Building biomedical materials layer-by-layer

In this materials perspective, the promise of water based layer-by-layer (LbL) assembly as a means of generating drug-releasing surfaces for biomedical applications, from small molecule therapeutics to biologic drugs and nucleic acids, is examined. Specific advantages of the use of LbL assembly versus traditional polymeric blend encapsulation are discussed. Examples are provided to present potential new directions. Translational opportunities are discussed to examine the impact and potential for true biomedical translation using rapid assembly methods, and applications are discussed with high need and medical return

Spray Layer-by-Layer Assembled Clay Composite Thin Films as Selective Layers in Reverse Osmosis Membranes

Spray layer-by-layer assembled thin films containing laponite (LAP) clay exhibit effective salt barrier and water permeability properties when applied as selective layers in reverse osmosis (RO) membranes. Negatively charged LAP platelets were layered with poly(diallyldimethylammonium) (PDAC), poly(allylamine) (PAH), and poly(acrylic acid) (PAA) in bilayer and tetralayer film architectures to generate uniform films on the order of 100 nm thick that bridge a porous poly(ether sulfone) support to form novel RO membranes. Nanostructures were formed of clay layers intercalated in a polymeric matrix that introduced size-exclusion transport mechanisms into the selective layer. Thermal cross-linking of the polymeric matrix was used to increase the mechanical stability of the films and improve salt rejection by constraining swelling during operation. Maximum salt rejection of 89% was observed for the tetralayer film architecture, with an order of magnitude increase in water permeability compared to commercially available TFC-HR membranes. These clay composite thin films could serve as a high-flux alternative to current polymeric RO membranes for wastewater and brackish water treatment as well as potentially for forward osmosis applications. In general, we illustrate that by investigating the composite systems accessed using alternating layer-by-layer assembly in conjunction with complementary covalent cross-linking, it is possible to design thin film membranes with tunable transport properties for water purification applications.Center for Clean Water and Clean Energy at MIT and KFUPM (project R5-CW-08

Catalytic, Conductive Bipolar Membrane Interfaces through Layer-by-Layer Deposition for the Design of Membrane-Integrated Artificial Photosynthesis Systems

In the presence of an electric field, bipolar membranes (BPMs) are capable of initiating water disassociation (WD) within the interfacial region, which can make water splitting for renewable energy in the presence of a pH gradient possible. In addition to WD catalytic efficiency, there is also the need for electronic conductivity in this region for membrane-integrated artificial photosynthesis (AP) systems. Graphene oxide (GO) was shown to catalyze WD and to be controllably reduced, which resulted in electronic conductivity. Layer-by-layer (LbL) film deposition was employed to improve GO film uniformity in the interfacial region to enhance WD catalysis and, through the addition of a conducting polymer in the process, add electronic conductivity in a hybrid film. Three different deposition methods were tested to optimize conducting polymer synthesis with the oxidant in a metastable solution and to yield the best film properties. It was found that an approach that included substrate dipping in a solution containing the expected final monomer/oxidant ratio provided the most predictable film growth and smoothest films (by UV/Vis spectroscopy and atomic force microscopy/scanning electron microscopy, respectively), whereas dipping in excess oxidant or co-spraying the oxidant and monomer produced heterogeneous films. Optimized films were found to be electronically conductive and produced a membrane ohmic drop that was acceptable for AP applications. Films were integrated into the interfacial region of BPMs and revealed superior WD efficiency (≥1.4 V at 10 mA cm⁻²) for thinner films (<10 bilayers≈100 nm) than for either the pure GO catalyst or conducting polymer individually, which indicated that there was a synergistic effect between these materials in the structure configured by the LbL method.National Science Foundation (Grant CHE‐1305124

Charge based intra-cartilage delivery of single dose dexamethasone using Avidin nano-carriers suppresses cytokine-induced catabolism long term

Objective: Avidin exhibits ideal characteristics for targeted intra-cartilage drug delivery: its small size and optimal positive charge enable rapid penetration through full-thickness cartilage and electrostatic binding interactions that give long half-lives in vivo. Here we conjugated Avidin with dexamethasone (DEX) and tested the hypothesis that single-dose Avidin-delivered DEX can ameliorate catabolic effects in cytokine-challenged cartilage relevant to post-traumatic OA. Methods: Avidin was covalently conjugated with DEX using fast (ester) and slow, pH-sensitive release (hydrazone) linkers. DEX release kinetics from these conjugates was characterized using 3H-DEX-Avidin (scintillation counting). Cartilage explants treated with IL-1α were cultured with or without Avidin-DEX conjugates and compared to soluble DEX. Sulfated-glycosaminoglycan (sGAG) loss and biosynthesis rates were measured using DMMB assay and 35S-incorporation, respectively. Chondrocyte viability was measured using fluorescence staining. Results: Ester linker released DEX from Avidin significantly faster than hydrazone under physiological buffer conditions. Single dose Avidin-DEX suppressed cytokine-induced sGAG loss over 3-weeks, rescued IL-1α-induced cell death, and restored sGAG synthesis levels without causing cytotoxicity. The two Avidin-DEX conjugates in 1:1 combination (fast:slow) had the most prominent bioactivity compared to single dose soluble-DEX, which had a shorter-lived effect and thus needed continuous replenishment throughout the culture period to ameliorate catabolic effects. Conclusion: Intra-cartilage drug delivery remains inadequate as drugs rapidly clear from the joint, requiring multiple injections or sustained release of high doses in synovial fluid. A single dose of Avidin-conjugated drug enables rapid uptake and sustained delivery inside cartilage at low intratissue doses, and potentially can minimize unwanted drug exposure to other joint tissues.Deshpande Center for Technological InnovationNational Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Award DMR-1419807

Multimonth controlled small molecule release from biodegradable thin films

Long-term, localized delivery of small molecules from a biodegradable thin film is challenging owing to their low molecular weight and poor charge density. Accomplishing highly extended controlled release can facilitate high therapeutic levels in specific regions of the body while significantly reducing the toxicity to vital organs typically caused by systemic administration and decreasing the need for medical intervention because of its long-lasting release. Also important is the ability to achieve high drug loadings in thin film coatings to allow incorporation of significant drug amounts on implant surfaces. Here we report a sustained release formulation for small molecules based on a soluble charged polymer–drug conjugate that is immobilized into nanoscale, conformal, layer-by-layer assembled films applicable to a variety of substrate surfaces. We measured a highly predictable sustained drug release from a polymer thin film coating of 0.5–2.7 μm that continued for more than 14 mo with physiologically relevant drug concentrations, providing an important drug delivery advance. We demonstrated this effect with a potent small molecule nonsteroidal anti-inflammatory drug, diclofenac, because this drug can be used to address chronic pain, osteoarthritis, and a range of other critical medical issues.United States. Army Research Office (Contract W911NF-13-D-0001)United States. Air Force (Contract W911NF-07-D-0004

Helix versus coil polypeptide macromers: gel networks with decoupled stiffness and permeability

As a platform for investigating the individual effects of substrate stiffness, permeability, and ligand density on cellular behavior, we developed a set of hydrogels with stiffness tuned by polymer backbone rigidity, independent of cross-link density and concentration. Previous studies report that poly(propargyl-L-glutamate) (PPLG), synthesized by ring-opening polymerization of the N-carboxy anhydride of γ-propargyl-L-glutamate (γpLglu), adopts a rigid a-helix conformation: we hypothesized that a random copolymer (PPDLG) with equal amounts of γpLglu and γ-propargyl-D-glutamate (γpDglu) monomers would exhibit a more flexible random coil conformation. The resulting macromers exhibited narrow molecular weight distributions (PDI = 1.15) and were grafted with ethylene glycol groups using a highly efficient “click” azide/alkyne cycloaddition reaction with average grafting efficiency of 97% for PPLG and 85% for PPDLG. The polypeptide secondary structure, characterized via circular dichroism spectroscopy, FTIR spectroscopy, and dynamic light scattering, is indeed dependent upon monomer chirality: PPLG exhibits an α-helix conformation while PPDLG adopts a random coil conformation. Hydrogel networks produced by cross-linking either helical or random coil polypeptides with poly(ethylene glycol) (PEG) were analyzed for amount of swelling, gelation efficiency, and permeability to a model protein. In addition, the elastic modulus of helical and coil polypeptide gels was determined by AFM indentation in fluid. Importantly, we found that helical and coil polypeptide gels exhibited similar swelling and permeability but different stiffnesses, which correspond to predictions from the theory of semi-flexible chains.National Institutes of Health (U.S.) (R01 EB10246)National Science Foundation (U.S.). Emergent Behaviors of Integrated Cellular System

Preferential Association of Segment Blocks in Polyurethane Nanocomposites

Submitted to MacromoleculesControlling the level of dispersion of silicate layers in polymer matrices through intermolecular interactions and exploiting these interactions to enhance thermomechanical behavior are key challenges in the field of polymer nanocomposites. In this investigation, unmodified Laponite platelets are dispersed in a segmented polyurethane containing polar, hydrophilic soft segments and a hydrophobic hard segment using a novel solvent exchange method and compared to polyurethane nanocomposites containing more hydrophobic hard and soft domains. It was determined that the silicate layers were preferentially, but not exclusively, attracted to the hydrophilic, polar soft domains. An apparent micro-phase segregated morphology was observed in transmission electron microscopy for this system, revealing regions of exfoliation and intercalation. According to polarizing optical microscopy, strain-induced alignment is inhibited for this polyurethane nanocomposite, which is reflected in dramatic reductions in tensile strength and ultimate extensibility. In comparison, the Laponite discs appear to be preferentially, but not exclusively, embedded to the hard domains in the segmented polyurethanes containing more hydrophobic hard and soft domains. Exfoliation of the clay platelets leads to enhanced modulus and toughness without a reduction in extensibility. This study provides clues for exploiting silicate-polymer interactions to tune material properties without chemical modification.Institute for Soldier Nanotechnology (ISN) at MI

Highly stable, ligand-clustered “patchy” micelle nanocarriers for systemic tumor targeting

A novel linear-dendritic block copolymer has been synthesized and evaluated for targeted delivery. The use of the dendron as the micellar exterior block in this architecture allows the presentation of a relatively small quantity of ligands in clusters for enhanced targeting, thus maintaining a long circulation time of these “patchy” micelles. The polypeptide linear hydrophobic block drives formation of micelles that carry core-loaded drugs, and their unique design gives them extremely high stability in vivo. We have found that these systems lead to extended time periods of increased accumulation in the tumor (up to 5 days) compared with nontargeted vehicles. We also demonstrate a fourfold increase in efficacy of paclitaxel when delivered in the targeted nanoparticle systems, while significantly decreasing in vivo toxicity of the chemotherapy treatment.National Institute for Biomedical Imaging and Bioengineering (U.S.)National Cancer Institute (U.S.) (R01EB008082-01A2

Self-assembled RNA interference microsponges for efficient siRNA delivery

The encapsulation and delivery of short interfering RNA (siRNA) has been realized using lipid nanoparticles1, 2, cationic complexes3, 4, inorganic nanoparticles5, 6, 7, 8, RNA nanoparticles9, 10 and dendrimers11. Still, the instability of RNA and the relatively ineffectual encapsulation process of siRNA remain critical issues towards the clinical translation of RNA as a therapeutic1, 12, 13. Here we report the synthesis of a delivery vehicle that combines carrier and cargo: RNA interference (RNAi) polymers that self-assemble into nanoscale pleated sheets of hairpin RNA, which in turn form sponge-like microspheres. The RNAi-microsponges consist entirely of cleavable RNA strands, and are processed by the cell’s RNA machinery to convert the stable hairpin RNA to siRNA only after cellular uptake, thus inherently providing protection for siRNA during delivery and transport to the cytoplasm. More than half a million copies of siRNA can be delivered to a cell with the uptake of a single RNAi-microsponge. The approach could lead to novel therapeutic routes for siRNA delivery.National Institutes of Health (U.S.) (NIH) NIBIB Grant R01-EB008082)United States. American Recovery and Reinvestment Act of 2009 ((ARRA) grant)National Science Foundation (U.S.) (Division of Materials Research Polymers Program grant #0705234)David H. Koch Institute for Integrative Cancer Research at MIT (Nanotechnology grant

Hydrogen-bonded multilayer of pH-responsive polymeric micelles with tannic acid for surface drug delivery

We report the design of a platform for the delivery of hydrophobic drugs conjugated to block copolymer micelles via pH-responsive linkage that are assembled within hydrogen-bonded polymer multilayer thin films.close465