De Novo Design of Entropy-Driven Polymers Resistant to Bacterial Attachment via Multicomponent Reactions.

Nonbactericidal polymers that prevent bacterial attachment are important for public health, environmental protection, and avoiding the generation of superbugs. Here, inspired by the physical bactericidal process of carbon nanotubes and graphene derivatives, we develop nonbactericidal polymers resistant to bacterial attachment by using multicomponent reactions (MCRs) to introduce molecular "needles" (rigid aliphatic chains) and molecular "razors" (multicomponent structures) into polymer side chains. Computer simulation reveals the occurrence of spontaneous entropy-driven interactions between the bacterial bilayers and the "needles" and "razors" in polymer structures and provides guidance for the optimization of this type of polymers for enhanced resistibility to bacterial attachment. The blending of the optimized polymer with commercially available polyurethane produces a film with remarkably superior stability of the resistance to bacterial adhesion after wear compared with that of commercial mobile phone shells made by the Sharklet technology. This proof-of-concept study explores entropy-driven polymers resistant to bacterial attachment via a combination of MCRs, computer simulation, and polymer chemistry, paving the way for the de novo design of nonbactericidal polymers to prevent bacterial contamination.

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.

4D printed hydrogel scaffold with swelling-stiffening properties and programmable deformation for minimally invasive implantation.

The power of three-dimensional printing in designing personalized scaffolds with precise dimensions and properties is well-known. However, minimally invasive implantation of complex scaffolds is still challenging. Here, we develop amphiphilic dynamic thermoset polyurethanes catering for multi-material four-dimensional printing to fabricate supportive scaffolds with body temperature-triggered shape memory and water-triggered programmable deformation. Shape memory effect enables the two-dimensional printed pattern to be fixed into temporary one-dimensional shape, facilitating transcatheter delivery. Upon implantation, the body temperature triggers shape recovery of the one-dimensional shape to its original two-dimensional pattern. After swelling, the hydrated pattern undergoes programmable morphing into the desired three-dimensional structure because of swelling mismatch. The structure exhibits unusual soft-to-stiff transition due to the water-driven microphase separation formed between hydrophilic and hydrophobic chain segments. The integration of shape memory, programmable deformability, and swelling-stiffening properties makes the developed dynamic thermoset polyurethanes promising supportive void-filling scaffold materials for minimally invasive implantation.

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.

Injectable immunomodulation-based porous chitosan microspheres/HPCH hydrogel composites as a controlled drug delivery system for osteochondral regeneration.

The inappropriate regenerated fibrous cartilage and subchondral bone of the injured chondral defect ultimately cause degeneration of the regenerated cartilage, which eventually leads to the failure of cartilage repair. In this study, we developed a macrophage-modulated and injectable 'building block' drug delivery system comprised of porous chitosan (CS) microspheres and hydroxypropyl chitin (HPCH) hydrogel, where the dimethyloxallyl glycine (DMOG) was encapsulated in the thermosensitive HPCH hydrogel (HD) while kartogenin (KGN) was conjugated on the porous CS microspheres (CSK-PMS). The developed HD/CSK-PMS composite scaffold effectively modulated the microenvironment at the defect site, achieved local macrophage M2 polarization and promoted cartilage regeneration. The fast-degradable HD favored hyaline cartilage regeneration, while the highly stable CSK-PMS supported the endochondral ossification and regenerated the subchondral bone. In vitro and in vivo evaluations revealed that the newly developed HD/CSK-PMS as a controlled drug delivery system could effectively create M2 macrophage microenvironment and orchestrate osteochondral (OC) regeneration. These findings indicate the importance of the immune microenvironment and subchondral bone for high-quality cartilage repair, and thus the immunomodulation-based hydrogel/PMS composite system could be a promising candidate for OC regeneration.

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.

Enhanced Heterogeneous Diffusion of Nanoparticles in Semiflexible Networks.

The transport of nanoparticles in semiflexible networks, which form diverse principal structural components throughout living systems, is important in biology and biomedical applications. By combining large-scale molecular simulations as well as theoretical analysis, we demonstrate here that nanoparticles in polymer networks with semiflexible strands possess enhanced heterogeneous diffusion characterized by more evident hopping dynamics. Particularly, the hopping energy barrier approximates to linear dependence on confinement parameters in the regime of moderate rigidity, in contrast to the quadratic dependence of both its soft and hard counterparts. This nonmonotonic feature can be attributed to the competition between the conformation entropy and the bending energy regulated by the chain rigidity, captured by developing an analytical model of a hopping energy barrier. Moreover, these theoretical results agree reasonably well with previous experiments. The findings bear significance in unraveling the fundamental physics of substance transport confined in network-topological environments and would provide an explanation for the dynamics diversity of nanoparticles within various networks, biological or synthetic.

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.

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.

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.