A synthetic mimic of mussel adhesive protein, dopamine-modified four-armed poly(ethylene glycol) (PEG-D4), was combined with a synthetic nanosilicate, Laponite (Na0.7+(Mg5.5Li0.3Si8)O20(OH)4)0.7–), to form an injectable naoncomposite tissue adhesive hydrogel. Incorporation of up to 2 wt % Laponite significantly reduced the cure time while enhancing the bulk mechanical and adhesive properties of the adhesive due to strong interfacial binding between dopamine and Laponite. The addition of Laponite did not alter the degradation rate and cytocompatibility of PEG-D4 adhesive. On the basis of subcutaneous implantation in rat, PEG-D4 nanocomposite hydrogels elicited minimal inflammatory response and exhibited an enhanced level of cellular infiltration as compared to Laponite-free samples. The addition of Laponite is potentially a simple and effective method for promoting bioactivity in a bioinert, synthetic PEG-based adhesive while simultaneously enhancing its mechanical and adhesive properties.
Due to the increasing needs for organ transplantation and a universal shortage of donated tissues, tissue engineering emerges as a useful approach to engineer functional tissues. Although different synthetic materials have been used to fabricate tissue engineering scaffolds, they have many limitations such as the biocompatibility concerns, the inability to support cell attachment, and undesirable degradation rate. Fibrin gel, a biopolymeric material, provides numerous advantages over synthetic materials in functioning as a tissue engineering scaffold and a cell carrier. Fibrin gel exhibits excellent biocompatibility, promotes cell attachment, and can degrade in a controllable manner. Additionally, fibrin gel mimics the natural blood-clotting process and self-assembles into a polymer network. The ability for fibrin to cure in situ has been exploited to develop injectable scaffolds for the repair of damaged cardiac and cartilage tissues. Additionally, fibrin gel has been utilized as a cell carrier to protect cells from the forces during the application and cell delivery processes while enhancing the cell viability and tissue regeneration. Here, we review the recent advancement in developing fibrin-based biomaterials for the development of injectable tissue engineering scaffold and cell carriers.
The remarkable underwater adhesion strategy employed by mussels has inspired bioadhesives that have demonstrated promise in connective tissue repair, wound closure, and local delivery of therapeutic cells and drugs. While the pH of oxygenated blood and internal tissues is typically around 7.4, skin and tumor tissues are significantly more acidic. Additionally, blood loss during surgery and ischemia can lead to dysoxia, which lowers pH levels of internal tissues and organs. Using 4-armed PEG end-capped with dopamine (PEG-D) as a model adhesive polymer, the effect of pH on the rate of intermolecular cross-linking and adhesion to biological substrates of catechol-containing adhesives was determined. Adhesive formulated at an acidic pH (pH 5.7–6.7) demonstrated reduced curing rate, mechanical properties, and adhesive performance to pericardium tissues. Although a faster curing rate was observed at pH 8, these adhesives also demonstrated reduced mechanical and bioadhesive properties when compared to adhesives buffered at pH 7.4. Adhesives formulated at pH 7.4 demonstrated a good balance of fast curing rate, elevated mechanical properties and interfacial binding ability. UV–vis spectroscopy evaluation revealed that the stability of the transient oxidation intermediate of dopamine was increased under acidic conditions, which likely reduced the rate of intermolecular cross-linking and bulk cohesive properties for hydrogels formulated at these pH levels. At pH 8, competing cross-linking reaction mechanisms and reduced concentration of dopamine catechol due to auto-oxidation likely reduced the degree of dopamine polymerization and adhesive strength for these hydrogels. pH plays an important role in the adhesive performance of mussel-inspired bioadhesives and the pH of the adhesive formulation needs to be adjusted for the intended application.
A simple strategy is provided to construct novel supramolecular hydrogels with both self-healing and shape memory properties. Starting from achieving self-healable hydrogel based on the dynamic interactions of phenylboronic acid modified sodium alginate (Alg-PBA) and poly(vinyl alcohol) (PVA), further formation of a complex of alginate with Ca(2+) renders this hydrogel with the capability of shape memory at the macro-/microscopic scales.
Engineering bioadhesives to bind and conform to the complex contour of tissue surfaces remains a challenge. We developed a novel moldable nanocomposite hydrogel by combining dopamine-modified poly(ethylene glycol) and nano-silicate, Laponite, without using cytotoxic oxidants. The hydrogel transitioned from a reversibly crosslinked network formed from dopamine-Laponite interfacial interactions to a covalently crosslinked network through the slow autoxidation and crosslinking of catechol moieties. Initially, the hydrogel can be remolded to different shapes, can recover from large strain deformation, and can be injected through a syringe to adhere to the convex contour of a tissue surface. With time, the hydrogel solidified to adopt the new shape and sealed defects on the tissue. This fit-to-shape sealant has potential in sealing tissues with non-flat geometries, such as a sutured anastomosis.
To decouple the extracellular oxidative toxicity of catechol adhesive moiety from its intracellular non-oxidative toxicity, dopamine was chemically bound to a non-degradable polyacrylamide hydrogel through photo-initiated polymerization of dopamine methacrylamide (DMA) with acrylamide monomers. Network-bound dopamine released cytotoxic levels of H2O2 when its catechol side chain oxidized to quinone. Introduction of catalase at a concentration as low as 7.5 U/mL counteracted the cytotoxic effect of H2O2 and enhanced the viability and proliferation rate of fibroblasts. These results indicated that H2O2 generation is one of the main contributors to the cytotoxicity of dopamine in culture. Additionally, catalase is a potentially useful supplement to suppress the elevated oxidative stress found in typical culture conditions and can more accurately evaluate the biocompatibility of mussel-mimetic biomaterials. The release of H2O2 also induced a higher foreign body reaction to catechol-modified hydrogel when it was implanted subcutaneously in rat. Given that H2O2 has a multitude of biological effects, both beneficiary and deleterious, regulation of H2O2 production from catechol-containing biomaterials is necessary to optimize the performance of these materials for a desired application.
A simple strategy is provided to construct a novel pH- and sugar-induced shape memory hydrogel based on dynamic phenylboronic acid (PBA)-diol interactions formed by PBA-modified sodium alginate (Alg-PBA) and poly(vinyl alcohol) (PVA). The dynamic PBA-diol ester bonds serve as temporary cross-links and stabilize the deformed shape of the hydrogel. The disassociation of the PBA-diol ester bonds is explored in acidic conditions and aqueous solutions of glucose and fructose, which endow the hydrogel with shape memory performances.
Microgels that can generate antipathogenic levels of hydrogen peroxide (H2O2) through simple rehydration in solutions with physiological pH are described herein. H2O2 is a widely used disinfectant but the oxidant is hazardous to store and transport. Catechol, an adhesive moiety found in mussel adhesive proteins, was incorporated into microgels, which generated 1–5 mM of H2O2 for up to four days as catechol autoxidized. The sustained release of low concentrations of H2O2 was antimicrobial against both gram-positive (Staphylococcus epidermidis) and gram-negative (Escherichia coli) bacteria and antiviral against both non-enveloped porcine parvovirus (PPV) and enveloped bovine viral diarrhea virus (BVDV). The amount of released H2O2 is several orders of magnitude lower than H2O2 concentration previously reported for antipathogenic activity. Most notably, these microgels reduced the invectively of the more biocide resistant non-envelope virus by 3 log reduction value (99.9% reduction in infectivity). By controlling the oxidation state of catechol, microgels can be repeatedly activated and deactivated for H2O2 generation. These microgels do not contain a reservoir for storing the reactive H2O2 and can potentially function as a lightweight and portable dried powder source for the disinfectant for a wide range of applications.
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