Hydrogels for biomedical applications.

The native chemical ligation reaction (NCL) involves reacting a C-terminal peptide thioester with an N-terminal cysteinyl peptide to produce a native peptide bond between the two fragments. This reaction has considerably extended the size of polypeptides and proteins that can be produced by total synthesis and has also numerous applications in bioconjugation, polymer synthesis, material science, and micro- and nanotechnology research. The aim of the present review is to provide a thorough mechanistic overview of NCL and extended methods. The most relevant properties of peptide thioesters, Cys peptides, and common solvents, reagents, additives, and catalysts used for these ligations are presented. Mechanisms, selectivity and reactivity are, whenever possible, discussed through the insights of computational and physical chemistry studies. The inherent limitations of NCL are discussed with insights from the mechanistic standpoint. This review also presents a palette of O, S-, N, S-, or N, Se-acyl shift systems as thioester or selenoester surrogates and discusses the special molecular features that govern reactivity in each case. Finally, the various thiol-based auxiliaries and thiol or selenol amino acid surrogates that have been developed so far are discussed with a special focus on the mechanism of long-range N, S-acyl migrations and selective dechalcogenation reactions.

Native Chemical Ligation and Extended Methods: Mechanisms, Catalysis, Scope, and Limitations

Stimuli-Responsive Nanocomposite Hydrogels for Biomedical Applications

Injectable hydrogels have received considerable interest in the biomedical field due to their potential applications in minimally invasive local drug delivery, more precise implantation, and site-specific drug delivery into poorly reachable tissue sites and into interface tissues, where wound healing takes a long time. Injectable hydrogels, such as in situ forming and/or shear-thinning hydrogels, can be generated using chemically and/or physically crosslinked hydrogels. Yet, for controlled and local drug delivery applications, the ideal injectable hydrogel should be able to provide controlled and sustained release of drug molecules to the target site when needed and should limit nonspecific drug molecule distribution in healthy tissues. Thus, such hydrogels should sense the environmental changes that arise in disease states and be able to release the optimal amount of drug over the necessary time period to the target region. To address this, researchers have designed stimuli-responsive injectable hydrogels. Stimuli-responsive hydrogels change their shape or volume when they sense environmental stimuli, e.g., pH, temperature, light, electrical signals, or enzymatic changes, and deliver an optimal concentration of drugs to the target site without affecting healthy tissues.

Recent Advances in Injectable Hydrogels for Controlled and Local Drug Delivery

Owing to their unique chemical and physical properties, hydrogels are attracting increasing attention in both basic and translational biomedical studies. Although the classical hydrogels with static networks have been widely reported for decades, a growing number of recent studies have shown that structurally dynamic hydrogels can better mimic the dynamics and functions of natural extracellular matrix (ECM) in soft tissues. These synthetic materials with defined compositions can recapitulate key chemical and biophysical properties of living tissues, providing an important means to understanding the mechanisms by which cells sense and remodel their surrounding microenvironments. This review begins with the overall expectation and design principles of dynamic hydrogels. We then highlight recent progress in the fabrication strategies of dynamic hydrogels including both degradation-dependent and degradation-independent approaches, followed by their unique properties and use in biomedical applications such as regenerative medicine, drug delivery, and 3D culture. Finally, challenges and emerging trends in the development and application of dynamic hydrogels are discussed.

Structurally Dynamic Hydrogels for Biomedical Applications: Pursuing a Fine Balance between Macroscopic Stability and Microscopic Dynamics.

https://pubs.acs.org/doi/pdf/10.1021/acs.biomac.8b00908

Native Chemical Ligation for Cross-Linking of Flower-Like Micelles.

Conversion of an Injectable MMP-Degradable Hydrogel into Core-Cross-Linked Micelles.

Inhibition of Octreotide Acylation Inside PLGA Microspheres by Derivatization of the Amines of the Peptide with a Self-Immolative Protecting Group

Figure 1.1 Chemical structure of poly(Nisopropylacrylamide) (PNIPAM). Poly(N-isopropylacrylamide) (PNIPAM) (Figure 1.1) has attracted a lot of attention during the past decades because of its thermoresponsive behavior in a biomedically interesting temperature window. This polymer exhibits inverse solubility in aqueous media and precipitates upon increasing the temperature [1, 2]. The temperature at which this polymer converts from a soluble state to an insoluble state, known as the cloud point (CP) or the lower critical solution temperature (LCST), is 32 ∘C [3]. The first study on the PNIPAM phase diagram was reported by Heskins and Guillet [2] Since then this polymer has been known as a thermosensitive polymer. PNIPAM has been prepared by a wide range of polymerization techniques such as free radical polymerization (FRP) [4], redox polymerization [5], ionic polymerization [6], radiation polymerization [7], and living radical polymerization [8]. The focus of this chapter is on polymerization techniques, and examples are given addressing PNIPAM’s potential applications as biomaterial in drug and gene delivery and bioseparation. For other applications of PNIPAM in, e.g. membranes, sensors, thin films, and brushes, the reader is referred to reviews published elsewhere [9–12]. After introducing the general physicochemical properties of PNIPAM, an overview of the most frequently used polymerization techniques (free and living radical polymerization) is given, and a variety of copolymers and structures obtained by these methods are highlighted. Copolymerization with other monomers or conjugation/grafting of PNIPAM with other stimuli-responsive polymers/materials results in dual responsive materials, of which the physical properties can be changed by several stimuli, e.g. changes in pH or redox conditions, light, and magnetic field. Examples of these systems along with the effect of copolymer composition on the LCST of PNIPAM are provided in this chapter. In addition, different methods of chemical and physical crosslinking and their effects on properties of the final materials are discussed.

Poly(N‐isopropylacrylamide): Physicochemical Properties and Biomedical Applications

ABC triblock copolymers with a poly(ethylene glycol) (PEG) midblock have attractive properties for biomedical applications because of PEG’s favorable properties regarding biocompatibility and hydrophilicity. However, easy strategies to synthesize polymers containing a PEG midblock are limited. In this study, the successful synthesis of a heterofunctional PEG macroinitiator containing both an azoinitiator and an atom transfer radical polymerization (ATRP) initiator is demonstrated. This novel PEG macroinitiator allows the development of elegant synthesis routes for PEG midblock-containing ABC copolymers that does not require protection of initiating sites or polymer end-group postmodification. Polymers with outer blocks composed of different monomers were synthesized to illustrate the versatility of this macroinitiator. N-Isopropylacrylamide (NIPAM) was included to obtain thermosensitive polymers, 2-(dimethylamino)ethyl methacrylate (DMAEMA) provided pH-sensitive properties, and 2-hydroxyethyl acrylate (HE...

Marzieh Najafi

Papers

Native Chemical Ligation for Cross-Linking of Flower-Like Micelles.

Conversion of an Injectable MMP-Degradable Hydrogel into Core-Cross-Linked Micelles.

Inhibition of Octreotide Acylation Inside PLGA Microspheres by Derivatization of the Amines of the Peptide with a Self-Immolative Protecting Group

Poly(N‐isopropylacrylamide): Physicochemical Properties and Biomedical Applications

Heterofunctional Poly(ethylene glycol) (PEG) Macroinitiator Enabling Controlled Synthesis of ABC Triblock Copolymers