2D‐Black‐Phosphorus‐Reinforced 3D‐Printed Scaffolds:A Stepwise Countermeasure for Osteosarcoma

With the ever‐deeper understanding of nano–bio interactions and the development of fabrication methodologies of nanomaterials, various therapeutic platforms based on nanomaterials have been developed for next‐generation oncological applications, such as osteosarcoma therapy. In this work, a black phosphorus (BP) reinforced 3D‐printed scaffold is designed and prepared to provide a feasible countermeasure for the efficient localized treatment of osteosarcoma. The in situ phosphorus‐driven, calcium‐extracted biomineralization of the intra‐scaffold BP nanosheets enables both photothermal ablation of osteosarcoma and the subsequent material‐guided bone regeneration in physiological microenvironment, and in the meantime endows the scaffolds with unique physicochemical properties favoring the whole stepwise therapeutic process. Additionally, a corrugated structure analogous to Haversian canals is found on newborn cranial bone tissue of Sprague–Dawley rats, which may provide much inspiration for the future research of bone‐tissue engineering.     

Cell-laden photocrosslinked GelMA–DexMA copolymer hydrogels with tunable mechanical properties for tissue engineering

To effectively repair or replace damaged tissues, it is necessary to design three dimensional (3D) extracellular matrix (ECM) mimicking scaffolds with tunable biomechanical properties close to the desired tissue application. In the present work, gelatin methacrylate (GelMA) and dextran glycidyl methacrylate (DexMA) with tunable mechanical and biological properties were utilized to prepared novel bicomponent polymeric hydrogels by cross-linking polymerization using photoinitiation. We controlled the degree of substitution (DS) of glycidyl methacrylate in DexMA so that they could obtain relevant mechanical properties. The results indicated that copolymer hydrogels demonstrated a lower swelling ratio and higher compressive modulus as compared to the GelMA. Moreover, all of the hydrogels exhibited a honeycomb-like architecture, the pore sizes decreased as DS increased, and NIH-3T3 fibroblasts encapsulated in these hydrogels all exhibited excellent viability. These characteristics suggest a class of photocrosslinkable, tunable mechanically copolymer hydrogels that may find potential application in tissue engineering and regenerative medicine applications.     

The fabrication of biomineralized fiber-aligned PLGA scaffolds and their effect on enhancing osteogenic differentiation of UCMSC cells

The key factor of scaffold design for bone tissue engineering is to mimic the microenvironment of natural bone extracellular matrix (ECM) and guide cell osteogenic differentiation. The biomineralized fiber-aligned PLGA scaffolds (a-PLGA/CaPs) was developed in this study by mimicking the structure and composition of native bone ECM. The aligned PLGA fibers was prepared by wet spinning and then biomineralized via an alternate immersion method. Introduction of a bioceramic component CaP onto the PLGA fibers led to changes in surface roughness and hydrophilicity, which showed to modulate cell adhesion and cell morphology of umbilical cord mesenchymal stem cells (UCMSCs). It was found that organized actin filaments of UCMSCs cultured on both a-PLGA and a-PLGA/CaP scaffolds appeared to follow contact guidance along the aligned fibers, and those cells grown on a-PLGA/CaP scaffolds exhibited a more polarized cellular morphology. The a-PLGA/CaP scaffold with multicycles of mineralization facilitated the cell attachment on the fiber surfaces and then supported better cell adhesion and contact guidance, leading to enhancement in following proliferation and osteogenic differentiation of UCMSCs. Our results give some insights into the regulation of cell behaviors through design of ECM-mimicking structure and composition and provide an alternative wet-spun fiber-aligned scaffold with HA-mineralized layer for bone tissue engineering application.     

Self-assembling peptide nanofiber hydrogels for central nervous system regeneration

Central nervous system (CNS) presents a complex regeneration problem due to the inability of central neurons to regenerate correct axonal and dendritic connections. However, recent advances in developmental neurobiology, cell signaling, cell--matrix interaction, and biomaterials technologies have forced a reconsideration of CNS regeneration potentials from the viewpoint of tissue engineering and regenerative medicine. The applications of a novel tissue regeneration-inducing biomaterial and stem cells are thought to be critical for the mission. The use of peptide nanofiber hydrogels in cell therapy and tissue engineering offers promising perspectives for CNS regeneration. Self-assembling peptide undergo a rapid transformation from liquid to gel upon addition of counterions or pH adjustment, directly integrating with the host tissue. The peptide nanofiber hydrogels have mechanical properties that closely match the native central nervous extracellular matrix, which could enhance axonal growth. Such materials can provide an optimal three dimensional microenvironment for encapsulated cells. These materials can also be tailored with bioactive motifs to modulate the wound environment and enhance regeneration. This review intends to detail the recent status of self-assembling peptide nanofiber hydrogels for CNS regeneration.     

Highly Elastic and Ultratough Hybrid Ionic–Covalent Hydrogels with Tunable Structures and Mechanics

Hybrid ionically–covalently crosslinked double‐network (DN) hydrogels are attracting increasing attention on account of their self‐recovery ability and fatigue resistance, but their relative low mechanical strength and tedious performance adjustment severely limit their applications. Herein, a new strategy to concurrently fabricate hybrid ionic–covalent DN hydrogels and modulate their structures and mechanics is reported, in which an in situ formed chitosan ionic network is incorporated by post‐crosslinking the chitosan‐based composite hydrogel using multivalent anions solutions. The obtained hybrid DN hydrogels exhibit predominant mechanical properties including superior elastic modulus, high tensile strength, and ultrahigh fracture energy because of the more efficient energy dissipation of rigid short‐chain chitosan network. Notably, the swollen hydrogels still remain mechanically strong and tough even after immersion in water for 24 h. More significantly, simply changing the post‐crosslinking time can vary the compactness and rigidity of the chitosan network in situ, achieving flexible and efficient modulation of the structures and mechanics of the hybrid DN hydrogels. This study opens up a new horizon in the preparation and regulation of DN hydrogels for promising applications in tissue scaffolds, actuators, and wearable devices.     

Skin‐Inspired Multifunctional Autonomic‐Intrinsic Conductive Self‐Healing Hydrogels with Pressure Sensitivity,Stretchability, and 3D Printability

The advent of conductive self‐healing (CSH) hydrogels, a class of novel materials mimicking human skin, may change the trajectory of the industrial process because of their potential applications in soft robots, biomimetic prostheses, and health‐monitoring systems. Here, the development of a mechanically and electrically self‐healing hydrogel based on physically and chemically cross‐linked networks is reported. The autonomous intrinsic self‐healing of the hydrogel is attained through dynamic ionic interactions between carboxylic groups of poly(acrylic acid) and ferric ions. A covalent cross‐linking is used to support the mechanical structure of the hydrogel. Establishing a fair balance between the chemical and physical cross‐linking networks together with the conductive nanostructure of polypyrrole networks leads to a double network hydrogel with bulk conductivity, mechanical and electrical self‐healing properties (100% mechanical recovery in 2 min), ultrastretchability (1500%), and pressure sensitivity. The practical potential of CSH hydrogels is further revealed by their application in human motion detection and their 3D‐printing performance.     

多价金属离子增强琼脂-聚丙烯酸复合双网络水凝胶及其自修复性能

使水凝胶同时具备高强度和自修复性能,采用"一锅法"制备了多价金属离子Ca~(2+)、Al~(3+)、Fe~(3+)增强琼脂(Agar)-聚丙烯酸(PAAc)复合双网络水凝胶Ca~(2+)/Agar-PAA、Al~(3+)/Agar-PAA和Fe~(3+)/Agar-PAAc双网络水凝胶。研究不同多价金属离子对Agar-PAAc双网络水凝胶的增强作用及Fe~(3+)/Agar-PAAc的自修复自愈合性能。结果表明,Fe~(3+)/Agar-PAAc的拉伸强度(320.7kPa)和断裂伸长率(1 130%)分别为Ca~(2+)/Agar-PAAc的12倍和9倍,Fe~(3+)/Agar-PAAc的断裂伸长率与Al~(3+)/Agar-PAAc相当,但拉伸强度为Al~(3+)/Agar-PAAc的5倍。对样品实施定应变拉伸使内部发生破坏,被破坏的Fe~(3+)/Agar-PAAc在Fe~(3+)溶液中浸泡30 min,修复率达到100%。被破坏的Fe~(3+)/Agar-PAAc在50℃环境中处理15min,修复率达到100%。切断的Fe~(3+)/Agar-PAAc凝胶断面被固定在一起,在密封环境中放置48小时,试样断面可自愈合,且可拉伸至约8倍初始长度。Fe~(3+)/AgarPAAc双网络水凝胶具有优异力学性能和自修复性能,不施加温度、化学物质等外界刺激,实现两重网络均具有自修复性能的效果。     

Ionic Colloidal Molding as a Biomimetic Scaffolding Strategy for Uniform Bone Tissue Regeneration

Inspired by the highly ordered nanostructure of bone, nanodopant composite biomaterials are gaining special attention for their ability to guide bone tissue regeneration through structural and biological cues. However, bone malformation in orthopedic surgery is a lingering issue, partly due to the high surface energy of traditional nanoparticles contributing to aggregation and inhomogeneity. Recently, carboxyl‐functionalized synthetic polymers have been shown to mimic the carboxyl‐rich surface motifs of non‐collagenous proteins in stabilizing hydroxyapatite and directing intrafibrillar mineralization in‐vitro. Based on this biomimetic approach, it is herein demonstrated that carboxyl functionalization of poly(lactic‐co‐glycolic acid) can achieve great material homogeneity in nanocomposites. This ionic colloidal molding method stabilizes hydroxyapatite precursors to confer even nanodopant packing, improving therapeutic outcomes in bone repair by remarkably improving mechanical properties of nanocomposites and optimizing controlled drug release, resulting in better cell in‐growth and osteogenic differentiation. Lastly, better controlled biomaterial degradation significantly improved osteointegration, translating to highly regular bone formation with minimal fibrous tissue and increased bone density in rabbit radial defect models. Ionic colloidal molding is a simple yet effective approach of achieving materials homogeneity and modulating crystal nucleation, serving as an excellent biomimetic scaffolding strategy to rebuild natural bone integrity.     

Adhesive Hemostatic Conducting Injectable Composite Hydrogels with Sustained Drug Release and Photothermal Antibacterial Activity to Promote Full‐Thickness Skin Regeneration During Wound Healing

Developing injectable nanocomposite conductive hydrogel dressings with multifunctions including adhesiveness, antibacterial, and radical scavenging ability and good mechanical property to enhance full‐thickness skin wound regeneration is highly desirable in clinical application. Herein, a series of adhesive hemostatic antioxidant conductive photothermal antibacterial hydrogels based on hyaluronic acid‐graft‐dopamine and reduced graphene oxide (rGO) using a H₂O₂/HPR (horseradish peroxidase) system are prepared for wound dressing. These hydrogels exhibit high swelling, degradability, tunable rheological property, and similar or superior mechanical properties to human skin. The polydopamine endowed antioxidant activity, tissue adhesiveness and hemostatic ability, self‐healing ability, conductivity, and NIR irradiation enhanced in vivo antibacterial behavior of the hydrogels are investigated. Moreover, drug release and zone of inhibition tests confirm sustained drug release capacity of the hydrogels. Furthermore, the hydrogel dressings significantly enhance vascularization by upregulating growth factor expression of CD31 and improve the granulation tissue thickness and collagen deposition, all of which promote wound closure and contribute to a better therapeutic effect than the commercial Tegaderm films group in a mouse full‐thickness wounds model. In summary, these adhesive hemostatic antioxidative conductive hydrogels with sustained drug release property to promote complete skin regeneration are an excellent wound dressing for full‐thickness skin repair.     

Amorphous/Crystalline Hetero‐Phase Pd Nanosheets: One‐Pot Synthesis and Highly Selective Hydrogenation Reaction

Similar to heterostructures composed of different materials, possessing unique properties due to the synergistic effect between different components, the crystal‐phase heterostructures, one variety of hetero‐phase structures, composed of different crystal phases in monometallic nanomaterials are herein developed, in order to explore crystal‐phase‐based applications. As novel hetero‐phase structures, amorphous/crystalline heterostructures are highly desired, since they often exhibit unique properties, and hold promise in various applications, but these structures have rarely been studied in noble metals. Herein, via a one‐pot wet‐chemical method, a series of amorphous/crystalline hetero‐phase Pd nanosheets is synthesized with different crystallinities for the catalytic 4‐nitrostyrene hydrogenation. The chemoselectivity and activity can be fine‐tuned by controlling the crystallinity of the as‐synthesized Pd nanosheets. This work might pave the way to preparing various hetero‐phase nanostructures for promising applications.     

Hierarchical Hydrogel Composite Interfaces with Robust Mechanical Properties for Biomedical Applications

Cells sense and respond to a wide range of external signals, including chemical signals, topography, and interface mechanics, via interactions with the extracellular matrix (ECM), triggering the regulation of behavior and function. The ECM can be considered a hierarchical multiphase porous matrix with various components. Highly porous hydrogel‐based biomaterials can mimic the critical ECM properties, to provide mechanical support for tissues and to regulate cellular behaviors, such as adhesion, proliferation, and differentiation. Herein, based on micro/nanoscale‐topography‐coupled mechanical action, recent advances in the fabrication and application of hydrogel composites with tunable mechanical properties and topography in biomedicine are summarized. In particular, recent findings showing that hydrogels with specifically designed structures not only influence a range of cellular processes and fit the needs of engineered tissues but also have pharmacological effects are emphasized.     

Modell zur Analyse des knöchernen Anwachsverhaltens auf bioaktiv beschichteten Implantatoberflächen

Model to analyse the bone on‐growth on bioactive coated implant surfaces Especially on the field of bone regeneration, transient and permanent implants are an important method of therapy in the Orthopaedic Surgery. In this context, bioactive surfaces on metallic implants provide an improved contact to the surrounding bone. The goal of our study was to establish an in‐vitro test system to evaluate the on‐growth of bone‐derived cells on different surface coatings. Therefore, we invented a special kind of clamps made of commercially‐pure (c‐p) titanium and blasted with hydroxyapatite particles followed by electrochemically coating with calcium phosphate (BONIT®‐HA, BONIT®). Definite pieces of human cancellous bone were attached to these clamps, inserted onto tissue culture plates and cultivated in DMEM for ten days. Finally, the contact area between human cancellous bone and the implant surface was analyzed and the spreading of osteoblast‐like cells evaluated by scanning electron microscopy (SEM). A well‐spread morphology of bone cells was observed on the implant surfaces coated with calcium phosphate (CaP). In comparison the clamps without CaP coatings showed only a marginal growth of bone cells on the clamp surface. The presented newly in‐vitro test setup using titanium clamps coated with bioactive layers attached to human cancellous bone represents a well‐functioning model for qualitative evaluation of bone on‐growth.     

Black Phosphorus Nanosheets Passivation Using a Tripeptide

In the past several years, 2D black phosphorus (BP) has captured the research community's interest because of its unique electronic, photonic, and mechanical properties. However, the intrinsic instability of BP limits its preservation and practical application. Despite kinds of BP passivation strategies being well‐documented, the use of metal ligand coordination or polymer modification may have potential long‐term detrimental effects on human bodies. Here, a tailored tripeptide Fmoc‐Lys‐Lys‐Phe (Fmoc‐KKF) is synthesized for surface modification of BP nanosheets. Compared with bare BP with rapid degradation, the BP@FKK complex exhibits excellent stability, thereby significantly increasing the life span. Significantly, the BP@FKK shows favorable cell compatibility and enhanced cellular uptake compared to the bare BP.     

How Degradation of Calcium Phosphate Bone Substitute Materials is influenced by Phase Composition and Porosity

The chemical composition of calcium phosphate (CaP) materials for the regenerative therapy of large bone defects is similar to that of bone. Additionally, calcium phosphates show an excellent biocompatibility. Besides the support of defect healing calcium phosphate implants should be completely degraded within an adequate time period to be replaced by newly formed bone. Although degradation of CaP‐implants occurs mainly by dissolution of the material, it is important to characterize the osteoclastic resorption as well, which is involved in native bone remodeling. The degradation of bone substitutes made of calcium phosphate ceramics is influenced by various parameters, such as defect size and localization, the general health situation, and age of the patient, but also material properties are important. Especially, the calcium phosphate composition is crucial for the degradation behavior of a calcium phosphate material. Additionally, at the cellular level the micro‐ and macroporosity, including interconnecting pores, influences both, the dissolution and the osteoclastic resorption. In our study, three different calcium phosphate materials (hydroxyapatite, tricalcium phosphate, and a biphasic calcium phosphate) and two different geometries (dense 2D samples and porous 3D scaffolds) are compared regarding their dissolution and resorption behavior. The results show, that the dissolution of CaP‐ceramics, as examined by the incubation in a degradation solution, depends mainly on the calcium phosphate phase but also on the porosity of the implant. Regarding the resorption, cell proliferation and differentiation of a monocytic cell line as well as the formation of resorption lacunas are analyzed. Cell proliferation is comparable on all phase compositions. Cell differentiation and resorption, however, are influenced by the calcium phosphate phase composition and by the implant porosity as well. By understanding these two mechanisms of degradation, bone substitute materials and, as a result, the bone regeneration of large bone defects using CaP‐ceramics can be improved.     

Mechanical Cues Regulating Proangiogenic Potential of Human Mesenchymal Stem Cells through YAP‐Mediated Mechanosensing

Stem cells secrete trophic factors that induce angiogenesis. These soluble factors are promising candidates for stem cell–based therapies, especially for cardiovascular diseases. Mechanical stimuli and biophysical factors presented in the stem cell microenvironment play important roles in guiding their behaviors. However, the complex interplay and precise role of these cues in directing pro‐angiogenic signaling remain unclear. Here, a platform is designed using gelatin methacryloyl hydrogels with tunable rigidity and a dynamic mechanical compression bioreactor to evaluate the influence of matrix rigidity and mechanical stimuli on the secretion of pro‐angiogenic factors from human mesenchymal stem cells (hMSCs). Cells cultured in matrices mimicking mechanical elasticity of bone tissues in vivo show elevated secretion of vascular endothelial growth factor (VEGF), one of representative signaling proteins promoting angiogenesis, as well as increased vascularization of human umbilical vein endothelial cells (HUVECs) with a supplement of conditioned media from hMSCs cultured across different conditions. When hMSCs are cultured in matrices stimulated with a range of cyclic compressions, increased VEGF secretion is observed with increasing mechanical strains, which is also in line with the enhanced tubulogenesis of HUVECs. Moreover, it is demonstrated that matrix stiffness and cyclic compression modulate secretion of pro‐angiogenic molecules from hMSCs through yes‐associated protein activity.     

Fabrication of glycidyl methacrylate-modified silk fibroin/poly(L-lactic acid-co-ε-caprolactone)–polyethylene glycol diacrylate hybrid 3D nanofibrous scaffolds for tissue engineering

In order to provide a biomimetic natural extracellular matrix microenvironment with excellent mechanical capacity for tissue regeneration, a novel porous hybrid glycidyl methacrylate-modified silk fibroin/poly(L-lactic acid-co-ε-caprolactone)–polyethylene glycol diacrylate (SFMA/P(LLA-CL)–PEGDA) hybrid three-dimensional (3D) nanofibrous scaffolds was successfully fabricated through the combination of 3D nanofibrous platforms and divinyl PEGDA based photocrosslinking, and then further improved water resistance by ethanol vapor post-treatment. Scanning electron microscopy and micro-computed tomography results demonstrated significant PEGDA hydrogel-like matrices bonded nanofibers, which formed a 3D structure similar to that of “steel bar (nanofibers)‒cement (PEGDA)”, with proper pore size, high porosity, and high pore connectivity density. Meanwhile, the hybrid 3D nanofibrous scaffolds showed outstanding swelling properties as well as improved compressive and tensile properties. Furthermore, these hybrid 3D nanofibrous scaffolds could provide a biocompatible microenvironment, capable of inducing the material‒cell hybrid and regulating human umbilical vein endothelial cells proliferation. They thus present significant potential in tissue regeneration.     

Mechanical properties and in vitro behavior of nanofiber-hydrogel composites for tissue engineering applications

Hydrogel-based biomaterial systems have great potential for tissue reconstruction by serving as temporary scaffolds and cell delivery vehicles for tissue engineering (TE). Hydrogels have poor mechanical properties and their rapid degradation limits the development and application of hydrogels in TE. In this study, nanofiber reinforced composite hydrogels were fabricated by incorporating electrospun poly(ε-caprolactone) (PCL)/gelatin 'blend' or 'coaxial' nanofibers into gelatin hydrogels. The morphological, mechanical, swelling and biodegradation properties of the nanocomposite hydrogels were evaluated and the results indicated that the moduli and compressive strengths of the nanofiber reinforced hydrogels were remarkably higher than those of pure gelatin hydrogels. By increasing the amount of incorporated nanofibers into the hydrogel, the Young's modulus of the composite hydrogels increased from 3.29 ± 1.02 kPa to 20.30 ± 1.79 kPa, while the strain at break decreased from 66.0 ± 1.1% to 52.0 ± 3.0%. Compared to composite hydrogels with coaxial nanofibers, those with blend nanofibers showed higher compressive strength and strain at break, but with lower modulus and energy dissipation properties. Biocompatibility evaluations of the nanofiber reinforced hydrogels were carried out using bone marrow mesenchymal stem cells (BM-MSCs) by cell proliferation assay and immunostaining analysis. The nanocomposite hydrogel with 25 mg ml(-1) PCL/gelatin 'blend' nanofibers (PGB25) was found to enhance cell proliferation, indicating that the 'nanocomposite hydrogels' might provide the necessary mechanical support and could be promising cell delivery systems for tissue regeneration.     

Modulating the mechanical properties of photopolymerised polyethylene glycol–polypropylene glycol hydrogels for bone regeneration

Hydrogels formulated from single polymers are often insufficient in terms of their mechanical properties for use as bone substitute materials. Hence, hydrogels synthesised from combinations of polymers have been investigated to optimise the performance of such materials. In the current study, polypropylene glycol dimethacrylate was added to polyethylene glycol dimethacrylate of a variety of molecular weights and photopolymerised to form a series of hydrogels. Polyethylene glycol and polypropylene glycol have the same chemical structure with the exception of a methyl group on the later. Herein, the influence of the methyl group of polypropylene glycol on the mechanical properties of hydrogels for bone regeneration applications is reported. For both unconfined and cyclic compression testing, results demonstrated that the incorporation of PEGDMA into the precursor improves the compression strength of the hydrogels. For example, in unconfined compression tests the Young’s modulus varied between 6.62?±?0.31?MPa and 8.08?±?0.81?MPa with the incorporation of PEGDMA 400.     

Highly Dynamic Nanocomposite Hydrogels Self‐Assembled by Metal Ion‐Ligand Coordination

Hydrogels are emerging biomaterials with desirable physicochemical characteristics. Doping of metal ions such as Ca²⁺, Mg²⁺, and Fe²⁺ provides the hydrogels with unique attributes, including bioactivity, conductivity, and tunability. Traditionally, this doping is achieved by the interaction between metal ions and corresponding ligands or the direct incorporation of as‐prepared metal‐based nanoparticles (NPs). However, these approaches rely on a complex and laborious preparation and are typically restricted to few selected ion species. Herein, by mixing aqueous solutions of ligands (bisphosphonates, BPs), polymer grafted with ligands, and metal ions, a series of self‐assembled metallic‐ion nanocomposite hydrogels that are stabilized by the in situ formed ligand‐metal ion (BP‐M) NPs are prepared. Owing to the universal coordination between BPs and multivalent metal ions, the strategy is highly versatile and can be generalized for a wide array of metal ions. Such hydrogels exhibit a wide spectrum of mechanical properties and remarkable dynamic properties, such as excellent injectability, rapid stress relaxation, efficient ion diffusion, and triggered disassembly for harvesting encapsulated cells. Meanwhile, the hydrogels can be conveniently coated or patterned onto the surface of metals via electrophoresis. This work presents a universal strategy to prepare designer nanocomposite materials with highly tunable and dynamic behaviors.