New hydrophilic polyesters and related polymers as bioerodible polymeric matrices

A survey is reported on our activity performed in the last few years on the preparation of new synthetic and semisynthetic polymeric materials endowed with bioerodible-biodegradable characteristics and designed for applications in the practice of controlled release of active principles of pharmaceutical and agrochemical significance. The presentation of the results will be arranged into the following sections: (1) hydroxyl containing polyesters, that comprise polymerization products based on racemic and optically active glyceric acid, or attained by polyaddition reactions among cyclic anhydrides, including also carbon dioxide, with monoglycidyl ethers of reversibly protected polyols. In this class are also presented the related polyhydroxylated systems obtained by selective grafting functional epoxides on cyclodextrins. (2) Bioerodible carboxyl containing plolymeric systems as derived from the alternating copolymerization of maleic anhydride with alkyl vinyl ethers followed by partial esterification of maleic anhydride groups. (3) Linear and cross-linked functional polymers of synthetic and semisynthetic origin with hydrogel forming capability. Typical examples of their applications in the release of drugs and phytodrugs are also presented.     

The Unusual Mechanical Evolution of Biodegradable Double Hydrogen Bonding Strengthened Hydrogels in Response to pH Change

Conventionally, biodegradable hydrogels end up with quick disintegration and consequently fail to bear external loading after degradation. Here, a biocleavable high‐strength hydrogel prepared by copolymerization of 2‐vinyl‐4,6‐diamino‐1,3,5‐triazine (alkali active H‐bonding monomer), 3‐acrylamidophenylboronic acid (acid active H‐bonding monomer), oligo(ethylene glycol) methacrylate, and crosslinker N,N′‐bis(acryloyl)cystamine is reported. The hydrogel is shown to be degraded after the disulfide bonds in the chemical crosslinkers are broken down in a reducible medium. Remarkably, the degraded hydrogel evolves into supramolecular network, which is strengthened by diaminotriazine–diaminotriazine and phenylboronic acid–phenylboronic acid dual H‐bonded physical crosslinks despite the loss of chemical crosslinking. It is demonstrated that over a broad pH range, the degraded hydrogels are able to retain macroscopic integrity and withstand high external loading due to the existence of at least one kind of hydrogen bonding crosslinking. This biodegradable double hydrogen bonding strengthened hydrogel may push forward the research on a new type of high‐strength hydrogels.

     

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.Neuronal migration and maturation is a key step in brain development. Defects in this process have been implicated in many disorders, including autism (1) and schizophrenia (2). Thoroughly understanding how neural progenitor cell (NPC) migration is affected in neurodevelopmental disorders requires a means of dissecting the process using cells with genetic alterations matching those in patients. Existing in vitro assays of migration generally involve measurement of cell movement across a scratch or gap or through a membrane toward a chemoattractant in 2D culture systems. Although widely used, such assays may not accurately reveal in vivo differences, as neuronal migration is tightly regulated by physical and chemical cues in the extracellular matrix (ECM) that NPCs encounter as they migrate.In vitro 3D culture systems offer a solution to these limitations (3–7). Compared with 2D culture, a 3D arrangement allows neuronal cells to interact with many more cells (4); this similarity to the in vivo setting has been shown to lengthen viability, enhance survival, and allow formation of longer neurites and more dense networks in primary neurons in uniform matrices or aggregate culture (8, 9). Indeed, 3D culture systems have been used to study nerve regeneration, neuronal and glial development (10–12), and amyloid-β and tau pathology (13). Thus, measuring neuronal migration through a soft 3D matrix would continue this trend toward using 3D systems to study neuronal development and pathology.We sought to develop a 3D assay to examine potential migration and neuronal maturation defects in Rett syndrome (RTT), a genetic neurodevelopmental disorder that affects 1 in 10,000 children in the United States and is caused by mutations in the X-linked methyl-CpG-binding protein-2 (MECP2) gene (14). Studies using induced pluripotent stem cells (iPSCs) from RTT patients in traditional 2D adherent culture have revealed reduced neurite outgrowth and synapse number, as well as altered calcium transients and spontaneous postsynaptic currents (1). However, 2D migration assays seemed unlikely to reveal inherent defects in this developmental process, which could be affected because MeCP2 regulates multiple developmental related genes (15). Migration of RTT iPSC-derived NPCs has not previously been studied.Using a previously unidentified 3D tissue culture system that allows creation of layered architectures, we studied differences in migration of MeCP2-mutant iPSC-derived versus control iPSC-derived NPCs. This approach revealed a defect in migration of MeCP2-mutant iPSC-derived NPCs induced by either astrocytes or neurons. Further, this 3D system accelerated maturation of neurons from human iPSC-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. With mature neurons derived from RTT patients and controls, we further confirmed defective neurite outgrowth and synaptogenesis in MeCP2-mutant neurons. Thus, this 3D system enables study of morphological features accessible in 2D system as well as previously unexamined phenotypes.     

A Redox‐Responsive Supramolecular Hydrogel for Controllable Dye Release

A novel and simple strategy for preparing a redox‐responsive supramolecular hydrogel coassembled from phenylalanine derivative gelator and 4,4′‐dipyridine disulfide is reported in this study. The driving force for the coassembly process is intermolecular hydrogen bonds, as confirmed by various characterization methods, such as ¹H NMR, Fourier transform infrared (FTIR) spectroscopy, and circular dichroism spectroscopy. The disulfide‐containing nanofibrous hydrogel is able to control over the release of encapsulated dyes in response to the reductive condition mimicking the intracellular environment like tumor tissues and should be a promising system for controllable drug release in the fields of nanomedicine and cancer therapy.

     

Meniscus ECM‐functionalised hydrogels containing infrapatellar fat pad‐derived stem cells for bioprinting of regionally defined meniscal tissue

Injuries to the meniscus of the knee commonly lead to osteoarthritis. Current therapies for meniscus regeneration, including meniscectomies and scaffold implantation, fail to achieve complete functional regeneration of the tissue. This has led to increased interest in cell and gene therapies and tissue engineering approaches to meniscus regeneration. The implantation of a biomimetic implant, incorporating cells, growth factors, and extracellular matrix (ECM)‐derived proteins, represents a promising approach to functional meniscus regeneration. The objective of this study was to develop a range of ECM‐functionalised bioinks suitable for 3D bioprinting of meniscal tissue. To this end, alginate hydrogels were functionalised with ECM derived from the inner and outer regions of the meniscus and loaded with infrapatellar fat pad‐derived stem cells. In the absence of exogenously supplied growth factors, inner meniscus ECM promoted chondrogenesis of fat pad‐derived stem cells, whereas outer meniscus ECM promoted a more elongated cell morphology and the development of a more fibroblastic phenotype. With exogenous growth factors supplementation, a more fibrogenic phenotype was observed in outer ECM‐functionalised hydrogels supplemented with connective tissue growth factor, whereas inner ECM‐functionalised hydrogels supplemented with TGFβ3 supported the highest levels of Sox‐9 and type II collagen gene expression and sulfated glycosaminoglycans (sGAG) deposition. The final phase of the study demonstrated the printability of these ECM‐functionalised hydrogels, demonstrating that their codeposition with polycaprolactone microfibres dramatically improved the mechanical properties of the 3D bioprinted constructs with no noticeable loss in cell viability. These bioprinted constructs represent an exciting new approach to tissue engineering of functional meniscal grafts.     

Altering the release of tobramycin by incorporating poly(ethylene glycol) into model silicone hydrogel contact lens materials

Abstract

Delivery of drugs from contact lens materials is attractive for a number of reasons. However, the controlled delivery of hydrophilic drugs can be difficult to achieve due to the burst release of drug that is associated with materials of high water content, such as hydrogels. Silicone hydrogels have significant potential for drug delivery due to their increased hydrophobicity and the tortuous nature of the pores, overcoming some of the limitations associated with conventional hydrogel materials. The aim of this study was to examine the potential of model poly(ethylene glycol) (PEG) containing silicone hydrogels for delivery of hydrophilic aminoglycoside antibiotics. It was hypothesized that PEG, a polymer that has seen extensive use in biomedical applications, will provide in addition to hydrophilicity and protein repulsion, a mechanism for controlling the delivery of this hydrophilic antibiotic. PEG was combined with the macromer TRIS to create the model silicone hydrogel materials. The optical and physical properties of the novel TRIS-co-PEG silicone hydrogels exhibited excellent transparency, appropriate refractive index and high transmittance indicating minimal phase separation. Desirable properties such as wettability and protein repulsion were maintained across a wide range of formulations. The water content was found to be highly correlated with the ethylene oxide content. Drug release could be influenced through PEG content and was found to fit Higuchi-like kinetics. Overall, the study demonstrates that incorporation of PEG into a model silicone hydrogel could be used to control the release of a hydrophilic compound. Data suggests this is related to the unique structure and properties of PEG, which alter the types of water found in each formulation and the water content.     

Polyvinyl pyrrolidone/carrageenan blend hydrogels with nanosilver prepared by gamma radiation for use as an antimicrobial wound dressing

Hydrogels were prepared using polyvinyl pyrrolidone (PVP) blended with carrageenan by gamma irradiation at different doses of 25 and 40 kGy. Gel fraction of hydrogels prepared using 10 and 15% PVP in combination with 0.25 and 0.5% carrageenan was evaluated. Based on gel fraction, 15% PVP in combination with 0.25% carrageenan and radiation dose of 25 kGy was selected for the preparation of hydrogels with nanosilver. Radiolytic synthesis of silver nanoparticles within the PVP hydrogel was carried out. The hydrogels with silver nanoparticles were assessed for antimicrobial effectiveness and physical properties of relevance to clinical performance. Fluid handling capacity (FHC) for PVP/carrageenan was 2.35 ± 0.39–6.63 ± 0.63 g/10 cm² in 2–24 h. No counts for Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Candida albicans were observed in the presence of hydrogels containing 100 ppm nanosilver after 3–6 h. The release of silver from hydrogels containing 100 ppm nanosilver was 20.42 ± 1.98 ppm/100 cm² in 24 h. Hydrogels containing 100 ppm nanosilver with efficient FHC demonstrated potential microbicidal activity (≥3 log₁₀ decrease in CFU/ml) against wound pathogens, P. aeruginosa, S. aureus, E. coli, and C. albicans. PVP/carrageenan hydrogels containing silver nanoparticles can be used as wound dressings to control infection and facilitate the healing process for burns and other skin injuries.     

Clickable Poly(ethylene glycol)‐Microsphere‐Based Cell Scaffolds

Clickable poly(ethylene glycol) (PEG) derivatives are used with two sequential aqueous two‐phase systems to produce microsphere‐based scaffolds for cell encapsulation. In the first step, sodium sulfate causes phase separation of the clickable PEG precursors and is followed by rapid geleation to form microspheres in the absence of organic solvent or surfactant. The microspheres are washed and then deswollen in dextran solutions in the presence of cells, producing tightly packed scaffolds that can be easily handled while also maintaining porosity. Endothelial cells included during microsphere scaffold formation show high viability. The clickable PEG‐microsphere‐based cell scaffolds open up new avenues for manipulating scaffold architecture as compared with simple bulk hydrogels.

     

Cellulose-Based Hydrogels as Sustained Drug-Delivery Systems

Hydrogels, three-dimensional (3D) polymer networks, present unique properties, like biocompatibility, biodegradability, tunable mechanical properties, sensitivity to various stimuli, the capacity to encapsulate different therapeutic agents, and the ability of controlled release of the drugs. All these characteristics make hydrogels important candidates for diverse biomedical applications, one of them being drug delivery. The recent achievements of hydrogels as safe transport systems, with desired therapeutic effects and with minimum side effects, brought outstanding improvements in this area. Moreover, results from the utilization of hydrogels as target therapy strategies obtained in clinical trials are very encouraging for future applications. In this regard, the review summarizes the general concepts related to the types of hydrogel delivery systems, their properties, the main release mechanisms, and the administration pathways at different levels (oral, dermal, ocular, nasal, gastrointestinal tract, vaginal, and cancer therapy). After a general presentation, the review is focused on recent advances in the design, preparation and applications of innovative cellulose-based hydrogels in controlled drug delivery.     

Blended Natural Support Materials—Collagen Based Hydrogels Used in Biomedicine

Due to their unique properties—the are biocompatible, easily accessible, and inexpensive with programmable properties—biopolymers are used in pharmaceutical and biomedical research, as well as in cosmetics and food. Collagen is one of the most-used biomaterials in biomedicine, being the most abundant protein in animals with a triple helices structure, biocompatible, biomimetic, biodegradable, and hemostatic. Its disadvantages are its poor mechanical and thermal properties and enzymatic degradation. In order to solve this problem and to use its benefits, collagen can be used blended with other biomaterials such as alginate, chitosan, and cellulose. The purpose of this review article is to offer a brief paper with updated information on blended collagen-based formulations and their potential application in biomedicine.