Subbu S. Venkatraman

Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent.

Antimicrobial cationic peptides are of interest because they can combat multi-drug-resistant microbes. Most peptides form alpha-helices or beta-sheet-like structures that can insert into and subsequently disintegrate negatively charged bacterial cell surfaces. Here, we show that a novel class of core-shell nanoparticles formed by self-assembly of an amphiphilic peptide have strong antimicrobial properties against a range of bacteria, yeasts and fungi. The nanoparticles show a high therapeutic index against Staphylococcus aureus infection in mice and are more potent than their unassembled peptide counterparts. Using Staphylococcus aureus-infected meningitis rabbits, we show that the nanoparticles can cross the blood-brain barrier and suppress bacterial growth in infected brains. Taken together, these nanoparticles are promising antimicrobial agents that can be used to treat brain infections and other infectious diseases.

Skin adhesives and skin adhesion: 1. Transdermal drug delivery systems

The use of pressure-sensitive adhesives (PSAs) for skin-contact applications is discussed. The requirements of such adhesives in various applications are examined in detail. Commercially available classes of PSAs used for skin-contact applications are the acrylics, the polyisobutylenes, and the silicones. The main application examined in this review is transdermal drug delivery. The roles played by the PSA in two types of transdermal designs are described. Correlations between in vivo and ex vivo measurements of adhesion are discussed. Also, the reported human studies of various commercially available transdermals are examined critically, with a view to assessing the relative performance capabilities of each type of transdermal design. Finally, a comprehensive listing of currently commercialized transdermals is given.

Microstructure of poly(vinyl alcohol) hydrogels produced by freeze/thaw cycling

To understand the reversible gelation and subsequent aging of hydrogels prepared by freeze/thaw processing of poly(vinyl alcohol) (PVOH) solutions, the microstructures of gels prepared by different freeze/thaw protocols and aged to varying extents are studied by cryogenic transmission electron microscopy, solid-state nuclear magnetic resonance, X-ray scattering, and differential scanning calorimetry (DSC). As discussed in the literature, gelation by the freeze/thaw process occurs as a homogeneous aqueous poly(vinyl alcohol) solution is cycled, perhaps multiple times, between temperatures above 0 °C and well below 0 °C. The current investigation has determined that a few percent of chain segments crystallize during the first cycle, organizing themselves into 3-8 nm primary crystallite junctions separated on an irregular mesh by an average spacing of ∼ 30 nm. Aging or imposition of additional freeze/thaw cycles augments the level of crystallinity and transforms the as-formed liquid-like microstructure, characterized in the electron microscope by rounded ∼ 30 nm pores, into a fibrillar network. Observation that the transformation occurs at fixed mesh spacing and approximately constant average crystallite size suggests the formation of secondary crystallites that do not affect network connectivity. Dendritic ice crystallization and possibly spinodal decomposition superimpose on this nanoscale structure a matrix of much larger pores.

Accelerating the Translation of Nanomaterials in Biomedicine

Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples.

Photopolymerization of cell-encapsulating hydrogels: crosslinking efficiency versus cytotoxicity.

Cell-encapsulating hydrogels used in regenerative medicine are designed to undergo a rapid liquid-to-solid phase transition in the presence of cells and tissues so as to maximize crosslinking and minimize cell toxicity. Light-activated free-radical crosslinking (photopolymerization) is of particular interest in this regard because it can provide rapid reaction rates that result in uniform hydrogel properties with excellent temporal and spatial control features. Among the many initiator systems available for photopolymerization, only a few have been identified as suitable for cell-based hydrogel formation owing to their water solubility, crosslinking properties and non-toxic reaction conditions. In this study, three long-wave ultraviolet (UV) light-activtied photoinitiators (PIs) were comparatively tested in terms of cytotoxicity, crosslinking efficiency and crosslinking kinetics of cell-encapsulating hydrogels. The hydrogels were photopolymerized from poly(ethylene glycol) (PEG) diacrylate or PEG-fibrinogen precursors using Irgacure® PIs I2959, I184 and I651, as well as with a chemical initiator/accelerator (APS/TEMED). The study specifically evaluated the PI type, PI concentration and UV light intensity, and how these affected the mechanical properties of the hydrogel (i.e. maximum storage modulus), the crosslinking reaction times and the reactions cytotoxicity to encapsulated cells. Only two initiators (I2959 and I184) were identified as being suitable for achieving both high cell viability and efficient crosslinking of the cell-encapsulating hydrogels during the photopolymerization reaction. Optimization of PI concentration or irradiation intensity was particularly important for achieving maximum mechanical properties; a sub-optimal choice of PI concentration or irradiation intensity resulted in a substantial reduction in hydrogel modulus. Cytocompatibility may be compromised by unnecessarily prolonging exposure to cytotoxic free radicals or inadvertently enhancing the instantaneous dose of radicals in solution, both of which are dependent on the PI type/concentration and irradiation intensity. In the absence of a radical initiator, the short exposures to long-wave UV light irradiation (up to 5 min, 20 mW cm(-2), 365 nm) did not prove to be cytotoxic to cells. Therefore, it is important to understand the relationship between PIs, light irradiation conditions and crosslinking when attempting to identify a suitable hydrogel formation process for cell encapsulating hydrogels.

Modeling of drug release from bulk-degrading polymers

This paper aims to provide a comprehensive review of the various models or simulations for predicting drug release from bulk-degrading systems. A brief description of bulk degradation processes and factors affecting the degradation rate, and consequently the release kinetics, is presented first. Next, several important classical models, often used as the basis for subsequent model development, are discussed. Both mathematical models and Monte-Carlo based simulations have been developed for controlled release from bulk-degrading systems. The mathematical models can be further subdivided into two categories. First, the diffusion-based models whose transport mechanism is mainly governed by diffusion, but with degradation-dependent diffusion coefficients. These are generally simpler and easier to use and are sufficient to illustrate mono-phasic release. Second, comprehensive models that combine diffusion with other theories such as erosion, drug dissolution and/or pore percolations. These models usually involve more complex equations but provide good matches for multi-phasic release profiles.

The effect of topography of polymer surfaces on platelet adhesion

In this study, the effect of surface topography on fibrinogen and platelet adsorption was investigated. High aspect ratio surface features, in the submicron to nanometer range, were constructed on the poly- (lactic-co-glycolic-acid) (PLGA) films. The topographic surfaces were fabricated by solvent-mediated polymer casting on a master template. Fibrinogen adsorption and platelets adhesion on these topographic surfaces were quantified by enzyme linked immunosorbent assay (ELISA) and lactate dehydrogenase (LDH) assay respectively, while the activation of platelets was quantified by flow cytometric analysis using fluorescein isothiocyanate (FITC) tagging. The lowest fibrinogen adsorption amount and platelet activity was observed on surfaces with specific topographical features in the submicron range with a significant reduction in adhesion when compared to the pristine PLGA films. The topographical parameters found to induce low levels of fibrinogen adsorption and platelet response were high aspect ratio structures (>3:1) with reduced interspacing (<200 nm) or high density. The results signify that topographical manipulation of thrombogenic surfaces of biodegradable polymers is a feasible approach for reducing their thrombogenicity.

Modeling of drug release from biodegradable polymer blends

Numerous mathematical models that predict drug release from degradable systems have been reported. Most of these models cater only to single step, diffusion-controlled release while a few attempt to describe bi-phasic release. All these models, however, are only applicable to drug release from single (unblended) degradable polymer systems. In this paper, we propose and test novel models for drug (notably paclitaxel) release from films made of neat poly (epsilon-caprolactone) PCL, neat poly (dl-lactide-co-glycolide) PLGA and their blends. The model developed for neat PCL consists of two terms: initial burst and diffusional release. On the other hand, a more complex model proposed for tri-phasic release from neat PLGA consists of burst release, degradative (relaxation-induced) drug dissolution release and diffusional release. Finally, this very first model to predict release from blend of PLGA and PCL was developed based on a heuristic approach. Drug distribution between PCL-rich and PLGA-rich phases is dictated by partition coefficient, and the overall fraction of drug release is a summation of drug released from the two phases. The proposed models exhibited good prediction of the experimental data.

Micro‐/Nano‐engineered Cellular Responses for Soft Tissue Engineering and Biomedical Applications

The development of biomedical devices and reconstruction of functional ex vivo tissues often requires the need to fabricate biomimetic surfaces with features of sub-micrometer precision. This can be achieved with the advancements in micro-/nano-engineering techniques, allowing researchers to manipulate a plethora of cellular behaviors at the cell-biomaterial interface. Systematic studies conducted on these 2D engineered surfaces have unraveled numerous novel findings that can potentially be integrated as part of the design consideration for future 2D and 3D biomaterials and will no doubt greatly benefit tissue engineering. In this review, recent developments detailing the use of micro-/nano-engineering techniques to direct cellular orientation and function pertinent to soft tissue engineering will be highlighted. Particularly, this article aims to provide valuable insights into distinctive cell interactions and reactions to controlled surfaces, which can be exploited to understand the mechanisms of cell growth on micro-/nano-engineered interfaces, and to harness this knowledge to optimize the performance of 3D artificial soft tissue grafts and biomedical applications.

Collapse pressures of biodegradable stents

Biodegradable stent prototypes were produced from poly L-lactic acid polymers with different molecular weights. The effects of molecular weight, drug incorporation and stent design on the collapse pressure of the stents were evaluated. While molecular weights did not show a significant effect on the collapse pressure of the stents, drug incorporation at high percentage decreased the collapse pressure of the stents substantially. Cryogenic fracture surfaces showed significant drug agglomeration as the concentration increased. The design of the stent was also found to a have significant effect on the collapse pressure. The stent produced from the same material has a higher collapse pressure when the load bearing surface area is increased.