Eric A. Appel is an Assistant Professor of Materials Science & Engineering at Stanford University. He received his BS in Chemistry and MS in Polymer Science from Cal Poly, San Luis Obispo. Eric performed his MS thesis research with Robert D. Miller and James L. Hedrick at the IBM Almaden Research Center in San Jose, CA. He then obtained his PhD in Chemistry working in the lab of Dr. Oren A. Scherman in the Melville Laboratory for Polymer Synthesis at the University of Cambridge. His PhD research focused on the preparation of dynamic and stimuli-responsive supramolecular polymeric materials. For his PhD work, Eric was the recipient of the Jon Weaver PhD prize from the Royal Society of Chemistry and a Graduate Student Award from the Materials Research Society. Upon graduating from Cambridge in 2012, he was awarded a National Research Service Award from the NIH (NIBIB) and pursued a Wellcome Trust Postdoctoral Fellowship at MIT working with Robert S. Langer on the development of supramolecular biomaterials for drug delivery and tissue engineering. During his post-doctoral work, he received a Margaret A. Cunningham Immune Mechanisms in Cancer Research Award. He recently received a Terman Faculty Fellowship from the School of Engineering at Stanford University.
Assistant Professor, Materials Science and Engineering
Assistant Professor (By courtesy), Pediatrics - Endocrinology and Diabetes
Center Fellow (By courtesy), Stanford Woods Institute for the Environment
Member, Cardiovascular Institute
Faculty Fellow, Stanford ChEM-H
Member, Wu Tsai Neurosciences Institute
Honors & Awards
Junior Faculty Development Award, American Diabetes Association (2018-2022)
Hellman Faculty Fellowship, Hellman Fellows Fund (2016-2017)
PhRMA Research Starter Grant, PhRMA Foundation (2016-2017)
Margaret A. Cunningham Immune Mechanisms in Cancer Research Award, Proctor Foundation (2015-2016)
Wellcome Trust Fellowship, Wellcome Trust (2013-2017)
National Research Service Award, National Institute of Biomedical Imaging and Bioengineering (2013-2016)
Graduate Student Award, Materials Research Society (2012)
Jon Weaver PhD Prize, Royal Society of Chemistry of the United Kingdom (2013)
Postdoc, MIT, Bioengineering
Ph.D., University of Cambridge, Chemistry (2012)
M.S., Cal Poly, SLO, Polymer Science (2008)
B.S., Cal Poly, SLO, Chemistry (2008)
E.A. Appel. "United StatesMethods of producing moldable hydrogels and uses thereof", Leland Stanford Junior University
E.A. Appel, J.Y. Woo, L.M. Stapleton. "United StatesAdhesion Prevention with Shear-thinning Polymeric Hydrogels", Leland Stanford Junior University
Eric Appel. "United StatesCo-formulation of Amylin Analogues with Insulin Analogues", E.A. Appel, B. Buckingham, D. Maahs, C. Maikawa, G. Agmon
J.L. Hedrick, E.A. Appel, R.D. Miller, F. Nederberg, R.M. Waymouth. "United StatesMethods for Making Multi-Branched Polymers", Leland Stanford Junior University
E.A. Appel, J.L. Hedrick, V.Y. Lee, R.D. Miller, J. Sly. "United StatesStar Polymers, Methods of Preparation Thereof, and Uses Thereof", IBM
M.J. Webber, E.A. Appel, R. Langer, D.G. Anderson. "United StatesSupramolecular Modification of Proteins", Massachusetts Institute of Technology
O.A. Scherman, E.A. Appel, X.J. Loh, F. Biedermann, M. Rowland. "United KingdomCucurbituril-Based Hydrogels", Cambridge Enterprises Limited
E.A. Appel, M.W. Tibbitt, R. Langer. "United StatesShear-thinning Self-healing Networks", Massachusetts Institute of Technology
E. Abo-Hamed, O.A. Scherman, E.A. Appel. "United KingdomHydrogen Storage and Catalysts", The inventors
Y. Dong, W. Wang, E.A. Appel, B.C. Tang, M.J. Webber, O. Veiseh, K. Xue, R. Langer, D.G. Anderson. "United StatesPolymers, Hydrogels, and Uses Thereof", Massachusetts Institute of Technology
O.A. Scherman, E.A. Appel, T.L. Hughes. "United StatesViscous Wellbore Fluids", Schlumberger Technology Corp
Current Research and Scholarly Interests
The underlying theme of the Appel Lab at Stanford University integrates concepts and approaches from supramolecular chemistry, natural/synthetic materials, and biology. We aim to develop supramolecular biomaterials that exploit a diverse design toolbox and take advantage of the beautiful synergism between physical properties, aesthetics, and low energy consumption typical of natural systems. Our vision is to use these materials to solve fundamental biological questions and to engineer advanced healthcare solutions.
- Biomaterials for Drug Delivery
BIOE 385, MATSCI 385 (Win)
- Materials Science Colloquium
MATSCI 230 (Aut, Win, Spr)
- Organic and Biological Materials
MATSCI 190, MATSCI 210 (Spr)
Independent Studies (9)
- Bioengineering Problems and Experimental Investigation
BIOE 191 (Win, Spr)
- Directed Investigation
BIOE 392 (Aut, Win, Spr, Sum)
- Directed Study
BIOE 391 (Aut, Win)
- Graduate Independent Study
MATSCI 399 (Aut, Win, Spr)
- Master's Research
MATSCI 200 (Aut, Win, Spr)
- Ph.D. Research
MATSCI 300 (Aut, Win, Spr)
- Practical Training
MATSCI 299 (Win, Spr, Sum)
- Undergraduate Independent Study
MATSCI 100 (Spr)
- Undergraduate Research
MATSCI 150 (Aut, Win, Spr)
- Bioengineering Problems and Experimental Investigation
Prior Year Courses
- Biomaterials for Drug Delivery
BIOE 385, MATSCI 385 (Aut)
- Materials Science Colloquium
MATSCI 230 (Aut, Win, Spr)
- Organic and Biological Materials
MATSCI 190, MATSCI 210 (Spr)
- Soft Matter in Biomedical Devices, Microelectronics, and Everyday Life
BIOE 158, MATSCI 158 (Win)
- Materials Science Colloquium
MATSCI 230 (Aut, Win, Spr)
- Organic and Biological Materials
MATSCI 190, MATSCI 210 (Spr)
- Soft Matter in Biomedical Devices, Microelectronics, and Everyday Life
BIOE 158, CHEMENG 160, MATSCI 158 (Win)
- Materials Science Colloquium
MATSCI 230 (Win, Spr)
- Organic and Biological Materials
MATSCI 190, MATSCI 210 (Spr)
- Soft Matter in Biomedical Devices, Microelectronics, and Everyday Life
BIOE 158, CHEMENG 160, MATSCI 158 (Win)
- Biomaterials for Drug Delivery
Doctoral Dissertation Reader (AC)
Alyssa Cartwright, Camila Arantxa Cendra Guinassi, Sean Friedowitz, Nicolo Maganzini, Caitlyn Miller, Anton Molina, Riley Suhar, Ian Thompson, Jiechen Wang, Yang Wang
Postdoctoral Faculty Sponsor
Julie Baillet, Santiago Correa, Hector Lopez, Andrea d'Aquino
Doctoral Dissertation Advisor (AC)
Emily Gale, Abby Grosskopf, Carolyn Jons, John Klich, Celine Liong, Caitlin Maikawa, Joseph Mann, Emily Meany, Catie Meis, Leslee Nguyen, Ben Ou, Olivia Saouaf
Master's Program Advisor
Kushagra Agarwal, Pranjal Agarwal, Esteban Baeza Ruz, Brigitte Schmittlein, Jihan Zhuang
Doctoral Dissertation Co-Advisor (AC)
Gloria Chyr, Huada Lian
Postdoctoral Research Mentor
Santiago Correa, Hector Lopez
Rachel Huang, Catie Meis, Felipe de Quesada
Physical networks from entropy-driven non-covalent interactions.
2021; 12 (1): 746
Physical networks typically employ enthalpy-dominated crosslinking interactions that become more dynamic at elevated temperatures, leading to network softening. Moreover, standard mathematical frameworks such as time-temperature superposition assume network softening and faster dynamics at elevated temperatures. Yet, deriving a mathematical framework connecting the crosslinking thermodynamics to the temperature-dependent viscoelasticity of physical networks suggests the possibility for entropy-driven crosslinking interactions to provide alternative temperature dependencies. This framework illustrates that temperature negligibly affects crosslink density in reported systems, but drastically influences crosslink dynamics. While the dissociation rate of enthalpy-driven crosslinks is accelerated at elevated temperatures, the dissociation rate of entropy-driven crosslinks is negligibly affected or even slowed under these conditions. Here we report an entropy-driven physical network based on polymer-nanoparticle interactions that exhibits mechanical properties that are invariant with temperature. These studies provide a foundation for designing and characterizing entropy-driven physical crosslinking motifs and demonstrate how these physical networks access thermal properties that are not observed in current physical networks.
View details for DOI 10.1038/s41467-021-21024-7
View details for PubMedID 33531475
A Quantitative Description for Designing the Extrudability of Shear-Thinning Physical Hydrogels.
Physically associated hydrogels (PHs) capable of reversible transitions between solid and liquid-like states have enabled novel strategies for 3D printing, therapeutic drug and cell delivery, and regenerative medicine. Among the many design criteria (e.g., viscoelasticity, cargo diffusivity, biocompatibility) for these applications, engineering PHs for extrudability is a necessary and critical design criterion for the successful application of these materials. As the development of many distinct PH material systems continues, a strategy to determine the extrudability of PHs a priori will be exceedingly useful for reducing costly and time-consuming trial-and-error experimentation. Here, a strategy to determine the property-function relationships for PHs in injectable drug delivery applications at clinically relevant flow rates is presented. This strategy-validated with two chemically and physically distinct PHs-reveals material design spaces in the form of Ashby-style plots that highlight acceptable, application-specific material properties. It is shown that the flow behavior of PHs does not obey a single shear-thinning power law and the implications for injectable drug delivery are discussed. This approach for generating design criteria has potential for streamlining the screening of PHs and their utility in applications with varying geometrical (i.e., needle diameter) and process (i.e., flow rate) constraints.
View details for DOI 10.1002/mabi.202000295
View details for PubMedID 33164332
An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients.
Science translational medicine
2020; 12 (550)
Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput-controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.
View details for DOI 10.1126/scitranslmed.aba6676
View details for PubMedID 32611683
Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity.
ACS central science
2020; 6 (10): 1800–1812
Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.
View details for DOI 10.1021/acscentsci.0c00732
View details for PubMedID 33145416
View details for PubMedCentralID PMC7596866
A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs.
Nature biomedical engineering
Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbituril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.
View details for DOI 10.1038/s41551-020-0555-4
View details for PubMedID 32393892
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
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
A Multiscale Model for Solute Diffusion in Hydrogels.
2019; 52 (18): 6889–97
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
Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier.
Nature biomedical engineering
2019; 3 (8): 611–20
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
Modulation of injectable hydrogel properties for slow co-delivery of influenza subunit vaccine components enhance the potency of humoral immunity.
Journal of biomedical materials research. Part A
Vaccines are critical for combating infectious diseases across the globe. Influenza, for example, kills roughly 500,000 people annually worldwide, despite annual vaccination campaigns. Efficacious vaccines must elicit a robust and durable antibody response, and poor efficacy often arises from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery influenza vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the co-delivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique dynamic physical characteristics whereby physicochemically distinct influenza hemagglutinin antigen and a toll-like receptor 7/8 agonist adjuvant could be co-delivered over prolonged timeframes that were tunable through simple alteration of the gel formulation. We show a relationship between hydrogel physical properties and the resulting immune response to immunization. When administered in mice, hydrogel-based vaccines demonstrated enhancements in the magnitude and duration of humoral immune responses compared to alum, a widely used clinical adjuvant system. We found stiffer hydrogel formulations exhibited slower release and resulted in the greatest improvements to the antibody response while also enabling significant adjuvant dose sparing. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.
View details for DOI 10.1002/jbm.a.37203
View details for PubMedID 33955657
Translational Applications of Hydrogels.
Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposes-they can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast during imaging, protect tissues or organs during radiotherapy, and improve the biocompatibility of medical implants. These capabilities make hydrogels useful for many distinct and pressing diseases and medical conditions and even for less conventional areas such as environmental engineering. In this review, we cover the major capabilities of hydrogels, with a focus on the novel benefits of injectable hydrogels, and how they relate to translational applications in medicine and the environment. We pay close attention to how the development of contemporary hydrogels requires extensive interdisciplinary collaboration to accomplish highly specific and complex biological tasks that range from cancer immunotherapy to tissue engineering to vaccination. We complement our discussion of preclinical and clinical development of hydrogels with mechanical design considerations needed for scaling injectable hydrogel technologies for clinical application. We anticipate that readers will gain a more complete picture of the expansive possibilities for hydrogels to make practical and impactful differences across numerous fields and biomedical applications.
View details for DOI 10.1021/acs.chemrev.0c01177
View details for PubMedID 33938724
Full closed loop open-source algorithm performance comparison in pigs with diabetes.
Clinical and translational medicine
2021; 11 (4): e387
Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal announcements. Overall time-in-range (70-180mg/dl) for AndroidAPS was 58% ± 5%, while time-in-range for Loop was 35% ± 5%. The effect of the algorithms on time-in-range differed between meals and overnight. During the overnight monitoring period, pigs had an average time-in-range of 90% ± 7% when on AndroidAPS compared to 22% ± 8% on Loop. Time-in-hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/-0.8)% in hypoglycemia compared to 10% (+3/-6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.
View details for DOI 10.1002/ctm2.387
View details for PubMedID 33931977
- Controlling properties of thermogels by tuning critical solution behaviour of ternary copolymers dagger POLYMER CHEMISTRY 2021
- Enhanced Humoral Immune Response by High Density TLR Agonist Presentation on Hyperbranched Polymers ADVANCED THERAPEUTICS 2021
Injectable Supramolecular Polymer-Nanoparticle Hydrogels for Cell and Drug Delivery Applications.
Journal of visualized experiments : JoVE
These methods describe how to formulate injectable, supramolecular polymer-nanoparticle (PNP) hydrogels foruse as biomaterials. PNP hydrogels are composed of two components: hydrophobically modified cellulose as the network polymer and self-assembled core-shell nanoparticles that act as non-covalent cross linkers through dynamic, multivalent interactions. These methods describe both the formation of these self-assembled nanoparticles through nanoprecipitation as well as the formulation and mixing of the two components to form hydrogels with tunable mechanical properties. The use of dynamic light scattering (DLS) and rheology to characterize the quality of the synthesized materials is also detailed. Finally, the utility of these hydrogels for drug delivery, biopharmaceutical stabilization, and cell encapsulation and delivery is demonstrated through in vitro experiments to characterizedrug release, thermal stability, and cell settling and viability. Due to its biocompatibility, injectability, and mild gel formation conditions, this hydrogel system is a readily tunable platform suitable for a range of biomedical applications.
View details for DOI 10.3791/62234
View details for PubMedID 33616104
Seasonal Impact of Phosphate-Based Fire Retardants on Soil Chemistry Following the Prophylactic Treatment of Vegetation.
Environmental science & technology
A preventative treatment of fire retardants at high-risk locales can potentially stop a majority of wildfires. For example, over 80% of wildfire ignitions in California occur at high-risk locales such as adjacent to roadsides and utility infrastructure. Recently a new class of ammonium polyphosphate retardants was developed with enhanced adherence and retention on vegetation to enable prophylactic treatments of these high-risk locals to provide season-long prevention of ignitions. Here, we compare three different ammonium (poly)phosphate-based wildland retardant formulations and evaluate their resistance to weathering and analyze their seasonal impact on soil chemistry following application onto grass. Soil samples from all three treatments demonstrated no changes in soil pH and total soil carbon and nitrogen amounts. Total soil phosphorus amounts increased by 2-3* following early precipitation, always remaining within typical topsoil amounts, and returned to the same level as control soil before spring. Available indices of ammonium, nitrate, and phosphate levels for all groups were elevated compared to the untreated control samples, again remaining within typical topsoil ranges across all time points and rainfall amounts evaluated. Microbial activity was decreased, potentially because the addition of available nutrients from retardant application reduced the need for organic decomposition. These results demonstrate that the application of ammonium (poly)phosphate-based retardants does not alter soil chemistry beyond typical topsoil compositions and are thus suitable for use in prophylactic wildfire prevention strategies.
View details for DOI 10.1021/acs.est.0c05472
View details for PubMedID 33529000
- Dynamic Hydrogels for Prevention of Post-Operative Peritoneal Adhesions ADVANCED THERAPEUTICS 2021
Prolonged Codelivery of Hemagglutinin and a TLR7/8 Agonist in a Supramolecular Polymer-Nanoparticle Hydrogel Enhances Potency and Breadth of Influenza Vaccination.
ACS biomaterials science & engineering
The sustained release of vaccine cargo has been shown to improve humoral immune responses to challenging pathogens such as influenza. Extended codelivery of antigen and adjuvant prolongs germinal center reactions, thus improving antibody affinity maturation and the ability to neutralize the target pathogen. Here, we develop an injectable, physically cross-linked polymer-nanoparticle (PNP) hydrogel system to prolong the local codelivery of hemagglutinin and a toll-like receptor 7/8 agonist (TLR7/8a) adjuvant. By tethering the TLR7/8a to a NP motif within the hydrogels (TLR7/8a-NP), the dynamic mesh of the PNP hydrogels enables codiffusion of the adjuvant and protein antigen (hemagglutinin), therefore enabling sustained codelivery of these two physicochemically distinct molecules. We show that subcutaneous delivery of PNP hydrogels carrying hemagglutinin and TLR7/8a-NP in mice improves the magnitude and duration of antibody titers in response to a single injection vaccination compared to clinically used adjuvants. Furthermore, the PNP gel-based slow delivery of influenza vaccines led to increased breadth of antibody responses against future influenza variants, including a future pandemic variant, compared to clinical adjuvants. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.
View details for DOI 10.1021/acsbiomaterials.0c01496
View details for PubMedID 33404236
Engineering biopharmaceutical formulations to improve diabetes management.
Science translational medicine
2021; 13 (578)
Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the management of diabetes. With controlled delivery, these formulations could improve closed-loop glycemic control.
View details for DOI 10.1126/scitranslmed.abd6726
View details for PubMedID 33504649
miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury.
Basic research in cardiology
2021; 116 (1): 19
Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.
View details for DOI 10.1007/s00395-021-00858-8
View details for PubMedID 33742276
A fluorescence sandwich immunoassay for the real-time continuous detection of glucose and insulin in live animals.
Nature biomedical engineering
Biosensors that continuously measure circulating biomolecules in real time could provide insights into the health status of patients and their response to therapeutics. But biosensors for the continuous real-time monitoring of analytes in vivo have only reached nanomolar sensitivity and can measure only a handful of molecules, such as glucose and blood oxygen. Here we show that multiple analytes can be continuously and simultaneously measured with picomolar sensitivity and sub-second resolution via the integration of aptamers and antibodies into a bead-based fluorescence sandwich immunoassay implemented in a custom microfluidic chip. After an incubation time of 30s, bead fluorescence is measured using a high-speed camera under spatially multiplexed two-colour laser illumination. We used the assay for continuous quantification of glucose and insulin concentrations in the blood of live diabetic rats to resolve inter-animal differences in the pharmacokinetic response to insulin as well as discriminate pharmacokinetic profiles from different insulin formulations. The assay can be readily modified to continuously and simultaneously measure other blood analytes in vivo.
View details for DOI 10.1038/s41551-020-00661-1
View details for PubMedID 33349659
- Lipid Nanodiscs via Ordered Copolymers CHEM 2020; 6 (10): 2782–95
Highly Branched Polydimethylacrylamide Copolymers as Functional Biomaterials.
Controlled radical polymerization of vinyl monomers with multivinyl cross-linkers leads to the synthesis of highly branched polymers with controlled spatial density of functional chain ends. The resulting polymers synthesized in this manner have large dispersities resulting from a mixture of unreacted primary chains, low molecular weight branched species, and high molecular weight highly branched species. Through the use of fractional precipitation, we present a synthetic route to high molecular weight highly branched polymers that are absent of low molecular weight species and that contain reactivity toward amines for controlled postpolymerization modification. The controlled spatial density of functional moieties on these high molecular weight macromolecular constructs enable new functional biomaterials with the potential for application in regenerative medicine, immunoengineering, imaging, and controlled drug delivery.
View details for DOI 10.1021/acs.biomac.0c00539
View details for PubMedID 32786733
Site-selective modification of proteins using cucurbituril as supramolecular protection for N-terminal aromatic amino acids.
Organic & biomolecular chemistry
Cucurbit[7,8]urils are known to form inclusion complexes with aromatic amino acids, hosting the hydrohobic side chains within the cavity and adjacent cations within the portal of the macrocyclic host. Here we show that cucurbituril binding with N-terminal phenylalanine significantly reduces the nucleophilicity of the amine, likely due to an increase in stability of the ammonium ion, rendering it unreactive at neutral pH. Using insulin as a model protein, we show that this supramolecular protection strategy can drive selectivity of N-terminal amine conjugation away from the preferred B chain N-terminal phenylalanine towards the A chain N-terminal glycine. Cucurbituril can therefore be used as a supramolecular protecting group for site-selective protein modification.
View details for DOI 10.1039/d0ob01004a
View details for PubMedID 32459261
- Reply to Santin et al.: Viscoelastic retardant fluids enable treatments to prevent wildfire on landscapes subject to routine ignitions. Proceedings of the National Academy of Sciences of the United States of America 2020
A human mission to Mars: Predicting the bone mineral density loss of astronauts.
2020; 15 (1): e0226434
A round-trip human mission to Mars is anticipated to last roughly three years. Spaceflight conditions are known to cause loss of bone mineral density (BMD) in astronauts, increasing bone fracture risk. There is an urgent need to understand BMD progression as a function of spaceflight time to minimize associated health implications and ensure mission success. Here we introduce a nonlinear mathematical model of BMD loss for candidate human missions to Mars: (i) Opposition class trajectory (400-600 days), and (ii) Conjunction class trajectory (1000-1200 days). Using femoral neck BMD data (N = 69) from astronauts after 132-day and 228-day spaceflight and the World Health Organization's fracture risk recommendation, we predicted post-mission risk and associated osteopathology. Our model predicts 62% opposition class astronauts and 100% conjunction class astronauts will develop osteopenia, with 33% being at risk for osteoporosis. This model can help in implementing countermeasure strategies and inform space agencies' choice of crew candidates.
View details for DOI 10.1371/journal.pone.0226434
View details for PubMedID 31967993
Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment.
Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) adjuvants, which interact with immune cells to elicit potent immune activation. Despite their potential, use of many TLRa compounds has been limited clinically due to their extreme potency and lack of pharmacokinetic control, causing systemic toxicity from unregulated systemic cytokine release. Herein, we overcome these shortcomings by generating poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles (NPs) presenting potent TLR7/8a moieties on their surface. The NP platform allows precise control of TLR7/8a valency and resulting surface presentation through self-assembly using nanoprecipitation. We hypothesize that the pharmacokinetic profile of the NPs minimizes systemic toxicity, localizing TLR7/8a presentation to the tumor bed and tumor-draining lymph nodes. In conjunction with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade, peritumoral injection of TLR7/8a NPs slows tumor growth, extends survival, and decreases systemic toxicity in comparison to the free TLR7/8a in a murine colon adenocarcinoma model. These NPs constitute a modular platform for controlling pharmacokinetics of immunostimulatory molecules, resulting in increased potency and decreased toxicity.
View details for DOI 10.1021/acs.biomac.0c00812
View details for PubMedID 32816460
Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues.
2020; 3 (1)
Current "fast-acting" insulin analogues contain amino acid modifications meant to inhibit dimer formation and shift the equilibrium of association states toward the monomeric state. However, the insulin monomer is highly unstable and current formulation techniques require insulin to primarily exist as hexamers to prevent aggregation into inactive and immunogenic amyloids. Insulin formulation excipients have thus been traditionally selected to promote insulin association into the hexameric form to enhance formulation stability. This study exploits a novel excipient for the supramolecular PEGylation of insulin analogues, including aspart and lispro, to enhance the stability and maximize the prevalence of insulin monomers in formulation. Using multiple techniques, it is demonstrated that judicious choice of formulation excipients (tonicity agents and parenteral preservatives) enables insulin analogue formulations with 70-80% monomer and supramolecular PEGylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Comparatively, commercial "fast-acting" formulations contain less than 1% monomer and remain stable for only 10 h under the same stressed aging conditions. This simple and effective formulation approach shows promise for next-generation ultrafast insulin formulations with a short duration of action that can reduce the risk of post-prandial hypoglycemia in the treatment of diabetes.
View details for DOI 10.1002/adtp.201900094
View details for PubMedID 32190729
View details for PubMedCentralID PMC7079736
MRBLES 2.0: High-throughput generation of chemically functionalized spectrally and magnetically encoded hydrogel beads using a simple single-layer microfluidic device.
Microsystems & nanoengineering
2020; 6: 109
The widespread adoption of bead-based multiplexed bioassays requires the ability to easily synthesize encoded microspheres and conjugate analytes of interest to their surface. Here, we present a simple method (MRBLEs 2.0) for the efficient high-throughput generation of microspheres with ratiometric barcode lanthanide encoding (MRBLEs) that bear functional groups for downstream surface bioconjugation. Bead production in MRBLEs 2.0 relies on the manual mixing of lanthanide/polymer mixtures (each of which comprises a unique spectral code) followed by droplet generation using single-layer, parallel flow-focusing devices and the off-chip batch polymerization of droplets into beads. To streamline downstream analyte coupling, MRBLEs 2.0 crosslinks copolymers bearing functional groups on the bead surface during bead generation. Using the MRBLEs 2.0 pipeline, we generate monodisperse MRBLEs containing 48 distinct well-resolved spectral codes with high throughput (>150,000/min and can be boosted to 450,000/min). We further demonstrate the efficient conjugation of oligonucleotides and entire proteins to carboxyl MRBLEs and of biotin to amino MRBLEs. Finally, we show that MRBLEs can also be magnetized via the simultaneous incorporation of magnetic nanoparticles with only a minor decrease in the potential code space. With the advantages of dramatically simplified device fabrication, elimination of the need for custom-made equipment, and the ability to produce spectrally and magnetically encoded beads with direct surface functionalization with high throughput, MRBLEs 2.0 can be directly applied by many labs towards a wide variety of downstream assays, from basic biology to diagnostics and other translational research.
View details for DOI 10.1038/s41378-020-00220-3
View details for PubMedID 33299601
- Towards brain-tissue-like biomaterials. Nature communications 2020; 11 (1): 3423
Engineered biomaterials for heart disease.
Current opinion in biotechnology
2020; 66: 246–54
Ischemic heart disease is the most common type of heart disease, responsible for roughly 10 million deaths worldwide annually. While standard clinical interventions have resulted in improved patient outcomes, access to small diameter vessels required for cardiovascular interventions, and long-term patient mortality rates associated with eventual heart failure, remain critical challenges. In this current opinion piece we discuss novel methodologies for the advancement of vascular grafts, cardiac patches, and injectable drug delivery depot technologies as they relate to treatment of ischemic heart disease, including bilayered conduits, acellular bioactive extracellular matrix (ECM) scaffolds, and protease-responsive hydrogel delivery platforms. We address the motivation for innovation and current limitations in the field of engineered biomaterials for myocardial ischemia therapeutics and interventions.
View details for DOI 10.1016/j.copbio.2020.08.008
View details for PubMedID 33011453
Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model.
2020; 127: 154974
Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.
View details for DOI 10.1016/j.cyto.2019.154974
View details for PubMedID 31978642
Injectable supramolecular polymer-nanoparticle hydrogels enhance human mesenchymal stem cell delivery.
Bioengineering & translational medicine
2020; 5 (1): e10147
Stem cell therapies have emerged as promising treatments for injuries and diseases in regenerative medicine. Yet, delivering stem cells therapeutically can be complicated by invasive administration techniques, heterogeneity in the injection media, and/or poor cell retention at the injection site. Despite these issues, traditional administration protocols using bolus injections in a saline solution or surgical implants of cell-laden hydrogels have highlighted the promise of cell administration as a treatment strategy. To address these limitations, we have designed an injectable polymer-nanoparticle (PNP) hydrogel platform exploiting multivalent, noncovalent interactions between modified biopolymers and biodegradable nanoparticles for encapsulation and delivery of human mesenchymal stem cells (hMSCs). hMSC-based therapies have shown promise due to their broad differentiation capacities and production of therapeutic paracrine signaling molecules. In this work, the fundamental hydrogel mechanical properties that enhance hMSC delivery processes are elucidated using basic in vitro models. Further, in vivo studies in immunocompetent mice reveal that PNP hydrogels enhance hMSC retention at the injection site and retain administered hMSCs locally for upwards of 2 weeks. Through both in vitro and in vivo experiments, we demonstrate a novel scalable, synthetic, and biodegradable hydrogel system that overcomes current limitations and enables effective cell delivery.
View details for DOI 10.1002/btm2.10147
View details for PubMedID 31989036
View details for PubMedCentralID PMC6971438
- Structural considerations for physical hydrogels based on polymer-nanoparticle interactions MOLECULAR SYSTEMS DESIGN & ENGINEERING 2020; 5 (1): 401–7
Universal Scaling Behavior during Network Formation in Controlled Radical Polymerizations.
2019; 52 (24): 9456–65
Despite the ubiquity of branched and network polymers in biological, electronic, and rheological applications, it remains difficult to predict the network structure arising from polymerization of vinyl and multivinyl monomers. While controlled radical polymerization (CRP) techniques afford modularity and control in the synthesis of (hyper)branched polymers, a unifying understanding of network formation providing grounded predictive power is still lacking. A current limitation is the inability to predict the number and weight average molecular weights that arise during the synthesis of (hyper)branched polymers using CRP. This study addresses this literature gap through first building intuition via a growth boundary analysis on how certain environmental cues (concentration, monomer choice, and cross-linker choice) affect the cross-link efficiency during network formation through experimental gel point measurements. We then demonstrate, through experimental gel point normalization, universal scaling behavior of molecular weights in the synthesis of branched polymers corroborated by previous literature experiments. Moreover, the normalization employed in this analysis reveals trends in the macroscopic mechanical properties of networks synthesized using CRP techniques. Gel point normalization employed in this analysis both enables a polymer chemist to target specific number and weight average molecular weights of (hyper)branched polymers using CRP and demonstrates the utility of CRP for gel synthesis.
View details for DOI 10.1021/acs.macromol.9b02109
View details for PubMedID 31894160
- Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues ADVANCED THERAPEUTICS 2019
- A Nanoparticle Platform for Improved Potency, Stability, and Adjuvanticity of Poly(I:C) ADVANCED THERAPEUTICS 2019
- Injectable supramolecular polymer-nanoparticle hydrogels enhance human mesenchymal stem cell delivery BIOENGINEERING & TRANSLATIONAL MEDICINE 2019
- Block copolymer composition drives function of self-assembled nanoparticles for delivery of small-molecule cargo JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY 2019; 57 (12): 1322–32
- A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering ADVANCED HEALTHCARE MATERIALS 2019; 8 (5)
A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering.
Advanced healthcare materials
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
Injectable Polymer-Nanoparticle Hydrogels for Local Immune Cell Recruitment.
The ability to engineer immune function has transformed modern medicine, highlighted by the success of vaccinations and recent efforts in cancer immunotherapy. Further directions in programming the immune system focus on the design of immunomodulatory biomaterials that can recruit, engage with, and program immune cells locally in vivo. Here, we synthesized shear-thinning and self-healing polymer-nanoparticle (PNP) hydrogels as a tunable and injectable biomaterial platform for local dendritic cell (DC) recruitment. PNP gels were formed from two populations of poly(ethylene glycol)-block-polylactide (PEG-b-PLA) NPs with the same diameter but different PEG brush length (2 or 5 kDa). PEG-b-PLA NPs with the longer PEG brush exhibited improved gel formation following self-assembly and faster recovery after shear-thinning. In all cases, model protein therapeutics were released via Fickian diffusion in vitro, and minor differences in the release rate between the gel formulations were observed. PNP hydrogels were loaded with the DC cytokine CCL21 and injected subcutaneously in a murine model. CCL21-loaded PNP hydrogels recruited DCs preferentially to the site of injection in vivo relative to non-CCL21-loaded hydrogels. Thus, PNP hydrogels comprise a simple and tunable platform biomaterial for in vivo immunomodulation following minimally invasive subcutaneous injection.
View details for DOI 10.1021/acs.biomac.9b01129
View details for PubMedID 31682423
- Non-Newtonian Polymer-Nanoparticle Hydrogels Enhance Cell Viability during Injection MACROMOLECULAR BIOSCIENCE 2019; 19 (1)
Non-Newtonian Polymer-Nanoparticle Hydrogels Enhance Cell Viability during Injection.
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 2018: 205–31
Supramolecular polymeric biomaterials.
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
Engineering the Mechanical Properties of Polymer Networks with Precise Doping of Primary Defects.
ACS applied materials & interfaces
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
2017; 139 (37): 12985–93
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 cucurbituril (CB) 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 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
2017; 29 (19)
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
2017; 18 (4): 1434-1439
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 2017; 9: 42217-42224
Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics.
2017; 8 (1): 777
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 2017; 29: e1606944
- Distinguishing the Respective Mechanical Contributions of Polymer and Supramolecular Dynamics in Transiently Crosslinked Polymeric Networks Polymer Chemistry 2017; 8: 5336-5343
- Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes Journal of the American Chemical Society 2017; 139: 12985-12993
- Supramolecular Polymeric Biomaterials Biomaterials Science 2017; 6: 10-37
- Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics Nature Communication 2017; 8: e777
Supramolecular PEGylation of biopharmaceuticals
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (50): 14189-14194
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 cucurbituril (CB)-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 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
2016; 113 (50): 14255-14260
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
2016; 32 (34): 8743-8747
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
2016; 28 (15): 2939-2943
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 2016; 15 (1): 13-26
- Injectable Self-Healing Glucose Responsive Hydrogels with pH-Regulated Mechanical Properties Advanced Materials 2016; 28: 86-91
- Water soluble, biodegradable amphiphilic polymeric nanoparticles and the molecular environment of hydrophobic encapsulates: Consistency between simulation and experiment POLYMER 2015; 79: 255-261
Formation of Cucurbituril-Based Supramolecular Hydrogel Beads Using Droplet-Based Microfluidics
2015; 16 (9): 2743-2749
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, cucurbituril (CB). The microdroplets were formed containing diluted hydrogel precursors in solution, including the functional polymers and CB, in a microfluidic device. Subsequent evaporation of water from collected microdroplets concentrated the contents, driving the formation of the CB-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 2015; 4 (8): 848-852
- A Facile Method for the Stain-Free Visualization of Hierarchical Structures with Electron Microscopy JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY 2015; 53 (7): 842-845
Non-Cell-Adhesive Substrates for Printing of Arrayed Biomaterials
ADVANCED HEALTHCARE MATERIALS
2015; 4 (4): 501-505
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 2015; 6: e6295
The control of cargo release from physically crosslinked hydrogels by crosslink dynamics
2014; 35 (37): 9897-9903
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 cucurbituril 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 2014; 13 (3): 231-232
- Activation Energies Control Macroscopic Properties of Supramolecular Crosslinked Materials Angewandte Chemie International Edition 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 2014; 24: 2706-2713
- Dynamically crosslinked materials via recognition of amino acids by cucurbituril JOURNAL OF MATERIALS CHEMISTRY B 2013; 1 (23): 2904-2910
- Triggered insulin release studies of triply responsive supramolecular micelles POLYMER CHEMISTRY 2012; 3 (11): 3180-3188
- Ultra-High Water-Content Hydrogels from Renewable Resources Exhibiting Multi-Stimuli Responsiveness J. Am. Chem. Soc. 2012; 134: 11767-11773
Triply Triggered Doxorubicin Release From Supramolecular Nanocontainers
2012; 13 (1): 84-91
The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbituril (CB) 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
2012; 48 (49): 6163-6165
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. 2012; 50: 181-186
- Metastable single-chain polymer nanoparticles prepared by dynamic cross-linking with nor-seco-cucurbituril CHEMICAL SCIENCE 2012; 3 (7): 2278-2281
- Enhanced Stability and Activity of Temozolomide in Primary GBM Cells with Cucurbit[n]uril Chemical Communications 2012: 9843-9845
Supramolecular polymeric hydrogels
CHEMICAL SOCIETY REVIEWS
2012; 41 (18): 6195-6214
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 2012; 51 (17): 4185-4189
- Sustained Release of Proteins from a High-Water-Content Supramolecular Polymer Hydrogel Biomaterials 2012; 33: 4646-4652
- Postpolymerization Modification of Hydroxyl-Functionalized Polymers with Isocyanates MACROMOLECULES 2011; 44 (12): 4828-4835
Supramolecular gold nanoparticle-polymer composites formed in water with cucurbituril
2011; 47 (1): 164-166
A gold nanoparticle-polymer composite material has been prepared in water using cucurbituril 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 Cucurbituril
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2010; 132 (40): 14251-14260
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 cucurbituril (CB) 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) or naphthoxy derivatives (good second guests for CB). 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 addition. Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB/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 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 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 2009; 5 (13): 1504-1507
Simple Approach to Stabilized Micelles Employing Miktoarm Terpolymers and Stereocomplexes with Application in Paclitaxel Delivery
2009; 10 (6): 1460-1468
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