Bing Xu, Brandeis University
Shawn Chen, National Institute of Biomedical Imaging and Bioengineering
Honggang Cui, The Johns Hopkins University
Brandeis University, MRSEC, MilliporeSigma (Sigma-Aldrich Materials Science), Cell Press
BM1.1: Young Investigators
Monday AM, November 28, 2016
Hynes, Level 1, Room 102
9:30 AM - BM1.1.01
Molecular Engineering of Polymeric Materials for Innovative Medical Solutions
Shiyi Zhang 1
1 Shanghai Jiao Tong University Shanghai ChinaShow Abstract
The innovative engineering methodologies that allow for the preparation of functional polymer materials by simple strategies have significant fundamental interest and enormous potential to address unmet clinical needs. This talk will focus on the design principle that is simple, novel and applicable, for the development of polymeric materials for distinct applications. In treating three pulmonary diseases, two degradable nanoparticle systems based on one functional polyphosphoester will be discussed, with the highlight of the simple, efficient and versatile chemistry involved in each stage of the production. For the prolonged gastric retention with improved safety profile, the development of three polymer systems will be presented, giving the emphasis to a novel pH-responsive supramolecular gel that helped to achieve a 5-7 days gastric retention in a large animal model promising the application to solve the poor medication adherence.
9:45 AM - BM1.1.02
Refilling Drug-Eluting Hydrogels through Systemic Administration of Inert Prodrugs
Yevgeny Brudno 1 , David Mooney 1 , Michael Aizenberg 1
1 Harvard University Cambridge United StatesShow Abstract
Drug-eluting material systems have proven useful in a variety of clinical settings, including preventing restenosis with stenting, treating cancer and enhancing wound healing. These systems benefit from tunable drug release kinetics, continuous drug release, and local delivery, which together provide spatiotemporal control over drug availability and diminish drug toxicity. I will describe our efforts to overcome one major hurdle to widespread use of drug-eluting systems in vivo – that they carry a finite depot of drug and require invasive procedures to refill. I will describe a technology to modify materials so as to capture blood-circulating drug refills, allowing for repeated refilling of the depots for local release. Bioorthogonal chemistry and nucleic acid-based methods for selective depot replenishment will be discussed. Repeated drug refilling and release improved outcomes in cancer models and allowed for selective drug homing in models of lower limb ischemia and osteomyelitis. Refillable drug delivery devices that enable repeated and spatiotemporally controlled drug release may have clinical applications in cancer therapy, wound healing, immunotherapy, and drug-eluting vascular grafts and stents.
10:00 AM - BM1.1.03
Synthesis, Assembly and Characterization of POMaC Elastomer Used in Biodegradable Strain and Pressure Sensor for Tendons Recovery Monitoring
Clementine Boutry 1 , Anais Legrand 1 , Bob Schroeder 2 , Zhenan Bao 1
1 Stanford University Stanford United States, 2 Queen Mary University of London London United KingdomShow Abstract
New biosensors, entirely made of biodegradable materials and designed for being implanted in the human body, are currently emerging. These sensors open the field for new therapeutic applications, without need for a second surgery to remove the devices after their predefined period of use. The development of new spatiotemporally-controlled biomaterials is required for being used in such sensors.
In the present work, we investigate the use of the biodegradable elastomer POMaC in a new stretchable strain and pressure sensor developed in the context of tendons recovery monitoring. This biomaterial is used both as a key structural and packaging material. Various synthesis approaches, combining exposure to UV irradiation (photocrosslinked POMaC) and oven curing (polycondensation crosslinked POMaC), are evaluated. The material response to long-term mechanical cycling before and after in vitro degradation in PBS solution is also investigated. We show in particular that the tensile modulus and resistance to cycling of POMaC can be adjusted using an appropriate synthesis approach, to better fit the final therapeutic application. Moreover, a strategy for the final packaging of the sensor based on sealing with UV-exposed prePOMaC is investigated. We show efficient packaging properties, with negligible sensor signal variation after hours of immersion in PBS solution.
Our investigations on the synthesis and assembly of this biodegradable elastomer permit the development of a sensor with high sensitivity, fast response time and long-term stability, allowing its use in the context of tendon tissues recovery monitoring.
10:15 AM - BM1.1.04
Design of Self-Assembling Bio-Inks for Cell-Based 3D Printing
Karen Dubbin 1 , Yuki Hori 1 , Kazuomori Lewis 1 , Sarah Heilshorn 1
1 Stanford University Stanford United StatesShow Abstract
Despite the rise of 3D printing of thermoplastics both in industry and the general public, a key limitation preventing the widespread use of cell-based 3D printing is the lack of suitable bio-inks that are cell-compatible and have the required properties for printing. Current commonly used biomaterials have distinct limitations when used as a bio-ink including difficulty maintaining a homogeneous cell suspension, avoiding cell damage during extrusion, customizing the printed matrix properties to facilitate cell-matrix interactions, and printing within a bath to prevent cell dehydration while preserving high print resolution. We designed a new family of tunable biomaterials specifically designed for cell-based 3D printing. These hydrogel-based bio-inks are produced from a blend of engineered recombinant proteins and peptide-modified, alginate polysaccharides. The use of engineered proteins provides control of ligand presentation for cellular attachment and signaling, while the alginate enables cyto-compatible, rapid crosslinking within a hydrated sample. This design is advantageous due to the ability of the bio-ink to undergo two-stages of crosslinking: (i) weak, peptide-based, self-assembly to homogeneously encapsulate cells within the ink cartridge, to prevent cell settling in the print cartridge, and to mechanically shield the cells from damaging forces during extrusion and (ii) electrostatic crosslinking of alginate upon printing within a calcium bath to rapidly stabilize the construct and to tailor the final mechanical properties for optimal cell-matrix interactions with full cell hydration.
10:30 AM - BM1.1.05
Enzyme-Triggered Peptide Folding and Self-Assembly of Phosphopeptides
Junfeng Shi 1 , Joel Schneider 1
1 National Cancer Institute Frederick United StatesShow Abstract
Enzymatic transformation is essential mechanism for signal transduction in the cell. In this work, we report the use of enzyme to regulate the peptide folding and self-assembly, thus induced the supramolecular hydrogelation. HPLC and LC-MS analysis identify that the designed phosphopeptide is the substrate of protein phosphatase. Circular dichroism (CD) spectra show the enzyme is able to modulate the rate of peptide folding and self-assembly. Electron microscopy reveals that the enzymatic reaction converts the unfolding peptide to protofibrils, and nanofibrils. Rheology confirmed the formation of stable hydrogel. As the first case of enzyme-triggered peptide folding and self-assembly, this work not only provide an approach to generate sophisticated materials, but also offer insight how to modulate the interaction of peptide and cellular environment.
10:45 AM - BM1.1.06
Programmable Self-Assembly of Peptide-Polymer Hybrid Hydrogels
Daniel Aili 1 , Christopher Aronsson 1 , Robert Selegard 1 , Staffan Danmark 1
1 Department of Physics, Chemistry and Biology Linköping University Linköping SwedenShow Abstract
Hydrogels are attractive as cell carriers and bioinks in injection-based therapies and 3D bioprinting as they can protect cells from damaging shear forces during the injection or the additive manufacturing process. Hydrogels can also offer extracellular matrix mimicking environments for both tissue engineering applications and 3D cell culture. Different applications and processing conditions require hydrogels with significantly different properties. To this end, we have established a flexible modular strategy for fabrication of supramolecular hydrogels that offer means to tightly control both the self-assembly process as well as the mechanical and structural properties of the hydrogels. A set of different modular peptide-polymer hybrids have been synthesized using de novo designed peptides that dimerize and fold into well-defined alpha-helical motifs.[1,2] The peptides were grafted to four-arm PEGs and hyaluronic acid using click chemistry. Self-assembly of physical hydrogels was triggered by peptide dimerization and folding. The properties of the hydrogels can be rationally and dynamically modulated using peptides with different affinities for dimerization and by complexation of cations. In addition to offer means to dynamically assemble and disassemble the hydrogels, the storage modulus of the hydrogels can be varied from about 200 to 1000 Pa when using peptides with affinities for dimerization spanning from the nanomolar to the picomolar range. This novel strategy thus enables fabrication of dynamic stimuli-responsive soft materials for biomedical applications with properties that can be programmed using defined and tunable peptide-mediated interactions.
 D. Aili, F.-I. Tai, K. Enander, L. Baltzer, B. Liedberg, “Self-assembling fibers and nano-rings from disulphide linked helix-loop-helix polypeptides”, Angew. Chem., Int. Ed., 2008, 47, 5554-5556.
 C. Aronsson, S. Dånmark, F. Zhou, P. Öberg, K. Enander, H. Su, D. Aili, "Self-Sorting Heterodimeric Coiled Coil Peptides with Defined and Tuneable Self-Assembly Properties”, Sci. Rep., 2015, 5, 14063; doi:10.1038/srep14063.
 S. Dånmark, C. Aronsson, D. Aili, "Tailoring Supramolecular Peptide-Poly(ethylene glycol) Hydrogels by Coiled Coil Self-Assembly and Self-Sorting", Biomacromolecules, 2016, 17, 2260–2267.
11:30 AM - BM1.1.07
Tie Up Actin Cytoskeleton to Suppress Cancer Metastasis
Ye Zhang 1
1 Okinawa Institute of Science and Technology Kunigami-gun JapanShow Abstract
Cancer therapeutics that are designed to inhibit metastasis by targeting signaling pathways have not proven to be effective in clinical trials because cancer cells can modify their migration mechanism in response to different conditions. To cope with the dynamic transform, we developed a novel access to inhibit metastasis by tying up actin cytoskeleton through physical interaction for restriction of cancer cell migration by mechanical force. We designed and synthesized multi-dimensional luminescent molecules that self-assemble into nanoscale morphologies and selectively forms extracellular matrix (ECM) on ovarian cancer cell filopodia. The ECM fixate adhesion receptors and block their redistribution. The actin skeleton linked with adhesion receptors were tied up results into physically restrained cancer cell deformability and migration.
11:45 AM - BM1.1.08
Three-Dimensional Micro-Patterning of Biodegradable Polymers for Controlled Drug Delivery
Thanh Nguyen 1 , Robert Langer 2
1 University of Connecticut Storrs United States, 2 Koch Institute Massachusetts Institute of Technology Cambridge United StatesShow Abstract
The ability to create three-dimensional (3D) biomaterial structures with high resolution and aspect-ratio enables significant biomedical applications. Numerous methods including 3D printing technologies have been developed to fabricate microdevices and particles with well-defined 3D structure. However, these techniques are limited in terms of shape, aspect ratio, scalability, and either require potentially toxic additives or lack the fine resolution demanded for some applications. Here we present a novel method - termed StampEd Assembly of polymer Layers (SEAL) - which can create versatile 3D microstructures of pure biodegradable polymers such as poly-lactic-glycolid acid (PLGA), and use this method to create a robust drug delivery platform with unique pulsatile release kinetics. SEAL combines computer-chip manufacturing technologies, micromolding, and a novel layer-by-layer assembly process to fabricate 3D microstructures of biomedically relevant materials without processing additives. We employed SEAL to create PLGA/drug core-shell microparticles for controlled drug delivery applications. These SEAL-fabricated particles exhibited delayed, pulsatile release for up to 2 months, which is particularly exciting to the development of single-injection vaccines. We also demonstrate the use of SEAL for creating particles using an enteric polymer that exhibits pH-dependent release following oral administration for selective colon targeting. Finally, we show that the SEAL method is compatible with sensitive biomacromolecules such as the highly instable inactivated polio vaccine (IPV). As such, SEAL is a powerful method that can supplement 3D printing when high resolution, high-throughput, and biocompatibility are required for proper device function. We anticipate many applications from this platform technology such as the creation of 3D tissue synthetic scaffolds with well-defined microstructure and injectable drug delivery devices with unique targeting or release kinetics based on complex 3D architecture and/or material composition.
12:00 PM - BM1.1.09
Membrane-Embedded Nanoparticles Facilitate the Rapid Translocation of Charged Species across Lipid Bilayers
Reid Van Lehn 1
1 University of Wisconsin-Madison Madison United StatesShow Abstract
Functionalized nanoparticles (NPs) are versatile materials with heterogeneous surface properties that can be engineered to mimic typical biological macromolecules. Recently, a particular class of charged, amphiphilic NPs were shown to embed within lipid bilayers to obtain configurations similar to transmembrane proteins. Embedding involves the dynamic rearrangement of NP surface properties to adapt to the bilayer environment. This behavior is surprising, however, because the NPs must also transport charged groups across the hydrophobic bilayer core within short timescales to stably insert into the bilayer. Here, we use atomistic molecular dynamic simulations to gain a mechanistic understanding of this rapid charge transport. We show that charged species grafted to a bilayer-embedded scaffold – such as the NPs or multispanning transmembrane proteins – translocate across the bilayer more rapidly than isolated ions. We further study the system features that affect translocation rates in order to identify methods to facilitate the translocation of specific charged groups. This work suggests design guidelines for synthetic materials capable of transporting charged, soluble small molecules across bilayers, which may be useful for ferrying therapeutic molecules to the interior of cells for drug delivery applications.
12:15 PM - BM1.1.10
Micro-Robotic Devices for Localized Actuation and Selective Positioning
in the Gastrointestinal Tract
Jinxing Li 1 , Soracha Kun Thamphiwatana 1 , Liangfang Zhang 1 , Joseph Wang 1
1 University of California, San Diego La Jolla United StatesShow Abstract
Robotics deals with automated machines that can locomote themselves and operate tasks in various environments over many orders of magnitudes in scale. One of the most inspiring goals is the construction of smart and powerful nanorobotic systems for operation in the human body. However, viscous forces dominate inertial forces at such small scales, leading to the “low-Reynolds number challenge” for nanoscale propulsion. This presentation will discuss newly created multi-functional nanorobots which can overcome this challenge by utilizing local chemical reactions to achieve efficient movement in biological matrices. With selectively engineered materials, the nanorobots possess numerous attractive properties, including biocompatibility, biodegradability, high loading capacity, and the ability to autonomously release of payloads ‘on-the-fly’. The increased capabilities and sophistication of these tiny robots hold considerable promise for a variety of biomedical applications ranging from drug delivery to minimally invasive surgery. Particularly, using zinc-based micromotors as model robots, we reported the first in vivo study of artificial micromotors in a living organism. Such in vivo evaluation examines the distribution, retention, cargo delivery, and acute toxicity profile of synthetic motors in mouse stomachs via oral administration. We demonstrate that the acid-driven propulsion in the stomach effectively enhances the binding and retention of the motors as well as of cargo payloads on the stomach wall.
In another design, we demonstrate an enteric micromotor system capable of precise positioning and controllable retention in desired segments of the Gastrointestinal (GI) tract. These motors, consisting of magnesium-based tubular micromotors coated with an enteric polymer layer, act as a robust nanobiotechnology tool for site-specific GI delivery. The micromotors can deliver payload to particular location via dissolution of their enteric coating to activate their propulsion at the target site towards localized tissue penetration and retention. Our work is anticipated to significantly advance the emerging field of biomedical nanorobots and to open the door to in vivo evaluation and clinical applications of these biomedical nanorobots.
 Artificial Micromotors in the Mouse’s Stomach: A Step toward in Vivo Use of Synthetic Motors. ACS Nano, 2015, 9, 117–123.
 An Enteric Micromotor can Selectively Position and Spontaneously Propel in the Gastrointestinal Tract. Submitted to Nature Mater.
12:30 PM - *BM1.1.11
Targeting Siglecs with a Sialic Acid-Decorated Nanoparticle Abrogates Inflammation
Michelle Greene 1 , Shaun Spence 1 , Francois Fay 3 , Emily Hams 2 , Sean Saunders 2 , Umar Hamid 1 , Marianne Fitzgerald 1 , Cecilia O'Kane 1 , Denise Fitzgerald 1 , James Johnston 4 , Padraic Fallon 2 , Daniel McAuley 1 , Adrien Kissenpfennig 1 , Christopher Scott 1
1 Queen's University Belfast Belfast United Kingdom, 3 Icahn School of Medicine at Mount Sinai New York United States, 2 Trinity College Dublin Dublin Ireland, 4 Amgen Inc. Thousand Oaks United StatesShow Abstract
Sepsis is the most common cause of death in hospitalised patients, with an annual incidence of 1 million cases and 200,000 deaths in the USA alone1. Moreover, approximately 25% of sepsis cases are complicated by the development of Acute Respiratory Distress Syndrome (ARDS), which also incurs a high mortality rate2. Both sepsis and ARDS are characterised by excessive pro-inflammatory responses, for which there are currently no effective treatments. Instead, supportive therapy within the critical care setting forms the mainstay of treatment and so novel therapeutic strategies are urgently required.
Given the fundamental role of sialic acid-binding immunoglobulin-like lectins (Siglecs) in modulating immune responses, these receptors represent potential anti-inflammatory targets in sepsis and ARDS. In particular, previous studies demonstrated that engagement of murine Siglec-E negatively regulates Toll-like receptor (TLR)-mediated inflammation3. In this current work, a novel sialylated nanoparticle was developed to actively target Siglec receptors expressed on macrophages, with potential therapeutic utility in sepsis and ARDS.
Polylactic-co-glycolic acid (PLGA) nanoparticles were formulated via a salting-out approach and decorated with α2,8 N-acetylneuraminic acid targeting moieties (α2,8 NANA-NP). Physicochemical characterisation of α2,8 NANA-NP revealed an average diameter of 152 ± 13 nm and a polydispersity index of 0.16 ± 0.08, indicative of a monodisperse size distribution. When tested in cultures of lipopolysaccharide (LPS)-stimulated murine macrophages, α2,8 NANA-NP potently inhibited the secretion of pro-inflammatory tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) cytokines in a Siglec-E dependent manner. Therapeutic efficacy was also confirmed in both systemic and pulmonary in vivo models of inflammation, where α2,8 NANA-NP enhanced survival rates, attenuated neutrophil infiltration, inhibited pro-inflammatory cytokine production and augmented anti-inflammatory IL-10 levels, amongst other readouts. Mechanistic studies uncovered that the functionality of α2,8 NANA-NP was both macrophage- and IL-10-dependent, given the loss of efficacy in clodronate-treated and IL-10 knockout mice, respectively. Moreover, the translational potential of this nanoplatform was demonstrated in cultures of primary human monocytes and macrophages, and also in a human ex vivo lung perfusion model, where α2,8 NANA-NP significantly attenuated LPS-induced inflammation.
Collectively, these findings demonstrate that the targeted cross-linking and activation of Siglecs can be exploited therapeutically in models of sepsis and ARDS. In addition to these syndromes, α2,8 NANA-NP may also find potential application in other conditions underpinned by aberrant pro-inflammatory signalling.
1 Immunity 2014, 40(4), 463-75
2 Intensive Care Med 2004, 30(1), 51-61
3 J Immunol 2009, 183(12), 7703-9
Monday PM, November 28, 2016
Hynes, Level 1, Room 102
2:30 PM - *BM1.2.01
Surface-Engineered Nanocrystals—Synthesis, Assembly, and Applications
Peng Wang 1 , Qirong Xiong 1 , Jiajing Zhou 1 , Hongwei Duan 1
1 Nanyang Technological University Singapore SingaporeShow Abstract
Inorganic nanocrystals with unique optical, electronic, magnetic, and structural properties have found widespread use in biosensing, bioimaging, surface-enhanced spectroscopy, drug delivery, and catalysis. Organization of the nanocrystals into superstructures often leads to collective properties that are different from those in the discrete units. Controlled assembly of the nanocrystals is currently under intense research and development for a wide range of applications in electronic devices, biosensing, and drug delivery. This talk summarizes our recent results in developing plasmonic and magnetic superstructures for cancer diagnostic and therapeutic applications. Metallic nanostructures with localized surface plasmon resonance arising from the collective excitation of conduction electrons LSPR spectral shifts induced by interparticle plasmonic coupling have attracted considerable research interest in controlled assembly of plasmonic nanoparticles, which, in conjugation with responsive “smart” coatings, has been exploited to detect a wide range of molecular targets and environmental factors. We have developed versatile approaches to engineer nanoparticle surface with polymer ligands and assemble the nanoparticles into well-defined structures in aqueous dispersion and at oil-water interfaces, which hold great promise in traceable drug delivery, surface enhanced Raman scattering, and biosensing. We have developed a new approach, built upon the use of mussel-inspired polydopamine, to preparing robust multifunctional nanochains of magnetic nanoparticles with readily tailorable surface chemistry for applications in different environments. We have found that the resulting rigid magnetic nanochains undertake localized rotation when placed in a spinning magnetic field, making it possible for the nanochains to serve as nanomotors and nanoscale stir bars to promote molecular transport and mixing in extremely small spaces, which is highly desirable for applications in microreactors and ultrasmall sensing devices. More interestingly, conjugation of DNA aptamer ligands of specific receptors overexpressed on cancer cell membrane led to targeted nanochains that bound to selective cancer cells, and subsequent exposure to a spinning magnetic field caused pronounced cell death via magnetolysis of cell membranes.
3:00 PM - *BM1.2.02
Membrane Fusion Delivery of siRNA Using Nanoparticle Nanocapsules—Applications of Direct Cytosol Delivery In Vitro and In Vivo
Vincent Rotello 1
1 University of Massachusetts Amherst United StatesShow Abstract
Therapeutic delivery of proteins and nucleic acids is a difficult goal. Of the many challenges in the delivery process, perhaps the most demanding is providing these biologics with access to the cytosol. Most delivery strategies employ endosomal uptake, requiring endosomal escape for the payload biologics to be effective. In our research, we have developed an alternative strategy that uses nanoparticle-stabilized nanocapsules (NPSCs) to deliver proteins and nucleic acids (siRNA and DNA) directly to the cytosol. These NPSCs use a membrane fusion process to bypass the endosomal pathway, providing highly effective payload delivery. The direct access to the cytosol makes NPSCs effective tools for therapeutic delivery, particularly in conjunction with intracellular targeting. Mechanistic studies of NPSCs and their use in vivo for immunomodulation will be discussed.
3:30 PM - BM1.2.03
Diagnosis of Tropical Viruses Using Gold Nanoparticles in Lateral Flow Immunoassays
Helena de Puig Guixe 1 , Marc Carre-Camps 1 , Irene Bosch 1 , Kimberly Hamad-Schifferli 2 , Lee Gehrke 1
1 Massachusetts Institute of Technology Cambridge United States, 2 University of Massachusetts Boston United StatesShow Abstract
In the currently ongoing outbreak, zika (ZIKV) is co-circulating with dengue virus (DENV) and chikungunya (CHKV), which also share the same vector, the mosquitoes Aedes aegypti and Aedes albopictus. Infection by any of the three diseases leads to similar flu-like symptoms, complicating proper disease management. Point-of-care diagnostics are critically needed for rapid response in patient treatment, resource allocation and to predict epidemics. Lateral flow devices are ideal candidates to diagnose diseases in remote areas because they can be operated by non-experts, are cheap, portable, and do not require electric power to be operated. We present results on a machine-readable multiplexed lateral flow device for the detection of several tropical disease markers. By making the device readable by a mobile phone, it is able to provide real-time epidemiologic data to monitor disease distribution. The device relies on a lateral flow immunoassay, which uses capillary flow and the accumulation of ligand-coated nanoparticles to detect the presence of target proteins. Gold nanoparticle-antibody conjugates are critical to ensure that the device will have enough sensitivity to detect the illness even at low concentrations of target protein, such as in early stages of the disease. The sensitivity of lateral flow devices greatly depends on the nature of the ligand-target pair and their binding thermodynamics on the nanoparticle interface. We engineer the nanoparticle shape, size, surface chemistry, and biofunctionalization in order to lower the overall detection limit of the device. The nanoparticle surface properties and biofunctionalization are characterized by gel electrophoresis, DLS, and fluorescence/optical spectroscopy in conjunction with chemical displacement.
These new, effective, low-cost devices would be very useful in developing countries, but also for developed countries, where they can contribute to lowering the overall cost of healthcare and enable widespread use for other applications such as crowdsourcing.
3:45 PM - BM1.2.04
Overcoming the Blood-Brain Barrier—Post-Resection Drug Delivery to Glioblastoma Multiforme Using Supramolecular Hydrogels
Oren Scherman 1
1 University of Cambridge Cambridge United KingdomShow Abstract
Glioblastoma multiforme (GBM) is a devastating disease with extremely poor survival statistics owing to high rates of disease recurrence. Typical treatment of patients diagnosed with GBM is surgical resection of accessible tumorous tissue followed by radiotherapy and chemotherapy. Chemotherapeutic choices are limited on account of most drugs’ poor propensity to cross the blood brain barrier. Systemic treatment with unspecified concentrations of chemotherapy is ineffective and risks adverse side effects. An alternative approach involves the use of supramolecular hydrogels, which can be readily loaded with therapeutic agents for sustained localized delivery.
High water content (99%) and biocompatible hydrogels based on hyaluronic acid (HA) backbones developed within the our group rely on non-covalent cross-links between polymers, formed by utilizing the dynamic host-guest chemistry of cucurbituril (CB). In this system, amino acid derived “guest moieties” that are bound to HA polymers complex in a 2:1 fashion with a “host-molecule” CB, creating multiple cross-links resulting in gelation. As these complexes are non-covalent they can be broken with mechanical stress and instantly reformed upon relaxation due to fast binding kinetics. This material can encapsulate water-soluble drug compounds, be injected through a needle and rapidly self heal preventing any cargo loss. Tissue strength and elasticity can also be replicated in the hydrogel properties by simply modulating the polymer or CB concentration.
In vitro release studies of various drug compounds encapsulated in the hydrogel have been performed and efficacy against multiple patient-derived human GBM cell lines determined. In vivo experiments with a mouse model are currently underway. We envisage that access to such drug-delivery technology will lead to clinical studies in the near future with an overall goal to prevent disease recurrence and improve patient survival rates.
4:30 PM - *BM1.2.05
Intra-Mitochondrial Assembly of Peptide Amphiphiles as Novel Cancer Therapy
Ja-Hyoung Ryu 1 , M. T. Jeena 1
1 Ulsan National Institute of Science and Technology Ulsan Korea (the Republic of)Show Abstract
Mitochondria are vital organelles to eukaryotic cells. Since damage and dysfunction of mitochondria cause cell apoptosis, mitochondrial specific targeting gains lots of interest in cancer therapeutics. Delivery of cancer specific drug into mitochondria has already been established in recent years by various approaches such as conjugation of drug molecule with mitochondria targeting ligands. However, mitochondrial damage due to self-assembly of amphiphilic molecules inside mitochondria still remains challenging. It is already well proved that peptides have intrinsic ability to form various self-assembled structure such as fiber, ribbon, sphere and vesicle. Study of selfassembling behavior of peptide inside the live cell organelle is least established till now. Here, we introduce mitochondria targeting short peptide containing sequence as Py-FFK(TPP) [Py = Pyrenebutyric acid, TPP = Triphenyl phosphonium, F = phenyl alanine, K = lysine]. The TPP moiety can provide mitochondrial specific targeting to mitochondria and pyrene butyric acid provides both a self-assembling building block and a fluorescent probe. The peptide exhibited well-defined morphology in water, high mitochondrial localization and cancer-cell cytotoxicity. The improved mitochondrial localization of peptide is attributed to the TPP moiety and high hydrophobicity. Under the mitochondrial environment the peptide can undergo aggregation due to increased concentration above the critial aggregation cocnetraion (40 uM). The self-assembly of the peptide induces mitochondrial stress and thereby generates ROS and causes cell death.
5:00 PM - *BM1.2.06
Durable Bio-Inert Coating for Biomedical Applications
Xinhua Li 1
1 Nano Terra, Inc Cambridge United StatesShow Abstract
A surface that can suppress nonspecific binding and resist biofouling is critical for the performance of biomedical and analytical devices. A number of bio-inert chemical functions has been identified using self-assembled monolayers (SAM). Significant effort has been made to apply these chemistries in the development of biomedical products; however, a durable and easy to use bio-inert coating is still lacking. We developed coating formulations for the treatment of various surfaces to reduce protein binding and cell adhesion. We demonstrated that the bio-inert coating is stable under gamma irradiation and the treated plastic surface strongly resists adhesion of various cells including 3T3, MCF-7 and MDA-MB-231.
5:30 PM - *BM1.2.07
The Art of Falling Apart—Exploiting Nanomaterial Disassembly for Health Sciences
Adah Almutairi 1
1 University of California, San Diego La Jolla United StatesShow Abstract
This presentation will cover several recent advances in the development of light- and inflammation-responsive polymers as tools for biological research and drug delivery. In the area of light-responsive materials, four exciting strategies will be discussed: chemically amplifying the light signal to accelerate degradation, single-photon absorption of red light, novel upconverting structures enabling efficient conversion of more biologically compatible wavelengths, and application of previously reported polymers to the treatment of various diseases. The chemical amplification strategy relies on phototriggered unmasking of acidic groups that hydrolyze adjacent ketals, which overcomes ketals’ requirement of low pH for efficient degradation. Particles composed of the photocaged-acid/ ketal polymer degrade rapidly upon brief irradiation. The red light-degradable polymer incorporates a photocage not previously used in responsive materials, which cleaves in hydrophobic environments (unlike coumarins). Particles composed of this polymer, when subcutaneously injected and irradiated through tissue, release sufficient drug to significantly reduce carrageenan-induced paw inflammation in mice. Finally, we have evidence that a UV-degradable polymer (Fomina et al., J Am Chem Soc 2010) may be useful for the delivery of anti-angiogenics in the eye to treat macular degeneration. This strategy would preserve clinician control over dose timing while reducing the frequency of intravitreal injections. UV-degradable particles are stable in the eye for months and release a therapeutically effective dose of a small molecule anti-angiogenic; the irradiation required for release is well-tolerated by the eye.
Inflammation-responsive materials have been recently applied in the lab towards prevention of systemic inflammatory response syndrome (SIRS), treatment of Age Related Macular Degeneration with a single annual injection of a drug depot of VEGF Trap and detection of atherosclerotic plaque likely to disrupt and cause a heart attack or stroke. The first project involves delivering anti-inflammatory drugs in nanoparticles composed of our polythioether ketal (published in 2011). Using this strategy to deliver drugs 12 h prior to the bacterial toxin LPS reduces mortality in mice, suggesting that such nanoparticles could lead to a means of preventing organ failure following systemic infection or trauma. In the second, particles composed of dextran modified to be acid- and H2O2-responsive encapsulate Gd-based nanocrystals with unprecedented relaxivity, such that MRI signal is silenced until encountering inflammation, where particles loosen and nanocrystals can relax surrounding water molecules. This material’s ability to detect inflammation in vivo has been demonstrated using fluorescence activation;
Bing Xu, Brandeis University
Shawn Chen, National Institute of Biomedical Imaging and Bioengineering
Honggang Cui, The Johns Hopkins University
Brandeis University, MRSEC, MilliporeSigma (Sigma-Aldrich Materials Science), Cell Press
BM1.3: Responsive Materials
Tuesday AM, November 29, 2016
Hynes, Level 1, Room 102
9:30 AM - *BM1.3.01
From Nano to Micro and Back—Porphyrin Supramolecular Assembly for Cancer Imaging and Therapy
Gang Zheng 1 2
1 Department of Medical Biophysics University of Toronto Toronto Canada, 2 Princess Margaret Cancer Centre Toronto CanadaShow Abstract
Porphyrins are aromatic, organic, light-absorbing molecules that occur abundantly in nature, especially in the form of molecular self-assemblies. In 2011, we first discovered ‘porphysomes’, the self-assembled porphyrin-lipid nanoparticles with intrinsic multimodal photonic properties. The high-density porphyrin packing in bilayers enables the absorption and conversion of light energy to heat with extremely high efficiency, making them ideal candidates for photothermal therapy and photoacoustic imaging. Upon nanostructure dissociation, fluorescence and photodynamic activity of porphyrin monomers are restored. In addition, metal ions can be directly incorporated into the porphyrin building blocks of the preformed porphysomes thus unlocking their potential for PET and MRI. By changing the way porphyrin-lipid assembles, we developed HDL-like porphyrin nanoparticles (<20nm), porphyrin microbubbles (~2um), giant porphyrin vesicle (~100um) and hybrid porphyrin-gold nanoparticles, expanding the purview of porphyrin nanophotonics. By mimicking light harvest systems in photosynthetic bacteria, we introduced high-ordered porphyrin aggregates into supramolecular assemblies, resulting unprecedented photonic properties (e.g., reversible photoacoustic nanosensors). Such optical properties are also responsible for our discovery of the ultrasound-induced microbubbles-to-nanoparticle conversion phenomenon, which may open the door to bypass the enhanced permeability and retention effect when delivering drugs to tumors. By closing the nano-micro-nano loop, the simple yet intrinsic multimodal nature of porphyrin self-assembly represents a new frontier in cancer imaging and therapy.
10:00 AM - *BM1.3.02
From Filomicelles to 'Self' Recognition
Dennis Discher 1
1 University of Pennsylvania Philadelphia United StatesShow Abstract
Drug carriers have traditionally been spherical and designed to be more difficult to clear by using synthetic polymers that are hydrophilic such as PEG. We have explored filamentous shapes and also 'Self' signaling by peptides rather than PEG in various efforts to advance delivery science. In the first example (1), we sought to improve the delivery of aromatic drugs using micelles, particularly elongated filomicelles, and to that end aromatic groups were integrated into the hydrophobic block of a degradable di-block copolymer. These aromatic filomicelles were formed by self-directed assembly of amphiphilic di-block copolymer PEG-PBCL with suitable block ratios. Long and flexible worm-like micelles with an aromatic core were loaded with a common chemotherapeutic, Paclitaxel, for tests of release as well as effects on cancer cell lines in vitro and in vivo. For carcinoma lines in vitro and initial tests in vivo, flexible filomicelles with an aromatic core form an efficient drug delivery system that leads to higher cell death than previously reported systems, while inducing aneuploidy in surviving cells. In the second example, we explore better biomimickry with a 'Self' polypeptide. ‘Self’ cells are spared due to a polypeptide found on all cells that marks cells as ‘Self’, limiting their phagocytic clearance in vitro and in vivo – even when displayed on nanoparticles (2). Application to nanoparticle-based tumor imaging will be illustrated, as will application of the pathway to a cell-based therapy for cancer that exploits the ability of phagocytic cells to deeply penetrate into disease sites such as tumors.
(1) P.R. Nair, K. S. Anbazhagan, K.R. Spinler, M.R. Vakili A. Lavasanifar, and D.E. Discher. Filomicelles from aromatic di-block copolymers increase paclitaxel-induced tumor cell death and aneuploidy compared to aliphatic copolymer. Nanomedicine (May/June 2016).
(2) Rodriguez, P.L.; Harada, T.; Christian, D.A.; Pantano, D.A.; Tsai, R.K.; and Discher, D.E. Minimal 'Self' peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 2013 339: 971-975
10:30 AM - *BM1.3.03
Target-Enabled In Situ Ligand Assembly (TESLA) for Molecular Imaging Applications
Jianghong Rao 1
1 Stanford University Palo Alto United StatesShow Abstract
Molecules or materials that can undergo property changes upon stimulation by a specific biological target promise a myriad of biomedical applications. We have been interested in a molecular ligand scaffold that can undergo in situ assembly, ideally even in the complex in vivo settings, after the activation by a specific molecular target. This assembling process would transform small ligands to large molecular complexes even nanoparticles at the target-presenting location. We envision that such systems can then be applied to in vivo imaging of the target activity and drug delivery. There are many reported examples of these small ligand assemblies, however, few could take place in vivo. This presentation will introduce our effort in developing such a molecular ligand scaffold for in vivo molecular imaging. We call it Target-Enabled in Situ Ligand Assembly (TESLA).
Our TESLA platform is based on a biocompatible chemical condensation reaction between two chemical groups -- 1,2-aminothiol and 2-cyanobenzothiazole. TESLA ligands possess both groups and upon the activation by the target, TESLA ligands will chemically condense, followed by assembly and formation of nanoparticles. Several TESLA ligands have been designed to validate the strategy in vitro, in living cells under the control of pH, disulfide reduction and/or enzymatic cleavage. Importantly, this TESLA platform is also working in living animals, and I will describe examples of TESLA probes in image treatment-induced apoptosis in tumor cells in vivo with whole-body fluorescence imaging, positron emission tomography (PET), and magnetic resonance imaging (MRI). We expect more TESLA probes may be designed to image many molecular targets and enable medical applications beyond imaging.
11:30 AM - *BM1.3.04
Soft Functional Actuators—Biomemetics and Materials
George Whitesides 1
1 Department of Chemistry and Chemical Biology Harvard University Cambridge United StatesShow Abstract
Biology offers an endless variety of functional solutions to motion, sensing, and control. This talk will summarize parts of a program focused on biomimetic and biostimulated soft actuators.
12:00 PM - *BM1.3.05
Fuel-Driven Active Materials
Jan van Esch 1 , Wouter Hendriksen 1 , R. Eelkema 1 , G. Koper 1
1 Department of Chemical Engineering Delft University of Technology Delft NetherlandsShow Abstract
It remains a huge scientific challenge to understand and mimic the utilisation of chemical energy in
biological systems to achieve the highly adaptable organisation and sophisticated functions like
active transport, motility, self-repair, replication, and adaptability. The development of biomimetic
systems with similar energy consuming organisation and functions requires a radical departure
from equilibrium self-assembly approaches, towards out-of-equilibrium systems driven by the
continuous input of energy.
In our research we focus on the development of active materials driven by chemicals fuels. First, I
will discuss how active materials can result from the transient self-assembly of synthetic molecules,
driven by the consumption of a chemical fuel. In these materials, reaction rates and fuel levels,
instead of equilibrium composition, determine properties such as lifetime, stiffness, and selfregeneration
capability. Then, I will discuss our recent steps to achieve temporal and spatial over
fuel-driven self-assembly by the development of a chemical reaction network that allow for
feedback control. Such systems will form the basis for self-organising systems and for design and
construction of energy-consuming dynamic devices and materials.
 J. Boekhoven, A.M. Brizard, K.N. Kowlgi, G.J. Koper, R. Eelkema, J.H. van Esch, Angew. Chem. Int. Ed. 2010, 49
 J. Boekhoven, W. Hendriksen, G. Koper, R. Eelkema, J.H. van Esch, Science 2015, 349, 1075.
 A.G.L. Olive, N. Hakimin Abdullah, I. Ziemecka, E. Mendes, R. Eelkema, J.H. van Esch, Angew. Chem. Int. Ed. 2014,
12:30 PM - *BM1.3.06
Sankaran Thayumanavan 1
1 University of Massachusetts Amherst United StatesShow Abstract
Molecular designs that afford tunable supramolecular assemblies are of interest in a variety of applications, including drug delivery, sensing, and diagnostics. When these assemblies are nanoscopic in size and are responsive to specific stimulus, then the interests in these nanoscale scaffolds are even higher. We have developed amphiphilic supramolecular assemblies featuring these characteristics. In addition, these assemblies also can bind guest molecules efficiently and release them in response to specific triggers. Our utlimate goal is to develop design algorithms that lend themselves to predictably design nanoscale assembleis that respond to physical, chemical, or biological stimuli. Fundamental and translational implications of these findings would be numerous. We will report our progress in this area.
BM1.4: Materials for Medicine
Tuesday PM, November 29, 2016
Hynes, Level 1, Room 102
2:30 PM - *BM1.4.01
Translational Anticancer Nanomedicines through Controlled Chemistry
Jianjun Cheng 1 , Hua Wang 2
1 University of Illinois at Urbana-Champaign Urbana United States, 2 Harvard University Cambridge United StatesShow Abstract
Nanomedicine has offered new solutions for cancer diagnosis and therapy. However, the survival improvement offered by current nanomedicines remains modest. To further advance the development of nanomedicines, it is crucial to investigate and understand the correlation between the properties of nanomedicines (e.g., particle size) and biological responses to lay the foundation for the design of next-generation nanomedicines with optimum efficacy against cancers. Here, we report the development of size-controlled, monodisperse drug-silica nanoconjugates and systematically evaluation of their size effect on antitumor efficacy in both primary and metastatic tumor models. We find that the 50-nm nanoconjugate has the most optimal antitumor efficacy compared to 200- and 20-nm nanoconjugates. The silica-drug nanoconjugates show great potential for clinical applications because of their long-term biocompatibility and their capability of in vivo clearance. I will also present our recent progress of developing polymeric nanoparticles for cancer treatment.
3:00 PM - *BM1.4.02
Role of Nanoparticle Morphology in Crossing Biological Barriers
Samir Mitragotri 1
1 University of California, Santa Barbara Santa Barbara United StatesShow Abstract
Nanoparticles find intriguing applications in drug delivery. The morphological properties of nanoparticles can greatly impact their ability to cross biological barriers such as cell membranes, intestinal epithelium, blood brain barrier and vascular endothelium. Several recent studies, including our own, have outlined the role of particle morphology in their transport across these barriers and these studies have shown that particle morphology can indeed significantly alter their transport. In many cases, morphology operates in synergy with other parameters such as size and surface chemistry to bring out unique interplay between these key parameters. My talk will present an overview of the current understanding of the role of particle morphology in crossing these varied barriers and lessons learned about the similarity and differences in the role of particle morphology in determining delivery across the barriers.
3:30 PM - *BM1.4.03
Artificial Spores—Cytocompatible Nanoencapsulation of Individual Living Cells
Insung Choi 1
1 KAIST Daejeon Korea (the Republic of)Show Abstract
Nature has developed a fascinating strategy of cryptobiosis (“secret life”) for counteracting the stressful, and often lethal, environmental conditions that fluctuate sporadically over time. For example, certain bacteria sporulate to transform from a metabolically active, vegetative state to an ametabolic endospore state. The bacterial endospores, encased within tough biomolecular shells, withstand the extremes of harmful stressors, such as radiation, desiccation, and malnutrition, for extended periods of time and return to a vegetative state by breaking their protective shells apart when their environment becomes hospitable for living. Certain ciliates and even higher organisms, e.g., tardigrades, and others are also found to adopt a cryptobiotic strategy for their survival. A common feature of cryptobiosis is the structural presence of tough sheaths on cellular structures. However, most cells and cellular assemblies are not “spore-forming” and vulnerable to the outside threats. In particular, mammalian cells, enclosed with labile lipid bilayers, are highly susceptible to in vitro conditions in the laboratory and daily-life settings, making manipulation and preservation difficult outside of specialized conditions. The instability of living cells has been a main bottleneck to the advanced development of cell-based applications, such as cell therapy and cell-based sensors.
Recent studies have sought to chemically control and tailor the metabolic behaviors of non-spore-forming cells, as well as enhancing their viability against adverse environmental conditions, by forming thin (< 100 nm), tough artificial shells. These living “cell-in-shell” structures, called artificial spores (chemically-formed spore-like structures), enable control of cell division, protection against physical and chemical stresses, and cell-surface functionalizability, as well as providing the cells with exogenous properties that are not innate to the cells but are introduced chemically, such as magnetism, heat-tolerance, and UV-resistance. In addition, recent developments in the field have further advanced the synthetic tools available to the stage of chemical sporulation and germination of mammalian cells, where cytoprotective shells are formed on labile mammalian cells and broken apart on demand. Based on these demonstrations, the (degradable) cell-in-shell hybrids are anticipated to find their applications in various biomedical and bionanotechnological areas, such as cytotherapeutics, high-throughput screening, sensors, and biocatalysis, as well as providing a versatile research platform for single-cell biology.
4:30 PM - *BM1.4.04
Nanolayered Staged Delivery Approaches to Trauma Treatment and Wound Healing
Paula Hammond 2 1
2 Department of Chemical Engineering Massachusetts Institute of Technology Cambridge United States, 1 Koch Institute of Integrative Cancer Research Massachusetts Institute of Technology Cambridge United StatesShow Abstract
The use of alternating layer-by-layer (LbL) assembly enables a modular platform that can control release of therapeutics over a broad range of time scales, from several seconds to multiple months. We have developed systems that can address a range of different wound healing needs by taking advantage of this tunable platform and the ability to incorporate drugs programmed to release at a range of different rates and with staged release behavior. The nature of the layering process enables the incorporation of different drugs within different regions of the thin film architecture; the result is an ability to uniquely tailor both the independent release profiles of different therapeutics from the same film, and the order of release of molecules to targeted regions of the body.
This approach can be used to assemble thrombin protein and self-assembling peptides in a dry film conformal coating on a fully resorbable sponge to engage rapid hemostasis over a period of seconds to minutes; these systems can be stored for extended time periods in medical facilities, thus allowing rapid deployment by medical staff and a means of introducing more effective hemostasis for cases of internal bleeding and hemorrhage. The addition of the co-release of anti-infective agents such as vancomycin to these systems adds additional value to the soldier by preventing infection across a broad spectrum, which is particularly relevant on the battlefield. On the other hand, staging of release of multiple growth factor proteins can achieve the regeneration of collagen and remodeling of tissue in wounds at appropriate time points to facilitate wound closure and tissue vascularization. Moreover, multilayered release coatings as thin as a half micron to several microns can be designed to deliver different growth factor proteins or siRNA and other biologic drugs directly to wounds to correct the dysregulation of wound healing processes that have gone awry, from burn and scar tissue to the closure of chronic wounds such as diabetic ulcers.
5:00 PM - *BM1.4.05
A Powerful CD8+ T-Cell Stimulating D-Tetra-Peptide Hydrogel as a Very Promising Vaccine Adjuvant
Huaimin Wang 1 , Chengbiao Yang 1 , Zhimou Yang 1
1 Nankai University Tianjin ChinaShow Abstract
Subunit vaccines are well-defined at molecular level and have been widely developed in modern vaccine industry due to their good safety, great ease of manufacture and storage. However, compared with live vaccines, their immunogenicity is poor, particularly for the CD8+ T-cell responses. Subunit vaccines and adjuvants have therefore been formulated into nanomaterials to raise immune responses, but only few of them can elicit CD8+ T-cell responses. More importantly, the antigens and adjuvants are needed to be covalently conjugated or simultaneously formulated into the same nano-carrier, which makes their production in large scale more challenging. We had developed an injectable supramolecular hydrogel of a self-assembling D-tetrapeptide as a very promising adjuvant to raise both humoral and cellular immune responses. Antigens including OVA and attenuated tumor cells can be simply incorporated within the hydrogel by vortex or gentle shaking before injections. We found that the resulting hydrogels with physically entrapped antigens are extremely potent vaccines that can significantly stimulate CD8+ T-cell response and remarkably inhibited tumor growth. Our hydrogel should enable a wide range of subunit vaccines and make the manufacture of modern vaccines much easier.
Zichao Luo, Qinjie Wu, Chengbiao Yang, Huaimin Wang, Tao He, Hao Chen, Xingyi Li,* Changyang Gong*, Zhimou Yang* A powerful CD8+ T-cell stimulating D-tetra-peptide hydrogel as a very promising vaccine adjuvant, Adv. Mater. Under Revision.
Huaimin Wang，Zichao Luo，Youzhi Wang，Tao He，Chengbiao Yang，Chunhua Ren，Linsha Ma，Changyang Gong*，Xingyi Li*，Zhimou Yang*，Enzyme-catalyzed Formation of Supramolecular Hydrogels as Promising Vaccine Adjuvants，Adv. Funct. Mater., 2016, 26(11): 1822-1829.
Yue Tian, Huaimin Wang, Ye Liu, Lina Mao, Wenwen Chen, Zhening Zhu, Wenwen Liu, Wenfu Zheng, Yuyun Zhao, Deling Kong, Zhimou Yang*, Wei Zhang, Yiming Shao*, Xingyu Jiang*, A Peptide-based Nanofibrous Hydrogel as a Promising DNA Nanovector for Optimizing the Efficacy of HIV Vaccine, Nano Lett., 2014, 14(3): 1439-1445.
5:30 PM - *BM1.4.06
Inverse Opal Scaffolds for Tissue Engineering and Regenerative Medicine
Younan Xia 1
1 Georgia Institute of Technology Atlanta United StatesShow Abstract
Three-dimensionally porous scaffolds are indispensable for tissue engineering and regenerative medicine as they provide physical supports and adjustable microenvironments for cells to attach, stretch, migrate, proliferate, and differentiate. An ideal scaffold should possess certain properties such as appropriate pore size, porosity, and interconnectivity, among others. To this end, porous scaffolds with an inverse opal structure emerged. Unlike other scaffolds that are fabricated by stochastic porogen methods with random structures, an inverse opal scaffold is characterized by uniform and well-controlled pores and interconnecting windows, in addition to their highly reproducible structure among different batches of production. In this talk, I will start with a biref discussion of the motivation for developing the inverse opal scaffolds and an introduction to the fabrication method. I will then highlight the advantages of using such porous scaffolds over their counterparts with non-uniform structures through side-by-side comparisons. Finally, I will discuss a few examples on the unique applications of the inverse opal scaffolds in regenerative medicine and offer some perspectives on the future directions.