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As an alternative strategy to achieve the desired bone augmentation, tenting screw technology (TST) has considerably broadened the indications for implant treatment. Titanium tenting screws are typically used in TST to maintain the space for bone regeneration. However, a high degree of osteogenic integration complicate titanium tenting screw removal and impact the bone healing micro-environment. Previous efforts have been focused on modifying titanium surfaces to enhance osseointegration while ignoring the opposite process. Due to the vital role of bone marrow mesenchymal stem cells (BMSCs) in bone regeneration, it might be feasible to reduce osseointegration around titanium tenting screws by resisting the adhesion of BMSCs. Herein, poly(ethylene glycol)methyl ether methacrylate (poly(PEGMA)) with an optimal length of PEG chain was incorporated with a Ti surface in terms of surface-initiated activators regenerated by electron transfer atom transfer radical polymerization (SI-ARGET ATRP). The cell apoptosis analysis showed that the new surface would not induce the apoptosis of BMSCs. Then, the adhesive and proliferative behaviors of BMSCs on the surface were analyzed which indicated that the poly(PEGMA) surface could inhibit the proliferation of BMSCs through resisting the adhesion process. Furthermore, in vivo experiments revealed the presence of the poly(PEGMA) on the surface resulted in a lower bone formation and osseointegration compared with the Ti group. Collectively, this dense poly(PEGMA) surface of Ti may serve as a promising material for clinical applications in the future. STATEMENT OF SIGNIFICANCE: The poly(ethylene glycol)methyl ether methacrylate (poly(PEGMA)) with an optimal length of PEG chain was grafted onto a Ti surface by surface-initiated activators regenerated by electron transfer atom transfer radical polymerization (SI-ARGET ATRP). The PEGMA surface could reduce the osteogenic integration by preventing the adhesion of cells, resulting in a lower pullout force of the modified implant and thereby desirable and feasible applications in dental surgery.

Branched polyethylene (B-PE) elastomer was investigated for its potential medical application as a tarsus construct. The in vitro results showed that the B-PE and processed B-PE films or scaffolds did not exhibit noticeable cytotoxicity to the NIH3T3 fibroblasts and human vascular endothelial cells (ECs). The B-PE scaffolds with a pore size of 280–480 µm were prepared by using a gelatin porogen-leaching method. The porous scaffolds implanted subcutaneously in rats exhibited mild inflammatory response, collagen deposition and fast fibrovascularization, suggesting their good biocompatibility. Quantitative real-time PCR analysis showed low expression of pro-inflammatory genes and up-regulated expressions of collagen deposition and vascularization-related genes, validating the results of historical evaluation in a molecular level. The B-PE scaffolds and Medpor controls were transplanted in rabbits with eyelid defects. The B-PE scaffolds exhibited a similar elastic modulus and provided desirable repair effects with mild fibrous capsulation, less eyelid deformities, and were well integrated with the fibrovascular tissue compared with the Medpor controls.

Additive manufacture has recently been proposed as a versatile process for fabricating porous bioceramic scaffolds for bone repair and tissue engineering; however, to control or tailor the biodegradation of the porous biomaterials is still a challenge. Here, the core-shell-structured biphasic bioceramic porous scaffolds with tailorable ion release and biodegradation were prepared by direct ink writing technique with coaxially aligned bi-nozzle system. Our method employed rapidly gelling filaments of wollastonite (CSi) and diopside without and with Zn or Sr doping (Dio, ZnDio, SrDio) derived from bi-flow of sodium alginate-loaded bioceramic slurries, and varying the powder slurry design made it easy to create core-shell struts (e.g. CSi@Dio, CSi@ZnDio, CSi@SrDio) with adjustable bioceramic-phase distribution. It was found that the Zn- or Sr-doping could readily adjust the mechanical strength and biodegradation rate in the early stage. Furthermore, when 30% organic microspheres were pre-mixed into the powder slurry, the controllable high-density micropores could be introduced into the shell layer after sintering (e.g. CSi@Dio-p, CSi@ZnDio-p, CSi@SrDio-p), and thus permeability is maximally tuned and favorable for ion release through the porous shell layer. This new core-shell direct ink writing strategy can be used to fabricate a variety of biphasic bioceramic scaffolds with adjustable physicochemical properties which could be potentially beneficial for improving biological performance and bone repair in situ.

Regeneration and functional recovery of peripheral nerves remain formidable due to the inefficient physical and chemical cues in the available nerve guidance conduits (NGCs). Introducing micropatterns and bioactive substances into the inner wall of NGCs can effectively regulate the behavior of Schwann cells, the elongation of axons, and the phenotype of macrophages, thereby aiding the regeneration of injured nerve. In this study, linear micropatterns with ridges and grooves of 3/3, 5/5, 10/10, and 30/30 μm were created on poly(d,l-lactide-co-caprolactone) (PLCL) films following with surface aminolysis and electrostatic adsorption of graphene oxide (GO) nanosheets. The GO-modified micropatterns could significantly accelerate the collective migration of Schwann cells (SCs) and migration of SCs from their spheroids in vitro. Moreover, the SCs migrated directionally along the stripes with a fastest rate on the 3/3-GO film that had the largest cell adhesion force. The neurites of N2a cells were oriented along the micropatterns, and the macrophages tended to differentiate into the M2 type on the 3/3-GO film judged by the higher expression of Arg 1 and IL-10. The systematic histological and functional assessments of the regenerated nerves at 4 and 8 weeks post-surgery in vivo confirmed that the 3/3-GO NGCs had better performance to promote the nerve regeneration, and the CMAP, NCV, wet weight of gastrocnemius muscle, positive S100β and NF200 area percentages, and average myelinated axon diameter were more close to those of the autograft group at 8 weeks. This type of NGCs thus has a great potential for nerve regeneration.

The regeneration of osteochondral defects faces great challenges because of the limited self-regenerative capabilities of cartilage tissues. In situ inductive regeneration can be realized using bioactive scaffolds combined with endogenous reparative cells. Cell migration could be significantly facilitated by scaffolds with oriented channels. For this purpose, silk fibroin (SF) was composited with collagen (Col) to fabricate extracellular matrix (ECM)-mimetic SF/Col composite scaffolds with random pores, radially aligned pores or axially aligned pores by ice-templated assembly and temperature gradient-guided thermally-induced phase separation. Scanning electron microscopy (SEM) observation confirmed the random and aligned architectures in the respective scaffolds. The three kinds of SF/Col composite scaffolds exhibited a porous structure with a porosity of ∼85%, an appropriate elastic modulus with mechanical anisotropy in the aligned scaffolds, and good biocompatibility. The oriented channels could improve in vivo cell migration and infiltration. During the tissue remodeling processes, the regeneration of osteochondral tissues particularly cartilage was obviously faster in the radially aligned scaffold group than in the other two groups. Nevertheless, satisfactory regeneration was achieved in the two aligned scaffold groups with hyaline cartilage formation at 18 weeks post-surgery, while a hybrid of hyaline cartilage and fibrocartilage was formed in the random scaffold group.

The osteoarthritis (OA) symptoms cannot be fully remedied by using only a single functional component because of its complex pathogenesis. Herein, a MnO

Spinal cord injury (SCI) is an overwhelming and incurable disabling event accompanied by complicated inflammation-related pathological processes, such as excessive reactive oxygen species (ROS) produced by the infiltrated inflammatory immune cells and released to the extracellular microenvironment, leading to the widespread apoptosis of the neuron cells, glial and oligodendroctyes. In this study, a thioketal-containing and ROS-scavenging hydrogel was prepared for encapsulation of the bone marrow derived mesenchymal stem cells (BMSCs), which promoted the neurogenesis and axon regeneration by scavenging the overproduced ROS and re-building a regenerative microenvironment. The hydrogel could effectively encapsulate BMSCs, and played a remarkable neuroprotective role

Myocardial infarction (MI) is still a major cause of mortality and morbidity worldwide. Elastomer cardiac patches have shown great potential in preventing left ventricle (LV) remodeling post-MI by providing mechanical support to the infarcted myocardium. Improved therapeutic outcomes are expected by mediating pathological processes in the necrosis phase, inflammation phase, and fibrosis phase, through orchestrated biological and mechanical treatments. In this study, a mechanically robust multifunctional cardiac patch integrating reactive oxygen species (ROS)-scavenging, anti-inflammatory, and pro-angiogenic capabilities was developed to realize the integrative strategy. An elastomeric polyurethane (PFTU) containing ROS-sensitive poly (thioketal) (PTK) and unsaturated poly (propylene fumarate) (PPF) segments was synthesized, which was further clicked with pro-angiogenic Arg-Glu-Asp-Val (REDV) peptides to obtain PFTU-g-REDV (PR), and was formulated into a macroporous patch containing rosuvastatin (PRR). The mechanical support and multifunctional effects of the patch were confirmed in a rat MI model in vivo compared to the patches with only mechanical support, leading to reduced cell apoptosis, suppressed local inflammatory response, alleviated fibrosis, and induced angiogenesis. The cardiac functions and LV morphology were also well maintained. These results demonstrate the advantages of the integrated and orchestrated treatment strategy in MI therapy.

Pneumonia is a common but serious infectious disease, and is the sixth leading cause for death. The foreign pathogens such as viruses, fungi, and bacteria establish an inflammation response after interaction with lung, leading to the filling of bronchioles and alveoli with fluids. Although the pharmacotherapies have shown their great effectiveness to combat pathogens, advanced methods are under developing to treat complicated cases such as virus-infection and lung inflammation or acute lung injury (ALI). The inflammation modulation nanoparticles (NPs) can effectively suppress immune cells and inhibit inflammatory molecules in the lung site, and thereby alleviate pneumonia and ALI. In this review, the pathological inflammatory microenvironments in pneumonia, which are instructive for the design of biomaterials therapy, are summarized. The focus is then paid to the inflammation-modulating NPs that modulate the inflammatory cells, cytokines and chemokines, and microenvironments of pneumonia for better therapeutic effects. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease.

Acute lung injury (ALI) is associated with excessive inflammatory response, leading to acute respiratory distress syndrome (ARDS) without timely treatment. A fewer effective drugs are available currently to treat the ALI/ARDS. Herein, a therapeutic nanoplatform with reactive oxygen species (ROS)-responsiveness was developed for the regulation of inflammation. Dexamethasone acetate (Dex) was encapsulated into poly(thioketal) polymers to form polymeric nanoparticles (NPs) (PTKNPs@Dex). The NPs were composed of poly(1,4-phenyleneacetonedimethylene thioketal) (PPADT) and polythioketal urethane (PTKU), in which the thioketal bonds could be cleaved by the high level of ROS at the ALI site. The PTKNPs@Dex could accumulate in the pulmonary inflammatory sites and release the encapsulated payloads rapidly, leading to the decreased ROS level, less generation of pro-inflammatory cytokines, and reduced lung injury and mortality of mice. RNA sequencing (RNA-seq) analysis showed that the therapeutic efficacy of the NPs was associated with the modulation of many immune and inflammation-linked pathways. These findings provide a newly developed nanoplatform for the efficient treatment of ALI/ARDS.

Selective adhesion and migration of urethral epithelial cells (HUCs) over fibroblasts (FIBs) are very important in the reconstruction of the urethral epithelial layer and prevention of ureteral scarring and stenosis. In this study, unsaturated polyurethane (PPFU-CO-SS) films were co-grafted with a cell-resisting poly(ethylene glycol) (PEG) layer and HUC-selective Cys-Ala-Gly (CAG) peptides, whose physicochemical changes were confirmed by X-ray photon spectroscopy, fluorescence spectroscopy and water contact angle measurements. The adhesion and activation of platelets on the PEG/CAG grafted surface were significantly reduced compared to those on the PPFU-CO-SS, resulting in a similar status as that on a PEG-grafted surface. The HUC-selective material could obviously promote the adhesion and migration of HUCs. The ratio of the urethral epithelial cells to fibroblasts on the PEG/CAG grafted surface was nearly 3-fold that on the unmodified PPFU-CO-SS in a co-culture competitive environment. The urethral epithelial cells cultured on the PEG/CAG grafted surface also had the highest migration rate, which was 2.24-fold compared to that on the PPFU-CO-SS control.

Immune response is critical to tissue repair. Designing biomaterials with immunomodulatory functions has become a promising strategy to facilitate tissue repair. Considering the key roles of macrophages in tissue repair and the significance of the balance of M1 and M2, smart biomaterials, which can harness macrophage phenotypes dynamically to match the tissue healing process on demand, have attracted a lot of attention to be set apart from the traditional anti-inflammatory biomaterials. Here, we prepare a gold nanorod-contained shape memory polycaprolactone film with dynamic surface topography, which has the ability to be transformed from flat to microgrooved under near-infrared (NIR) irradiation. Based on the close relationships between the morphologies and the phenotypes of macrophages, the NIR-triggered surface transformation induces the elongation of macrophages, and consequently the upregulated expressions of arginase-1 and IL-10 in vitro, indicating the change of macrophage phenotypes. The sequential modulation of macrophage phenotypes by dynamic surface topography is further confirmed in an in vivo implantation test. The healing-matched modulation of macrophage phenotypes by dynamic surface topography without the stimuli of cytokines offers an effective and noninvasive strategy to manipulate tissue regenerative immune reactions to achieve optimized healing outcomes.

Dynamic control of mesenchymal stem cell (MSC) behaviors on biomaterial surface is critically involved in regulating the cell fate and tissue regeneration. Herein, a stimuli-responsive surface based on host-guest interaction with cell selectivity was developed to regulate migration of MSCs in situ by dynamic display of cell-specific peptides. Azobenzene-grafted MSC-affinitive peptides (EPLQLKM, Azo-E7) were grafted to β-cyclodextran (β-CD)-modified poly(2-hydroxyethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) (PHG) brushes, which were prepared by using surface-initiated atom transfer radical polymerization (SI-ATRP). X-ray photoelectron spectroscopy (XPS), quartz crystal microbalance (QCM), and water contact angle were used to characterize their structure and property. Cell adhesion assay showed that the combination effect of resisting property of PHG and MSC-affinity of E7 could promote the selective adhesion of MSCs over other types of cells such as RAW264.7 macrophages and NIH3T3 fibroblasts to some extent. UV-Vis spectroscopy proved that the competing guest molecules, amantadine hydrochloride (Ama), could release Azo-E7 peptides from the CD surface to different extents, and the effect was enhanced when UV irradiation was employed simultaneously. As a result, the decrease of cell adhesion density and migration rate could be achieved in situ. The cell density and migration rate could be reduced by over 40% by adding 20 μmol/L Ama, suggesting that this type of surface is a new platform for dynamic regulation of stem cell behaviors in situ.

Inspired by natural hemin structure, the fabrication of metal organic framework (MOF) nanomaterials constructed by metal ions and iron porphyrin for peroxidase mimicking has attracted extensive attention recently due to their high concentration of active sites and great channeling for substrate diffusion. Herein, by using benzoic acid as capping agent, we fabricated uniform PCN-224 nanoparticles (NPs), which were composed of Zr6 cluster and tetrakis(4-carboxyphenyl)porphyrin (H2TCPP). Then Fe(Ⅲ) ions were incorporated into the center of H2TCPP producing iron porphyrin unit similar to hemin serving as catalytic active site. The procedure of iron incorporation didn't change the size and morphology of PCN-224 NPs. The newly formed Fe@PCN-224 NPs possessed peroxidase-like activity with much lower Km values and higher Kcat values than most of peroxidase-like nanozymes as well as natural horseradish peroxidase (HRP), indicating their enhanced catalytic activity. Taking advantage of the excellent peroxidase-like activity of Fe@PCN-224 NPs, we successfully developed a colorimetric method for simple and sensitive detection of hydrogen peroxide and glucose in combination with glucose oxidase.

In women of reproductive age, severe injuries to the endometrium are often accompanied by endometrial scar formation or intrauterine adhesions (IUAs), which can result in infertility or miscarriage. Although many approaches have been used to treat severe IUAs, high recurrence rates and endometrial thinning have limited therapeutic efficiency. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrial regeneration. The CS/UC-MSCs promoted human endometrial stromal cell proliferation and inhibited apoptosis in vitro through paracrine effects. In a model of endometrial damage, transplantation with the CS/UC-MSCs maintained normal luminal structure, promoted endometrial regeneration and collagen remodeling, induced intrinsic endometrial cell proliferation and epithelium recovery, and enhanced the expression of estrogen receptor α and progesterone receptor. An improved ability of the regenerated endometrium to receive embryos was confirmed. Together, our results indicate that the CS/UC-MSCs promoted endometrial structural reconstruction and functional recovery. Topical administration of the CS/UC-MSCs after trans-cervical resection of adhesions might prevent re-adhesion, promote endometrium regeneration and improve pregnancy outcomes for patients with severe IUAs. STATEMENT OF SIGNIFICANCE: Intrauterine adhesions due to severe endometrium injuries happen frequently in clinic and become one of the crucial reasons for women's infertility or miscarriage. Therefore, how to regenerate the damaged endometrium is a big challenge. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrium regeneration. Herein, UC-MSCs, known for low immunogenicity and high proliferative potential, exhibit promising potential for endometrium regeneration; and collagen scaffolds provide suitable physical support. It was proved that transplantation with CS/UC-MSCs promoted endometrial regeneration and fertility restoration. It suggested that topical administration of CS/UC-MSCs in uterus could be a promising strategy for patients suffering severe intrauterine adhesion and infertility.

Nanosize metal-organic frameworks (MOFs) are a class of promising porous nanomaterials for biomedical applications, in which their size control and surface modification are critical. Current approaches for fabrication of zeolitic imidazolate framework (ZIF-8) nanoparticles (NPs) with controlled size and poly(ethylene glycol) (PEG) surface modification are separated and time-consuming. Here, we report a simple and rapid synthetic method that combines the size control of ZIF-8 NPs and their surface modification of PEG at the same time. Monovalent amino PEG (PEG-NH2) was used as capping agent to control the size of ZIF-8 and simultaneously realize surface modification through coordination interaction. The size of ZIF-8 was tuned in a board range. The coated NPs showed intact crystalline structure with improved colloidal stability. By further adding the anticancer drug doxorubincin (DOX) into the reaction mixture, ZIF-8 NPs with encapsulated DOX and PEG surface modification (DOX@ZIF-8/PEG) can be synthesized in one-pot. They showed pH-responsive drug release property and efficacy in killing of cancer cells. Our facile one-pot process can be used to design MOFs NPs as multifunctional delivery systems for a variety of cargos such as therapeutic and imaging agents.

The increasing demands of surgical implantation highlight the significance of anti-infection of medical devices, especially antibiofilm contamination on the surface of implants. The biofilms developed by colonized microbes will largely hinder the adhesion of host cells, leading to failure in long-term applications. In this work, UV-responsive multilayers were fabricated by stepwise assembly of poly(pyrenemethyl acrylate- co-acrylic acid) (P(PA- co-AA)) micelles and chitosan on different types of substrates. Under UV irradiation, the cleavage of pyrene ester bonds in the P(PA- co-AA) molecules resulted in the increase of roughness and hydrophilicity of the multilayers. During this process, reactive oxygen species were generated in situ within 10 s, which destroyed the biofilms of Staphylococcus aureus, leading to the degradation of the bacterial matrix. The antibacterial rate was above 99.999%. The UV-irradiated multilayers allowed the attachment and proliferation of fibroblasts, endothelial cells, and smooth muscle cells, benefiting tissue integration of the implants. When poly(dimethylsiloxane) slices with the multilayers were implanted in vivo and irradiated by UV, the density of bacteria and the inflammatory level (judging from the number of neutrophils) decreased significantly. Moreover, formation of neo blood vessels surrounding the implants was observed after implantation for 7 days. These results reveal that the photoresponsive multilayers endow the implants with multifunctions of simultaneous antibiofilm and tissue integration, shedding light for applications in surface modification of implants in particular for long-term use.

We have developed the new core-shell bioceramic CSi-Sr4@CaP-px microspheres with tuning porous shell layer so that the biodegradation of both CSi-Sr4 core and CaP shell is readily adjusted synergistically. This is for the first time, to the best of our knowledge, that the bioceramic scaffolds concerning gradient distribution and microstructure-tailoring design is available for tailoring biodegradation and ion release (bioactivity) to optimizing osteogenesis. Furthermore, it is possibly helpful to develop new bioactive scaffold system for time-dependent tailoring bioactivity and microporous structure to significantly enhance bone regeneration and repair applications, especially in some non-load-bearing arbitrary 3D anatomical bone and teeth defects.

Enzymatic cascade reactions in confined microenvironments play important roles in cellular chemical transformation. They also have important biotechnological and therapeutic applications. Here, enzymatic cascade microreactors (MRs) coupling glucose oxidase (GOx) and hemoglobin (Hb) (GOx-Hb MRs) were successfully fabricated by co-precipitation of GOx and Hb into a MnCO3 template, followed by the assembly of a multilayer film on a template surface, slight cross-linking, and final removal of MnCO3. In the presence of glucose with blood-relevant concentration, the GOx-Hb MRs exhibited a higher cascade reaction activity under mild acidic conditions than that under neutral conditions at physiological temperature. The GOx-Hb MRs effectively consumed glucose to generate HO· at pH = 5, which significantly inhibited bacterial growth and biofilm formation. This kind of enzymatic cascade microreactors might be useful for applications in biomedical fields.

Self-assembly in living systems is important for developing biological functional materials and regulating cellular processes, which have potential applications in disease diagnosis and treatment. However, the controllable fabrication of complex self-assemblies such as micro/nanocomposite structures and the direct observation of morphology-defined nanostructures in a cell milieu are still challenging. We report here a facile strategy for achieving the intracellular stimuli-responsive fabrication of micro/nanocomposite structures by using reduction-responsive microgels as a platform. Amphiphilic polymers (CSEG-g-Chol) that contained disulfide bonds in side chains and grafted cholesterol groups (Chol) were synthesized and used to prepare microgels (MGs) by a method based on a calcium carbonate template, in which the template was removed after the polymer was loaded and crosslinked. In the presence of reductants such as glutathione (GSH) and dithiothreitol (DTT), nanospikes gradually protruded from the surface of CSEG-g-Chol MGs. After internalization into cells, reduction-responsive self-assembly and the protrusion of nanospikes in the cell milieu were observed. No obvious influence on the cytoskeleton and endoplasmic reticulum was observed via light microscopy. However, co-incubation of the MGs caused a certain extent of cytotoxicity depending on the co-incubation concentration and stimulated the secretion of tumor necrosis factor-α (TNF-α), which was several times higher than in the control group. This work may serve as a paradigm for the study of intracellular and in vivo self-assembly and may also provide important insights for the investigation of biological self-assembly and interactions between micro/nanomaterials and cells.

The ability of repair and regeneration of tissues or organs has been significantly improved by using biomaterials-based constructs. Our previous studies found the regeneration of both articular cartilage and subchondral bone by implantation of a poly(lactide-co-glycolide) (PLGA)/fibrin gel/bone marrow stem cells (BMSCs)/(lipofectamine/pDNA-transforming growth factor (TGF)-β1) construct in vivo, without the step of pre-induced differentiation of the laden stem cells in vitro. To substantiate the ability to regenerate multi-types of tissues by the same constructs, in this study the constructs were implanted into three types of tissues or tissue defects in vivo, including subcutaneous fascia layer, and ear cartilage and eyelid tarsal plate defects. The ear cartilage and eyelid tarsal plate defects were fully regenerated 8 w post-implantation, showing a similar morphology to the corresponding native tissues. In the neo ear cartilage, abundant chondrocytes with obvious lacunas and cartilage-specific extracellular matrices (ECMs) were found. Neo eyelid tarsal plate with mature meibomian gland acinar units was regenerated. Furthermore, expressions of the ECMs-specific genes and proteins, as well as the cell behavior modulatory factors, Sry related HMG box 9 (Sox9) and TGF-β1 were significantly up-regulated in the regenerated ear cartilages and eyelid tarsal plate than those in the subcutaneously implanted constructs, which were filled with fibrocytes, inflammatory cells, obvious vascularization and slight ECMs deposition. These results confirm firmly the ability to regenerate multi-types of tissues by a stem cells-laden construct via adapting to the microenvironments of corresponding tissues.

Endothelialization of vascular implants plays a vital role in maintaining the long-term vascular patency. In situ endothelialization and re-endothelialization is generally achieved by selectively promoting endothelial cell (EC) adhesion and, meanwhile, suppressing smooth muscle cell (SMC) adhesion. Currently, such EC versus SMC selectivity is achieved and extensively used in vascular-related biomaterials utilizing extracellular-matrix-derived EC-selective peptides, dominantly REDV and YIGSR. Nevertheless, the application of EC-selective peptides is limited due to their easy proteolysis, time-consuming synthesis, and expensiveness. To address these limitations, a polymeric strategy in designing and finding EC-selective biomaterials using amphiphilic β-peptide polymers by tuning serum protein adsorption is reported. The optimal β-peptide polymer displays EC versus SMC selectivity even superior to EC-selective REDV peptide regarding cell adhesion, proliferation, and migration of ECs versus SMCs. Study of the mechanism indicates that surface adsorption of bovine serum albumin, an abundant and anti-adhesive serum protein, plays a critical role in the ECs versus SMCs selectivity of β-peptide polymer. In addition, surface modification of the optimal β-peptide polymer effectively promotes the endothelialization of vascular implants and inhibits intimal hyperplasia. This study provides an alternative strategy in designing and finding EC-selective biomaterials, implying great potential in the vascular-related biomaterial study and application.

The diabetic wound is easily to develop into a chronic wound because of the extremely serious and complex inflammatory microenvironment including biofilm formation, over-expressed reactive oxygen species (ROS), hypoxia and insufficiency of nitric oxide (NO) synthesis. In this work, a multifunctional hydrogel was designed and prepared by crosslinking hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

Cellular metabolism plays a major role in the regulation of inflammation. The inflammatory macrophages undergo a wide-range of metabolic rewriting due to the production of significant amount of itaconate metabolite from cis-aconitate in the tricarboxylic acid cycle. This itaconate molecule has been recently described as a promising immunoregulator. However, its function and mode of action on macrophages and tissue repair and regeneration are yet unclear. Herein, the itaconate-derivative dimethyl itaconate (DMI) suppresses the IL-23/IL-17 inflammatory axis-associated genes and promotes antioxidant nuclear factor erythroid 2-related factor 2 target genes. The poly-e-caprolactone (PCL)/DMI nanofibers implanted in mice initially maintain inflammation by suppressing anti-inflammatory activity and particular inflammation, while at later stage promotes anti-inflammatory activity for an appropriate tissue repair. Furthermore, the PCL/DMI nanofiber patches show an excellent myocardial protection by reducing infarct area and improving ventricular function via time-dependent regulation of myocardium-associated genes. This study unveils potential DMI macrophage modulatory functions in tissue microenvironment and macrophages rewriting for proper tissue repair.

Osteochondral defect refers to the damage of cartilage as well as subchondral bone. Cartilage tissue engineering focusing on the regeneration of cartilage and disregarding the subchondral bone always leads to partial regeneration of the damage, resulting in poor mechanical and physiological properties. A scaffold suitable for in situ inductive regeneration of both types of tissues is urgently needed. In this study, a biphasic scaffold integrated by macro-porous fibrin and 3D-printed wollastonite (containing 8% MgSiO3 (CS-Mg8)) scaffolds, either preloaded with rabbit bone marrow mesenchymal stem cells (BMSCs) or not, were fabricated and used to repair osteochondral defects in vivo (full thickness osteochondral defects in rabbits, 4 mm in diameter and 4 mm in depth with bone marrow blood effusion). The fibrin scaffold had a pore size of 100–200 μm, and was degraded gradually and reached weight loss over 80% at 28 days. The presence of BMSCs could accelerate the degradation rate. BMSCs could well proliferate...

Tissue integration of orbital implants, following orbital enucleation treatment, represents a challenge for rapid fibrovascularization, long-time stability, anti-infection, and even induction of vascule regeneration. The objective of this study was to develop porous calcium-magnesium silicate materials, with good stability, bioactivity, and antibacterial potential as new orbital fillers. Three-dimensional (3D) diopside scaffolds (low dissolvability) were fabricated by direct ceramic ink writing assembly and then followed by one-step sintering at 1150 °C for 3 h. The pore wall of the scaffold was modified by another calcium-magnesium silicate, such as bredigite or akermanite, which dissolves quickly but shows greater angiogenic potential. These two Ca-Mg-silicates can be coated onto the pore strut, and the coating layers were observed to slowly dissolve in Tris buffer. The vascularization-favorable Cu ions, which had been doped into the bredigite or akermanite coating, could also be measured in the immersion medium. A primary angiogenic test in a panniculus carnosus muscle model in rabbit indicated that the Cu-doped bredigite and akermanite coatings were significantly beneficial for the neovascularization in the early stages. These results suggest that the diopside-based porous materials modified with functional coatings hold great potential for application in orbital reconstruction.

Tissue regeneration is an active multiplex process involving the dynamic inflammatory microenvironment. Under a normal physiological framework, inflammation is necessary for the systematic immunity including tissue repair and regeneration as well as returning to homeostasis. Inflammatory cellular response and metabolic mechanisms play key roles in the well-orchestrated tissue regeneration. If this response is dysregulated, it becomes chronic, which in turn causes progressive fibrosis, improper repair, and autoimmune disorders, ultimately leading to organ failure and death. Therefore, understanding of the complex inflammatory multiple player responses and their cellular metabolisms facilitates the latest insights and brings novel therapeutic methods for early diseases and modern health challenges. This review discusses the recent advances in molecular interactions of immune cells, controlled shift of pro- to anti-inflammation, reparative inflammatory metabolisms in tissue regeneration, controlling of an unfavorable microenvironment, dysregulated inflammatory diseases, and emerging therapeutic strategies including the use of biomaterials, which expand therapeutic views and briefly denote important gaps that are still prevailing.

Stem cell especially mesenchymal stem cell (MSC) transplantation is a promising therapeutic strategy for myocardial infarction (MI) repair. However, major obstacles remain due to the poor retention and survival rate of transplanted MSCs in the harmful MI microenvironment (e.g., oxidative stress and hypoxia). Here, a novel injectable hydrogel (RCGel) with dual functions of reactive oxygen species (ROS)-scavenging and O2-generating was employed to encapsulate MSCs for MI treatment. The RCGel encapsulating exhibited anti-ROS protection through inhibiting JNK/p38 apoptosis signaling pathway to improve the viability of MSCs under oxidative stress conditions in vitro. The survival of cardiomyocytes was also improved both in the oxidative stress and hypoxia environments when being co-cultured with MSCs-encapsulated RCGel (MSC/RCGel). The RCGel encapsulating boosted the engraftment of transplanted MSCs in vivo. More viable MSCs endowed with regenerative abilities in the infarcted rat heart along with the ameliorated MI microenvironment (decreased oxidative stress and hypoxia) by the RCGel substantially inhibited cardiac apoptosis, enhanced cardiomyocyte viability, promoted angiogenesis and reduced fibrosis to improve the cardiac functions. The encapsulation of MSCs in RCGel, which exhibits beneficial effects in resisting harsh environments, provides a new way in MI repair and stem cell delivery, and has great potential in cell-based regenerative medicine.

The excessive reactive oxygen species (ROS) and hypoxia deteriorate the inflammation-related diseases such as myocardial infarction (MI), and thereby deter the normal tissue repair and recovery and further lead to severe fibrosis and malfunction of tissues and organs. In particular, the MI has become one of the leading causes of death nowadays. In this study, a novel type of injectable hydrogel with dual functions of ROS scavenging and O

The dual functional implants of antibacteria and osteointegration are highly demanded in orthopedic and dentistry, especially for patients who suffer from diabetes or osteoporosis simultaneously. However, there is lack of the facile and robust method to produce clinically applicable implants with this dual function although coatings possessing single function have been extensively developed. Herein, hyperbranched poly-L-lysine (HBPL) polymers were covalently immobilized onto the alkali-heat treated titanium (Ti) substrates and implants by using 3-glycidyloxypropyltrimethoxysilane (GPTMS) as the coupling agent, which displayed excellent antibacterial activity against S. aureus and E. coli with an efficiency as high as 89.4% and 92.2% in vitro, respectively. The HBPL coating also significantly promoted the adhesion, spreading, proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro. Furthermore, the results of a S. aureus infection rat model in vivo ulteriorly verified that the HBPL-modified screws had good antibacterial and anti-inflammatory abilities at an early stage of implantation and better osteointegration compared with the control Ti screws.

Corneal chemical injury is a general but intractable ocular emergency, the sequelae of which are particularly challenging to treat. Human amniotic membrane (HAM) is one of the resources as a wound dressing for damaged corneal reconstruction, but the concerns related to the possible transmission of infectious diseases are the main drawbacks. Here we present a versatile method utilizing electrospinning and surface modification processes to develop optically highly transparent, microstructurally stable (>20 MPa in tensile strength in the wet state) biomimetic nanofibrous membranes. These membrane nanofibers, mainly consisting of a collagen–hyaluronate interior and a chitosan surface coating, showed superior mechanical and biological performances compared to HAM, and were favorable to the selective adhesion of epithelial cells (corneal, conjunctival) and fibroblasts. The alkali-burned corneal damage model in rats demonstrated that the biomimetic membranes could markedly improve re-epithelialization in corneal tissue within one week. Therefore, such bioactive multifunctional membranes may find widespread biomedical applications in wound healing and postoperative anti-adhesion in the near future.

The integration of physicochemical and biological performances in root canal treatment represents a challenge for long-time antileakage, antibacterial, and even inducing periradicular cementum/bone tissue regeneration. The objective of this work is to develop a β-Ca2SiO3 (β-C2Si)-based cement as a new root canal filler with good antibacterial ability, sealability and bioactivity. β-C2Si powders with controllable free CaO content were prepared by regulating the calcium/silicate molar ratio in reaction medium. It was demonstrated that a composite paste with 10-30 wt% α-gypsum at a liquid-to-powder ratio of 0.6 ml g-1 remained injectable for 12 min and provided a significant pH rise during setting. Notably, the hydraulic cements with high free CaO contents exhibited bactericidal or bacteriostatic properties against three bacterial strains, Streptococci mutans, Actinomyces naeslundii, and Actinomyces viscosus, which were demonstrated by the agar diffusion method. Also, the injected paste in root canal ex vivo showed extremely low microleakage of Rhodamine B but a good apatite-mineralization response. Therefore, these intrinsic antibacterial activity, bioactivity, injectability and tight adaption to root canal sealability make β-C2Si/α-gypsum composites preferential candidates for application in endodontics, such as root-end filling, pulp capping therapy, microleakage prevention, as well as for inducing hard tissue regeneration.

Gypsum is a promising material for bone defect repair due to its osteoconductivity, whereas it is still limited in orthopedic and dental surgeries due to its low bioactivity and too rapid resorption so that one major concern is the significant loss in microstructural stability in vivo. In the present strategy some key features were significantly improved by introducing rapidly biodegradable but highly bioactive calcium silicate (CS) for regulating the physicochemical properties and biological performances of the gypsum-based cements at the same liquid/solid ratio. We demonstrated that introduction of 23% CS into β-calcium sulfate hemihydrate (CSH) could improve the physicochemical properties but would not compromise the mechanical strength of the composite. The surface bioactivity was significantly enhanced by introducing 23% CS, and these biphasic composites were favorable for decelerating the biodegradation rate by nearly 18.5% in 28 days in vitro. A mild bioresorption rate, with 39.6% of composite residual 4 weeks after operation, was determined when implanted in subcutaneous tissue of rats. 8 weeks after implantation, the composite cement containing 23% CS significantly enhanced new bone tissue regeneration with a much higher relative bone content (∼68.6%) than pure gypsum in critical size femoral defects in rabbits. The novel CSH–CS biocements represent promising candidates for rapid bone resconstruction and repair in trauma and pathological conditions.

A great number of stimuli-responsive particles have been developed and used for biomedical applications such as intracellular drug delivery. It is of paramount importance to study the intracellular responsive process of these particles, offering insight into the understanding of their structure variation and design criteria for better performance. In this study polyethyleneimine (PEI)-coated poly(lactide-co-glycolide) (PLGA) particles with a diameter of 430 nm were prepared via a one-step emulsion method. The amino groups in the PEI molecules allowed further covalent linking of fluorescein isothiocyanate (FITC), bifunctional coupling agents 3,3′-dithiobispropionimidate, amino-ended polyethylene glycol (NH2–PEG–NH2) and tetramethylrhodamine isothiocyanate (TRITC), resulting in fluorescence resonance energy transfer (FRET) pairs on the particles. The particles exhibited glutathione-responsive ability, and lost the FRET effect due to the separation of FITC/TRITC pairs from the particle surface as a result of the cleavage of disulfide bonds. The particles showed different FRET change rates in A549 cells and HEK293 cells depending on the intracellular GSH concentration. Moreover, a much slower degradation rate was found inside cells than in simulated buffer with a similar GSH concentration. The results suggest that the responsive behaviors of the particles obtained in simulated buffer may not match fully/correctly with the real situation in a complicated intracellular environment.

In this study, four kinds of TiO2 nanorods (TiO2 NRs), with similar aspect ratios but different surface functional groups, i.e. amines (–NH2), carboxyl groups (–COOH) and poly(ethylene glycol) (–PEG), were used to study their interaction with rat bone marrow stem cells (MSCs). The aspect ratios of the TiO2 NRs were measured (50 to 65 nm in length and 8 nm in width) under transmission electron microscopy (TEM). The cellular uptake of the TiO2 NRs was qualitatively studied by TEM and then quantified by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that the MSCs ingested larger amounts of TiO2–core NRs and TiO2–NH2 NRs than those of TiO2–COOH NRs and TiO2–PEG NRs, with similar intracellular distribution patterns. TiO2–core NRs induced the highest cytotoxicity, as a result of the highest intracellular level of reactive oxygen species (ROS), which was lowered upon surface functionalization. The genotoxicity of the TiO2 NRs was neglectable at tested concentrations, studied by the comet assay. The adipogenic and osteogenic differentiation potentials of the MSCs were firstly evaluated in terms of lipid droplet formation and calcium deposition respectively in the presence of the TiO2 NRs. All of the TiO2 NRs did not show an obvious influence on the adipogenic differentiation potential of the MSCs. But TiO2–COOH NRs showed a significant impairment on the osteogenic differentiation behaviors. The influence of TiO2 NRs on the osteogenic differentiation of the MSCs was further quantitatively studied by the expression of osteogenic markers (collagen type I and osteocalcein), at both gene and protein levels. The results confirmed the strongest hindrance of the osteogenic differentiation of the MSCs by TiO2–COOH NRs, due to the up-regulation of transforming growth factor beta 1 (TGF-β1) and fibroblast growth factor (FGF-2). The results provide new information that the differentiation potential of the MSCs can be influenced by the presence of TiO2 NRs with different surface functionalities, suggesting a careful analysis of the biological impact of nanomaterials.

The extensive development and application of engineered nanoparticles (NPs) in various fields worldwide have been subjected to increasing concern due to their potential hazards to human health and the environment. Therefore, a simple, economical, and effective method for suppressing the toxicity of metal-based nanomaterials is needed. In this study, glutaraldehyde-crosslinked chitosan nanoparticles (CS NPs) were prepared and further modified with lysine (Ly-CS), glutamic acid (Glu-CS), or sodium borohydride reduction (R-CS), and used to suppress cytotoxicity induced by copper oxide NPs (CuO NPs) through chelation with intracellularly released copper ions. All three kinds of CS NPs had similar sizes of ∼100 nm in a dry state and ∼200 nm in cell culture medium, as determined by scanning electron microscopy, transmission electron microscopy, and dynamic light scattering. The chelating efficiency of different CS NPs followed the order Ly-CSGlu-CSR-CS. The CS NPs showed minimal or no toxicity to three different cell lines (HepG2, A549, and RAW264.7 cells) at 100 μg mL

Poly(lactide-co-glycolide) (PLGA) is one of the most attractive biodegradable polymers for loading and delivering payloads, especially in the form of nanoparticles (NPs). In this work, NPs of PLGA with 3 different molecular weights were fabricated using bovine serum albumin (BSA) and polyethyleneimine (PEI) as dispersing agents. Elemental analysis revealed that the loading amounts of BSA and PEI were 40-60 μg mg-1 and 12-15 μg mg-1 in the BSA/PLGA NPs and PEI/PLGA NPs, respectively. About 13-18 μg mg-1 BSA was exposed onto the surface of the BSA/PLGA NPs. No degradation of the PLGA NPs was detected after being incubated in artificial lysosomal fluid or with macrophages in a culture medium for 7 days. The innate immune activation behavior of the BSA/PLGA and PEI/PLGA NPs was evaluated by co-incubation with RAW264.7 cells in vitro. PLGA NPs fabricated with different molecular weights of PLGA showed no difference in stimulating RAW264.7 cells. The PEI/PLGA NPs did not show significant immune activation in terms of secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) too. By contrast, the BSA/PLGA NPs induced a significantly higher expression of TNF-α, likely due to the heterogeneous albumin and existence of endotoxin, and the synergistic role of larger uptake of the BSA/PLGA NPs by macrophages.

Engineering microstructures with bioactive molecules critically influences Schwann cell (SC) behaviors in terms of cellular spatial arrangement and directional migration, which are advantageous for expediting the repair of peripheral nerve defects. In this study, stripe micropatterns were fabricated on poly(D,L-lactide-co-caprolactone) (PLCL) films by thermo-pressing using polydimethylsiloxane (PDMS) stamps with ridges/grooves of 3/3 and 10/10 μm in width. Their surfaces were further entrapped with 0.7 μg cm−2 and 1.9 μg cm−2 gelatin by a facile swelling–shrinking entrapment technique using lower and higher concentrations of gelatin solutions, respectively. The surfaces entrapped with gelatin became more hydrophilic. On the micropatterned surfaces, the water droplet had an ellipse shape and exhibited an orientation along the stripes. The gelatin-entrapped and micropatterned PLCL surfaces could guide the adhered SCs to form an elongated shape with a higher length to width ratio along the stripes. The migration rate of the SCs was significantly enhanced parallel to the stripe direction, and was fastest on the 3/3 μm PLCL films entrapped with 1.9 μg cm−2 gelatin. The vinculin expression, adhesion force and expression of adhesion and migration-related genes such as integrin β1, Rac1, RhoA and Cdc42 revealed a stronger affinity of the SCs to the 3/3 μm PLCL films with a higher gelatin density.

Hypoxia, defined as inadequate oxygen supply at the tissue level, is a common pathological condition in the tumor microenvironment of certain solid tumors, leading to the limited efficiency of oxygen-dependent photodynamic therapy (PDT). To overcome this problem, tumor-targeting oxygen self-carrying nanoparticles are developed for photothermal therapy (PTT) and enhanced PDT to completely eradicate solid tumors. Hydrogen peroxide (H2O2) is a strong oxidant that can release oxygen in the presence of a catalyst or when being heated. The core-shell poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are obtained by a double emulsion method: the hydrophilic H2O2/poly(vinylpyrrolidone) complex as an oxygen source and hydrophobic IR780 as a PTT/PDT agent are encapsulated into the core and shell of the NPs respectively. The tumor binding molecule, folic acid, is conjugated onto the surface of obtained PLGA NPs to enabling efficient cell uptake and tumor targeting. Once the PLGA-FA/IR780-H2O2 NPs are ingested by HepG2 cells, they can induce the photothermal effect and reactive oxygen species (ROS) are released to kill cancer cells under an 808 nm laser irradiation. The encapsulated H2O2 can supply additional oxygen and in turn significantly enhance the PDT effect. This innovative nanoplatform has exhibited excellent antitumor efficiency, verified vividly by the in vitro and in vivo assays, and may serve as a versatile platform for future cancer therapy.

Nanomaterials have been extensively used in the biomedical field. These nanoscale objects may either promote or restrain immune responses depending on their surface characteristics and compositions. In this study, chitosan (CS) particles prepared using an emulsion-crosslinking method were modified with different amounts of human serum albumin (HSA) and ovalbumin (OVA), resulting in four types of modified CS particles, i.e. CS@HSA-10, CS@HSA-57, CS@OVA-13 and CS@OVA-65, respectively. They had a similar size of about 150 nm in a dry state, and were swollen 2-3 fold in PBS. No significant cytotoxicity was determined toward in vitro cultured RAW264.7 and THP-1 cells. However, all the modified CS particles, in particular the OVA-modified ones (CS@OVA-13 and CS@OVA-65), induced significantly higher secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) compared with the negative control. In human whole blood, CS@OVA-13 and CS@OVA-65 were phagocytosed with a significantly higher ratio by granulocytes and monocytes, leading to the higher secretion of TNF-α, IL-1β and IL-8, and a larger extent of platelet activation than CS@HSA-10 and CS@HSA-57, respectively.

Recruitment of endogenous mesenchymal stem cells (MSCs) has become an attractive strategy for in situ tissue regeneration. However, it is of great importance to endow an implant with a specific affinity to MSCs, for many types of cells such as immune cells and fibroblasts can also be recruited. It has been demonstrated that E7 peptides have a specific affinity to MSCs, but their selectivity for MSCs when co-cultured with other cells, especially in flow conditions, has rarely been investigated. In this study, E7-modified collagen substrates were prepared using sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) as the coupling agent. The results of X-ray photoelectron spectroscopy (XPS) and quartz crystal microbalance (QCM) proved that the densities of the immobilized E7 peptides could be modulated by changing the amounts of sulfo-SMCC. The results of cell adhesion rate, adhesion area and adhesion force demonstrated that the immobilization of E7 peptides led to a significant enhancement of the adhesion of bone marrow-derived MSCs (BMSCs) compared to RAW264.7 cells and NIH3T3 cells. The selective adhesion was verified by co-culturing BMSCs with RAW264.7 cells and NIH3T3 cells, which indicated that higher proportions of BMSCs were adhered on the E7-immobilized substrates. By mimicking in vivo flow circumstances, the selective capture of BMSCs by the E7-modified substrates was revealed by a flow model. All these results suggest that E7 immobilization might be a promising strategy for an implant to achieve a better regeneration outcome by enhancing the affinity to the recruited MSCs.

Due to the poor self-repair capabilities of articular cartilage, chondral or osteochondral injuries are difficult to be recovered. In this study, an N-cadherin mimetic peptide sequence HAVDIGGGC (HAV) was conjugated to direct cell–cell interactions, and an aggrecanase-1 cleavable peptide sequence CRDTEGE-ARGSVIDRC (ACpep) was used to crosslink hyperbranched PEG-based multi-acrylate polymer (HBPEG) with cysteamine-modified chondroitin sulfate (Cys-CS), obtaining an aggrecanase-1 responsively degradable and HAV-conjugated hydrogel ((HAV-HBPEG)-CS-ACpep). A HBPEG-CS-ACpep hydrogel without the HAV motif was also prepared. The two hydrogels exhibited similar equilibrium swelling ratios, elastic moduli and pore sizes after lyophilization, indicating the negligible influence of conjugated HAV on the crosslinking networks and mechanical properties of the hydrogels. After being degraded in PBS, aggrecanase-1 (ADAMTS4) and trypsin, the HBPEG-CS-ACpep hydrogel exhibited significantly decreased elastic moduli with a much lower value when incubated in enzyme solutions. The two hydrogels could maintain the viability of encapsulated bone marrow-derived mesenchymal stem cells (BMSCs), and the (HAV-HBPEG)-CS-ACpep hydrogel better promoted the cell–cell interactions. After being implanted into osteochondral defects in rabbits for 18 weeks, the two cell-laden hydrogel groups achieved better repair effects than the blank control group. Moreover, hyaline cartilage was formed in the (HAV-HBPEG)-CS-ACpep/BMSCs hydrogel group, while a hybrid of hyaline cartilage and fibrocartilage was found in the HBPEG-CS-ACpep/BMSCs hydrogel group.

Regeneration and functional recovery of peripheral nerves remain formidable due to the inefficient physical and chemical cues in the available nerve guidance conduits (NGCs). Introducing micropatterns and bioactive substances into the inner wall of NGCs can effectively regulate the behavior of Schwann cells, the elongation of axons, and the phenotype of macrophages, thereby aiding the regeneration of injured nerve. In this study, linear micropatterns with ridges and grooves of 3/3, 5/5, 10/10, and 30/30 μm were created on poly(d,l-lactide

Cell migration plays a pivotal role in many pathological and physiological processes. So far, most of the studies have been focused on 2-dimensional cell adhesion and migration. Herein, the migration behaviors of cell spheroids in 3D hydrogels obtained by polymerization of methacrylated hyaluronic acid (HA-MA) and fibrinogen (Fg) with different ratios were studied. The Fg could be released to the medium gradually along with time prolongation, achieving the dynamic change of hydrogel structures and properties. Three types of cell spheroids, i.e., endothelial cell (EC), smooth muscle cell (SMC), and EC-SMC spheroids, were prepared with 10,000 cells in each, whose diameters were about 343, 108, and 224 μ m, respectively. The composite hydrogels with an intermediate ratio of Fg allowed the fastest 3D migration of cell spheroids. The ECs-SMCs migrated longest up to 3200 μ m at day 14, whereas the SMC spheroids migrated slowest with a distance of only ~400 μ m at the same period of time. The addition of free RGD or anti-CD44 could significantly reduce the migration distance, revealing that the cell-substrate interactions take the major roles and the migration is mesenchymal dependent. Moreover, addition of anti-N-cadherin and MMP inhibitors also slowed down the migration rate, demonstrating that the degradation of hydrogels and cell-cell interactions are also largely involved in the cell migration. RT-PCR measurement showed that expression of genes related to cell adhesion and antiapoptosis, and angiogenesis was all upregulated in the EC-SMC spheroids than single EC or SMC spheroids, suggesting that the use of composite cell spheroids is more promising to promote cell-substrate interactions and maintenance of cell functions.

Bacterial infection is a major obstacle to the wound healing process. The hydrogel dressings with a simpler structure and good antibacterial and wound healing performance are appealing for clinical application. Herein, a robust hydrogel was synthesized from acrylamide (AM), acrylic acid (AA) and N,N′-methylene diacrylamide (MBA) via a redox initiating polymerization. The polymerization conditions were optimized to obtain the hydrogel with minimum unreacted monomers, which were 0.25% and 0.12% for AM and AA, respectively. The hydrogel had good mechanical strength, and could effectively resist damage by external forces and maintain a good macroscopic shape. It showed large water uptake capacity, and could post load a wide range of molecules via hydrogen bonding and electrostatic interaction. Loading of antibiotic doxycycline (DOX) enabled the hydrogel with good antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria in vitro and in vivo. In a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin defect wound, the DOX-loaded hydrogel showed good therapeutic effect. It could significantly promote the wound closure, increased the collagen coverage area, down-regulate the expressions of pro-inflammatory TNF-α and IL-1β factors, and up-regulate the expressions of anti-inflammatory IL-4 factor and CD31 neovascularization factor.