Layer-by-Layers of Polymeric Micelles as a Biomimetic Drug-Releasing Network.

Mucin networks are lubricous biofunctional coats formed through the continuous deposition of mucin glycoproteins. Previously, we demonstrated the synthesis of a mucin mimic using biotinylated-filomicelles crosslinked via streptavidin using a layer-by-layer approach. These networks recreate the fibrous nature of mucin and can serve as a drug-releasing network. In this work, the ability to vary the network properties by blending filomicelles with spherical micelles is demonstrated. In addition, the deposition of a dense polymer coating on the mucin network was shown to act as a barrier to control diffusion and improved the structural stability under simulated oral chemical conditions. These biomimetic coatings can be utilized as a delivery system, providing a tunable drug release for oral applications.

Biopolymeric Mucin and Synthetic Polymer Analogs: Their Structure, Function and Role in Biomedical Applications.

Mucin networks are viscoelastic fibrillar aggregates formed through the complex self-association of biopolymeric glycoprotein chains. The networks form a lubricious, hydrated protective shield along epithelial regions within the human body. The critical role played by mucin networks in impacting the transport properties of biofunctional molecules (e.g., biogenic molecules, probes, nanoparticles), and its effect on bioavailability are well described in the literature. An alternate perspective is provided in this paper, presenting mucin's complex network structure, and its interdependent functional characteristics in human physiology. We highlight the recent advances that were achieved through the use of mucin in diverse areas of bioengineering applications (e.g., drug delivery, biomedical devices and tissue engineering). Mucin network formation is a highly complex process, driven by wide variety of molecular interactions, and the network possess structural and chemical variations, posing a great challenge to understand mucin's bulk behavior. Through this review, the prospective potential of polymer based analogs to serve as mucin mimic is suggested. These analog systems, apart from functioning as an artificial model, reducing the current dependency on animal models, can aid in furthering our fundamental understanding of such complex structures.

Quercetin conjugated poly(ß-amino esters) nanogels for the treatment of cellular oxidative stress.

PßAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compounds which suffer from poor aqueous solubility, low bioavailability and are biologically unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact molecule which is perfectly timed with the polymer degradation. While formulating these quercetin conjugated PßAE matrix into nanocarriers would allow for multiple delivery routes (oral, intravenous, inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-precipitation method was developed to formulate quercetin conjugated PßAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dilute conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aqueous stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concentrations, achieving drug loadings of 25-38wt%. Uniform release of quercetin over 45-48h was observed upon PßAE ester hydrolysis under physiological conditions with its retained antioxidant activity over the extended times. STATEMENT OF SIGNIFICANCE: Here we present the first demonstration of using poly(beta amino ester) chemistry to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chemistry due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chemistry and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells.

Synthetic oral mucin mimic from polymer micelle networks.

Mucin networks are formed in the oral cavity by complexation of glycoproteins with other salivary proteins, yielding a hydrated lubricating barrier. The function of these networks is linked to their structural, chemical, and mechanical properties. Yet, as these properties are interdependent, it is difficult to tease out their relative importance. Here, we demonstrate the ability to recreate the fibrous like network through a series of complementary rinses of polymeric worm-like micelles, resulting in a 3-dimensional (3D) porous network that can be deposited layer-by-layer onto any surface. In this work, stability, structure, and microbial capture capabilities were evaluated as a function of network properties. It was found that network structure alone was sufficient for bacterial capture, even with networks composed of the adhesion-resistant polymer, poly(ethylene glycol). The synthetic networks provide an excellent, yet simple, means of independently characterizing mucin network properties (e.g., surface chemistry, stiffness, and pore size).

Affinity based multilayered polymeric self-assemblies for oral wound applications.

Oral mucositis, a painful and debilitating ulcerative wound condition, is a frequently occurring complication following chemo- and/or radiotherapy. While the current standards of therapy (e.g., gels and mouth rinses) provide temporary relief, there is still an unmet need for a robust, long acting barrier that can provide lubricating protection in oral wounds, thereby enhancing the wound healing response. It is proposed that an affinity based layer-by-layer (LBL) self-assembly that can be administered as a series of mouth rinses could permit the formation of protective barriers, providing a modular approach to regenerative oral therapy. In this study, biotinylated poly(acrylic acid) was synthesized for developing LBL assemblies using biotin-streptavidin affinity linkages. To explore the ability of developed LBL assemblies to potentially resist the harsh intraoral environment, in vitro chemical and ex vivo mechanical tests were performed. The stability results demonstrated significant LBL barrier stability with wear resistance. From statistical analyses, it was deduced that polymer MW and the number of LBL layers contributed significantly to chemical barrier stability. Also, the extent of biotin conjugation played a key role for LBL development and in mechanical barrier stability. Thus, the proposed affinity based LBLs with their excellent barrier properties offer a modular treatment approach in oral mucosal injuries.