Achieving sustained drug delivery to mucosal surfaces is a major challenge due to the presence of the protective mucus layer that serves to trap and rapidly remove foreign particulates. Nanoparticles engineered to rapidly penetrate mucosal barriers (mucus-penetrating particles, “MPP”) have shown promise for improving drug distribution, retention and efficacy at mucosal surfaces. MPP are densely coated with polyethylene glycol (PEG), which shields the nanoparticle core from adhesive interactions with mucus. However, the PEG density required to impart the “stealth” properties to nanoparticles in mucus, and thus, uniform distribution in vivo, is still unknown. We prepared biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a range of PEG surface densities by blending various ratios of a diblock copolymer of PLGA and 5 kDa poly(ethylene glycol) (PLGA-PEG5k) with PLGA. We then evaluated the impact of PEG surface density, measured using an 1H NMR method, on mucin binding in vitro, nanoparticle transport in freshly obtained human cervicovaginal mucus (CVM) ex vivo, and nanoparticle distribution in the mouse cervicovaginal tract in vivo. We found that at least 5% PEG was required to effectively shield the nanoparticle core from interacting with mucus components in vitro and ex vivo, thus leading to enhanced nanoparticle distribution throughout the mouse vagina in vivo. We then demonstrated that biodegradable MPP could be formulated from blends of PLGA and PLGA-PEG polymers of various molecular weights, and that these MPP provide tunable drug loading and drug release rates and durations. Overall, we describe a methodology for rationally designing biodegradable, drug-loaded MPP for more uniform delivery to the vagina.

Intravitreal injection of biodegradable nanoparticles (NP) holds promise for gene therapy and drug delivery to the back of the eye. In some cases, including gene therapy, NP need to diffuse rapidly from the site of injection in order to reach targeted cell types in the back of the eye, whereas in other cases it may be preferred for the particles to remain at the injection site and slowly release drugs that may then diffuse to the site of action. We studied the movements of polystyrene (PS) nanoparticles of various sizes and surface chemistries in fresh bovine vitreous. PS NP as large as 510 nm rapidly penetrated the vitreous gel when coated with polyethylene glycol (PEG), whereas the movements of NP 1190 nm in diameter or larger were highly restricted regardless of surface chemistry owing to steric obstruction. PS NP coated with primary amine groups (–NH2) possessed positively charged surfaces at the pH of bovine vitreous (pH = 7.2), and were immobilized within the vitreous gel. In comparison, PS NP coated with –COOH (possessing negatively charged surfaces) in the size range of 100–200 nm and at particle concentrations below 0.0025% (w/v) readily diffused through the vitreous meshwork; at higher concentrations (~0.1% w/v), these nanoparticles aggregated within vitreous. Based on the mobility of different sized PS-PEG NP, we estimated the average mesh size of fresh bovine vitreous to be ~550 ± 50 nm. The bovine vitreous behaved as an impermeable elastic barrier to objects sized 1190 nm and larger, but as a highly permeable viscoelastic liquid to non-adhesive objects smaller than 510 nm in diameter. Guided by these studies, we next sought to examine the transport of drug- and DNA-loaded nanoparticles in bovine vitreous. Biodegradable NP with diameter of 227 nm, composed of a poly(lactic-co-glycolic acid) (PLGA)-based core coated with poly(vinyl alcohol) rapidly penetrated vitreous. Rod-shaped, highly-compacted CK30PEG10k/DNA with PEG coating (neutral surface charge; diameter ~60 nm) diffused rapidly within vitreous. These findings will help guide the development of nanoparticle-based therapeutics for the treatment of vision-threatening ocular diseases.

Immunologic graft rejection is one of the main causes of short and long-term graft failure in corneal transplantation. Steroids are the most commonly used immunosuppressive agents for postoperative management and prevention of corneal graft rejection. However, steroids delivered in eye drops are rapidly cleared from the surface of the eye, so the required frequency of dosing for corneal graft rejection management can be as high as once every 2 h. Additionally, these eye drops are often prescribed for daily use for 1 year or longer, which can result in poor patient compliance and steroid-related side effects. Here, we report a biodegradable nanoparticle system composed of Generally Regarded as Safe (GRAS) materials that can provide sustained release of corticosteroids to prevent corneal graft rejection following subconjunctival injection provided initially during transplant surgery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing dexamethasone sodium phosphate (DSP) exhibited a size of 200 nm, 8 wt.% drug loading, and sustained drug release over 15 days in vitro under sink conditions. DSP-loaded nanoparticles provided sustained ocular drug levels for at least 7 days after subconjunctival administration in rats, and prevented corneal allograft rejection over the entire 9-week study when administered weekly. In contrast, control treatment groups that received weekly injections of either placebo nanoparticles, saline, or DSP in solution demonstrated corneal graft rejection accompanied by severe corneal edema, neovascularization and opacity that occurred in ≤ 4 weeks. Local controlled release of corticosteroids may reduce the rate of corneal graft rejection, perhaps especially in the days immediately following surgery when risk of rejection is highest and when typical steroid eye drop administration requirements are particularly onerous.

Fixing chain orientation within polymeric materials can impart anisotropic mechanical, optical, and electrical properties. Although macroscopic anisotropy in amorphous or liquid crystalline phases has been achieved by cross-linking or by thermoreversible bond shuffling under strain, these methods lack spatial and temporal resolution. Here, we demonstrate a method to controllably write chain anisotropy into polymer networks containing both permanent and light-sensitive bonds. While held under mechanical stress or strain, light initiates a cascade of addition–fragmentation chain transfer reactions, causing photosensitive functional groups to reshuffle, thereby stabilizing the deformed network. Photoinscription of chain anisotropy allows for simplified processing on fully cross-linked networks with spatial and temporal control over chain orientation, thus enabling a spectrum of anisotropic polymeric materials. As an example, we demonstrate how built-in anisotropy of a semicrystalline network encourages crystallization along a preferred direction, leading to fully reversible shape actuation.

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Shape Memory PolymersPoly(caprolactone) networks are well-studied shape-memory polymers owing to their high fixity and recovery, their ability to store large amounts of elastic energy, and their tunable shape-triggering temperature. To elucidate the influence of network structure on shape-memory features, poly(caprolactone) networks are prepared by reacting different molecular weight diacrylate prepolymers with trifunctional (trimethylolpropane tris(3-mercaptopropionate), 3T) or tetrafunctional (pentaerythritol tetrakis(3-mercaptopropionate), 4T) crosslinkers. Networks from 4T crosslinkers generally exhibit higher gel fractions, more elastically active strands, and superior shape-memory properties compared with networks from 3T. Melted elastomers exhibit stress-strain behavior well described by the neo-Hookean model. How the state of crystallization during the cold-drawing process has a large effect on the draw stress, the network's shape fixity, and its elastic storage capacity is shown. Finally, the working strain range of networks is evaluated. Cured elastomers prepared from prepolymers with different molecular weights can store and release large amounts of elastic energy (>2 MJ m −3 ), over different ranges of tensile strain.

When crystallized under constant strain, conventional semicrystalline networks exhibit a loss in tension due to directionally preferred crystallization of chains along the strain axis. This study shows that a dual-cured, semicrystalline polymer network with programmed chain bias can generate ∼400 kPa of tensile stress upon crystallization. Constant strain experiments were conducted to monitor stress in configurationally biased networks as they were cooled and crystallized. Time resolved wide-angle X-ray scattering was used to study crystallization kinetics and the evolution of crystallite orientation. In configurationally biased networks without external load, initial crystallization along the internal chain bias direction is rapidly followed by crystal growth in the orthogonal direction. Under external loads, crystallization first occurs along the external load direction followed by the configurational chain bias direction. Calorimetry measurements indicate that two distinct crystal populations form upon cooling with different crystallization temperatures. In summary, embedding chain bias can act as a source of tension. The magnitude of tensile stress can be controlled though different crystallization temperatures. These findings open up new opportunities for engineering of thermoresponsive networks in applications where stress must be retained or generated upon crystallization.

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