Research on the fabrication and properties of injectable antimicrobial hydrogels composed of mesoporous polydopamine

Endoscopic submucosal dissection (ESD) is a widely used procedure for the treatment of early and precancerous gastrointestinal lesions and has become the standard treatment. In this procedure, the commonly used materials have a short retention time and a limited lifting capacity, which will prolong the duration of the ESD procedure. Furthermore, these liquids tend to diffuse after ESD surgery, failing to adequately protect the wound. Therefore, we designed and developed injectable hydrogels based on hyaluronic acid. A series of oxidized hyaluronic acid (OHA) and hydrazide hyaluronic acid (AHA) were synthesized, and 16 kinds of injectable hydrogels were fabricated to investigate the effects of molecular structures on the properties of the hydrogels. Among these, the O1A3 hydrogel exhibited a suitable injection performance, gelation time, and mechanical properties, along with good blood and cell compatibility in vitro. Subsequently, in a porcine model of the ESD procedure, the results demonstrated that the O1A3 hydrogel exhibited a good retention time and lifting performance while also significantly reducing the operation time from 1-2 h to ∼10 min. Furthermore, the adhesive property of the O1A3 hydrogel on small bleeding spots and wounds could be observed, which was beneficial in protecting the wound from the complex environment of the gastrointestinal tract. The present work of injectable hyaluronic acid-based hydrogels could be promising to improve the efficiency of ESD surgery.

Acceleration of gelation in the biological environment and improvement of overall biological properties of a hydrogel is of enormous importance. Biopolymer stabilized gold (Au) nanoparticles (NPs) exhibit cytocompatibility and therapeutic activity. Hence, in situ gelation and subsequent improvement in the property of a hydrogel by employing Au NPs is an attractive approach. We report that stable Au NPs accelerate the conventional nucleophilic substitution reaction of activated halide-terminated poly(ethylene glycol) and tertiary amine functional macromolecules, leading to the rapid formation of injectable nanocomposite hydrogels in vivo and ex vivo with improved modulus, cell adhesion, cell proliferation, and cytocompatibility than that of a pristine hydrogel. NP surfaces with low chain grafting density and good colloidal stability are crucial requirements for the use of these NPs in the hydrogel formation. Influence of the structure of the amine functional prepolymer, the spacer connecting the halide leaving groups of the substrate, and the structure of the stabilizer on the rate promoting activity of the NPs have been evaluated with model low-molecular-weight substrates and macromolecules by 1H NMR spectroscopy, rheological experiments, and density functional theory. Results indicate a significant effect of the spacer connecting the halide leaving group with the macromolecule. The Au nanocomposite hydrogels show sustained co-release of methotrexate, an anti-rheumatic drug, and the Au NPs. This work provides insights for designing an injectable nanocomposite hydrogel system with multifunctional property. The strategy of the use of cytocompatible Au NPs as a promoter provides new opportunity to obtain an injectable hydrogel system for biological applications.

Injectable PEG-induced silk nanofiber hydrogel for vancomycin delivery

Injectable hydrogelsviabio-orthogonal chemistry.

Event Abstract Back to Event Engineering an injectable nanocomposite hydrogel to deliver angiogenic growth factors Settimio Pacelli1, Divya Murali1, Kartikeya Singh Jodha1, Jon Whitlow1 and Arghya Paul1 1 University of Kansas, Chemical and Petroleum Engineering, United States Introduction: Injectable hydrogels represent an useful strategy for drug delivery and tissue engineering as they can be easily placed into the defect site with minimum invasiveness[1]. Moreover, the introduction of nanoparticles in the polymer network can be a strategy to improve their general properties and influence their ability to act as carrier of biological factors[2]. Here we present the synthesis and characterization of a nanocomposite injectable hydrogel made of biocompatible polymers such as gelatin and chitosan in combination with nanodiamonds (ND)[3] as a carrier of the vascular endothelial growth factor (VEGF165) to promote angiogenesis in vitro. Materials and Methods: Injectable hydrogels were prepared by combining chitosan (1.5% w/v) with beta-glycerophosphate (2% w/v) and gelatin (2% w/v) using genipin (0.02% w/v) as crosslinker. The ND suspension in water (0.05% w/v) with a dimension distribution of 20-60 nm was sonicated for 10 minutes prior mixing with the polymeric solution. Time sweep at 37°C along with frequency sweep studies in the range of 0.01 up to 10 Hz were carried out to investigate respectively the time of gelation and the influence of ND on the final strength. Young's elastic modulus was calculated from the slope of the curve stress strain in the range of 5-10% of strain. VEGF165 was complexed with ND suspension using a ratio ND/VEGF165 500:1 and the amount of VEGF165 loaded in each gel was 10 ng. Human umbilical vein endothelial cells (HUVECs) were seeded on the gels with a cell density of 50,000 cells and cultured in media without VEGF165 and bFGF. MTT assay to test ND cytotoxicity and actin and DAPI staining were assessed in vitro. Results and Discussion: Genipin was kept constant in all formulations while the concentration of gelatin was varied up to 2% w/v (Gel 2%) and was found to reduce significantly the time of gelation (Fig 1A). Regarding the influence of ND on the gel mechanical properties, an increase in the value of G’ was detected in all formulations (Fig 1B) indicating a possible interaction of the ND with the polymeric network. The same trend was observed studying the Young’s modulus values obtained by compressing the hydrogels up to the point of breakage (Fig 1C). ND were able also to influence the swelling degree, reducing the amount of water uptaken by the hydrogels (Fig 1D) which can indirectly influence the release of loaded growth factors although no difference in porosity was observed among the different groups. Biocompatibility of the hydrogels were tested using HUVECs which were able to spread all over the surface at day 3 (Fig 1E) and a higher proliferation was observed when VEGF was loaded in the hydrogel (Fig 1F). Conclusions: The presence of ND positively influenced the mechanical properties of the biocompatible injectable hydrogels. Morever ND were not cytotoxic and a higher proliferation of HUVECs was obtained when VEGF165 was loaded inside the gel in the presence of ND. Overall these results suggest the possible use of this injectable hydrogel to promote angiogenesis in vitro. Arghya Paul likes to acknowledge the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences, National Institutes of Health (NIH), under Award Number P20GM103638.

Fabrication of composite hydrogels by assembly of okara cellulose nanofibers and gum Arabic in ionic liquids: Structure and properties

On account of minimally invasive procedure and of filling irregular defects of tissues, injectable hydrogels are increasingly attractive in biomedical fields. However, traditional hydrogel formed by simple physical interaction or in situ crosslinking had inevitably some drawbacks such as low mechanical strength and lack of multifunctional properties. Though many investigations had successfully modified traditional injectable hydrogel to obtain both mechanical and functional properties, an acetalated β-cyclodextrin (Ac-β-CD) nanoparticle composite injectable hydrogel designed in the research was another effective and efficient choice to solve the drawbacks. First of all, gelatin derivative (G-AA) and Ac-β-CD were synthesized to prepare hydrogel and nanoparticle, respectively. In order to ensure good compatibility between nanoparticle and macromonomer and provide crosslink points between nanoparticle and macromonomer, G-AA was simultaneously functionalized onto the surface of Ac-β-CD nanoparticle during the fabrication of Ac-β-CD nanoparticle using one-step method. Finally, injectable composite hydrogel was obtained by photoinitiated polymerization in situ. Hydrogel properties like gelation time and swelling ratio were investigated. The viscoelastic behavior of hydrogels confirmed that typical characteristics of crosslinked elastomer for all hydrogel and nanoparticle in hydrogel could improve the mechanical property of hydrogel. Moreover, the transparency with time had verified obvious acid-response properties of hydrogels.

Poly(N-isopropylacrylamide)-based dual-crosslinking biohybrid injectable hydrogels for vascularization

A self-healing, magnetic and injectable biopolymer hydrogel generated by dual cross-linking for drug delivery and bone repair

Fabrication, characteristics and properties of α-lactalbumin fibril-derived hydrogels: Effects of metal ions type.

Enzymatically catalyzed cross-linking is a hydrogel fabrication method that generally is considered to have lower cytotoxicity than traditional chemical cross-linking methods. In order to optimize the properties of injectable hydrogels and expand their applications, an enzyme-catalyzed cross-linked injectable hydrogel was designed. The tyramine-modified gelatin (G-T) was formed into a stable injectable hydrogel by the combination of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) catalysis. 1H NMR spectroscopy was used to demonstrate the successful modification of gelatin by tyramine. The surface morphology of the prepared hydrogels was characterized jointly by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Rheological tests demonstrated the tunable mechanical strength, formation kinetics, shear thinning and good self-recovery properties of the hydrogels. In addition, the hydrogels can be formed into various shapes by injection. The hydrogel network structure is complex and interlaced, as such it is suitable to encapsulate drugs for controlled release. The drug release from the prepared hydrogels followed the Peppas–Sahlin model and belonged to Fickian diffusion. This study constructed injectable hydrogels through the enzyme-catalyzed cross-linking of modified gelatin and applied the hydrogels for drug release, which is expected to expand the application in biomedical fields.

Biocompatible hydrogels are materials that hold great promise in medicine and biology since the porous structure, the ability to entrap a large amount of water, and the tunability of their mechanical and tissue adhesive properties make them suitable for several applications, including wound healing, drug and cell delivery, cancer treatment, bioelectronics, and tissue regeneration. Among the possible developed systems, injectable hydrogels, owing to their properties, are optimal candidates for in vivo minimally invasive procedures. To be injectable, a hydrogel must be liquid before and during the injection, but it must quickly jellify after injection to form a soft, self-standing, solid material. The possibility to work with a liquid precursor encoding the functions that will be available after gelation allows the development of biocompatible materials that can be employed in surgery and, in particular, in noninvasive procedures. The underlying idea is to reach the target tissue by using just a needle, or by exploiting the natural body orifices, reducing surgery procedure time, induced pain, and risk of infections. Hydrogels with different properties can be obtained by changing the type of cross-linking, the cross-linking density or the molecular weight of the polymer, or by introducing pending functional groups. The introduction of a nanofiller in the hydrogel network allows for expanding the suite of the structural and functional properties and for better mimicking native tissues. In this Account, we discuss how to provide a hydrogel network with designed properties by playing with both the polymeric chains and the fillers. We present selected examples from the literature that show how to introduce stiffness, stretchability, adhesiveness, self-healing, anisotropy, antimicrobial activity, biodegradability, and conductivity in injectable hydrogels. We further describe how the chemical composition, the mechanical properties, and the microarchitecture of the hydrogel influence cell adhesion, proliferation, and differentiation. Examples of injectable hydrogels for innovative minimally invasive procedures are then discussed in detail; in particular, we showcase the use of hydrogels for tumor resection and as vascular chemoembolization agents. We further discuss how one can improve the rheological properties of injectable hydrogels to exploit them in osteochondral tissue engineering. The effect of the introduction of a conductive filler is then presented in relation to the development of electroactive scaffolds for cardiac-tissue engineering and neural and nerve repair. We believe that the rational design of biocompatible, injectable hybrid hydrogels with tunable properties will likely play a crucial role in reducing the invasiveness and improving the outcome of several clinical and surgical setups.

Long-term controlled release in drug-loaded injectable hydrogels is challenging in the injection-based treatments of ocular diseases. Herein, injectable hyaluronic acid (HA)-based hydrogels were synthesized in situ via Schiff base reaction between amino-functionalized hyaluronic acid (NHA) and three aldehyde-functionalized β-cyclodextrin (β-CD) derivatives: aldehyde β-cyclodextrin (ACD), aldehyde linear poly-β-cyclodextrin (ALCD), and aldehyde branched poly-β-cyclodextrin (ABCD). The composition, structure, and properties of the prepared hydrogels were analyzed using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and dynamic rheometry. The hydrogels exhibited a pore size range of 50-250 μm, a swelling degree of 27.1-45.0%, and a gelation time of 60-300 s, demonstrating suitable microstructural and rheological properties for clinical applications. By leveraging the dual functionality of the aldehyde β-CD derivatives as both crosslinking agents and drug carriers (Voriconazole (VCZ) was as a model drug), the hydrogels achieved long-term controlled release (> 60 days) with quasi-zero-order kinetics in the later stage, alongside excellent cellular compatibility, particularly for NHA/ACD (R2 = 0.99701) and NHA/ABCD (R2 = 0.98931). This study presents the first comparative analysis of the effects of structurally distinct aldehyde β-CD/poly-β-CD derivatives on hydrogel properties. The findings provide novel insights into the structural design of aldehyde-functionalized β-CD derivatives for the development of long-term controlled release injectable hydrogels in about 30-60 days as well as tuned. Simultaneously, the corresponding in vivo animal safety and efficacy experiments could further validate the practical application potential of this gel platform in the future work. Conclusively, the injectable HA-based hydrogels have potential as promising candidates for treating chronic ocular pathologies requiring long-term therapy.

Acute myocardial infarction (AMI) has been treated via injectable hydrogels and biomaterial patches invented using tissue engineering advancements over the past decade. Yet the curative potential of injectable hydrogels and stem cells is limited. Here, we propose the development of an injectable and conductive hydrogel composed of oxidised macromolecular hyaluronic acid and chitosan-grafted aniline tetramer polymeric components. In an attempt to enhance the therapeutic potential of AMI therapy, mesenchymal stem cells derived from human umbilical cord blood (HUCB-MSC) have been integrated into the formulation of a conductive hydrogel. For reliable connection to the beating hearts, the hydrogel exhibited suitable adhesive properties. Hydrogel’s potent biocompatibility was determined by in vitro investigations of cell viability and proliferation of NRCMs and H9C2 cardiomyocytes. After myocardial injection, longer HUCB-MSCs survival length, cardiac functioning, and histology in SD rat myocardium were demonstrated, greatly associated by up-regulation and downregulation of cardiac-related relative gene expressions of angiogenic factors and inflammatory factors, respectively. The injectable hydrogel that contained HUCB-MSCs substantially enhanced the therapeutic benefits, indicating a potentially beneficial therapeutic approach to AMI therapy.

Osteoarthritis (OA) is a serious chronic and degenerative disease that increasingly occurs in the aged population. Its current clinical treatments are limited to symptom relief and cannot regenerate cartilage. Although a better understanding of OA pathophysiology has been facilitating the development of novel therapeutic regimen, delivery of therapeutics to target sites with minimal invasiveness, high retention, and minimal side effects remains a challenge. Biocompatible hydrogels have been recognized to be highly promising for controlled delivery and release of therapeutics and biologics for tissue repair. In this review, the current approaches and the challenges in OA treatment, and unique properties of injectable natural polymer hydrogels as delivery system to overcome the challenges are presented. The common methods for fabrication of injectable polysaccharide-based hydrogels and the effects of their composition and properties on the OA treatment are detailed. The strategies of the use of hydrogels for loading and release cargos are also covered. Finally, recent efforts on the development of injectable polysaccharide-based hydrogels for OA treatment are highlighted, and their current limitations are discussed.