3D printing sequentially strengthening high-strength natural polymer hydrogel bilayer scaffold for cornea regeneration.

3D printing of high-strength natural polymer biodegradable hydrogel scaffolds simultaneously resembling the biomechanics of corneal tissue and facilitating tissue regeneration remains a huge challenge due to the inherent brittleness of natural polymer hydrogels and the demanding requirements of printing. Herein, concentrated aqueous solutions of gelatin and carbohydrazide-modified alginate (Gel/Alg-CDH) are blended to form a natural polymer hydrogel ink, where the hydrazides in Alg-CDH are found to form strong hydrogen bonds with the gelatin. The hydrogen-bonding-strengthened Gel/Alg-CDH hydrogel demonstrates an appropriate thickened viscosity and shear thinning for extrusion printing. The strong hydrogen bonds contribute to remarkably increased mechanical properties of Gel/Alg-CDH hydrogel with a maximum elongation of over 400%. In addition, sequentially Ca2+-physical crosslinking and then moderately chemical crosslinking significantly enhance the mechanical properties of Gel/Alg-CDH hydrogels that ultimately exhibit an intriguing J-shaped stress-strain curve (tensile strength of 1.068 MPa and the toughness of 677.6 kJ/m2). The dually crosslinked Gel-Alg-CDH-Ca2+-EDC hydrogels demonstrate a high transparency, physiological swelling stability and rapid enzymatic degradability, as well as suturability. The growth factor and drug-loaded biomimetic bilayer hydrogel scaffold are customized via a multi-nozzle printing system. This bioactive bilayer hydrogel scaffold considerably promotes regeneration of corneal epithelium and stroma and inhibits cornea scarring in rabbit cornea keratoplasty.

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.

Wet adhesive hydrogel cardiac patch loaded with anti-oxidative, autophagy-regulating molecule capsules and MSCs for restoring infarcted myocardium.

Hydrogel patch-based stem cell transplantation and microenvironment-regulating drug delivery strategy is promising for the treatment of myocardial infarction (MI). However, the low retention of cells and drugs limits their therapeutic efficacies. Here, we propose a prefixed sponge carpet strategy, that is, aldehyde-dextran sponge (ODS) loading anti-oxidative/autophagy-regulating molecular capsules of 2-hydroxy-ß-cyclodextrin@resveratrol (HP-ß-CD@Res) is first bonded to the rat's heart via capillary removal of interfacial water from the tissue surface, and the subsequent Schiff base reaction between the aldehyde groups on ODS and amino groups on myocardium tissue. Then, an aqueous biocompatible hydrazided hyaluronic acid (HHA) solution encapsulating mesenchymal stem cells (MSCs) is impregnated into the anchored carpet to form HHA@ODS@HP-ß-CD@Res hydrogel in situ via click reaction, thus prolonging the in vivo retention time of therapeutic drug and cells. Importantly, the HHA added to outer surface consumes the remaining aldehydes to contribute to nonsticky top surface, avoiding adhesion to other tissues. The embedded HP-ß-CD@Res molecular capsules with antioxidant and autophagy regulation bioactivities can considerably improve cardiac microenvironment, reduce cardiomyocyte apoptosis, and enhance the survival of transplanted MSCs, thereby promoting cardiac repair by facilitating angiogenesis and reducing cardiac fibrosis.

An anticoagulant/hemostatic indwelling needle for oral glucose tolerance test.

Indwelling needles are widely used in the clinic for their advantages of reducing the pain and discomfort caused by repeated venipuncture. Achieving anticoagulation and hemostasis with one single indwelling needle is highly desired from perspective of implantation patency and the prevention of needle-withdrawal-induced uncontrolled bleeding. Herein, we develop a sophisticated indwelling needle with an anticoagulant/hemostatic dual function by anchoring an anticoagulant heparin coating and a hemostatic hydrogel coating on the inner surface and the outer surface of the indwelling needle, respectively. The results of in vitro tests and continuous blood collections from the rabbit ear vein indicate that the anticoagulant coating can resist the adhesion of proteins and blood cells, and its anticoagulant effect can maintain the patency of the indwelling needle for 3 hours after implantation. Meanwhile, the xerogel-hydrogel transition of the hemostatic coating upon contacting blood promotes the aggregation of blood cells, thus sealing the puncture site to achieve complete hemostasis after needle removal. Importantly, this anticoagulant/hemostatic indwelling needle can replace traditional repeated puncture, and can be used to monitor blood glucose concentration changes in diabetic rats through continuous blood collection, portending its promising application in the oral glucose tolerance test.

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.

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.