Extracellular matrix (ECM)-inspired high-strength gelatin-alginate based hydrogels for bone repair.

It has always been a huge challenge to construct high-strength hydrogels that are composed entirely of natural polymers. In this study, inspired by the structural characteristics of the extracellular matrix (ECM), gelatin and hydrazide alginate were employed to mimic the composition of collagen and glycosaminoglycans (GAGs) in the ECM, respectively, to develop natural polymer (NP) high-strength hydrogels crosslinked by physical and covalent interactions (Gelatin-HAlg-DN). First, HAlg and gelatin can form physically crosslinked hydrogels (Gelatin-HAlg) due to electrostatic and hydrogen bond interactions. Then, the Gelatin-HAlg hydrogels can be further covalently crosslinked in the presence of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to obtain Gelatin-HAlg-DN hydrogels. The obtained Gelatin-HAlg-DN hydrogels exhibit considerably enhanced mechanical properties (tensile strength: 0.9 MPa; elongation at break: 177%) with a maximum 16- and 3.2-fold increase in tensile strength and elongation at break, respectively, compared with gelatin methacrylate (GelMA) hydrogels. Importantly, the Gelatin-HAlg-DN hydrogels exhibit excellent biodegradability and swelling stability under physiological conditions, and the capability to support cell adhesion and proliferation. In a rat critical size bone defect model, Gelatin-HAlg-DN hydrogels loaded with psoralen could effectively promote bone regeneration, showing appealing potential as tissue engineering scaffolds.

A gel microparticle-based self-thickening strategy for 3D printing high-modulus hydrogels skeleton cushioned with PNAGA hydrogel mimicking anisotropic mechanics of meniscus.

Developing a meniscus substitute mimicking the anisotropic mechanics (higher circumferential tensile modulus and lower compressive modulus) of native tissue remains a great challenge. In this work, based on the pendant group structure-dependent H-bonding strengthening mechanism, two kinds of amide-based H-bonding crosslinked hydrogels with distinct mechanical behaviors, that is, the flexible poly(N-acryloyl glycinamide) (PNAGA) and the ultra-stiff poly(N-acryloylsemicarbazide) (PNASC) hydrogels are employed to construct the biomimetic meniscus substitute. To this end, a gel microparticle-based self-thickening strategy is first proposed to fabricate PNASC (GMP-PNASC) high-modulus hydrogels skeleton by extrusion printing technology in mimicking the collagen fibers in native meniscus to resist the circumferential tensile stress. Then, the PNAGA hydrogel is infused into the PNASC skeleton to replicate the proteoglycan, providing a lower compressive modulus. By regulating the structural features at the interior and peripheral regions, the GMP-PNASC/PNAGA hydrogel meniscus scaffold with the higher tensile modulus (87.28 ± 6.06 MPa) and lower compressive modulus (2.11 ± 0.28 MPa) can be constructed. In vivo outcome at 12 weeks post-implantation of rabbit's medial meniscectomy model confirms the effects of GMP-PNASC/PNAGA meniscus scaffold on alleviating the wear of articular cartilage and ameliorating the development of osteoarthritis (OA).

Injectable hydrogel based on dodecyl-modified N-carboxyethyl chitosan/oxidized konjac glucomannan effectively prevents bleeding and postoperative adhesions after partial hepatectomy.

Hemostasis and prevention of postoperative adhesions after hepatectomy are still challenges. In this work, we chose chitosan, a competitive candidate hemostatic material, as the backbone, and konjac glucomannan as the functional moieties, to form an injectable hydrogel. The hydrogel was prepared by the Schiff base reaction of dodecyl-modified N-carboxyethyl chitosan (DCEC) and oxidized konjac glucomannan (OKGM), which could effectively prevent bleeding and postoperative adhesions. The resultant hydrogel possessed self-healing and tissue adhesive capability, and combined the unique bioactivities of two polysaccharides: DCEC endowed the hydrogel with excellent antibacterial and hemostatic ability by the electrostatic and hydrophobic interactions between the cell membrane and amine/dodecyl groups, and OKGM imparted hydrogel anti-inflammatory action by activating macrophages. Moreover, the notable hemostatic efficacy of the hydrogel was confirmed in a rat hepatectomy model. The hydrogel could prevent postoperative adhesions and down-regulate the inflammatory factor TNF-α and the pro-fibrotic factor TGF-ß1 in situ, which might be caused by the combination of the barrier function of hydrogel and instinct bioactivities of DCEC and OKGM. Thus, this multifunctional injectable hydrogel is potentially valuable for preventing bleeding and postoperative adhesions after hepatectomy.

3D printing of lubricative stiff supramolecular polymer hydrogels for meniscus replacement.

3D printing of a stiff and lubricative hydrogel-based meniscus substitute has been challenging since printability and stiffness compromise each other. In this work, based on an upgraded self-thickening and self-strengthening strategy, a unique multiple H-bonding monomer N-acryloylsemicarbazide (NASC) is firstly copolymerized with a super-hydrophilic monomer carboxybetaine acrylamide (CBAA) in dimethyl sulfoxide (DMSO)/H2O to form a soft poly(NASC-co-CBAA) gel, in which PCBAA serves to weaken the H-bonding interaction and avoid hydrophobic phase separation. The poly(NASC-co-CBAA) gel is then loaded with concentrated NASC and CBAA, followed by heating to form a thickening sol ink, which is printed into different objects that are further photoirradiated to initiate the copolymerization of entrapped NASC and CBAA, resulting in the formation of a high performance hydrogel with a Young's modulus of 10.98 MPa, tensile strength of 1.87 MPa and tearing energy of 5333 J m-2 after DMSO is completely replaced with water, due to the re-establishment of NASC H-bonds. Importantly, PCBAA affords high lubricity in printed hydrogels. The printed PNASC-PCBAA meniscus substitute can substitute rabbit's native meniscus and ameliorate the cartilage surface wear within a set 12-week time window, portending great potential as a meniscal substitute and other soft-supporting tissue scaffolds.

Tea eggs-inspired high-strength natural polymer hydrogels.

Natural polymer (NP) hydrogels are an irreplaceable class of biomaterials owing to their identified biosafety; however, the intrinsic poor mechanical strengths severely limit their applications as structural tissue engineering scaffolds. Inspired by the stiffening albumen gel of tea eggs, a traditional Chinese snack, high-strength NP hydrogels are constructed by simply soaking in aqueous solution of tea polyphenols (TP), an active ingredient extracted from tea. The TP-treated representative NP hydrogels exhibit considerably enhanced multifaceted mechanical properties with maximum 19-/30-, 8.4-, 6.1-, 72-fold increases in tensile/compressive strengths, Young's modulus, elongation at break and facture toughness, respectively, compared with pristine hydrogels, primarily due to the hydrogen bonding interactions between TP and NP chains. The TP-treated NP hydrogels can resist different large deformations, which cannot be achieved by their original species at all. In aqueous solution, the TP-treated NP hydrogels can still maintain robust mechanical performances, in spite of somewhat decline in strengths with release of TP, which just favorably affords increased water contents, antibacterial and antioxidant activities. GelMA-TP hydrogel is shown to facilitate wound healing in a full-thickness skin defect model. Importantly, the weak 3D printed GelMA scaffolds are significantly strengthened by TP treatment, broadening the possibility for customizing individualized bioscaffolds.

An Ultrasoft Self-Fused Supramolecular Polymer Hydrogel for Completely Preventing Postoperative Tissue Adhesion.

The intermolecular H-bonding density heavily influences the gelation and rheological behavior of hydrogen-bonded supramolecular polymer hydrogels, thus offering a delicate pathway to tailor their physicochemical properties for meeting a specific biomedical application. Herein, one methylene spacer between two amides in the side chain of N-acryloyl glycinamide (NAGA) is introduced to generate a variant monomer, N-acryloyl alaninamide (NAAA). Polymerization of NAAA in aqueous solution affords an unprecedented ultrasoft and highly swollen supramolecular polymer hydrogel due to weakened H-bonds caused by an extra methylene spacer, which is verified by variable-temperature Fourier transform infrared (FTIR) spectroscopy and simulation calculation. Intriguingly, poly(N-acryloyl alaninamide) (PNAAA) hydrogel can be tuned to form a transient network with a self-fused and excellent antifouling capability that results from the weakened dual amide H-bonding interactions and enhanced water-amide H-bonding interactions. This self-fused PNAAA hydrogel can completely inhibit postoperative abdominal adhesion and recurrent adhesion after adhesiolysis in vivo. This transient hydrogel network allows for its disintegration and excretion from the body. The molecular mechanism studies reveal the signal pathway of PNAAA hydrogel in inhibiting inflammatory response and regulating fibrinolytic system balance. This self-fused, antifouling ultrasoft supramolecular hydrogel is promising as a barrier biomaterial for completely preventing postoperative tissue adhesion.

A Solvent-Free and Water-Resistant Dipole-Dipole Interaction-Based Super Adhesive.

Water-resistant and high-strength adhesion on different surfaces has attracted considerable attention for decades. However, the adhesion performances of conventional adhesives suffer from deterioration in adhesion performances under water or wet conditions. This work proposes a dipole-dipole interaction strategy for fabricating a solvent-free adhesive that is synthesized via simple one-step copolymerization of dipole monomer acrylonitrile (AN), crosslinker poly(ethylene glycol) diacrylate (PEGDA) with variable length, and a monomer-soluble initiator that initiates room-temperature polymerization. The dipole-dipole interactions from cyan groups in AN concurrently contribute to strong cohesion and adhesion strength in bonding to a wide range of substrates including aluminum, ceramic, glass fiber, epoxy resin, polyethylene terephthalate, wood, and fractured large segmental bone. The adhesion strengths are dependent upon the length of PEGDA, and the shorter PEGDA-crosslinked PAN adhesive demonstrates outstanding water-resistant adhesion spanning pH 2 to pH 10 for 30 days with adhesion strength ranging from 3.31 to 3.97 MPa due to strong dipole-dipole pairing shielding. This dipole-dipole interaction and co-dissolution strategy open a new avenue for creating high-strength water-resistant adhesives for promising applications in engineering and hard-tissue repair.

A robust poly(N-acryloyl-2-glycine)-based sponge for rapid hemostasis.

The development of a hemostatic sponge that can be used for treating both arterial hemorrhage and non-compressible bleeding remains a challenge. In this work, we propose the fabrication of a robust hemostatic sponge by a hydrogen bond strengthening and in situ bubble expanding strategy in thermo-initiation polymerization. A thickening agent, carboxymethyl cellulose (CMC), is incorporated into a hydrogen bonding N-acryloyl-2-glycine (ACG) monomer and an initiator, and vortexing generates air bubbles in the viscous liquid. Heating initiates fast polymerization, and meanwhile aids in expanding of bubbles, which results in the fixation of bubbles throughout the network, and the formation of porous hydrogels. Further lyophilization of the foaming hydrogels leads to the final generation of PACG/CMC sponges with robust compressive strengths due to the hydrogen bonding interactions of PACG. PACG/CMC sponges are shown to demonstrate a tunable liquid absorption ability, in vitro hemostatic ability, better hemocompatibility and cytocompatibility. In a rat liver injury model and a femoral artery injury model, the PACG/CMC sponge can significantly reduce the bleeding time and blood loss compared with gauze and commercial gelatin sponge because of the high blood absorption ability and effective concentration of blood coagulation factors. This PACG sponge holds promising potential as a hemostatic agent applicable in an emergency.

A Fe3+-crosslinked pyrogallol-tethered gelatin adhesive hydrogel with antibacterial activity for wound healing.

In this work, a tunicate-inspired gelatin-based hydrogel is prepared by simply mixing 2,3,4-trihydroxybenzaldehyde (THB)-tethered gelatin solution with a small amount of Fe3+ ions via the Schiff-base reaction and simultaneous formation of hexavalent Fe-complexes. The resulting hydrogel (termed GelTHB-Fe) exhibits not only tunable gelation time, rheological properties and self-healing ability by adjusting the composition, but also robust adhesion to a variety of materials, with an average adhesion strength of 136.7 kPa, 147.3 kPa, 153.7 kPa, 92.9 kPa, and 56.5 kPa to PMMA, iron, ceramics, glass and pigskin, respectively. Intriguingly, the pyrogallol moieties impart an antibacterial activity to the GelTHB-Fe hydrogel, which is shown to reduce infection and promote wound healing in a diabetic rat model. This GelTHB-Fe hydrogel holds great potential as a promising tissue adhesive.

Fabrication of strong hydrogen-bonding induced coacervate adhesive hydrogels with antibacterial and hemostatic activities.

In this work, a biocompatible poly(N-hydroxyethyl acrylamide) (PHEAA) polymer with hydrogen bonding acceptors and donors in its side chains is prepared and mixed with tannic acid (TA) to form a supramolecular coacervate hydrogel (TAHE) due to multiple hydrogen-bonding interactions between TA and PHEAA. The coacervate TAHE hydrogel exhibits not only self-healing and antibacterial properties, but also strong adhesion to various substrates, with average adhesion strengths of 722 kPa, 522 kPa, 484 kPa, and 322 kPa to the substrates of iron, PMMA, ceramics, and glass, respectively. Notably, the hydrogel reformed by the rehydration of freeze-dried and ground TAHE hydrogel powder retains the initial adhesive performance and exhibits an excellent hemostatic ability. This novel adhesive hydrogel holds great potential as an adhesive hemostatic material for self-rescue in emergency situations.

Coadministration of an Adhesive Conductive Hydrogel Patch and an Injectable Hydrogel to Treat Myocardial Infarction.

Over the past decade, tissue-engineering strategies, mainly involving injectable hydrogels and epicardial biomaterial patches, have been pursued to treat myocardial infarction. However, only limited therapeutic efficacy is achieved with a single means. Here, a combined therapy approach is proposed, that is, the coadministration of a conductive hydrogel patch and injectable hydrogel to the infarcted myocardium. The self-adhesive conductive hydrogel patch is fabricated based on Fe3+-induced ionic coordination between dopamine-gelatin (GelDA) conjugates and dopamine-functionalized polypyrrole (DA-PPy), which form a homogeneous network. The injectable and cleavable hydrogel is formed in situ via a Schiff base reaction between oxidized sodium hyaluronic acid (HA-CHO) and hydrazided hyaluronic acid (HHA). Compared with a single-mode system, injecting the HA-CHO/HHA hydrogel intramyocardially followed by painting a conductive GelDA/DA-PPy hydrogel patch on the heart surface results in a more pronounced improvement of the cardiac function in terms of echocardiographical, histological, and angiogenic outcomes.

Water-Triggered Hyperbranched Polymer Universal Adhesives: From Strong Underwater Adhesion to Rapid Sealing Hemostasis.

Despite recent advance in bioinspired adhesives, achieving strong adhesion and sealing hemostasis in aqueous and blood environments is challenging. A hyperbranched polymer (HBP) with a hydrophobic backbone and hydrophilic adhesive catechol side branches is designed and synthesized based on Michael addition reaction of multi-vinyl monomers with dopamine. It is demonstrated that upon contacting water, the hydrophobic chains self-aggregate to form coacervates quickly, displacing water molecules on the adherent surface to trigger increased exposure of catechol groups and thus rapidly strong adhesion to diverse materials from low surface energy to high energy in various environments, such as deionized water, sea water, PBS, and a wide range of pH solutions (pH = 3 to 11) without use of any oxidant. Also, this HBP adhesive (HBPA) exhibits a robust adhesion to fractured bone, precluding the problem of mismatched surface energy and mechanical properties. The HBPA's adhesion is repeatable in a wet condition. Intriguingly, the HBPA is capable of gluing dissimilar materials with distinct properties. Importantly, introducing long alkylamine into this modular hyperbranched architecture contributes to formation of an injectable hemostatic sealant that can rapidly stop visceral bleeding, especially hemorrhage from deep wound.