Degradable Nanohydroxyapatite-Reinforced Superglue for Rapid Bone Fixation and Promoted Osteogenesis.

Bone glue with robust adhesion is crucial for treating complicated bone fractures, but it remains a formidable challenge to develop a "true" bone glue with high adhesion strength, degradability, bioactivity, and satisfactory operation time in clinical scenarios. Herein, inspired by the hydroxyapatite and collagen matrix composition of natural bone, we constructed a nanohydroxyapatite (nHAP) reinforced osteogenic backbone-degradable superglue (O-BDSG) by in situ radical ring-opening polymerization. nHAP significantly enhances adhesive cohesion by synergistically acting as noncovalent connectors between polymer chains and increasing the molecular weight of the polymer matrix. Moreover, nHAP endows the glue with bioactivity to promote osteogenesis. The as-prepared glue presented a 9.79 MPa flexural adhesion strength for bone, 4.7 times that without nHAP, and significantly surpassed commercial cyanoacrylate (0.64 MPa). O-BDSG exhibited degradability with 51% mass loss after 6 months of implantation. In vivo critical defect and tibia fracture models demonstrated the promoted osteogenesis of the O-BDSG, with a regenerated bone volume of 75% and mechanical function restoration to 94% of the native tibia after 8 weeks. The glue can be flexibly adapted to clinical scenarios with a curing time window of about 3 min. This work shows promising prospects for clinical application in orthopedic surgery and may inspire the design and development of bone adhesives.

Tunable backbone-degradable robust tissue adhesives via in situ radical ring-opening polymerization.

Adhesives with both robust adhesion and tunable degradability are clinically and ecologically vital, but their fabrication remains a formidable challenge. Here we propose an in situ radical ring-opening polymerization (rROP) strategy to design a backbone-degradable robust adhesive (BDRA) in physiological environment. The hydrophobic cyclic ketene acetal and hydrophilic acrylate monomer mixture of the BDRA precursor allows it to effectively wet and penetrate substrates, subsequently forming a deep covalently interpenetrating network with a degradable backbone via redox-initiated in situ rROP. The resulting BDRAs show good adhesion strength on diverse materials and tissues (e.g., wet bone >16 MPa, and porcine skin >150 kPa), higher than that of commercial cyanoacrylate superglue (~4 MPa and 56 kPa). Moreover, the BDRAs have enhanced tunable degradability, mechanical modulus (100 kPa-10 GPa) and setting time (seconds-hours), and have good biocompatibility in vitro and in vivo. This family of BDRAs expands the scope of medical adhesive applications and offers an easy and environmentally friendly approach for engineering.

Highly Tough, Stretchable, Self-Adhesive and Strain-Sensitive DNA-Inspired Hydrogels for Monitoring Human Motion.

Hydrogels used as strain sensors often rely on splicing tapes to attach them to surfaces, which causes much inconvenience. Therefore, to develop strain sensor hydrogels that possess both good mechanical properties and self-adhesion is still a great challenge. Inspired by the multiple hydrogen bonding interactions of nucleobases in DNA, we designed and synthesized a series of hydrogels PAAm-GO-Aba/Tba/Aba+Tba comprising polyacrylamide (PAAm), graphene oxide (GO), acrylated adenine and thymine (Aba and Tba). The introduction of nucleobases helps hydrogels to adhere to various substrates through multiple hydrogen-bonding interactions. It has also been found that the adhesive strength of hydrogels with nucleobases for hogskin increased to 2.5 times that of those without nucleobases. Meanwhile, these hydrogels exhibited good dynamic mechanical and self-recovery properties. They can be directly attached to human skin as strain sensors to monitor the motions of finger, wrist, and elbow. Electrical tests indicate that they give precise real-time monitoring data and exhibit good strain sensitivity and electrical stability. This work provides a promising basis from which to explore the fabrication of tough, self-adhesive, and strain-sensitive hydrogels as strain sensors for applications in wearable devices and healthcare monitoring.

Aza-crown ether locked on polyethyleneimine: solving the contradiction between transfection efficiency and safety during in vivo gene delivery.

We proposed a method using an aza-crown ether derivative to lock a hyperbranched polyethyleneimine, which endows the PEI25k with tumor targeting ability, anti-serum ability and extended circulation in the blood meanwhile retaining the high gene complexation and high transfection efficiency. The method we proposed here simultaneously endows cationic materials with high transfection efficiency and high safety, which greatly pushed the cationic materials to be applied in in vivo gene delivery.

Redox-Responsive Multifunctional Polypeptides Conjugated with Au Nanoparticles for Tumor-Targeting Gene Therapy and Their 1 + 1 > 2 Synergistic Effects.

Gene therapy is regarded as one of the most potential technologies for tumor therapy. Gene delivery systems with high specificity and good biocompatibility are urgently demanded. Hence, in this research, we designed and synthesized a series of tumor targeting and redox-responsive gold nanoparticles conjugated with three kinds of functional polypeptides (AuNPPs) that consisted of targeting peptide GE11, cell-penetrating peptide octaarginine (R8), and polyhistidine. All the AuNPPs exhibited superior cancer cellular internalization ability and targeting gene transfection efficiency compared with commercial agent BPEI 25K. It is interesting to find that different relative positions of GE11 and R8 can cause the change of target ability and gene transfection efficiency, and the suitable relative position of R8 and GE11 can not only endow the gene vector with functions that peptides previously own but also bring the synergistic effects. The best-performed AuNPP6-1 was chosen to transport the epidermal growth factor receptor (EGFR)-shRNA into A549 tumor-bearing BALB/c nude mice, and in vivo fluorescence imaging showed AuNPP6-1 mainly accumulated in tumor sites and achieved a great targeting therapy effect. These results provide significantly important information on understanding and constructing the tumor-targeting gene vector.

DNA-Inspired Adhesive Hydrogels Based on the Biodegradable Polyphosphoesters Tackified by a Nucleobase.

Since adhesive hydrogels showed wide applications ranging from wearable soft materials to medical sealants, more and more attention has been paid toward the exploration of novel adhesive hydrogels. However, the difficulty in removing the residue caused by the excessive adhesive strength and sluggish degradation or nondegradation behaviors of the adhesive has always been challenging. Inspired by the multiple complementary hydrogen bond interactions in DNA, the bioinspired nucleobase (A, T, and U) monomers were first synthesized and used to tackify polyphosphoester hydrogels. The multiple hydrogen bonds and hydrophobic interactions between purine rings and pyrimidine functionalities endowed the hydrogels with excellent controllable adhesive properties. Besides this, it has been found that these nucleobase-tackified hydrogels could be easily peeled off without leaving any residue and could be totally degraded under alkaline conditions due to hydrolysis of phosphoester chains. At the same time, they also exhibited controllable biodegradation to different extents under the different pH conditions. The excellent adhesive performance, controllable biodegradation, and excellent biocompatibility showed by this nucleobase-tackified polyphosphoester adhesive hydrogel demonstrated its great potential in wound dressing, as a tissue sealant, and so on.

Hydrogen-Bond Cyclization Programming of Ultrasensitive Esters and Its Application in Gene Delivery.

The ester bond as a universal linker has recently been applied in gene delivery systems owing to its efficient gene release by electrostatic repulsion after its cleavage. However, the ester bond is nonlabile and is difficult to cleave in cells. This work reports a method in which a secondary amine was introduced to the ß-position of the ester bond to generate a hydrogen-bond cyclization (HBC) structure that can make the ester bond hydrolysis ultrafast. A series of molecules comprising ultrasensitive esters that can be activated by H2 O2 were synthesized, and it was found that those able to form an HBC structure showed complete ester hydrolysis within 5 h in both water and phosphate-buffered saline solution, which was several times faster than other methods reported. Then, a series of amphiphilic poly(amidoamine) dendrimers were constructed, comprising the ultrasensitive ester groups for gene delivery; it was found that they could effectively release genes under quite a low concentration of H2 O2 (<200 µm) and transport them into the nucleus within 2 h in Hela cells with high safety. Their gene transfection efficiencies were higher than that of PEI25k . The results demonstrated that the hydrogen-bond-induced ultrasensitive esters could be powerfully applied to construct gene delivery systems.

ROS-Response-Induced Zwitterionic Dendrimer for Gene Delivery.

As one of the most promising therapeutic methods, gene therapy has been playing a more and more important role in treating disease due to its ultra-high therapy efficiency. Even if nonviral gene vectors represented by polycation, liposomal, dendrimers, and zwitterionic materials have made great progress in gene complexation, low immunogenicity, and biocompatibility, intracellular gene release with low toxicity is effectively still a bottleneck restricting the clinical application of gene therapy. We designed and synthesized a reactive oxygen species (ROS)-responsive dendrimer poly(amido amine)- N-(4-boronobenzyl)- N, N-diethyl-2-(propionyloxy)ethan-1-aminium (PAMAM-(B-DEAEP)16) as a gene vector whose potential can vary from positive to negative under the elevated ROS (H2O2) in cancerous cells. Dynamic light scattering results showed that the zeta potential of PAMAM-(B-DEAEP)16 decreased from +12.3 to -5 mV under 80 mM H2O2 in PBS buffer. The 1H NMR results demonstrated that the intermediate status of PAMAM-(B-DEAEP)16 was zwitterionic in ∼6 h because it consisted of the positive quaternary ammonium and negative carboxylic acid simultaneously before the ester bond was completely hydrolyzed. Gel retardation assay showed that PAMAM-(B-DEAEP)16 can condense DNA at above N/P = 1; then, PAMAM-(B-DEAEP)16 transfers to zwitterionic, which begins to continuously release DNA with the decrease in the positive charges and increase in the negative charges, and finally to negatively charged poly(amido amine)-propionic acid (PAMAM-PAc16) in the 80 mM H2O2. Fluorescence-labeled Cy-5 DNA indicated that PAMAM-(B-DEAEP)16 can enter into the cell completely in ∼4 h. The results showed that this compound we designed exhibited higher gene transfection efficiency and lower cytotoxicity than commercial PEI. This is the first time that the positively charged dendrimer was transferred to zwitterionic dendrimer under the stimuli of H2O2 and was successfully applied to gene delivery. Unlike all of the previous reports, we did not seek a compromise between the high gene transfection and low toxicity but find a new avenue to make the gene carrier not only have higher gene transfection efficiency but also exhibit lower toxicity by introducing stimuli-sensitive groups into the positively charged dendrimer to make it capable of adjusting the charge property according to the microenvironment. This study not only provides a good method to design materials for gene delivery but also opens a new perspective to understand the process of gene delivery.