Enhancing the Properties of Self-Healing Gelatin Alginate Hydrogels by Hofmeister Mediated Electrostatic Effect.

The cross-linker-free hydrogels have gained attention due to their lack of need for chemically modified polymers, resulting in better biocompatibility. The hydrogel properties can be enhanced by altering physical forces such as electrostatics and H-bonds. Tuning the physical interactions between polymers, salts, and plasticisers can unlock new horizons in material properties. This article examines four different salts and mixtures to determine their impact on gelatin-alginate biomaterial design. Drug release, swelling, and rheological properties are represented using a 3-D plot, and optimum samples are identified. It is concluded that kosmotropes yield better release and swelling results than chaotropes. The physical interactions of these salts with polymers are explained using DLS and FTIR/ATR studies, and these findings are corroborated with release, swelling, and rheological analyses. Another aspect of the biomaterial, self-healing property, is also considered. A 3-D plot is prepared using release kinetics, gel strength, and recovery percentage (three important factors for self-healing hydrogels). Chaotropes are identified as better candidates for self-healing behaviour. However, when considering gel strength, release, and self-healing, kosmotropes are favourable. Hence, different salts can be selected based on the desired application for hydrogels. It is also concluded that electrostatic forces hinder the formation of H-bonds between polymer chains.

Elucidating the influence of electrostatic force on the re-arrangement of H-bonds of protein polymers in the presence of salts.

Polyampholytes/proteins have an intriguing network of hydrogen bonds (H-bonds), especially their secondary structure, which plays a crucial role in determining the conformational stability of the polymer. The changes in protein secondary structure in the protein-salt system have been extensively deciphered by researchers, yet their pathways for breakage and recreation are unknown. Understanding the mechanism of protein conformational changes towards their biological activities, like protein folding, remains one of the main challenges and requires multiscale analysis of this strongly correlated system. Herein, salts have been used to reveal the re-arrangement behavior in the H-bond network of proteins under the influence of electrostatic interactions, as the strength of electrostatic forces is much stronger than that of H-bonds. At lower salt concentrations, there are negligible changes in the secondary structures as the electrostatic forces induced by the salt ions are less. Later, the existing H-bonds break and reconstruct new H-bonds at higher salt concentrations due to the influence of the stronger electrostatic interaction induced by the large number of salt ions. Molecular dynamics (MD) simulations and FTIR studies have been used rigorously to decipher the reason behind the re-arrangement of the H-bonds within gelatin (protein). The re-arrangement in the H-bond has also been observed with time from simulations and experiments. Thus, this study could provide a fresh perspective on the conformational changes of polyampholytes/proteins and will also influence the studies of protein folding-unfolding interaction in the presence of salt ions.

Molecular interactions of acids and salts with polyampholytes.

The Hofmeister series characterizes the ability of salt anions to precipitate polyampholytes/proteins. However, the variation of protein size in the bulk solution of acids and the effect of salts on the same have not been studied well. In this article, the four acids (CH3COOH, HNO3, H2SO4, and HCl) and their effects on the hydrodynamic radius (RH) of gelatin in the bulk solution are investigated. The effects of Na salt with the same anions are also considered to draw a comparison between the interactions of acids and salts with polyampholytes. It is suggested that the interactions of polyampholytes with acids are different from those of salts. The interaction series of polyampholytes with acids with respect to the RH of the polyampholyte is CH3COO->NO3->Cl->SO42- whereas the interaction series with salts is SO42->CH3COO->Cl->NO3-. These different interactions are due to equilibration between acid dissociation and protonation of polyampholytes. Another important factor contributing to the interactions in weak acids is the fact that undissociated acid hinders the movement of dissociated acid. Experiments and simulations were performed to understand these interactions, and the results were identical in terms of the trend in RH (from the experiments) and the radius of gyration (Rg) (from the simulations). It is concluded that the valence of ions and dissociation affect the interaction in the case of acids. However, the interactions are influenced by the kosmotropic and chaotropic effect, hydration, and mobility in the case of salts.

Imaging Methods for the Assessment of a Complex Hydrogel as an Ocular Drug Delivery System for Glaucoma Treatment: Opportunities and Challenges in Preclinical Evaluation.

Glaucoma is one of the leading causes of loss of vision. The problems associated with the marketed formulations of anti-glaucoma drugs are low bioavailability, unwanted side effects, and low patient compliance. Hydrogels are an important class of soft materials that play a crucial role in developing an ocular drug delivery system. They assume a special significance in addressing the problems associated with the marketed formulations of eyedrops. An appropriate design of the hydrogel system capable of encapsulating single or multiple drugs for glaucoma has emerged in recent times to overcome such challenges. Although various modes of imaging play critical roles in assessing the efficacy of these formulations, evaluating hydrogels for drug permeation and retention remains challenging. Especially, the assessment of dual drugs in the hydrogel system is not straightforward due to the complexity in measuring drug penetration and retention for in vivo or ex vivo systems. There is a need to develop tools for the fabrication and validation of hydrogel-based systems that give insight into precorneal retention, biocompatibility, cellular uptake, and cell permeation. The current review highlights some of the complexities in formulating hydrogel and benchmarking technologies, including confocal laser scanning microscopy, fluorescent microscopy, slit-lamp biomicroscopy, and camera-based imaging. This review also summarizes recent evaluations of various hydrogel formulations using in vitro and in vivo models. Further the article will help researchers from various disciplines, including formulation scientists and biologists, set up preclinical protocols for evaluating polymeric hydrogels.

Electrostatic-Dominated Conformational Fluctuations and Transition States of Phase Separation in Charge-Balanced Protein Polymer.

Hydration of the protein/polymer is the most important aspect of stability. It is well-known that salts alter the charged polymer's electrostatic forces, ultimately impacting its conformations in solution. The solvent effects lead to certain conformational fluctuations. Previous studies have shown the screening of electrostatic repulsion within the charge-imbalanced protein following charge inversion owing to counterion condensation and phase separation. This article studies conformation stability and phase separation of charge-balanced gelatin (a protein polymer at the isoelectric point) with the addition of different salts. A phenomenon has been reported where the electrostatic effect of salts results in conformational fluctuations in gelatin due to its insufficient hydrations (termed as starvation), which scales with salt concentration. This article also presents different transition states for charge-balanced proteins prior to phase separation. It is concluded that phase separation of a charge-balanced protein passes through a stable state followed by an unstable transition state, where certain unique interactions with salts occur.

Interaction-Based Perspective for Designing Polymer Biomaterial: A Strategic Approach to the Chitosan-Glycerophosphate System.

The conventional approach for developing any polymeric biomaterial is to follow protocols available in the literature and/or perform trial-and-error runs without a scientific basis. Here, we propose an analysis of a complex overlay of molecular interactions between drugs and polymers that provides a strategic pathway for biomaterial development. First, this work provides an innovative interaction-based method for developing an ocular formulation involving in situ gelling chitosan, gelatin, and glycerophosphate systems. A systematic interaction study is conducted based on the measurement of hydrodynamic radius, zeta potential, and viscosity with the sequential addition of formulation components. The increase in the hydrodynamic radius of the polymer with the addition of drugs can be interpreted as better diffusion of the drug inside the charged polymer chains and vice versa. Based on the knowledge of these interactions, a formulation has been designed that shows better drug release results with extended and sustained release compared to literature protocols, hence accentuating the importance of this study. An in-depth analysis of interactions can lead to a better understanding of the system. Second, we demonstrate the development of two dual-drug biomaterial systems, i.e., an in situ gelling and a liquid formulation at ocular surface temperature from the same polymers, which can be used as an ocular antiglaucoma formulation. Prior knowledge of the interactions between the drug polymers can be used to design a better formulation. The demonstrated application of this interaction-based protocol development can be extended universally to any biomaterial. This would provide a comprehensive idea about the properties and interactions of polymers and drugs, which can also serve as a base/starting point for a new formulation/biomaterial development.

Unveiling the potentials of hydrophilic and hydrophobic polymers in microparticle systems: Opportunities and challenges in processing techniques.

Conventional drug delivery systems are associated with various shortcomings, including low bioavailability and limited control over release. Biodegradable polymeric microparticles have emerged as versatile carriers in drug delivery systems addressing all these challenges. This comprehensive review explores the dynamic landscape of microparticles, considering the role of hydrophilic and hydrophobic materials. Within the continuously evolving domain of microparticle preparation methods, this review offers valuable insights into the latest advancements and addresses the factors influencing microencapsulation, which is pivotal for harnessing the full potential of microparticles. Exploration of the latest research in this dynamic field unlocks the possibilities of optimizing microencapsulation techniques to produce microparticles of desired characteristics and properties for different applications, which can help contribute to the ongoing evolution in the field of pharmaceutical science.