Biocompatible Injectable Hydrogel Research Articles

Chitosan-PNIPAM Thermogel Associated with Hydrogel Microspheres as a Smart Formulation for MSC Injection.

Regenerative medicine based on cell therapy has emerged as a promising approach for the treatment of various medical conditions. However, the success of cell therapy heavily relies on the development of suitable injectable hydrogels that can encapsulate cells and provide a conducive environment for their survival, proliferation, and tissue regeneration. Herein, we address the medical need for cyto- and biocompatible injectable hydrogels by reporting on the synthesis of a hydrogel-forming thermosensitive copolymer. The copolymer was synthesized by grafting poly(N-isopropylacrylamide-co-carboxymethyl acrylate) (PNIPAM-COOH) onto chitosan through amide coupling. This chemical modification resulted in the formation of hydrogels that exhibit a sol-gel transition with an onset at approximately 27 °C, making them ideal for use in injectable applications. The hydrogels supported the survival and proliferation of cells for several days, which is critical for cell encapsulation. Furthermore, the study evaluates the addition of collagen/chitosan hybrid microspheres to support the adhesion of mesenchymal stem cells within the hydrogels. Altogether, these results demonstrate the potential of the PNIPAM-chitosan thermogel for cell encapsulation and its possible applications in regenerative medicine.

Naturally Derived Injectable Dual-Cross-Linked Adhesive Hydrogel for Acute Hemorrhage Control and Wound Healing.

Developing biocompatible injectable hydrogels with high mechanical strength and rapid strong tissue adhesion for hemostatic sealing of uncontrolled bleeding remains a prevailing challenge. Herein, we engineer an injectable and photo-cross-linkable hydrogel based on naturally derived gelatin methacrylate (GelMA) and N-hydroxysuccinimide-modified poly(γ-glutamic acid) (γPGA-NHS). The chemically dual-cross-linked hydrogel rapidly forms after UV light irradiation and covalently bonds to the underlying tissue to provide robust adhesion. We demonstrate a significantly improved hemostatic efficacy of the hydrogel using various injury models in rats compared to the commercially available fibrin glue. Notably, the hydrogel can achieve hemostasis in porcine liver and spleen incision, and femoral artery puncture models. Moreover, the hydrogel is used for sutureless repair of the liver defect in a rat model with a significantly suppressed inflammatory response, enhanced angiogenesis, and superior healing efficacy compared to fibrin glue. Together, this study offers a promising bioadhesive for treating severe bleeding and facilitating wound repair.

Injectable nanofibrillar hydrogels based on charge-complementary peptide co-assemblies.

Injectable hydrogels are attractive for therapeutic delivery because they can be locally administered through minimally-invasive routes. Charge-complementary peptide nanofibers provide hydrogels that are suitable for encapsulation of biotherapeutics, such as cells and proteins, because they assemble under physiological temperature, pH, and ionic strength. However, relationships between the sequences of charge-complementary peptides and the physical properties of the hydrogels that they form are not well understood. Here we show that hydrogel viscoelasticity, pore size, and pore structure depend on the pairing of charge-complementary "CATCH(+/-)" peptides. Oscillatory rheology demonstrated that co-assemblies of CATCH(4+/4-), CATCH(4+/6-), CATCH(6+/4-), and CATCH(6+/6-) formed viscoelastic gels that can recover after high-shear and high-strain disruption, although the extent of recovery depends on the peptide pairing. Cryogenic scanning electron microscopy demonstrated that hydrogel pore size and pore wall also depend on peptide pairing, and that these properties change to different extents after injection. In contrast, no obvious correlation was observed between nanofiber charge state, measured with ζ-potential, and hydrogel physical properties. CATCH(4+/6-) hydrogels injected into the subcutaneous space elicited weak, transient inflammation whereas CATCH(6+/4-) hydrogels induced stronger inflammation. No antibodies were raised against the CATCH(4+) or CATCH(6-) peptides following multiple challenges in vehicle or when co-administered with an adjuvant. These results demonstrate that CATCH(+/-) peptides form biocompatible injectable hydrogels with viscoelastic properties that can be tuned by varying peptide sequence, establishing their potential as carriers for localized delivery of therapeutic cargoes.

Adhesive, Self-Healing, and Antibacterial Chitosan Hydrogels with Tunable Two-Layer Structures

Hydrogels with multifunctional properties such as biocompatibility, adhesion, and self-healing and inherent antibacterial properties are of great significance in biomedical applications, especially for wound dressings and drug release. However, it remains a significant challenge to combine all of these properties in a one-component hydrogel system. Furthermore, most injectable hydrogels are mechanically weak and not self-healing, which limits their applications as wound dressings. Herein, we designed a hydrogel with a tunable two-layer structure that endows the hydrogel with adhesion, self-healing, and antibacterial properties in different layers. First, chitosan (CHI) was oxidized to aldehyde-chitosan (ACHI). The Schiff base reaction was then used to fabricate the CHI/ACHI hydrogel resulting in the first layer. For the second layer, a physical cross-linking process using phytic acid (PA) as a sequential cross-linker was achieved, resulting in a CHI/ACHI/PA hydrogel. The CHI/ACHI hydrogel exhibited good injectable, adhesion, and self-healing properties. After cross-linking with PA, the CHI/ACHI/PA hydrogel showed enhanced mechanical properties, which enabled it to act as a protective layer. Additionally, the antibacterial test and cytotoxicity tests performed on this two-layer structured CHI/ACHI hydrogel exhibited excellent inherent antibacterial activity and good biocompatibility. The biocompatible injectable hydrogel was endowed with more possibilities relying on its self-healing and antibacterial abilities. These properties endorse the CHI/ACHI two-layer hydrogel as an excellent candidate for biological applications, especially wound dressings.

Reinforcement of hydrogel scaffold using oxidized-guar gum incorporated with curcumin-loaded zein nanoparticles to improve biological performance

Newly, the use of biocompatible injectable hydrogel with appropriate features for application in the tissue engineering area as a perfect wound dressing has been more attracted. For this purpose, the curcumin loaded Zein nanoparticles/aldehyde-modified guar gum/silk fibroin (Cur-NPs/OGG/SF) hydrogel networks were successfully developed to increase the Cur bioavailability during the wound treatment procedure. Fabricated hydrogels were assessed for their morphological, thermal stability, degradation, and mechanical features. By varying the OGG/SF weight ratios, the physicochemical features of hydrogels without or with Cur-loaded Zein NPs were studied. The results showed that with enhancing the OGG content, the degradation behavior of hydrogels were improved. Besides, Cur-NPs/OGG/SF hydrogels increased the cell proliferation without any cytotoxic effect on mouse embryonic fibroblast (NIH-3T3) cells. The Cur-NPs/OGG/SF hydrogel exposed inhibition activity against Bacillus (15.26 ± 1.09 mm) and E. coli (11.54± 1.36 mm) bacteria. These achieved results recommended that the novel developed hydrogel could be suitable for wound healing application.

The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke: a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches.

Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans.

Development and novel design of clustery graphene oxide formed Conductive Silk hydrogel cell vesicle to repair and routine care of myocardial infarction: Investigation of its biological activity for cell delivery applications

Cell delivery therapy is a talented and hopeful strategic approach to repair the damaged cardiac tissues after myocardial infarction. The biocompatible injectable hydrogel with bioactive nanomaterials with effective self-healing capability has been highly required for the cell delivery and regeneration therapy. In the present study, we have developed the biopolymeric and biocompatible self-healing silk protein hydrogel matrix with graphene oxide nanoformulations as cell delivery vehicles for the treatment of myocardial infarction regeneration. The materials combinations, structural interactions, thermal stability and morphology of the designed hydrogel were investigated and elaborated. To improve therapeutic potential of the hydrogel matrix, growth factor was loaded and investigated its biological activity such as cell survival and cell proliferations properties by using endothelial progenitor cells. Collected, these developed materials are excellent vesicle for cell therapy in myocardial infarction.

Biocompatible Injectable Hydrogel with Potent Wound Healing and Antibacterial Properties.

Two component injectable hydrogels that cross-link in situ have been used as noninvasive wound-filling devices, i.e., sealants. These materials carry a variety of functions at the wound sites, such as sealing leaks, ceasing unwanted bleeding, binding tissues together, and assisting in wound healing processes. However, commonly used sealants typically lack antibacterial properties. Since bacterial infection at the wound site is very common, bioadhesive materials with intrinsic antibacterial properties are urgently required. Herein, we report a biocompatible injectable hydrogel with inherent bioadhesive, antibacterial, and hemostatic capabilities suitable for wound sealing applications. The hydrogels were developed in situ from an antibacterial polymer, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), and a bioadhesive polymer, polydextran aldehyde. The gels were shown to be active against both Gram-positive and Gram-negative bacteria, including drug-resistant ones such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiela pneumoniae. Mechanistic studies revealed that the gels killed bacteria upon contact by disrupting the membrane integrity of the pathogen. Importantly, the gels were shown to be efficacious in preventing sepsis in a cecum ligation and puncture (CLP) model in mice. While only 12.5% of animals survived in the case of mice with punctured cecam but with no gel on the punctured area (control), 62.5% mice survived when the adhesive gel was applied to the punctured area. Furthermore, the gels were also shown to be effective in facilitating wound healing in rats and ceasing bleeding from a damaged liver in mice. Notably, the gel showed negligible toxicity toward human red blood cells (only 2-3% hemolysis) and no inflammation to the surrounding tissue upon subcutaneous implantation in mice, thus proving it as a safe and effective antibacterial sealant.

Biodegradable Three-Layered Micelles and Injectable Hydrogels.

Polymeric micelles have found a growing interest as gene vectors due to the serious safety concerns associated with viral vectors. In particular, the cationic polymer polyethylene imine (PEI) has shown relatively high condensation and transfection efficiencies. Additionally, polyethylene glycol (PEG) modification of polymeric gene vectors has dramatically improved their biological properties, including enhanced biocompatibility, prolonged circulation time, and increased bio-distribution. However, PEG grafting of PEI for subsequent condensation of nucleic acids (NAs) does not necessarily result in the formation of a PEI/NAs core with a PEG corona. But often times, the presence of PEG interferes with PEI's electrostatic interaction with NAs. We describe here a facile method to prepare multilayered biodegradable micelles which address some of the critical drawbacks associated with current PEI-based systems. The polyplex micelles have superb stability and stealth properties. Moreover, we describe a method to prepare fully biodegradable and biocompatible injectable hydrogels for use in localized gene therapy.

Engineering an injectable nanocomposite hydrogel to deliver angiogenic growth factors

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.

Fenton reaction-initiated formation of biocompatible injectable hydrogels for cell encapsulation.

A chemical-crosslinked, biocompatible and injectable hydrogel was formed by Fenton reaction initiated polymerization. The gelation time of N-(2-hydroxyethyl)acrylamide and PEG-diacrylate, which are two representative monomers, was shown to be tunable from instant to 15 min at an H2O2 concentration below several mmol L-1 in neutral medium. The strength of the hydrogel could be regulated by the concentration of the monomer and the Fenton's reagent. The hydrogels prepared by H2O2/Fe2+ initiation showed low cytotoxicity. The bone marrow mesenchymal stem cells and L929 cells encapsulated in the gels exhibited high viability even after 7 days of co-culture. Both the L929 cells encapsulated in situ into the hydrogels and those co-cultured with the hydrogel showed negligible cell death and apoptosis. It is anticipated that the familiar Fenton reaction may act as a new initiator system to fabricate biocompatible injectable hydrogels.