Biomimetic Composite Scaffolds to Manipulate Stem Cells for Aiding Rheumatoid Arthritis Management

Stem cell transplantation is a promising alternative therapy for rheumatoid arthritis (RA) patients, with the potential to suppress autoimmune in?ammation and prevent joint damage. However, widespread application of RA therapy based on stem cell transplantation is limited due to poor migration, local retention, and uncontrolled differentiation of stem cells. Here, inspired by the dynamic construction of bone matrix, a structurally and functionally optimized scaffold for loading bone marrow stem cells (BMSCs) is designed to aid RA management. The composite scaffolds consist of stiff 3D printing porous metal scaffolds (3DPMS) and soft multifunctional polysaccharide hydrogels, wherein 3DPMS meet the requirements for large‐scale bone defects caused by RA. Attractively, the fabricated hydrogels on the composite scaffold are self‐healable, injectable, biocompatible, and biodegradable, which endow the resultant scaffold many aspects mimicking the extracellular matrix (ECM). After encapsulation of BMSCs, hydrogels are administered into the inner pores of 3DPMS, abbreviated as BMSCs@3DPMS/hydrogels. In this study, BMSCs@3DPMS/hydrogels have a good effect on improving RA, such as remodeling of knee joint articular cartilage, inhibition of in?ammatory cytokines, and promotion of subchondral bone regeneration. Besides RA, the innovative scaffolds may also serve as an ideal biomaterial for other bone regenerative therapies in various orthopedic diseases.     

Salt‐Assisted Toughening of Protein Hydrogel with Controlled Degradation for Bone Regeneration

Recently, strong polymer‐based hydrogels have been intensively investigated. However, the development of tough protein hydrogels with controlled degradation for bone regeneration has rarely been reported. Here, regenerated silk fibroin/gelatin (RSF/G) hydrogels with both strength and controlled degradation are prepared via physically and chemically double‐crosslinked networks. As a representative example, the 9%RSF/3%G hydrogel shows approximately 80% elongation and a compressive and tensile modulus of up to 0.25 and 0.21 MPa, respectively. It also shows a degradation rate that can be adjusted to approximately three months in vivo, a value between that of the rapidly degrading gelatin hydrogel and the slowly degrading RSF hydrogel. The 9%RSF/3%G hydrogel has good biocompatibility and promotes the proliferation and differentiation of bone marrow–derived stem cells compared with the control and pure RSF hydrogels. At 12 weeks after implantation of the gel in a calvarial defect, micro‐computed tomography shows greater bone volume and bone mineral density in the 9%RSF/3%G group. More importantly, histology reveals more mineralization and enhancements in the quality and rate of bone regeneration with less of a tissue response in the 9%RSF/3%G group. These results indicate the promising potential of this tough protein hydrogel with controlled degradation for bone regeneration applications.     

Direct 3D Printing of High Strength Biohybrid Gradient Hydrogel Scaffolds for Efficient Repair of Osteochondral Defect

The emerging 3D printing technique allows for tailoring hydrogel‐based soft structure tissue scaffolds for individualized therapy of osteochondral defects. However, the weak mechanical strength and uncontrollable swelling intrinsic to conventional hydrogels restrain their use as bioinks. Here, a high‐strength thermoresponsive supramolecular copolymer hydrogel is synthesized by one‐step copolymerization of dual hydrogen bonding monomers, N‐acryloyl glycinamide, and N‐[tris(hydroxymethyl)methyl] acrylamide. The obtained copolymer hydrogels demonstrate excellent mechanical properties—robust tensile strength (up to 0.41 MPa), large stretchability (up to 860%), and high compressive strength (up to 8.4 MPa). The rapid thermoreversible gel ? sol transition behavior makes this copolymer hydrogel suitable for direct 3D printing. Successful preparation of 3D‐printed biohybrid gradient hydrogel scaffolds is demonstrated with controllable 3D architecture, owing to shear thinning property which allows continuous extrusion through a needle and also immediate gelation of fluid upon deposition on the cooled substrate. Furthermore, this biohybrid gradient hydrogel scaffold printed with transforming growth factor beta 1 and β‐tricalciumphosphate on distinct layers facilitates the attachment, spreading, and chondrogenic and osteogenic differentiation of human bone marrow stem cells (hBMSCs) in vitro. The in vivo experiments reveal that the 3D‐printed biohybrid gradient hydrogel scaffolds significantly accelerate simultaneous regeneration of cartilage and subchondral bone in a rat model.     

3D Molecularly Functionalized Cell‐Free Biomimetic Scaffolds for Osteochondral Regeneration

Clinically, cartilage damage is frequently accompanied with subchondral bone injuries caused by disease or trauma. However, the construction of biomimetic scaffolds to support both cartilage and subchondral bone regeneration remains a great challenge. Herein, a novel strategy is adopted to realize the simultaneous repair of osteochondral defects by employing a self‐assembling peptide hydrogel (SAPH) FEFEFKFK (F, phenylalanine; E, glutamic acid; K, lysine) to coat onto 3D‐printed polycaprolactone (PCL) scaffolds. Results show that the SAPH‐coated PCL scaffolds exhibit highly improved hydrophilicity and biomimetic extracellular matrix (ECM) structures compared to PCL scaffolds. In vitro experiments demonstrate that the SAPH‐coated PCL scaffolds promote the proliferation and osteogenic differentiation of rabbit bone mesenchymal stem cells (rBMSCs) and maintain the chondrocyte phenotypes. Furthermore, 3% SAPH‐coated PCL scaffolds significantly induce simultaneous regeneration of cartilage and subchondral bone after 8‐ and 12‐week implantation in vivo, respectively. Mechanistically, by virtue of the enhanced deposition of ECM in SAPH‐coated PCL scaffolds, SAPH with increased stiffness facilitates and remodels the microenvironment around osteochondral defects, which may favor simultaneous dual tissue regeneration. These findings indicate that the 3% SAPH provides efficient and reliable modification on PCL scaffolds and SAPH‐coated PCL scaffolds appear to be a promising biomaterial for osteochondral defect repair.     

A Self-Thickening and Self-Strengthening Strategy for 3D Printing High-Strength and Antiswelling Supramolecular Polymer Hydrogels as Meniscus Substitutes

3D printing of high-strength and antiswelling hydrogel-based load-bearing soft tissue scaffolds with similar geometric shape to natural tissues remains a great challenge owing to insurmountable trade-off between strength and printability. Herein, capitalizing on the concentration-dependent H-bonding-strengthened mechanism of supramolecular poly(N-acryloyl glycinamide) (PNAGA) hydrogel, a self-thickening and self-strengthening strategy, that is, loading the concentrated NAGA monomer into the thermoreversible low-strength PNAGA hydrogel is proposed to directly 3D printing latently H-bonding-reinforced hydrogels. The low-strength PNAGA serves to thicken the concentrated NAGA monomer, affording an appropriate viscosity for thermal-assisted extrusion 3D printing of soft PNAGA hydrogels bearing NAGA monomer and initiator, which are further polymerized to eventually generate high-strength and antiswelling hydrogels, due to the reconstruction of strong H-bonding interactions from postcompensatory PNAGA. Diverse polymer hydrogels can be printed with self-thickened corresponding monomer inks. Further, the self-thickened high-strength PNAGA hydrogel is printed into a meniscus, which is implanted in rabbit's knee as a substitute with in vivo outcome showing an appealing ability to efficiently alleviate the cartilage surface wear. The self-thickening strategy is applicable to directly printing a variety of polymer-hydrogel-based tissue engineering scaffolds without sacrificing mechanical strength, thus circumventing problems of printing high-strength hydrogels and facilitating their application scope.     

A Smart MMP13-Responsive Injectable Hydrogel with Inflammatory Diagnostic Logic and Multiphase Therapeutic Ability to Orchestrate Cartilage Regeneration

Despite numerous attempts to engineer cartilage tissue in recent years, significant challenges remain regarding hyaline cartilage regeneration. One main reason is that the overactivated inflammatory response after injury suppresses inherent cartilage regenerative capabilities. Since the arthritic microenvironment is constantly changing during posttraumatic stress, an inflammatory diagnostic logic-based hydrogel for cartilage regeneration is developed for the first time through cross-linking of 4-arm poly(ethylene glycol)-vinyl sulfone (PEG-VS) and specific matrix metalloproteinase (MMP) 13-sensitive peptides. The hydrogel exhibits diagnostic logic to identify the pathological cue MMP13 and accordingly determine drug release kinetics in an inflammatory microenvironment. Additionally, multiphase therapeutic ability is designed to program different cargo release behaviors to match the inflammation-chondrogenesis cascade for better cartilage regeneration. Here, it is first proposed that MMP13 is a suitable diagnostic biomarker to modulate the inflammatory microenvironment in the early stage of cartilage injury. In vitro and in vivo studies show that the hydrogel has good injectability, on-demand anti-inflammation, and immunomodulation capabilities. Ultimately, loaded with multiple therapeutic factors, the hydrogel shows both microenvironmental modulation and chondrogenesis therapeutic ability, resulting in satisfactory hyaline cartilage regeneration. This study provides critical insight into the design and biological mechanism of both diagnostic and therapeutic ability-based cartilage tissue engineering strategies.     

C-Shaped Cartilage Development Using Wharton's Jelly-Derived Hydrogels to Assemble a Highly Biomimetic Neotrachea for use in Circumferential Tracheal Reconstruction

A highly biomimetic neotrachea with C-shaped cartilage rings has promising clinical applications in the treatment of circumferential tracheal defects (CTDs) owing to its structure and physiological function. However, to date, most fabricated tracheal cartilages are O-shaped. In this study, finite element analysis demonstrates C-shaped cartilage rings that exhibit better compliance than O-shaped. Hydrogel is developed using methacryloyl-modified decellularized Wharton's jelly matrix (DWJMA) for the regeneration of C-shaped cartilage rings. This novel hydrogel possesses adjustable physicochemical properties and favorable cytocompatibility. When loaded with chondrocytes, DWJMA hydrogels support the optimal cartilage regeneration both in vitro and in vivo. More importantly, a highly biomimetic neotrachea simultaneously simulating the structural and physiological properties of the normal trachea is regenerated via modular assembly of several individual C-shaped cartilage rings. The results demonstrate the highly biomimetic neotrachea have better patency (88.6 ± 6.1% vs 74.4 ± 9.4%, p < 0.05), improve the survival rate, alleviate weight loss and mucoid impaction, than its O-shaped counterpart when used for the treatment of CTDs in a rabbit model. Therefore, this study proposes a novel hydrogel for the regeneration of C-shaped cartilage and provides new insights into the treatment of CTDs using a highly biomimetic neotrachea with C-shaped cartilage rings.     

Magnesium Gradient-Based Hierarchical Scaffold for Dual-Lineage Regeneration of Osteochondral Defect

Osteochondral regeneration remains a great challenge due to the limited self-healing ability and the complexity of its hierarchical structure and composition. Mg²⁺ and hypoxia are two effective modulators in boosting chondrogenesis. To this end, a double-layered scaffold (D) consisting of a hydrogel layer on a porous cryogel is fabricated to mimic the hierarchical structure of osteochondral tissue. An Mg²⁺ gradient is incorporated into the double-layered scaffold with hypoxia-mimicking deferoxamine (DFO) embedded in the hydrogel (D-Mg-DFO), which remarkably augments the dual-lineage regeneration of both cartilage and subchondral bone. The higher Mg²⁺ supplementation from the upper hydrogel, associated with its hypoxia-mimicking situation and small pore size, exhibits promotive effects on chondrogenic differentiation. The lower Mg²⁺ supplementation from the bottom cryogel, associated with its interconnected macroporous structure, achieves multiple contributions in stem cell migration from bone marrow cavity, matrix mineralization, and osteogenesis. Furthermore, rabbits’ trochlea osteochondral defects are established to evaluate the regenerative outcome. Compared to control scaffolds containing only Mg²⁺ or DFO, the D-Mg-DFO scaffold presents the best regenerative effect under the synergistic contribution of multiple factors. Overall, this work provides a new design of scaffold toward an effective repair of cartilage defect.     

Light-Controlled Growth Factors Release on Tetrapodal ZnO-Incorporated 3D-Printed Hydrogels for Developing Smart Wound Scaffold

Advanced wound scaffolds that integrate active substances to treat chronic wounds have gained significant recent attention. While wound scaffolds and advanced functionalities have previously been incorporated into one medical device, the wirelessly triggered release of active substances has remained the focus of many research endeavors. To combine multiple functions including light-triggered activation, antiseptic, angiogenic, and moisturizing properties, a 3D printed hydrogel patch encapsulating vascular endothelial growth factor (VEGF) decorated with photoactive and antibacterial tetrapodal zinc oxide (t-ZnO) microparticles is developed. To achieve the smart release of VEGF, t-ZnO is modified by chemical treatment and activated through ultraviolet/visible light exposure. This process would also make the surface rough and improve protein adhesion. The elastic modulus and degradation behavior of the composite hydrogels, which must match the wound healing process, are adjusted by changing t-ZnO concentrations. The t-ZnO-laden composite hydrogels can be printed with any desired micropattern to potentially create a modular elution of various growth factors. The VEGF-decorated t-ZnO-laden hydrogel patches show low cytotoxicity and improved angiogenic properties while maintaining antibacterial functions in vitro. In vivo tests show promising results for the printed wound patches, with less immunogenicity and enhanced wound healing.     

3D Printing Hydrogel Scaffolds with Nanohydroxyapatite Gradient to Effectively Repair Osteochondral Defects in Rats

Osteochondral (OC) defects pose an enormous challenge with no entirely satisfactory repair strategy to date. Herein, a 3D printed gradient hydrogel scaffold with a similar structure to that of OC tissue is designed, involving a pure hydrogel-based top cartilage layer, an intermediate layer for calcified cartilage with 40% (w w⁻¹) nanohydroxyapatite (nHA) and 60% (w w⁻¹) hydrogel, and a 70/30% (w w⁻¹) nHA/hydrogel-based bottom subchondral bone layer. This study is conducted to evaluate the efficacy of the scaffold with nHA gradients in terms of its ability to promote OC defect repair. The fabricated composites are evaluated for physicochemical, mechanical, and biological properties, and then implanted into the OC defects in 56 rats. Overall, bone marrow stromal cells (BMSCs)-loaded gradient scaffolds exhibit superior repair results as compared to other scaffolds based on gross examination, micro-computed tomography (micro-CT), as well as histologic and immunohistochemical analyses, confirming the ability of this novel OC graft to facilitate simultaneous regeneration of cartilage-subchondral bone.     

Integrated and Bifunctional Bilayer 3D Printing Scaffold for Osteochondral Defect Repair

Bioinspired scaffolds with two distinct regions resembling stratified anatomical architecture provide potential strategies for osteochondral defect repair and are studied in preclinical animals. However, delamination of the two layers often causes tissue disjunction between the regenerated cartilage and subchondral bone, leading to few commercially available clinical applications. This study develops an integrated poly(ε-caprolactone) (PCL)-based scaffold for repairing osteochondral defects. An extracellular matrix (ECM)-incorporated 3D printing composite scaffold (ECM/PCL) coated with ECM hydrogel (E-co-E/PCL) is fabricated as the upper layer, and magnesium oxide nanoparticles coated with polydopamine (MgO@PDA)-incorporated composite scaffold (MD/PCL) is fabricated using 3D printing as the bottom layer. The physicochemical and mechanical properties of the bilayer scaffold meet the requirements in designing and fabricating the osteochondral scaffold, especially a strong interface possessed between the two layers. By in vitro study, the integrated scaffold stimulates proliferation, chondrogenic differentiation, and osteogenic differentiation of human bone mesenchymal stem cells. Moreover, the integrated bilayer scaffold exhibits well repair ability to facilitate simultaneous regeneration of cartilage and subchondral bone after implanting into the osteochondral defect in rats. In addition, cartilage “tidemarks” completely regenerated after 12 weeks of implantation of the bilayer scaffold, which indicates no tissue disjunctions formed between the regenerated cartilage and subchondral bone.     

Environmentally Adaptive Polymer Hydrogels: Maintaining Wet-Soft Features in Extreme Conditions

Hydrogels have been widely explored to adapt to different application circumstances. As typical wet-soft materials, the high-water content of hydrogels is beneficial to their wide biomedical applications. Moreover, hydrogels have been displaying considerable application potential in some high-tech areas, like brain-computer interface, intelligent actuator, flexible sensor, etc. However, traditional hydrogel is susceptive to freezing below zero, dehydration, performance swelling-induced deformation, and suffers from mechanical damage in extremely mechanical environments, which result in the loss of wet-soft peculiarities (e.g., flexibility, structure integrity, transparency), greatly limiting their applications. Therefore, reducing the freezing point, improving the dehydration/solution resistance, and designing mechanical adaptability are effective strategies to endow hydrogels with the extreme environmental adaptability, thus broadening their application fields. This review systematically summarizes research advances of environmentally adaptive hydrogels (EAHs), comprising anti-freezing, dehydration-resistant, acid/base/swelling deformation-resistant, and mechanical environment adaptive hydrogels (MEAHs). Firstly, fabrication methods are presented, including the deep eutectic solvent/ionic liquid substituent, the addition of salts, organogel, polymer network modification, and double network (DN) complex/nanocomposite strategy, etc. Meanwhile, the features of different approaches are overviewed. The mechanisms, properties, and applications (e.g., intelligent actuator, wound dressing, flexible sensor) of EAHs are demonstrated. Finally, the issues and future perspectives for EAHs’ researches are demonstrated.     

Thermochemotherapy Meets Tissue Engineering for Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is an autoimmune disease that progresses from inflammation to cartilage destruction. Inspired by the similar characteristics of inflammatory granulation tissue to those of tumors, the newly emerged tumor therapy called thermochemotherapy is proposed to treat RA. Meanwhile, the repair of cartilage injury via tissue engineering is paid attention simultaneously. A first-line antirheumatic drug (MTX; methotrexate) and transforming growth factor β1 (TGF-β1) are loaded in nano-Fe₃O₄ composite chitosan-polyolefin to construct a multifunctional hydrogel (DN-Fe-MTX-TGFβ1). The mechanical properties of the hydrogel are equivalent to that of articular cartilage to guarantee its role as a scaffold. A long-term release ability and the magnetocaloric properties of the hydrogel assure its effect to provide sustained local thermochemotherapy. The effective ability of the hydrogel for both anti-inflammation and cartilage repair is demonstrated. This work indicates a promising way to combine thermochemotherapy and tissue engineering for the effective treatment of RA for the first time.     

A Mineralized High Strength and Tough Hydrogel for Skull Bone Regeneration

Over the past decade, high strength hydrogels have been intensively investigated. However, developing high strength biofunctional hydrogels for eliciting bone regeneration has been rarely reported. In this work, a mineralized high strength and tough hydrogel is synthesized by one‐step copolymerization of acrylonitrile, 1‐vinylimidazole, and polyethylene glycol diacrylate, followed by in situ precipitation mineralization. It is demonstrated that the CN? CN dipole–dipole pairings combined with the interaction of CaP nanocrystals with polymer chains contribute to tremendous increase of tensile/compressive strength, modulus, and fracture energy up to 6.1 MPa, 11.5 MPa, 6.47 MPa, and 7935 J m^?2, respectively. The biomineralization is shown to facilitate the attachment and proliferation of C2C12 cells in vitro. This biomineralized hydrogel scaffold is implanted into an 8 mm diameter critical‐size of calvarial defect of rats to evaluate the bone regeneration. 12 week postsurgery results reveal that the mineralized hydrogel exhibits the highest bone volume and density within the defect as measured by computed tomography and histology. This mineralized high strength and tough hydrogel offers a broad range of possibilities to be developed as biofunctional scaffold to promote the reconstruction and regeneration of not only bone, but also load‐bearing connective tissue.     

Biomimetic Elastomeric Bioactive Siloxane‐Based Hybrid Nanofibrous Scaffolds with miRNA Activation: A Joint Physico‐Chemical‐Biological Strategy for Promoting Bone Regeneration

Rapid and efficient disease‐induced or critical‐size bone regeneration remains a challenge in tissue engineering due to the lack of highly bioactive biomaterial scaffolds. Physical structures such as nanostructures, chemical components such as silicon elements, and biological factors such as genes have shown positive effects on bone regeneration. Herein, a bioactive photoluminescent elastomeric silicate‐based nanofibrous scaffold with sustained miRNA release is reported for promoting bone regeneration based on a joint physico‐chemical‐biological strategy. Bioactive nanofibrous scaffolds are fabricated by cospinning poly (ε‐caprolactone) (PCL), elastomeric poly (citrates‐siloxane) (PCS), and bioactive osteogenic miRNA nanocomplexes (denoted PPM nanofibrous scaffolds). The PPM scaffolds possess uniform nanostructures, significantly enhanced tensile stress (≈15 MPa) and modulus (≈32 MPa), improved hydrophilicity (30–60°), controlled biodegradation, and strong blue fluorescence. Bioactive miRNA complexes are efficiently loaded into the nanofibrous matrix and exhibit long‐term release for up to 70 h. The PPM scaffolds significantly promote the adhesion, proliferation, and osteoblast differentiation of bone marrow stem cells in vitro and enhanced rat cranial defect restoration (12 weeks) in vivo. This work reports an attractive joint physico‐chemical‐biological strategy for the design of novel cell/protein‐free bioactive scaffolds for synergistic tissue regeneration.     

Injectable Biomimetic Hydrogel Guided Functional Bone Regeneration by Adapting Material Degradation to Tissue Healing

The treatment of irregular bone defects remains a clinical challenge since the current biomaterials (e.g., calcium phosphate bone cement (CPC)) mainly act as inert substitutes, which are incapable of transforming into a regenerated host bone (termed functional bone regeneration). Ideally, the implant degradation rate should adapt to that of bone regeneration, therefore providing sufficient physicochemical support and giving space for bone growth. This study aims to develop an injectable biomaterial with bone regeneration-adapted degradability, to reconstruct a biomimetic bone-like structure that can timely transform into new bone, facilitating functional bone regeneration. To achieve this goal, a hybrid (LP-CPC@gelatin, LC) hydrogel is synthesized via one-step incorporation of laponite (LP) and CPC into gelatin hydrogel, and the LC gel degradation rate is controlled by adjusting the LP/CPC ratio to match the bone regeneration rate. Such an LC hydrogel shows good osteoinduction, osteoconduction, and angiogenesis effects, with complete implant-to-new bone transformation capacity. This 2D nanoclay-based bionic hydrogel can induce ectopic bone regeneration and promote ligament graft osseointegration in vivo by inducing functional bone regeneration. Therefore, this study provides an advanced strategy for functional bone regeneration and an injectable biomimetic biomaterial for functional skeletal muscle repair in a minimally invasive therapy.     

Time Controlled Protein Release from Layer‐by‐Layer Assembled Multilayer Functionalized Agarose Hydrogels

Axons of the adult central nervous system exhibit an extremely limited ability to regenerate after spinal cord injury. Experimentally generated patterns of axon growth are typically disorganized and randomly oriented. Support of linear axonal growth into spinal cord lesion sites has been demonstrated using arrays of uniaxial channels, templated with agarose hydrogel, and containing genetically engineered cells that secrete brain‐derived neurotrophic factor (BDNF). However, immobilizing neurotrophic factors secreting cells within a scaffold is relatively cumbersome, and alternative strategies are needed to provide sustained release of BDNF from templated agarose scaffolds. Existing methods of loading the drug or protein into hydrogels cannot provide sustained release from templated agarose hydrogels. Alternatively, here it is shown that pH‐responsive H‐bonded poly(ethylene glycol)(PEG)/poly(acrylic acid)(PAA)/protein hybrid layer‐by‐layer (LbL) thin films, when prepared over agarose, provided sustained release of protein under physiological conditions for more than four weeks. Lysozyme, a protein similar in size and isoelectric point to BDNF, is released from the multilayers on the agarose and is biologically active during the earlier time points, with decreasing activity at later time points. This is the first demonstration of month‐long sustained protein release from an agarose hydrogel, whereby the drug/protein is loaded separately from the agarose hydrogel fabrication process.     

Rational Design of Bioactive Hydrogels toward Periodontal Delivery: From Pathophysiology to Therapeutic Applications

Periodontitis is a biofilm-induced, host-mediated inflammatory disease that results in periodontal tissue destruction. The design of functional biomaterials based on disease pathophysiology is essential for enhancing their therapeutic effects in periodontitis treatment. As promising localized drug delivery systems and tissue engineering scaffolds, hydrogels have gained significant interest for controlled and sustained release of bioactive agents in periodontal applications. The rational design of bioactive hydrogels can facilitate bacterial control and modulate destructive host inflammation, thereby preventing the progression of periodontitis. In this review, the pathophysiological mechanisms underlying periodontitis as fundamental principles for the design of functional hydrogel systems are first introduced. In the following part, an overview is systematically provided of the types and functions of the bioactive hydrogel systems loaded with anti-bacterial and anti-inflammatory agents for periodontal delivery. Finally, the remaining challenges and future perspectives of hydrogel delivery systems for periodontal applications are proposed. It is believed that this review will inspire the rational design and development of innovative functional hydrogel biomaterials toward periodontal therapy.     

Nanoporous Substrate‐Infiltrated Hydrogels: a Bioinspired Regenerable Surface for High Load Bearing and Tunable Friction

Nature has successfully combined soft matter and hydration lubrication to achieve ultralow friction even at relatively high contact pressure (e.g., articular cartilage). Inspired by this, hydrogels are used to mimic natural aqueous lubricating systems. However, hydrogels usually cannot bear high load because of solvation in water environments and are, therefore, not adopted in real applications. Here, a novel composite surface of ordered hydrogel nanofiber arrays confined in anodic aluminum oxide (AAO) nanoporous template based on a soft/hard combination strategy is developed. The synergy between the soft hydrogel fibers, which provide excellent aqueous lubrication, and the hard phase AAO, which gives high load bearing capacity, is shown to be capable of attaining very low coeffcient of friction (<0.01) under heavy load (contact pressures ≈2 MPa). Interestingly, the composite synthetic material is very stable, cannot be peeled off during sliding, and exhibits desirable regenerative (self‐healing) properties, which can assure long‐term resistance to wear. Moreover, the crosslinked polymethylacrylic acid hydrogels are shown to be able to promptly switch between high friction (>0.3) and superlubrication (≈10^?3) when their state is changed from contracted to swollen by means of acidic and basic actuation. The mechanisms governing ultralow and tunable friction are theoretically explained via an in‐depth study of the chemomechanical interactions responsible for the behavior of these substrate‐infiltrated hydrogels. These findings open a promising route for the design of ultra‐slippery and smart surface/interface materials.     

Smart Biomaterials for Articular Cartilage Repair and Regeneration

Articular cartilage defects bring about disability and worldwide socioeconomic loss, therefore, articular cartilage repair and regeneration is recognized as a global issue. However, due to its avascular and nearly acellular characteristic, cartilage tissue regeneration ability is limited to some extent. Despite the availability of various treatment methods, including palliative drugs and surgical regenerative therapy, articular cartilage repair and regeneration still face major challenges due to the lack of appropriate methods and materials. Smart biomaterials can regulate cell behavior and provide excellent tissue repair and regeneration microenvironment, thus inducing articular cartilage repair and regeneration. This process is adjusted by controlling drug/bioactive factors release via responding to exogenous/endogenous stimuli, tailoring materials’ structure and function similar to native cartilage or providing physiochemical and physical signaling factors. Herein, smart biomaterials, recently applied in articular cartilage repair and regeneration, are elaborated from two aspects: smart drug release system and smart scaffolds. Furthermore, articular cartilage and its defects and advanced manufacturing techniques of smart biomaterials are discussed in brief. Finally, perspectives for smart biomaterials used in articular cartilage repair and regeneration are presented and the clinical translation of smart biomaterials is emphasized.