewandte Chemie International Edition Appel, E. A., Forster, R. A., Koutsioumpas, A., , Scherman, O. A. 2014; 53: 10038-10043
• Rapidly Healable, Temporally Stable and Stiff Hydrogels: Combining Conflicting Properties Using Highly Dynamic and Selective Three-Component Recognition with Reinforcing Cellulose Nanorods Advanced Functional Materials Jason, M., Appel, E. A., Seitsonen, J., Kontturi, E., Scherman, O. A., Ikkala, O. 2014; 24: 2706-2713
• Dynamically crosslinked materials via recognition of amino acids by cucurbit[8]uril JOURNAL OF MATERIALS CHEMISTRY B Rowland, M. J., Appel, E. A., Coulston, R. J., Scherman, O. A. 2013; 1 (23): 2904-2910

  View details for DOI 10.1039/c3tb20180e

  View details for Web of Science ID 000319273100002

• Triggered insulin release studies of triply responsive supramolecular micelles POLYMER CHEMISTRY Loh, X. J., Tsai, M., del Barrio, J., Appel, E. A., Lee, T., Scherman, O. A. 2012; 3 (11): 3180-3188

  View details for DOI 10.1039/c2py20380d

  View details for Web of Science ID 000310421200021

• Ultra-High Water-Content Hydrogels from Renewable Resources Exhibiting Multi-Stimuli Responsiveness J. Am. Chem. Soc. Appel, E. A., Loh, X., Jones, S. T., Biedermann, F., Dreiss, C. A., Scherman, O. A. 2012; 134: 11767-11773
• Triply Triggered Doxorubicin Release From Supramolecular Nanocontainers BIOMACROMOLECULES Loh, X. J., del Barrio, J., Toh, P. P., Lee, T., Jiao, D., Rauwald, U., Appel, E. A., Scherman, O. A. 2012; 13 (1): 84-91

  Abstract

  The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers.

  View details for DOI 10.1021/bm201588m

  View details for Web of Science ID 000298897300009

  View details for PubMedID 22148638

• Toward biodegradable nanogel star polymers via organocatalytic ROP CHEMICAL COMMUNICATIONS Appel, E. A., Lee, V. Y., Nguyen, T. T., McNeil, M., Nederberg, F., Hedrick, J. L., Swope, W. C., Rice, J. E., Miller, R. D., Sly, J. 2012; 48 (49): 6163-6165

  Abstract

  Organocatalytic ring opening polymerization (OROP) is used to effect the rapid, scalable, room temperature formation of size-controlled, highly uniform, polyvalent, nanogel star polymer nanoparticles of biodegradable composition.

  View details for DOI 10.1039/c2cc31406a

  View details for Web of Science ID 000304363500028

  View details for PubMedID 22590707

• High Molecular Weight Polyacrylamides by ATRP: Enabling Advancements in Water-based Applications J. Poly. Sci. Part A: Polym. Chem. Appel, E. A., del Barrio, J., Loh, X., Dyson, J., Scherman, O. A. 2012; 50: 181-186
• Metastable single-chain polymer nanoparticles prepared by dynamic cross-linking with nor-seco-cucurbit[10]uril CHEMICAL SCIENCE Appel, E. A., del Barrio, J., Dyson, J., Isaacs, L., Scherman, O. A. 2012; 3 (7): 2278-2281

  View details for DOI 10.1039/c2sc20285a

  View details for Web of Science ID 000304919200014

• Enhanced Stability and Activity of Temozolomide in Primary GBM Cells with Cucurbit[n]uril Chemical Communications Appel, E. A., Rowland, M. J., Loh, X., Heywood, R. M., Watts, C., Scherman, O. A. 2012: 9843-9845
• Supramolecular polymeric hydrogels CHEMICAL SOCIETY REVIEWS Appel, E. A., del Barrio, J., Loh, X. J., Scherman, O. A. 2012; 41 (18): 6195-6214

  Abstract

  The supramolecular crosslinking of polymer chains in water by specific, directional and dynamic non-covalent interactions has led to the development of novel supramolecular polymeric hydrogels. These aqueous polymeric networks constitute an interesting class of soft materials exhibiting attractive properties such as stimuli-responsiveness and self-healing arising from their dynamic behaviour and that are crucial for a wide variety of emerging applications. We present here a critical review summarising the formation of dynamic polymeric networks through specific non-covalent interactions, with a particular emphasis on those systems based on host-guest complex formation, as well as the characterisation of their physical characteristics. Aqueous supramolecular chemistry has unlocked a versatile toolbox for the design and fine-tuning of the material properties of these hydrogels (264 references).

  View details for DOI 10.1039/c2cs35264h

  View details for Web of Science ID 000307779600021

  View details for PubMedID 22890548

• Formation of Single-Chain Polymer Nanoparticles in Water through Host-Guest Interactions ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Appel, E. A., Dyson, J., del Barrio, J., Walsh, Z., Scherman, O. A. 2012; 51 (17): 4185-4189

  View details for DOI 10.1002/anie.201108659

  View details for Web of Science ID 000303001000037

  View details for PubMedID 22422662

• Sustained Release of Proteins from a High-Water-Content Supramolecular Polymer Hydrogel Biomaterials Appel, E. A., Loh, X., Jones, S. T., Dreiss, C. A., Scherman, O. A. 2012; 33: 4646-4652
• Postpolymerization Modification of Hydroxyl-Functionalized Polymers with Isocyanates MACROMOLECULES Biedermann, F., Appel, E. A., del Barrio, J., Gruendling, T., Barner-Kowollik, C., Scherman, O. A. 2011; 44 (12): 4828-4835

  View details for DOI 10.1021/ma2008018

  View details for Web of Science ID 000291895700037

• Supramolecular gold nanoparticle-polymer composites formed in water with cucurbit[8]uril CHEMICAL COMMUNICATIONS Coulston, R. J., Jones, S. T., Lee, T., Appel, E. A., Scherman, O. A. 2011; 47 (1): 164-166

  Abstract

  A gold nanoparticle-polymer composite material has been prepared in water using cucurbit[8]uril as a supramolecular "handcuff" to hold together viologen-functionalised gold nanoparticles and a naphthol-functionalised acrylamide copolymer.

  View details for DOI 10.1039/c0cc03250f

  View details for Web of Science ID 000285068300008

  View details for PubMedID 20842297

• Supramolecular Cross-Linked Networks via Host-Guest Complexation with Cucurbit[8]uril JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Appel, E. A., Biedermann, F., Rauwald, U., Jones, S. T., Zayed, J. M., Scherman, O. A. 2010; 132 (40): 14251-14260

  Abstract

  The ability to finely tune the solution viscosity of an aqueous system is critical in many applications ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative medicine, controlled drug delivery, and 'green' self-healing materials. Herein we demonstrate the use of the macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers with high binding constants (K(a) > 10(11)-10(12) M(-2)) leading to a supramolecular hydrogel. Multivalent copolymers were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous, colored supramolecular hydrogel with the cross-link density being easily controlled through CB[8] addition. Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli. Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second guest dissociation rate constant (k(d)) of 1200 s(-1) for the ternary complex. These materials exhibited intermediate mechanical properties at 5 wt % in water (plateau modulus = 350-600 Pa and zero-shear viscosity = 5-55 Pa·s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution viscosity.

  View details for DOI 10.1021/ja106362w

  View details for Web of Science ID 000282660100064

  View details for PubMedID 20845973

• Hierarchical Supermolecular Structures for Sustained Drug Release SMALL Tan, J. P., Kim, S. H., Nederberg, F., Appel, E. A., Waymouth, R. M., Zhang, Y., Hedrick, J. L., Yang, Y. Y. 2009; 5 (13): 1504-1507

  View details for DOI 10.1002/smll.200801756

  View details for Web of Science ID 000267903200003

  View details for PubMedID 19326354

• Simple Approach to Stabilized Micelles Employing Miktoarm Terpolymers and Stereocomplexes with Application in Paclitaxel Delivery BIOMACROMOLECULES Nederberg, F., Appel, E., Tan, J. P., Kim, S. H., Fukushima, K., Sly, J., Miller, R. D., Waymouth, R. M., Yang, Y. Y., Hedrick, J. L. 2009; 10 (6): 1460-1468

  Abstract

  A simple and versatile approach to miktoarm co- and terpolymers from carbonate functional oligomers is described. The key building block employed is a carboxylic acid functional cyclic carbonate, derived from 2,2-bis(methylol)propionic acid, that was readily coupled to a hydroxyl functional monomethylether poly(ethylene glycol) oligomer. Ring-opening of the cyclic carbonate using functional amines generates a carbamate linkage bearing a functional group capable of initiating either controlled radical or ring-opening polymerization, together with a primary hydroxyl group for ring-opening polymerization. Two tandem polymerization steps were possible which add the second two arms, thus generating the targeted ABC miktoarm terpolymer. The resulting amphiphilic miktoarm terpolymers containing poly(D- and L-lactide) formed polylactide stereocomplexes in the bulk. In aqueous solution, the stereocomplex mixture of Y-shaped miktoarm copolymers, poly(ethylene glycol)-poly(D-lactide)-poly(D-lactide) and poly(ethylene glycol)-poly(L-lactide)-poly(L-lactide), or the stereoblock miktoarm poly(ethylene glycol)-poly(D-lactide)-poly(L-lactide) form stabilized micelles with a significantly lower critical micelle concentration than those derived from conventional stereo regular linear or Y-shaped amphiphiles. This simple and versatile approach provides a useful synthetic route to complex macromolecular architectures that can assemble into stable micelles. These micelles provide high capacity for loading of the anticancer drug paclitaxel and possess narrow size distribution as well as unique structure, leading to sustained and near zero-ordered release of drug without significant initial burst.

  View details for DOI 10.1021/bm900056g

  View details for Web of Science ID 000266860700018

  View details for PubMedID 19385659