BIOMIMETIC ORAL MUCIN FROM POLYMER MICELLE NETWORKS

Mucin networks are formed by the complexation of bottlebrush-like mucin glycoprotein with other small molecule glycoproteins. These glycoproteins create nanoscale strands that then arrange into a nanoporous mesh. These networks play an important role in ensuring surface hydration, lubricity and barrier protection. In order to understand the functional behavior in mucin networks, it is important to decouple their chemical and physical effects responsible for generating the fundamental property-function relationship. To achieve this goal, we propose to develop a synthetic biomimetic mucin using a layer-by-layer (LBL) deposition approach. In this work, a hierarchical 3-dimensional structures resembling natural mucin networks was generated using affinity-based interactions on synthetic and biological surfaces. Unlike conventional polyelectrolyte-based LBL methods, pre-assembled biotin-functionalized filamentous (worm-like) micelles was utilized as the network building block, which from complementary additions of streptavidin generated synthetic networks of desired thickness. The biomimetic nature in those synthetic networks are studied by evaluating its structural and bio-functional properties. Structurally, synthetic networks formed a nanoporous mesh. The networks demonstrated excellent surface hydration property and were able capable of microbial capture. Those functional properties are akin to that of natural mucin networks. Further, the role of synthetic mucin as a drug delivery vehicle, capable of providing localized and tunable release was demonstrated. By incorporating antibacterial curcumin drug loading within synthetic networks, bacterial growth inhibition was also demonstrated. Thus, such bioactive interfaces can serve as a model for independently characterizing mucin network properties and through its role as a drug carrier vehicle it presents exciting future opportunities for localized drug delivery, in regenerative applications and as bio-functional implant coats

STABILITY OF AFFINITY BASED LAYER-BY-LAYER POLYMERIC SELF-ASSEMBLIES FOR ORAL WOUND APPLICATIONS

Oral mucositis is a painful and debilitating chronic inflammatory condition that can result from chemo and/or radiotherapy. While current treatment strategies which provide temporary relief exist, there is still an unmet clinical need for a robust long active barrier strategy which can simultaneously provide protection and release drug to enhance the wound healing response. It is proposed that an affinity based layer-by-layer self-assembled barrier administered as a series of mouth rinses can allow for wound specific drug delivery, providing an effective regenerative therapy. In this work, biotinylated poly(acrylic acid) is used to develop LBL assemblies based upon biotin-streptavidin affinity interactions. To explore the ability of developed LBL assemblies to resist the harsh intraoral environment, in vitro chemical and ex vivo mechanical tests are performed. The stability results demonstrate significant LBL barrier stability with wear resistance. From principal component regression analysis, factors such as polymer MW and number of layers in assemblies contributed significantly to chemical barrier stability. Also it is observed that the extent of biotin conjugation plays a significant role in LBL development and in mechanical stability. Thus, the proposed affinity based multilayered assemblies with their excellent barrier properties offer a modular treatment approach in oral mucosal injuries

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

Human saliva and model saliva at bulk to adsorbed phases – similarities and differences

Human saliva, a seemingly simple aqueous fluid, is, in fact, an extraordinarily complex biocolloid that is not fully understood, despite many decades of study. Salivary lubrication is widely believed to be a signature of good oral health and is also crucial for speech, food oral processing and swallowing. However, saliva has been often neglected in food colloid research, primarily due to its high intra- to inter-individual variability and altering material properties upon collection and storage, when used as an ex vivo research material. In the last decade, colloid scientists have attempted designing model (i.e. ‘saliva mimicking fluid’) saliva formulations to understand saliva-food colloid interactions in an in vitro set up and its contribution on microstructural aspects, lubrication properties and sensory perception. In this Review, we critically examine the current state of knowledge on bulk and interfacial properties of model saliva in comparison to real human saliva and highlight how far such model salivary formulations can match the properties of real human saliva. Many, if not most, of these model saliva formulations share similarities with real human saliva in terms of biochemical compositions, including electrolytes, pH and concentrations of salivary proteins, such as α-amylase and highly glycosylated mucins. This, together with similarities between model and real saliva in terms of surface charge, has led to significant advancement in decoding colloidal interactions (bridging, depletion) of charged emulsion droplets and associated sensory perception in the oral phase. However, model saliva represents significant dissimilarity to real saliva in the lubricating properties. Based on in-depth examination of properties of mucins from animal sources (e.g. pig gastric mucins (PGM) or bovine submaxillary mucin (BSM)), we can recommend that BSM is currently the most optimal mucin source when attempting to replicate saliva based on surface adsorption and lubrication properties. Even though purification via dialysis or chromatographic techniques may influence various physicochemical properties of BSM, such as structure and surface adsorption, the lubricating properties of model saliva formulations based on BSM are generally superior and more reliable than PGM counterpart at orally relevant pH. Comparison of mucin-containing model saliva with ex vivo human salivary conditioning films suggests that mucin alone cannot replicate the lubricity of real human salivary pellicle. Mucin-based multi-layers containing mucin and oppositely charged polyelectrolytes may offer promising avenues in the future for engineering biomimetic salivary pellicle, however, this has not been explored in oral tribology experiments to date. Hence, there is a strong need for systematic studies with employment of model saliva formulations containing mucins with and without polycationic additives before a consensus on a standardized model saliva formulation can be achieved. Overall, this review provides a comprehensive framework on simulating saliva for a particular bulk or surface property when doing food oral processing experiments

Innovative Methods and Applications in Mucoadhesion Research.

The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described

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

Mucin networks are lubricous coatings formed through the continuous deposition and complexation of mucin glycoproteins. This nanoporous mesh covers many epithelial surfaces, providing surface hydration and tissue protection. Previously, we demonstrated the synthesis of a biomimetic mucin using biotinylated-filomicelles crosslinked via streptavidin using a layer-by-layer (LBL) approach. These networks recreate the fibrous nature of mucin and can serve as a drug release network, due to its formation from drug carrier building blocks. 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 contributed to improved structural stability under simulated oral chemical conditions. These biomimetic coatings can be utilized as a drug delivery system, providing a localized and tunable release of payload for oral applications

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)

The use of hydrocolloids in physical modelling of complex biological matrices

Hydrated biological matrices are widely distributed in nature, and the understanding of the complexity and functionality of such systems has increased quite dramatically over the recent years. A picture evolves where such systems are considered as being much more than a bulk filling material but rather represent important physical and biological properties that are pivotal for the survival of the individual organisms. Understanding these properties therefore becomes important in order to e.g. understand pathological conditions and how they can be combatted. Unfortunately, ex vivo investigations of complex biological matrices are not straight forward due to an inherent instability, lack of de novo synthesis and, occasionally, that they are present in very scarce amounts. Hence, it is of great interest to be able to model and study such systems based on available polymers such as hydrocolloids. This mini review describes some of the possibilities and limitations of such models.acceptedVersion© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0