Mussel-Inspired Injectable Adhesive Hydrogels for Biomedical Applications.

The impressive adhesive capacity of marine mussels has inspired various fascinating designs in biomedical fields. Mussel-inspired injectable adhesive hydrogels, as a type of promising mussel-inspired material, have attracted much attention due to their minimally invasive property and desirable functions provided by mussel-inspired components. In recent decades, various mussel-inspired injectable adhesive hydrogels have been designed and widely applied in numerous biomedical fields. The rational incorporation of mussel-inspired catechol groups endows the injectable hydrogels with the potential to exhibit many properties, including tissue adhesiveness and self-healing, antimicrobial, and antioxidant capabilities, broadening the applications of injectable hydrogels in biomedical fields. In this review, we first give a brief introduction to the adhesion mechanism of mussels and the characteristics of injectable hydrogels. Further, the typical design strategies of mussel-inspired injectable adhesive hydrogels are summarized. The methodologies for integrating catechol groups into polymers and the crosslinking methods of mussel-inspired hydrogels are discussed in this section. In addition, we systematically overview recent mussel-inspired injectable adhesive hydrogels for biomedical applications, with a focus on how the unique properties of these hydrogels benefit their applications in these fields. The challenges and perspectives of mussel-inspired injectable hydrogels are discussed in the last section. This review may provide new inspiration for the design of novel bioinspired injectable hydrogels and facilitate their application in various biomedical fields.

Recent Advances in the Degradability and Applications of Tissue Adhesives Based on Biodegradable Polymers.

In clinical practice, tissue adhesives have emerged as an alternative tool for wound treatments due to their advantages in ease of use, rapid application, less pain, and minimal tissue damage. Since most tissue adhesives are designed for internal use or wound treatments, the biodegradation of adhesives is important. To endow tissue adhesives with biodegradability, in the past few decades, various biodegradable polymers, either natural polymers (such as chitosan, hyaluronic acid, gelatin, chondroitin sulfate, starch, sodium alginate, glucans, pectin, functional proteins, and peptides) or synthetic polymers (such as poly(lactic acid), polyurethanes, polycaprolactone, and poly(lactic-co-glycolic acid)), have been utilized to develop novel biodegradable tissue adhesives. Incorporated biodegradable polymers are degraded in vivo with time under specific conditions, leading to the destruction of the structure and the further degradation of tissue adhesives. In this review, we first summarize the strategies of utilizing biodegradable polymers to develop tissue adhesives. Furthermore, we provide a symmetric overview of the biodegradable polymers used for tissue adhesives, with a specific focus on the degradability and applications of these tissue adhesives. Additionally, the challenges and perspectives of biodegradable polymer-based tissue adhesives are discussed. We expect that this review can provide new inspirations for the design of novel biodegradable tissue adhesives for biomedical applications.

Viscous, Hofmeister Effect-Enhanced Macromolecular Adhesives for Effective Bonding in Seawater.

Deployment of adhesives in natural seawater to in situ bonds is urgently needed in engineering fields. However, stable adhesion in natural seawater remains a challenge due to the turbulent environment and high ion concentration. Herein, we reported a viscous, macromolecular underwater adhesive enhanced by Hofmeister effect (EHUA) for practical application in dynamic seawater. EHUA was synthesized via a facile one-step copolymerization. After transferred into seawater, the solvent of EHUA was exchanged to seawater, and thereby hydrogen bonds inside the adhesive were activated and enhanced by Hofmeister effect. We demonstrated EHUA can adhere on the surface in turbulent seawater, and the adhesive strength could reach 1.691 MPa. In addition, the adhesives also exhibited long-term storage stability and convenient recyclability. These fascinating properties enable adhesives to seal leaky pipelines, repair damaged ships and construct buildings in turbulent seawater. This work may open an avenue for the design of adhesives for seawater environments.

Tissue-adhesive, stretchable and compressible physical double-crosslinked microgel-integrated hydrogels for dynamic wound care.

Integrated wound care through sequentially promoting hemostasis, sealing, and healing holds great promise in clinical practice. However, it remains challenging for regular bioadhesives to achieve integrated care of dynamic wounds due to the difficulties in adapting to dynamic mechanical and wet wound environments. Herein, we reported a type of dehydrated, physical double crosslinked microgels (DPDMs) which were capable of in situ forming highly stretchable, compressible and tissue-adhesive hydrogels for integrated care of dynamic wounds. The DPDMs were designed by the rational integration of the reversible crosslinks and double crosslinks into micronized gels. The reversible physical crosslinks enabled the DPDMs to integrate together, and the double crosslinked characteristics further strengthen the formed macroscopical networks (DPDM-Gels). We demonstrated that the DPDM-Gels simultaneously possess outstanding tensile (∼940 kJ/m3) and compressive (∼270 kJ/m3) toughness, commercial bioadhesives-comparable tissue-adhesive strength, together with stable performance under hundreds of deformations. In vivo results further revealed that the DPDM-Gels could effectively stop bleeding in various bleeding models, even in an actual dynamic environment, and enable the integrated care of dynamic skin wounds. On the basis of the remarkable mechanical and appropriate adhesive properties, together with impressive integrated care capacities, the DPDM-Gels may provide a new approach for the smart care of dynamic wounds. STATEMENT OF SIGNIFICANCE: Integrated care of dynamic wounds holds great significance in clinical practice. However, the dynamic and wet wound environments pose great challenges for existing hydrogels to achieve it. This work developed robust adhesive hydrogels for integrated care of dynamic wounds by designing dehydrated, physical double crosslinked microgels (DPDMs). The reversible and double crosslinks enabled DPDMs to integrate into macroscopic hydrogels with high mechanical properties, appropriate adhesive strength and stable performance under hundreds of external deformations. Upon application at the injury site, DPDM-Gels efficiently stopped bleeding, even in an actual dynamic environment and showed effectiveness in integrated care of dynamic wounds. With the fascinating properties, DPDMs may become an effective tool for smart wound care.

Epidermal growth factor-loaded, dehydrated physical microgel-formed adhesive hydrogel enables integrated care of wet wounds.

Integrated wound care, a sequential process of promoting wound hemostasis, sealing, and healing, is of great clinical significance. However, the wet environment of wounds poses formidable challenges for integrated care. Herein, we developed an epidermal growth factor (EGF)-loaded, dehydrated physical microgel (DPM)-formed adhesive hydrogel for the integrated care of wet wounds. The DPMs were designed using the rational combination of hygroscopicity and reversible crosslinking of physical hydrogels. Unlike regular bioadhesives, which consider interfacial water as a barrier to adhesion, DPMs utilize water to form desirable adhesive structures. The hygroscopicity allowed the DPMs to absorb interfacial water and subsequently, the interfacial adhesion was realized by the interactions between tissue and DPMs. The reversible crosslinks further enabled DPMs to integrate into hydrogels (DPM-Gels), thus achieving wet adhesion. Importantly, the water-absorbing gelation mode of DPMs enabled facile loading of biologically active EGF to promote wound healing. We demonstrated that the DPM-Gels possessed wet tissue adhesive performance, with about 40 times the wet adhesive strength of fibrin glue and about 4 times the burst pressure of human blood pressure. Upon application at the injury site, the EGF-loaded DPM-Gels sequentially promoted efficient wound hemostasis, stable sealing, and quick healing, achieving integrated care of wet wounds.

Microstructure-united heterogeneous sodium alginate doped injectable hydrogel for stable hemostasis in dynamic mechanical environments.

Injectable hydrogels that can withstand compressive and tensile forces hold great promise for preventing rebleeding in dynamic mechanical environments after emergency hemostasis of wounds. However, current injectable hydrogels often lack sufficient compressive or tensile performance. Here, a microstructure-united heterogeneous injectable hydrogel (MH) was constructed. The heterogeneous structure endowed MH with a unique "microstructures consecutive transmission" feature, which allowed it to exhibit high compressive and tensile performance simultaneously. In this work, two types of sodium alginate doped hydrogels with different microstructures were physically smashed into microgels, respectively. By mixing the microgels, MH with one micro-pores featured microstructure and another nano-pores featured microstructure can be formed. The obtained MH can withstand both compressive and tensile forces and showed high mechanical performance (compressive modulus: 345.67 ± 10.12 kPa and tensile modulus: 245.19 ± 7.82 kPa). Furtherly, MH was proven to provide stable and sustained hemostasis in the dynamic mechanical environment. Overall, this work provided an effective strategy for constructing injectable hydrogel with high compressive and tensile performance for hemostasis in dynamic mechanical environments.

Microgel-integrated, high-strength in-situ formed hydrogel enables timely emergency trauma treatment.

High-strength hydrogels formed in situ through a convenient gel transition process are highly desirable for emergency treatment due to their ability to quickly respond to accidents. However, current in-situ formed hydrogels require a laborious precursor preparation process or lack sufficient mechanical strength. Herein, we reported a series of microgels that were capable of convenient in-situ transition to high-strength hydrogels from their easily portable form, thereby facilitating emergency treatment. Three kinds of microgels were derived from two types of hydrogen bonds (H-bonds; OH⋯OC, NH⋯OC) crosslinked preformed hydrogels, and all exhibited excellent stability when stored at room temperature. After mixing with water, all these microgels could undergo a quick hydration process and then transform into high-strength hydrogels in situ through H-bonds. Specifically, stronger H-bond crosslinked microgels could build hydrogels with higher mechanical strength, albeit at the cost of longer hydration and operation time. Nevertheless, the whole operation process could be finished within several minutes, and the resultant hydrogels could exhibit maximally megapascal-level compressive strength and tens of kilopascal storage modulus. In the comparison of emergency application performance with commercial chitosan hemostatic powder (CHP), we found that the microgels could stop accidental bleeding almost immediately, and the whole process from taking out the stored microgels to hemostasis could be completed within 15 s, which was superior to CHP. Overall, the results indicated that the in-situ formed microgel-based hydrogels with convenient gel-transition ability and high strength showed great potential in emergency treatments.

PMPC Modified PAMAM Dendrimer Enhances Brain Tumor-Targeted Drug Delivery.

The excellent biocompatibility drug delivery system for effective treatment of glioma is still greatly challenged by the existence of blood-brain barrier, blood-brain tumor barrier, and the tissue toxicity caused by chemotherapy drugs. In this study, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) is used for the first time for modifying third-generation poly(amidoamine) (PAMAM) to enhance their brain tumor-targeted drug delivery ability as well as simultaneously reducing the toxicity of PAMAM dendrimers and the tissue toxicity of the loaded doxorubicin (DOX). The cytotoxicity, the therapeutic ability in vitro, and the brain tumor-targeted ability of the PMPC modified PAMAM nanoparticles are further studied. Results indicate that PMPC, as a dual-functional modifier, can significantly reduce the cytotoxicity of PAMAM dendrimers, while efficiently target the brain tumor. In addition, the therapeutic effect of DOX-loaded PAMAM-PMPC in mice inoculated with U-87 is also studied in vivo. In comparison with DOX solution, DOX-loaded PAMAM-PMPC alleviates weight loss of tumor-inoculated mice and reduces the cardiotoxicity of DOX. The tumor growth inhibition, in vivo, is significantly increased up to (80.76 ± 1.66)%. In conclusion, this strategy of PMPC dual-functional targeted nanocarrier provides a new method for the delivery of chemotherapeutic drugs to treat glioma.

Metal-crosslinked ɛ-poly-L-lysine tissue adhesives with high adhesive performance: Inspiration from mussel adhesive environment.

Strong glue of mussels has long been considered as an ideal model to design synthetic bio-adhesives but the adhesive strength of metal-crosslinked mussel-inspired glues is not often satisfactory. Herein, inspired by the adhesive environment of mussels, we obtained metal-crosslinked ε-poly-L-lysine adhesives with high adhesive performance by introducing the elements of suitable adhesive environment (SAE) into the adhesives. The elements of SAE were clarified as weak alkaline conditions (pH ∼ 7.4) and low Fe3+ contents. The adhesive strength (∼105 kPa) of the metal-crosslinked adhesives endowed with the elements of SAE (PL-Cat/Fe-SAE) was about 8 times higher than that of fibrin glues. The high adhesive strength was found to originate from distinctive interfacial adhesion and cohesion strength of PL-Cat/Fe-SAE. PL-Cat/Fe-SAE showed strong interfacial adhesion capacity and nearly comparable cohesion strength to those PL-Cat/Fe adhesives with higher Fe3+ contents. The nearly comparable cohesion strength of PL-Cat/Fe-SAE was then found to be due to more amount of stable tris-complex existed in PL-Cat/Fe-SAE. In addition, PL-Cat/Fe-SAE was able to efficiently close the full thickness skin incisions. The study highlighted the importance of introducing SAE elements into the design of tissue adhesives and provided a facile and efficient strategy for constructing tissue adhesives with high adhesive performance.

Injectable PAMAM/ODex double-crosslinked hydrogels with high mechanical strength.

In situ injectable double-crosslinked hydrogels containing thiol functionalized poly(amido-amine) dendrimers (Gn-PAMAM-NH2-X) and oxidized dextrans (ODex) were prepared under physiological conditions without using potentially cytotoxic cross-linkers. The double-crosslinked structure was created by Schiff's base reaction and the formation of disulfide bonds. The morphology of the hydrogels was characterized by scanning electron microscopy. The gelation time, swelling and rheological behaviors of the hydrogels were investigated. We also studied the adhesive strength and cytocompatibility of the hydrogels. The surface amino density, concentration and generation of PAMAM are the main factors affecting the gelation. Relatively high surface amino density contributes to quick gelation, whereas too great a surface amino may lead to the brittleness of the hydrogel. A moderate concentration of PAMAM (10% wt) is suitable for gelation considering its appropriate gelation time. Where surface amino density and the mass concentration of PAMAM-NH2 were identical, PAMAM with less generation was prone to gelation. The injectable PAMAM/ODex hydrogels have double-crosslinked structures and a high crosslinking density which lead to their high storage modulus. The adhesive strength of the hydrogels is about 2.4 times of commercial available fibrin glue and these hydrogels are nontoxic to L929 mouse fibroblast cells. The L929 cells can attach easily to the surface of hydrogels and proliferate on them, which demonstrates these novel injectable hydrogels are biocompatible and have potential uses in tissue engineering.