Hyaluronic acid (HA) is a naturally occurring biodegradable polymer with a variety of applications in medicine including scaffolding for tissue engineering, dermatological fillers, and viscosupplementation for osteoarthritis treatment. HA is available in most connective tissues in body fluids such as synovial fluid and the vitreous humor of the eye. HA is responsible for several structural properties of tissues as a component of extracellular matrix (ECM) and is involved in cellular signaling. Degradation of HA is a step-wise process that can occur via enzymatic or non-enzymatic reactions. A reduction in HA mass or molecular weight via degradation or slowing of synthesis affects physical and chemical properties such as tissue volume, viscosity, and elasticity. This review addresses the distribution, turnover, and tissue-specific properties of HA. This information is used as context for considering recent products and strategies for modifying the viscoelastic properties of HA in tissue engineering, as a dermal filler, and in osteoarthritis treatment.

Poloxamers are triblock copolymers with a center block of hydrophobic polypropylene oxide (PPO) flanked by two hydrophilic polyethyleneoxide (PEO) blocks. Among this family of copolymers, poloxamer 407 is a non-ionic surfactant with reversible gelation properties above a particular polymer concentration and a particular temperature. Easy preparation of poloxamer 407 based sterile injectable formulations have made this copolymer a good candidate for drug delivery, specifically when controlled release of the drug is required. Previously, the applications of compendial poloxamer 407 preparations were demonstrated; however, low viscosity, poor elasticity, and sol-to-gel transition temperature (Tsol-gel) over a wide temperature range were observed. A purification process was introduced to eliminate impurities and low molecular weight copolymer molecules from the compendial poloxamer 407 resulting in higher viscosity values with Tsol-gel in a narrow temperature range. Here, poloxamer 407 was purified based on the proposed process and the rheological and analytical evaluation of the purified poloxamer 407 was conducted and compared to unpurified, compendial poloxamer 407. Then, the impact of poloxamer 407 concentration on gel formation was evaluated. For drug delivery applications, the effect of relevant buffer salts and the effect of addition of ethanol to the poloxamer 407 solutions were rheologically evaluated.

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Purpose Typically, low molecular weight cationic peptides or polymers exhibit poor transfection efficiency due to an inability to condense plasmid DNA into small nanoparticles. Here, efficient gene delivery was attained using TAT/pDNA complexes containing calcium crosslinks. Methods Electrostatic complexes of pDNA with TAT or PEI were studied with increasing calcium concentration. Gel electrophoresis was used to determine DNA condensation. The morphology of the complexes was probed by transmission electron microscopy. Transfection efficiency was assessed using a luciferase reporter plasmid. The accessibility of phosphate and amine groups within complexes was evaluated to determine the effect of calcium on structure. Results TAT/pDNA complexes were condensed into small, 50–100 nm particles by optimizing the concentration of calcium. Complexes optimized for small size also exhibited higher transfection efficiency than PEI polyplexes in A549 cells. TAT and TAT complexes displayed negligible cytotoxicity up to 5 mg/mL, while PEI exhibited high cytotoxicity, as expected. Probing the TAT-Ca/pDNA structure suggested that calcium interacted with both phosphate and amine groups to compact the complexes; however, these “soft” crosslinks could be competitively disrupted to facilitate DNA release. Conclusion Small and stable TAT-Ca/pDNA complexes were obtained via “soft” calcium crosslinks leading to sustained gene expression levels higher than observed for control PEI gene vectors. TAT-Ca/pDNA complexes were stable, maintaining particle size and transfection efficiency even in the presence of 10% of FBS. TAT-Ca complexes offer an effective vehicle offering potential for translatable gene delivery.

During infection, pathogens utilize surface receptors to gain entry into intracellular compartments. Multiple receptor-ligand interactions that lead to pathogen internalization have been identified and the importance of multivalent ligand binding as a means to facilitate internalization has emerged. The effect of ligand density, however; is less well known. In this study, ligand density was examined using poly(dl-lactic-co-glycolic acid) nanoparticles (PLGA NPs). A cyclic peptide, cLABL, was used as a targeting moiety as it is a known ligand for intercellular cell adhesion molecule-1 (ICAM-1). To modulate the number of reactive sites on the surface of PLGA NPs, modified Pluronic® with carboxyl groups and Pluronic® with hydroxyl groups were combined at different ratios and the particle properties were examined. Utilizing a surfactant mixture directly affected the particle charge and the number of reactive sites for cLABL conjugation. The surface density of cLABL peptide increased as the relative amount of reactive Pluronic® was increased. Studies using carcinomic human alveolar basal epithelial cells (A549) showed that cLABL density may be optimized to improve cellular uptake. These results compliment other studies suggesting surface density of the targeting moiety on the NP surface should be considered to enhance the effect of ligands employed for cell targeting.

ABSTRACT. Presentation of antigen with immune stimulating "signal" has been a cornerstone of vaccine design for decades. Here, the antigen plus immune "signal" of vaccines is modified to produce antigen-specific immunotherapies (antigen-SITs) that can potentially reprogram the immune response toward tolerance of an autoantigen. The codelivery of antigen with a cell adhesion inhibitor using Soluble Antigen Arrays (SAgAs) was previously shown to slow or halt experimental autoimmune encephalomyelitis (EAE), a murine form of multiple sclerosis (MS). SAgAs are comprised of a hyaluronic acid backbone with cografted intercellular cell adhesion molecule-1 ligand derived from α L -integrin (CD11a 237-246 , "LABL") and an encephalitogenic epitope peptide of proteolipid protein (PLP 139-151 , "PLP"). Here, the physical characteristics of the carrier were investigated to evaluate how structure, size, and solubility drive the immune response when treating EAE. A bifunctional peptide (small, soluble), SAgAs (large, soluble), and PLGA nanoparticles (large, insoluble) all displaying PLP and LABL in equimolar ratios were compared. Maximum EAE suppression was achieved with coincident display of both peptides on a soluble construct.

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung facilitating systemic drug delivery via pulmonary administration. The efficacy and safety of many new and existing inhaled therapies may be enhanced through advanced controlled-release systems by using polymer particles. Poly (D,L-lactic-co-glycolic acid) (PLGA) is well known by its safety in biomedical preparations which has been approved for human use by the FDA. The optimum aerodynamic particle size distribution for most inhalation aerosols has generally been recognized to be in the range of 1-5 microns. PLGA microspheres, therefore, were prepared by a developed oil-in-oil solvent evaporation method and characterized. A four-factor, three levels Box-Behnken design was used for the optimization procedure with temperature, stirring speed, PLGA and surfactant concentration as independent variables. Particle size and polydispersity of microspheres were considered as dependent variables. PLGA microparticles were prepared successfully in desired size for pulmonary delivery by solvent evaporation method. It was found that the particle size of microspheres could be easily controlled. It was also proved that response surface methodology could efficiently be applied for size characterization and optimization of PLGA microparticles for pulmonary drug delivery.

Hyaluronic acid (HA) is a glycosaminoglycan with diverse biomedical applications including viscosupplementation of synovial fluid for the treatment osteoarthritis. Current HA viscosupplements such as Synvisc, Orthovisc, and Hyalgan have shown positive effects of reducing pain and improving joint function. The therapeutic efficacy, however, is highly transient, and these viscous fluids suffer from poor injectability. HA nanoparticles were found to modify the rheological properties of a model of the HA viscosupplement Orthovisc. Nanoparticles were successfully synthesized from 17 and 1500 kDa HA. Nanoparticle suspensions of HA were studied at different concentrations and in blends with the model viscosupplement. Nanoparticles made from 1500 kDa HA reduced the viscosupplement viscosity and elasticity to a much greater degree than nanoparticles made from 17 kDa HA. The difference in the nanoparticle effect on viscoelasticity suggested that nanoparticles made from 17 kDa HA may have dangling surface polymers that facilitated interactions with HA in solution. This hypothesis was supported by the greater compressibility of 17 kDa nanoparticles as determined by ultrasonic vibrational spectroscopy. Rheological investigations showed that the viscoelasticity of viscosupplements could be discretely titrated by modulating the concentration and type of HA nanoparticle additive (hard sphere or hairy). Thus, the injectability of viscosupplements may be enhanced while maintaining high elasticity.