Electrical Stimulated Polyvinyl Alcohol-Borax-Graphene Hydrogel for Drug Releasing and Delivery

Functional adhesive hydrogels have attracted tremendous attention due to their versatile potential applications in electronic skins and biomedical engineering. MXenes are emerging 2D materials that promised to be attractive ideal candidates as nanofillers for nanocomposite hydrogels. Herein, a super adhesive MXene‐based nanocomposite hydrogel with self‐healable and conductivity properties is successfully fabricated via a one‐step γ‐radiation polymerization of 2‐(dimethylamino) ethyl methacrylate (DMAEMA) and Ti3C2Tx MXene nanosheets with ultralow contents serve as a crosslinking agent and functional nanofiller simultaneously. It is found that Ti3C2Tx not only plays an important role in the formation of uniform polymer network structure, but also improves the mechanical strength, conductivity, and adhesive properties of composite hydrogels significantly. The Ti3C2Tx/poly(2‐(dimethylamino) ethyl methacrylate) (PDMAEMA) nanocomposite hydrogel exhibits an ionic conductivity of 1.6 mS cm−1, and a super adhesive strength of 5041 kPa to the copper substrate. The resultant hydrogel also exhibits fast automatic self‐healing ability due to the hydrogen bonds between Ti3C2Tx and PDMAEMA chains. This work provides a new method to synthesize the robust MXene‐based environmentally sensitive nanocomposite adhesive hydrogels.

Nanocomposite hydrogels are polymeric networks that possess a unique property of hydration. The presence of alcohols, carboxylic acids and amides as hydrophilic moieties in structure of nanocomposite hydrogels enhances their stiffness and water-absorbing capacity. Addition of cross-linker in the synthesis of hydrogels increases their stability under extreme conditions of temperature, pH and pressure. Natural polymer-based nanocomposite hydrogels are biodegradable, highly hydrophilic and possess good mechanical strength. Gelatin, chitin, cellulose, pectin, carrageenan, starch and alginate are natural polymers commonly used to fabricate nanocomposite hydrogels. Nanocomposite hydrogels have special characteristics such as high swelling rate, selectivity and stimuli-sensitive nature. Here we review nanocomposite hydrogels for environmental protection and biomedical engineering. Applications in biomedical engineering include drug delivery agents, wound dressing, tissue engineering and antibacterials. Applications in environmental protection include ion exchangers, adsorption, photocatalysis and soil conditioning. Many nanocomposite hydrogels show excellent adsorption selectivity for heavy metal ions: Cu2+ up to 30.35 mg/g, Pb2+ up to 35.94 mg/g, and Zn2+ and Fe3+ up to 94.34 mg/g. Xanthan gum-based nanocomposite hydrogel has removed 96% dye from industrial effluent as reported. In addition, most of the nanocomposite hydrogels showed better adsorption capacity for pollutants in the pH range from 5 to 7. The nanocomposite hydrogels could also be regenerated and successfully utilized for several times. Nanocomposite hydrogels are therefore good bio-absorbent materials for environmental detoxification.

In the past several decades, various types of nanostructured biomaterials have been developed. These nanostructured biomaterials have promising applications in biomedical fields such as bone repair, tissue engineering, drug delivery, gene delivery, antibacterial agents, and bioimaging. Nanostructured biomaterials with high biocompatibility, including calcium phosphate, hydroxyapatite, and calcium silicate, are ideal candidates for drug delivery. This review article is not intended to offer a comprehensive review of the nanostructured biomaterials and their application in drug delivery but rather presents a brief summary of the recent progress in this field. Our recent endeavors in the research of nanostructured biomaterials for drug delivery are also summarized. Special attention is paid to the synthesis and properties of nanostructured biomaterials and their application in drug delivery with the use of typical examples. Finally, we discuss the problems and future perspectives of nanostructured biomaterials in the drug delivery field.

Porous-based biomaterials for tissue engineering and drug delivery applications

Hyaluronic acid (HA) is made up of repeating disaccharide units (β-1,4-d-glucuronic acid and β-1,3-N-acetyl-d-glucosamine) and is a major constituent of the extracellular matrix. HA and its derivatives which possess excellent biocompatibility and physiochemical properties have been studied in drug delivery and tissue engineering applications. Tyramine-based HA hydrogel with good compatibility to cell and tissue has been reported recently. However, inferior mechanical property may limit the biomedical application of the HA hydrogel. In this study, HA/graphene oxide (GO) nanocomposite (NC) hydrogel was prepared through a horseradish peroxidase catalyzed in situ cross-linking process. As compared with pure HA hydrogels, incorporation of GO to the HA matrix could significantly enhance the mechanical properties (storage moduli 1800 Pa) of the hydrogel and prolong the release of rhodamine B (RB) as the model drug from the hydrogel (33 h) as well. In addition, due to the multiple interactions between GO and RB, the NC hydrogels showed excellent pH-responsive release behavior. The release of RB from the NC hydrogel was prolonged at low pH (pH 4.0) in the presence of GO, which could be attributed to the enhanced interactions between GO and HA as well as with RB. In situ three-dimensional encapsulation of mouse embryonic fibroblasts (BALB 3T3 cells) in the NC hydrogels and cytotoxicity results indicated the cytocompatibility of both the enzymatic cross-linking process and HA/GO NC hydrogels (cell viability 90.6 ± 4.25%). The enzymatically catalyzed fabrication of NC hydrogels proved to be an easy and mild approach, and had great potential in the construction of both tissue engineering scaffolds and stimuli-responsive drug release matrices.

SYNTHESIS AND CHARACTERIZATION OF POLYIONIC HYDROGELS By Pooja N Desai M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Biomedical Engineering at Virginia Commonwealth University. Virginia Commonwealth University, 2008 Major Director: Dr. Hu Yang Assistant Professor Biomedical Engineering In this study we describe novel polyionic dendrimer – PEG hydrogels for drug delivery. Hydrogels have a crosslinked insoluble network of polymer chains, which have found many applications including drug delivery and tissue regeneration. Dendrimers provide an ideal platform for drug delivery as they possess a well-defined highly branched nanoscale architecture with many reactive surface groups. Their highly clustered surface groups allow for targeted drug delivery and high drug payload to enhance therapeutic effectiveness. This study presented a new type of polyionic hydrogels based on dendrimers with potential applications in drug delivery and tissue engineering. Polyethylene glycol (PEG) with various chain lengths [1500, 6000 , 12000 Da] was first conjugated to the StarburstTM G3.0 PAMAM dendrimer to form stealth dendrimers through one ending site of PEG using p-nitro phenyl chloroformate and Triethylamine. The free hydroxyl group of PEG was further converted to an acrylate group using acrolyl chloride and Triethylamine. The conjugation was characterized with H-NMR. The Ninhydrin assay was used to estimate the loading degree of PEG on the dendrimer surface. The molecular weight and loading degree of PEG was varied. Hydrogel formation was realized by subjecting dendrimer-PEG acrylate to UV exposure for a brief period of time at the presence of Eosin Y, Triethanolamine [TEOA] and 1 vinyl 2 Pyrrolidinone [NVP] photo initiator system. Viscosity increase was observed after hydrogel formation. PEGylated G3.0 PAMAM dendrimer served as cross-linking agent to form hydrogels because of its multiple functionalities. PEGylated half generation dendrimer G3.5 was subjected to hydrogel formation and its swelling behavior was studied. Better hydrogel formation was observed with increased PEG arm length. The surface charges conferred by terminal groups on the dendrimer surface made the hydrogel polyionic with controllable charge density. This new type of hydrogel has many favorable biological properties such as non toxicity and non immunogenecity and multifunctional ties for a variety of in vivo applications. Current studies have demonstrated feasibility of chemistry and hydrogel formation. The swelling studies demonstrated pH sensitive behavior. Degradation of hydrogel was observed, for low PEGylated dendrimer degradation also demonstrated pH sensitivity. Controlled drug delivery and release were also investigated. Hydrophobic drug Cyclosprine A was used, we envision that hydrophobic dendrimer core will used for drug encapsulation and delivery, and later release in controlled fashion. The polymer and hydrogels were evaluated for in vitro cytotoxicity and cell internalization.

In the determination of the bioavailability of drugs administered orally, the drugs’ solubility and permeability play a crucial role. For absorption of drug molecules and production of a pharmacological response, solubility is an important parameter that defines the concentration of the drug in systemic circulation. It is a challenging task to improve the oral bioavailability of drugs that have poor water solubility. Most drug molecules are either poorly soluble or insoluble in aqueous environments. Polymer nanocomposites are combinations of two or more different materials that possess unique characteristics and are fused together with sufficient energy in such a manner that the resultant material will have the best properties of both materials. These polymeric materials (biodegradable and other naturally bioactive polymers) are comprised of nanosized particles in a composition of other materials. A systematic search was carried out on Web of Science and SCOPUS using different keywords, and 485 records were found. After the screening and eligibility process, 88 journal articles were found to be eligible, and hence selected to be reviewed and analyzed. Biocompatible and biodegradable materials have emerged in the manufacture of therapeutic and pharmacologic devices, such as impermanent implantation and 3D scaffolds for tissue regeneration and biomedical applications. Substantial effort has been made in the usage of bio-based polymers for potential pharmacologic and biomedical purposes, including targeted deliveries and drug carriers for regulated drug release. These implementations necessitate unique physicochemical and pharmacokinetic, microbiological, metabolic, and degradation characteristics of the materials in order to provide prolific therapeutic treatments. As a result, a broadly diverse spectrum of natural or artificially synthesized polymers capable of enzymatic hydrolysis, hydrolyzing, or enzyme decomposition are being explored for biomedical purposes. This summary examines the contemporary status of biodegradable naturally and synthetically derived polymers for biomedical fields, such as tissue engineering, regenerative medicine, bioengineering, targeted drug discovery and delivery, implantation, and wound repair and healing. This review presents an insight into a number of the commonly used tissue engineering applications, including drug delivery carrier systems, demonstrated in the recent findings. Due to the inherent remarkable properties of biodegradable and bioactive polymers, such as their antimicrobial, antitumor, anti-inflammatory, and anticancer activities, certain materials have gained significant interest in recent years. These systems are also actively being researched to improve therapeutic activity and mitigate adverse consequences. In this article, we also present the main drug delivery systems reported in the literature and the main methods available to impregnate the polymeric scaffolds with drugs, their properties, and their respective benefits for tissue engineering.

Electrospinning: Applications in drug delivery and tissue engineering

Polyurethanes (PUs) have properties that make them promising in biomedical applications. PU is recognized as one of the main families of blood and biocompatible materials. PU plays a vital role in the design of medical devices in various medical fields. The structure of PU contains two segments: soft and hard. Its elastomeric feature is due to its soft segment, and its excellent and high mechanical property is because of its hard segment. It is possible to achieve specific desirable and targeted properties by changing the soft and hard chemical structures and the ratio between them. The many properties of PU each draw the attention of different medical fields. This work reviews PU highlighted properties, such as biodegradability, biostability, shape memory, and improved antibacterial activity. Also, because PU has a variety of applications, this review restricts its focus to PU’s prominent applications in tissue engineering, cardiovascular medicine, drug delivery, and wound healing. In addition, it contains a brief review of PU’s applications in biosensors and oral administration.

Engineering nanocomposite hydrogels using dynamic bonds

The field of biomaterials has advanced significantly in the past decade. With the growing need for high-throughput manufacturing and screening, the need for modular materials that enable streamlined fabrication and analysis of tissue engineering and drug delivery schema has emerged. Microparticles are a powerful platform that have demonstrated promise in enabling these technologies without the need to modify a bulk scaffold. This building block paradigm of using microparticles within larger scaffolds to control cell ratios, growth factors and drug release holds promise. Gelatin microparticles (GMPs) are a well-established platform for cell, drug and growth factor delivery. One of the challenges in using GMPs though is the limited ability to modify the gelatin post-fabrication. In the present work, we hypothesized that by thiolating gelatin before microparticle formation, a versatile platform would be created that preserves the cytocompatibility of gelatin, while enabling post-fabrication modification. The thiols were not found to significantly impact the physicochemical properties of the microparticles. Moreover, the thiolated GMPs were demonstrated to be a biocompatible and robust platform for mesenchymal stem cell attachment. Additionally, the thiolated particles were able to be covalently modified with a maleimide-bearing fluorescent dye and a peptide, demonstrating their promise as a modular platform for tissue engineering and drug delivery applications.

Hydrogels are widely studied for their stimuli‐responsive properties. They adapt to external stimuli, including physical, chemical and biological ones. To enhance adaptability in complex environments, multi‐responsive hydrogels have been developed, which either react to multiple stimuli independently or cooperatively (multistimuli‐response) or exhibit multiple responses triggered by single or multiple stimuli (multi‐response). Their properties depend on polymer type, molecular weight, cross‐linking, and water content, which affect mechanical behavior and response. To address their inherent fragility, polymer‐inorganic nanocomposite hydrogels integrate the advantages of both components, yielding enhanced functionalities. Among various nanofillers, smectites have been extensively studied for improving mechanical strength and responsiveness. Polymer‐smectite nanocomposite hydrogels exhibit enhanced elasticity, toughness, thermal stability, gas barrier properties, and responsiveness to external stimuli, expanding their applications in biomedical engineering, environmental remediation, and smart materials. This review discusses the fundamentals of polymer‐smectite nanocomposite hydrogels, their design strategies, and the role of smectite in enabling multi‐responsive behavior. The classification based on the site of responsiveness (polymer network and smectite) is presented, highlighting the important role of smectite in controlling the response and potential applications. Finally, challenges are addressed, emphasizing smectite's role in advancing next‐generation smart materials.

Nanodiamonds (NDs) have unique optical and mechanical characteristics, surface chemistry, extensive surface area and biocompatibility, and they are nontoxic, rendering them suitable for a diverse range of applications. Recently, NDs have received significant attention in nano-biomedical engineering. This review discusses the recent advancement of NDs’ biomedical engineering, historical background, basic introduction to nanoparticles and development. We summarize NDs’ synthesis technique, properties and applications. Two methodologies are used in ND synthesis: bottom-up and top-down. We cover synthesis methods, including detonation, ball milling, laser ablation, chemical vapor deposition (CVD) and high pressure and high temperature (HPHT); discuss the properties of NDs, such as fluorescence and biocompatibility. Due to these properties, NDs have potential applications in biomedical engineering, including bioimaging, biosensing, drug delivery, tissue engineering and protein mimics. Further, it provides an outlook for future progress, development and application of NDs in biological and biomedical areas.

Hydrogels have emerged as a versatile class of materials with broad applications in biomedical engineering, drug delivery, and tissue engineering. Understanding their intricate structures and morphologies is crucial for tailoring their properties to meet specific biomedical needs. It has been clearly established that the composition and microarchitecture of the materials play a critical role in essential cellular mechanisms such as mechanosensing, adhesion, and remodeling. This question is essential in tissue engineering, where precisely characterizing the microarchitecture of the materials used to model the cell microenvironment is a critical step to ensure the reproducibility and relevance of reconstructed tissues. In this study, we present a comprehensive comparison of four advanced electron microscopy techniques, namely, scanning electron microscopy, cryo-scanning electron microscopy, environmental scanning electron microscopy, and transmission electron microscopy, to observe the hydrogel microarchitecture, including a comparison of the sample preparation methods for each technique. Each technique's specific advantages and limitations are discussed in detail, highlighting their unique capabilities in characterizing the hydrogel structures. We illustrate this study with two semisynthetic hydrogels, such as gelatin methacrylate and hyaluronic acid methacrylate. Moreover, we delve into the critical sample preparation steps necessary for each method, emphasizing the need to preserve the hydrogel's native state while obtaining high-resolution images. This comparative analysis aims to select the most suitable electron microscopy technique for their hydrogel studies, fostering deeper insights into the design and development of advanced biomaterials for tissue engineering applications.

ABSTRACTIntroduction: The applications of naturally obtained polymers are tremendously increased due to them being biocompatible, biodegradable, environmentally friendly and renewable in nature. Among them, polyhydroxyalkanoates are widely studied and they can be utilized in many areas of human life research such as drug delivery, tissue engineering, and other medical applications.Areas covered: This review provides an overview of the polyhydroxyalkanoates biosynthesis and their possible applications in drug delivery in the range of micro- and nano-size. Moreover, the possible applications in tissue engineering are covered considering macro- and microporous scaffolds and extracellular matrix analogs.Expert commentary: The majority of synthetic plastics are non-biodegradable so, in the last years, a renewed interest is growing to develop alternative processes to produce biologically derived polymers. Among them, PHAs present good properties such as high immunotolerance, low toxicity, biodegradability, so, they are promisingly using as biomaterials in biomedical applications.