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Chirality is one of the most distinctive biochemical signatures of life, and plays crucial roles in maintaining normal functions of living cells or organisms. Pioneering work from another group has demonstrated the dependency of cell differentiation on the chirality of nano-coated substrates, but the effect of the chiral surface of nanoparticles on stem cell fates has not been investigated. In this study, the influence of molecular chiral poly(acryloyl-L(D)-valine) (L(D)- PAV)-anchored gold nanoparticles (L(D)-PAV-AuNPs) on the differentiation of mesenchymal stem cells (MSCs) was investigated. Though osteogenic differentiation of MSCs was not affected by D-PAV-AuNPs, it was significantly promoted by L-PAV-AuNPs in terms of calcium deposition, alkaline phosphatase (ALP) activity, and expression of collagen type I and osteocalcin (OCN) at both mRNA and protein levels. L-PAV-AuNPs could activate the P38 mitogen-activated protein kinase (MAPK) pathway, and may exert mechanical stress on MSCs because of high amounts of internalization. These results provide new insights on surface chirality at the nanoscale as a direct regulator to guide the differentiation of MSCs, and the use of these nanomaterials for strategic regenerative medicine.

Selective cell adhesion and migration, which mimics the natural biological events in vivo, is very important for the right repair of damaged tissues. In this study, glycosylated hyperbranched polymers (LA-HPMA) were synthesized, and were grafted on glass slide through dopamine deposition with different densities adjusted by co-grafting of poly(ethylene glycol) (PEG). The LA-HPMA and PEG molecular brushes were characterized by X-ray photoelectron spectroscopy (XPS), quartz crystal microbalance with dissipation (QCM-d) and ellipsometry. The adhesion of human hepatoma (HepG2) cells was promoted on the surface of a higher LA-HPMA density, and the migration rate was accelerated from 6.4μm/h on PEG surface to 12.7μm/h on 75% LA-HPMA surface. By contrast, the density and spreading area of mouse embryonic fibroblast (NIH3T3) cells were not significantly influenced by the LA-HPMA density, and the migration rate did not change significantly on all types of surfaces either. Therefore, the specific interactions of carbohydrate-protein can be used to modulate cell behaviors in vitro, for example the selective adhesion and migration of HepG2 cells.

Submicron-sized poly(lactide-co-glycolide) nanoparticles (PLGA-NPs) stabilised with bovine serum albumin (BSA) are dual radiolabelled using gamma emitters with different energy spectra incorporated into the core and coating. PLGA core is labelled by encapsulation of 111In-doped iron oxide NPs inside PLGA-NPs during NP preparation, while the BSA coating is labelled by electrophilic substitution using 125I. After intravenous administration into rats, energy-discriminant single-photon emission computerised tomography (SPECT) resolved each radioisotope independently. Imaging revealed different fates for the core and coating, with a fraction of the two radionuclides co-localising in the liver and lungs for long periods of time after administration, suggesting that NPs are stable in these organs. The general methodology reported here represents an excellent alternative for visualising the degradation process of multi-labelled NPs in vivo and can be extended to a wide range of engineered NPs.

Chirality is one of the most fascinating and ubiquitous features in nature, especially in biological systems. The effects of chiral surfaces, especially in combination with degradable materials of good biocompatibility, on stem cell behaviors has not yet been tackled. In this communication, the chiral monomers N-acryloyl-l(d)-valine (l(d)-AV) are synthesized and are polymerized to obtain chiral (l(d)-PAV-SH) oligomers, which are covalently immobilized onto electron-deficient poly(propylene fumarate) polyurethane (PPFU) via Michael addition. The PPFU-l-PAV can interact more strongly and actively with bone marrow stem cells (BMSCs) than PPFU-d-PAV, leading to a larger cell spreading area, faster migration velocity, and stronger osteodifferentiation tendency.

The poly(allylamine hydrochloride)/trisodium citrate aggregates were fabricated and further covalently crosslinked via the coupling reaction of carboxylic sites on trisodium citrate with the amine groups on polyamine, onto which poly-L-lysine and hyaluronic acid were sequentially assembled, forming stable microspheres. The pH sensitive dye and pH insensitive dye were further labeled to enable the microspheres with pH sensing property. Moreover, these microspheres could be specifically targeted to HeLa tumor cells, since hyaluronic acid can specifically recognize and bind to CD44, a receptor overexpressed on many tumor cells. Quantitative pH measurement by confocal laser scanning microscopy demonstrated that the microspheres were internalized into HeLa cells, and accumulated in acidic compartments. By contrast, only a few microspheres were adhered on the NIH 3T3 cells surface. The microspheres with combined pH sensing property and targeting ability can enhance the insight understanding of the targeted drug vehicles trafficking after cellular internalization.

The surface chemistry of nanoparticles (NPs) is one of the critical factors determining their cellular responses. In this study, the cytotoxicity and genotoxicity of copper oxide (CuO) NPs with a similar size but different surface chemistry to rat bone marrow mesenchymal stem cells (MSCs) were investigated. The morphology, size and surface charge of four types of CuO NPs, i.e., CuO-core, CuO-COOH, CuO-NH2 and CuO-PEG NPs, were characterized by TEM, dynamic light scattering (DLS) and zeta-potential measurement, respectively. All of the four CuO NPs had a negative surface charge around -10 mV and showed a similar tendency to form agglomerates with a size of -200 nm in cell culture environment. The cytotoxicity of CuO NPs to MSCs at various concentrations and incubation periods were firstly evaluated. The CuO NPs showed dose-dependent and time-dependent toxicity to MSCs, and their surface chemistry had influence on the toxicity to some extent too. The intracellular reactive oxygen species (ROS) level of MSCs was then quantified. Finally, the genotoxicity of the CuO NPs was studied by comet assay. The results suggest that the genotoxicity of CuO NPs was mainly dependent on NPs concentration, and was only slightly influenced by their surface chemistry. The osteogenic and adipogenic differentiation abilities of the MSCs exposed to different CuO NPs were studied by Alizarin Res S and Oil Red O staining. The preliminary results showed that the exposure to 10 μg/mL CuO NPs will, not lead to significant impact on the differentiation potential of the MSCs.

The graphene oxide (GO) has attracted tremendous attention in biomedical fields. In order to combine the unique physicochemical properties of GO nanosheets with topological structure of aligned nanofibrous scaffolds for nerve regeneration, the GO nanosheets were coated onto aligned and aminolyzed poly- l -lactide (PLLA) nanofibrous scaffolds. Scanning electronic microscopy (SEM) and atomic force microscopy (AFM) revealed that the surface of aligned PLLA nanofibers after being coated with GO became rougher than those of the aligned PLLA and aminolyzed PLLA nanofibrous scaffolds. The GO nanosheets did not destroy the alignment of nanofibers. The characterizations of X-ray photoelectron spectroscopy (XPS) and water contact angle displayed that the aligned PLLA nanofibrous scaffolds were introduced with hydrophilic groups such as NH 2 , COOH, and OH after aminolysis and GO nanosheets coating, showing better hydrophilicity. The GO-coated and aligned PLLA nanofibrous scaffolds significantly promoted Schwann cells (SCs) proliferation with directed cytoskeleton along the nanofibers compared with the aligned PLLA and aminolyzed PLLA nanofibrous scaffolds. These scaffolds also greatly improved the proliferation of rat pheochromocytoma 12 (PC12) cells, and significantly promoted their differentiation and neurite growth along the nanofibrous alignment in the presence of nerve growth factor (NGF). This type of scaffolds with nanofibrous surface topography and GO nanosheets is expected to show better performance in nerve regeneration. Statement of Significance Recovery of damaged nerve functions remains a principal clinical challenge in spite of surgical intervention and entubulation. The use of aligned fibrous scaffolds provides suitable microenvironment for nerve cell attachment, proliferation and migration, enhancing the regeneration outcome of nerve tissue. Surface modification is generally required for the synthetic polymeric fibers by laminin, fibronectin and YIGSR peptides to stimulate specific cell functions and neurite outgrowth. Yet these proteins or peptides present the poor processibility, limited availability, and high cost, influencing their application in clinic. In this work, we combined GO nanosheets and topological structure of aligned nanofibrous scaffolds to direct cell migration, proliferation, and differentiation, and to induce neurite outgrowth for nerve regeneration. The GO coating improved several biomedical properties of the aligned PLLA nanofibrous scaffolds including surface roughness, hydrophilicity and promotion of cells/material interactions, which significantly promoted SCs growth and regulated cell orientation, and induced PC12 cells differentiation and neurite growth. The design of this type of structure is of both scientific and technical importance, and possesses broad interest in the fields of biomaterials, tissue engineering and regenerative medicine.

It is important to understand the safety issue and cell interaction pattern of polyelectrolyte microcapsules with different deformability before their use in biomedical applications. In this study, SiO2, poly(sodium-p-styrenesulfonate) (PSS) doped CaCO3 and porous CaCO3 spheres, all about 4 μm in diameter, were used as templates to prepare microcapsules with different inner structure and subsequent deformability. As a result, three kinds of covalently assembled poly(allylaminehydrochloride)/glutaraldehyde (PAH/GA) microcapsules with similar size but different deformability under external osmotic pressure were prepared. The impact of different microcapsules on cell viability and functions are studied using smooth muscle cells (SMCs), endothelial cells (ECs) and HepG2 cells. The results demonstrated that viabilities of SMCs, ECs and HepG2 cells were not significantly influenced by either of the three kinds of microcapsules. However, the adhesion ability of SMCs and ECs as well as the mobility of SMCs, ECs and HepG2 cells were significantly impaired after treatment with microcapsules in a deformability dependent manner, especially the microcapsules with lower deformability caused higher impairment on cell functions. The cellular uptake kinetics, uptake pathways, intracellular distribution of microcapsules are further investigated in SMCs to reveal the potential mechanism. The SMCs showed faster uptake rate and exocytosis rate of microcapsules with lower deformability (Cap@CaCO3/PSS and Cap@CaCO3), leading to higher intracellular accumulation of microcapsules with lower deformability and possibly larger retardation of cell functions. The results pointed out that the deformability of microcapsules is an important factor governing the biological performance of microcapsules, which requires careful adjustment for further biomedical applications.

The adverse effects of metal-based nanoparticles on human beings and the environment have received extensive attention recently. It is urgently required to develop a simple and effective method to suppress the toxicity of metal-based nanomaterials. In this study, a hydrophobic antioxidant and a chelation agent curcumin (CUR) were encapsulated into bovine serum albumin (BSA) particles by a simple co-precipitation method, and followed by glutaraldehyde cross-linking. The CUR/BSA particles had an average size of 300 nm in diameter with a negatively charged surface and sustained curcumin release properties. The cellular uptake and cytotoxicity of CUR/BSA particles were followed on A549 cells, HepG2 cells and RAW264.7 cells. The CUR/BSA particles had higher intracellular accumulation and lower cytotoxicity compared with the free curcumin at the same drug concentration. The CUR/BSA particles could suppress the cytotoxicity generated by CuO nanoparticles as a result of decrease of both the intracellular reactive oxygen species (ROS) level and Cu(2+) concentration, while the free curcumin did not show any obvious detoxicating effect. The detoxicating effects of CUR/BSA particles were further studied in an intratracheal instillation model in vivo, demonstrating significant reduction of toxicity and inflammatory response in rat lungs induced by CuO nanoparticles. The concept-proving study demonstrates the potential of the CUR/BSA particles in suppressing cytotoxicity of metal-based nanomaterials, which is a paramount requirement for the safe application of nanotechnology.

Surface modification of iron oxide nanoparticles may cause unexpected impact upon interaction with cells, such as cytotoxicity and change in the differentiation potential of stem cells. In this study, two kinds of iron oxide nanoparticles with different surface chemistries, i.e. one in its pristine form (P-NPs) without extra capping molecules and the other coated with citrate (C-NPs), and with similar sizes, ∼10 nm, as measured by transmission electron microscopy and X-ray diffractometry, were prepared. Both P-NPs and C-NPs aggregated to some extent in water, with hydrodynamic diameters of 211.4 ± 29 and 128.6 ± 6.3 nm, and surface zeta potential values of +23.5 ± 0.3 and -49.6 ± 0.5 mV, respectively. However, both NPs further aggregated to a similar extent with hydrodynamic diameters of 260 ± 5.5 and 214 ± 6.4 nm and with a slightly negative surface charge (∼-10 mV) in cell differentiation media. After being incubated with rat mesenchymal stem cells (MSCs) for 14 d, both types of NPs showed similar cell uptake kinetics and final intracellular iron content, i.e. 53.3 pg per cell for P-NPs and 59.9 pg per cell for C-NPs, and minimal cytotoxicity at a concentration below 100 μg mL-1. The adipogenic differentiation potential of MSCs was unaltered regardless of the NP types, and the P-NPs did not have an obvious impact on the osteogenic differentiation potential of MSCs. The osteogenic differentiation potential of the MSCs, however, was significantly impaired by incubation with the C-NPs, as evidenced by significantly reduced expression of osteogenic markers, namely collagen type I (COL) and osteocalcin (OCN) and calcium deposition. The uptake of C-NPs and surface-anchored citrate molecules were found to have a synergistic effect.

A root canal sealer plays some important roles in accomplishing various functions including antibacteria and anti-microleakage. Meanwhile, such a sealer is also expected to readily induce apatite mineralization in damaged periapical tissues and reconstruct the surrounding alveolar bone. Taking the potent antibacterial ability of some biologically essential trace elements into account, we explore the effects of Zn or Cu doping in β-dicalcium silicate (β-C2Si) on the physicochemical modification and biological functions of its self-curing cement and compare with the β-C2Si cement free of foreign ion doping. An interesting aspect of the Zn or Cu doping in β-C2Si was the prolongation of setting time and the decrease of mechanical strength, but retardation in the degradation and improvement of anti-microleakage. Furthermore, the β-C2Si doped with 10% Cu exhibited more excellent antibacterial properties against P. gingivalis and E. faecalis. Additionally, there was similar apatite formation ability and cell growth on the β-C2Si cements with and without Zn-/Cu-doping within the initial 1–5 d. Totally, it is demonstrated that the physicochemical and biological performances are favorably altered with Zn or Cu doping in β-C2Si with a consequent effect on setting time, chemical stability (ion release, degradation), anti-microleakage, and antibacterial activity. Therefore, it is indicated that the Zn or Cu-doped β-C2Si is promising as a multifunctional root canal sealer.

Although methylene blue (MB) has promising applications in photodynamic therapy (PDT) with its high quantum yield of singlet oxygen, its clinical application is restricted due to its rapid enzymatic reduction in the biological environment and its relatively high cytotoxicity. Therefore cell membrane capsules (CMCs) derived from mammalian cells were used to encapsulate MB (CMCs@MB) using temporary permeation of the plasma membrane and resealing. The resulting CMCs@MB exhibited a spherical shape with a diameter of about 1 μm. The MB encapsulation, confirmed using UV-Vis spectroscopy, reached a concentration of up to 1.5 mg mL−1 inside the CMCs (1.7 × 106 MB molecules per CMC), which is 7.5 times higher than that of the feeding solution. Encapsulation in the CMCs leads to sustained release of MB and significantly enhances its stability against enzymatic reduction. Furthermore, the CMCs@MB exhibited a much better cytocompatibility under dark conditions than that of free MB at the same concentrations. The viability of cells incubated with the CMCs@MB decreases significantly to a similar extent as free MB at the same concentration after laser irradiation, confirming that encapsulated MB is still efficient for PDT. The protection of MB against enzyme degradation and reduction of its dark toxicity, with retained PDT efficiency, is an important step toward the practical application of MB in cancer therapy.

Macro-porous fibrin scaffolds with regular and adjustable inter-connective pores were fabricated through a porogen-leaching method for the in situ inductive regeneration of full-thickness cartilage defects in vivo. In vitro tests proved the survival and proliferation of BMSCs in the scaffolds. In vivo repair experiment was conducted by implantation of the cell-free macro-porous fibrin scaffolds into full-thickness cartilage defects (4 mm in diameter and 4 mm in depth with bone marrow blood effusion) of New Zealand white rabbits for 6 and 12 w. The neo-cartilage integrated well with the surrounding cartilage as well as the subchondral bone. Immunochemical and GAG staining revealed the abundant deposition of type II collagen and GAGs in the neo-cartilage after regeneration for 12 w. Histological score of the regenerated tissues was 2.6. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting (WB) revealed that the cartilage-related genes and proteins were significantly up-regulated compared with those of the normal cartilage. With the cell-free advantage and positive restoration of full-thickness cartilage defect in vivo, the fibrin scaffold is shelf-ready and is expected to be conveniently used in clinics.

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 O2 generating is fabricated for MI treatment in vivo. The hydrogel is formed within 3 s from the synthetic ROS-cleavable hyperbranched polymers and methacrylate hyaluronic acid (HA-MA) under UV-irradiation. Addition of biocompatible and applicable catalase in vivo enables the further transition of H2 O2 , a major type of ROS, to O2 and H2 O. Results of rat MI model demonstrate that this hydrogel can significantly remove excessive ROS, inhibit cell apoptosis, increase M2/M1 macrophage ratio, promote angiogenesis, reduce infarcted area, and improve cardiac functions. With the appropriate degradation rate, simple structure and composition without cell seeding, and very excellent MI therapeutic effect, this ROS scavenging and O2 generating hydrogel has a great promise to be applied clinically.

One of the challenges facing by world nowadays is the generation of new pathogens that cause public health issues. Coronavirus (CoV) is one of the severe pathogens that possess the RNA (ribonucleic acid) envelop, and extensively infect humans, birds, and other mammals. The novel strain "SARS-CoV-2" (severe acute respiratory syndrome coronavirus-2) causes deadly infection all over the world and presents a pandemic situation nowadays. The SARS-CoV-2 has 40 different strains that create a worrying situation for health authorities. The virus develops serious pneumonia in infected persons and causes severe damage to the lungs. There is no vaccine available for this virus up to present. To cure this type of infections by making vaccines and antiviral drugs is still a major challenge for researchers. Nanotechnology covering a multidisciplinary field may find the solution to this lethal infection. The interaction of nanomaterials and microorganisms is considered as a potential treatment method because the nanomaterials owe unique physicochemical properties. The aim of this review is to present an overview of previous and recent studies of nanomaterials against coronaviruses and to provide possible new strategies for upcoming research using the nanotechnology platform.

The delivery of nanomaterials or therapeutics into cells takes a decisive role for their applications in nanomedicine. Nature's creations such as viruses provide valued inspiration for design of nano-architectures in cellular delivery. We report herein the fabrication of biodegradable and biocompatible nanoparticles (NPs) with viral-mimicking morphology and constituents as a nanoplatform, which has rarely been reported to the best of our knowledge, for promoting cellular uptake and achieving high therapeutic efficiency in vivo. The chitosan-porphyrin-based NPs were endowed with a viral-imitating morphology through a novel pH-responsive decomposition-induced self-assembly method. By successive conjugation of Tat peptides and modification of lipids, morphological and constituent viral-mimicking NPs were obtained. Compared with the counterpart of non-viral-mimicking NPs, the viral-mimicking NPs showed prominent superiority in enhancing cell internalization (10 times higher). Loading of near-infrared photosensitizer– indocyanine green into these NPs demonstrated the striking capability of the viral-mimicking nanoparticles in therapeautic delivery and photothermal anti-tumor effect in vitro and in vivo. This concept and strategy provides an enlightening methodology on the design and fabrication of therapeutic delivery systems, which is significant for nanobiotechnology.

The importance of inflammatory tissue microenvironment on the repair and regeneration of tissues and organs has been well recognized. In particular, the phenotypes of macrophages can significantly influence on the processes of tissue repair and remodeling. Among the many types of biomaterials, the particles in the range from nanometers to submicron meters have been extensively studied and applied in tissue engineering and regenerative medicine. They can actively interact with cells in different levels, and show the ability to regulate the polarization of macrophages. In this review, the influence of physicochemical properties such as size, surface charge, chemical components and surface modification of micro-nanoparticles on the immune behavior of macrophages, including endocytosis and phenotype switch, shall be introduced. The important roles of nanoparticles-based immunoregulation of macrophages on the chronic skin wounds regeneration, myocardial repair, liver repair and bone regeneration are discussed.

The immune system responds immediately to tissue trauma and to biomaterial implants under the participation of M1/M2 macrophages polarization. The surface properties of biomaterials can significantly influence the tissue repair progress through modulating the macrophage functions. In this study, the surface of poly(propylene fumarate) polyurethane films (PPFU) is grafted with a same density of enantiomeric poly-l-lysine (PPFU-g-PLL) and poly-d-lysine (PPFU-g-PDL), leading to a similar level of enhanced surface wettability for the PPFU-g-PLL and PPFU-g-PDL. The polylysine-grafted PPFU can restrict the M1 polarization, whereas promote M2 polarization of macrophages in vitro, judging from the secretion of cytokines and expression of key M1 and M2 related genes. Comparatively, the PPFU-g-PDL has a stronger effect in inducing M2 polarization in vivo, resulting in a thinner fibrous capsule surrounding the implant biomaterials. The CD44 and integrins of macrophages participate in the polarization process probably by activating focal adhesion kinase (FAK) and Rho-associated protein kinase (ROCK), and downstream PI3K/Akt1/mTOR signal axis to up regulate M2 related gene expression. This study confirms for the first time that polylysine coating is an effective method to regulate the immune response of biomaterials, and the polylysine-modified thermoplastic PPFU with the advantage to promote M2 polarization may be applied widely in regenerative medicine.

As the most frequent wound complication, infection has become a major clinical challenge in wound management. To overcome the “Black Box” status of the wound‐healing process, next‐generation wound dressings with the abilities of real‐time monitoring, diagnosis during early stages, and on‐demand therapy has attracted considerable attention. Here, by combining the emerging development of bioelectronics, a smart flexible electronics‐integrated wound dressing with a double‐layer structure, the upper layer of which is polydimethylsiloxane‐encapsulated flexible electronics integrated with a temperature sensor and ultraviolet (UV) light‐emitting diodes, and the lower layer of which is a UV‐responsive antibacterial hydrogel, is designed. This dressing is expected to provide early infection diagnosis via real‐time wound‐temperature monitoring by the integrated sensor and on‐demand infection treatment by the release of antibiotics from the hydrogel by in situ UV irradiation. The integrated system possesses good flexibility, excellent compatibility, and high monitoring sensitivity and durability. Animal experiment results demonstrate that the integrated system is capable of monitoring wound status in real time, detecting bacterial infection and providing effective treatment on the basis of need. This proof‐of‐concept research holds great promise in developing new strategies to significantly improve wound management and other pathological diagnoses and treatments., A smart flexible electronics‐integrated wound dressing is designed for real‐time monitoring and on‐demand therapy of infected wounds. It is demonstrated that the integrated wound dressing can diagnose infection during early stages by real‐time wound‐temperature monitoring and provide antibacterial treatment based on the collected data via Bluetooth to achieve a closed‐loop wound healing system.

The feasible fabrication of nerve guidance conduits (NGCs) with good biological performance is important for translation in clinics. In this study, poly(d,l-lactide-co-caprolactone) (PLCL) films loaded with various amounts (wt; 5%, 15%, 25%) of methylcobalamin (MeCbl) are prepared, and are further rolled and sutured to obtain MeCbl-loaded NGCs. The MeCbl can be released in a sustainable manner up to 21 days. The proliferation and elongation of Schwann cells, and the proliferation of Neuro2a cells are enhanced on these MeCbl-loaded films. The MeCbl-loaded NGCs are implanted into rats to induce the regeneration of 10 mm amputated sciatic nerve defects, showing the ability to facilitate the recovery of motor and sensory function, and to promote myelination in peripheral nerve regeneration. In particular, the 15% MeCbl-loaded PLCL conduit exhibits the most satisfactory recovery of sciatic nerves in rats with the largest diameter and thickest myelinated fibers.

Degradation adhesive is required in many applications such as skin grafting operation. In this study, a kind of hydrogel adhesive was prepared from poly(ethylene glycol) diacrylate (PEGDA) and poly(allylamine hydrochloride) (PAH) by aza-Michael addition between the amino groups of PAH and diacrylate groups of PEGDA. The PAH-PEGDA hydrogels could be fabricated at 37 °C when the pH value of PAH solution was above 6. Rheology tests showed that the gelation time was prolonged along with the decrease of pH value of PAH solution, which was over 1 h and 30 s at pH 6 and pH 8, respectively. The hydrogels could offer strong enough adhesion force between different types of substrates including hydrophilic matrix and pig skin. This kind of PAH-PEGDA hydrogel adhesives was spontaneously degraded in 2–3 days due to the large number of β-amino ester structures which facilitate the degradation. No noticeable influence on pig skin was observed after the gauze was peeled off from the skin 1 day post adhesion. Moreover, the extracted solution of the hydrogel did not influence on the cell viability compared with the control. This kind of hydrogel adhesives has the potential for skin grafting operation.

External stimuli-responsive biomaterials represent a type of promising candidates for addressing the complexity of biological systems. In this study, a platform based on the combination of temperature-sensitive polymers and a nanotube array was developed for loading sphingosine 1-phosphate (S1P) and regulating the migration of endothelial cells (ECs) at desired conditions. The localized release dosage of effectors could be controlled by the change of environmental temperature. At a culture temperature above the lower critical solution temperature, the polymer "gatekeeper" with a collapsed conformation allowed the release of S1P, which in turn enhanced the migration of ECs. The migration rate of single cells was significantly enhanced up to 58.5%, and the collective migration distance was also promoted to 25.1% at 24 h and 33.2% at 48 h. The cell morphology, focal adhesion, organization of cytoskeleton, and expression of genes and proteins related to migration were studied to unveil the intrinsic mechanisms. The cell mobility was regulated by the released S1P, which would bind with the S1PR1 receptor on the cell membrane and trigger the Rho GTPase pathway.

It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models. These results suggest that multifunctional peptide coated AuNRs sensitive to MMP-9 are promising nanomaterials, conferring both extended systemic circulation and enhanced tumor tissue accumulation, for more specific and efficient tumor therapy. STATEMENT OF SIGNIFICANCE: It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models.

Bioactive stimulation and spatiotemporal evolution of porous scaffolds with time are crucial for bone regeneration rate in bone repair process. Granule-type bioceramic scaffolds have attracted significant interest in biomedical applications in recent years. However, the major limitation of such porous architecture is that the low initial porosity is disadvantageous for enhancing new bone tissue ingrowth. Here we reported that the yolk-shell-structured biphasic bioceramic granules with adjustable shell microstructures were favorable for controllable ion release in vitro, superior to the granules with the conventional homogenous hybrid structures. Also, we illustrated a significant difference in biodegradation of the granules in vivo, and especially the porous-shell granules exhibited appreciable new bone tissue ingrowth with time. The underlying fundamental mechanisms governing the new bone tissue ingrowth behavior of the yolk-shell granule scaffolds were elucidated based on microCT analyses and histological observation. It was underscored that during biodegradation in vivo, the highly bioactive ions in yolk layer were continuously released due to the porous structures of the sparingly dissolvable shell layer, thereby resulting in hollow shell and rapid new bone tissue ingrowth. Hence, these results demonstrate that the slight tailoring in microstructure and component distribution of biphasic composites is beneficial for adjusting the bone regeneration, and may help us to precisely control bone repair efficiency for a variety of clinical conditions.

Nanomedicines have achieved several breakthroughs in cancer treatment over the past decades; however, their potential immunotoxicities are ignored, which results in serious adverse effects and greatly reduces the potential in clinical translation. Herein, we innovatively develop a theranostic supramolecular polymer using β-cyclodextrin as the host and camptothecin (CPT) as the guest linked by a glutathione-cleavable disulfide bond. The supramolecular polymerization remarkably increases the solubility of CPT by a factor of 232 and effectively inhibits its lactone ring opening in physiological environment, which is favorable for intravenous formulation and maintenance of the therapeutic efficacy. Supramolecular nanoparticles can be prepared through orthogonal self-assembly driven by π-π stacking interaction, host-guest complexation, and hydrogen bonds. The sophisticated nanomedicine constructed from the obtained supramolecular polymer can be specifically delivered to tumor sites and rapidly excreted from body after drug release, thus effectively avoiding systemic toxicity, especially long-term immunotoxicity. In vivo investigations demonstrate this supramolecular nanomedicine possesses superior antitumor performance and antimetastasis capability. This pioneering example integrating the advantages of the dynamic nature of supramolecular chemistry and nanotechnology provides a promising platform for cancer theranostics.

Controllable mechanical strength and biodegradation of bioceramic scaffolds is a great challenge to treat the load-bearing bone defects. Herein a new strategy has been developed to fabricate porous bioceramic scaffolds with adjustable component distributions based on varying the core-shell-structured nozzles in three-dimensional (3D) direct ink writing platform. The porous bioceramic scaffolds composed of different nonstoichiometic calcium silicate (nCSi) with 0%, 4% or 10% of magnesium-substituting-calcium ratio (CSi, CSi-Mg4, CSi-Mg10) was fabricated. Beyond the mechanically mixed composite scaffolds, varying the different nCSi slurries through the coaxially aligned bilayer nozzle makes it easy to create core-shell bilayer bioceramic filaments and better control of the different nCSi distribution in pore strut after sintering. It was evident that the magnesium substitution in CSi contributed to the increase of compressive strength for the single-phasic scaffolds from 11.2 MPa (CSi), to 39.4 MPa (CSi-Mg4) and 80 MPa (CSi-Mg10). The nCSi distribution in pore struts in the series of core-shell-strut scaffolds could significantly adjust the strength [e.g. CSi@CSi-Mg10 (58.9 MPa) vs CSi-Mg10@CSi (30.4 MPa)] and biodegradation ratio in Tris buffer for a long time stage (6 weeks). These findings demonstrate that the nCSi components with different distributions in core or shell layer of pore struts lead to tunable strength and biodegradation inside their interconnected macropore architectures of the scaffolds. It is possibly helpful to develop new bioactive scaffolds for time-dependent tailoring mechanical and biological performances to significantly enhance bone regeneration and repair applications, especially in some load-bearing bone defects.

Tissue regeneration involves versatile types of cells. The accumulation and disorganized behaviors of undesired cells impair the natural healing process, leading to uncontrolled immune response, restenosis, and/or fibrosis. Cell-selective surfaces and interfaces can have specific and positive effects on desired types of cells, allowing tissue regeneration with restored structures and functions. This review outlines the importance of surfaces and interfaces of biomaterials with cell-selective properties. The chemical and biological cues including peptides, antibodies, and other molecules, physical cues such as topography and elasticity, and physiological cues referring mainly to interactions between cells-cells and cell-chemokines or cytokines are effective modulators for achieving cell selectivity upon being applied into the design of biomaterials. Cell-selective biomaterials have also shown practical significance in tissue regeneration, in particular for endothelialization, nerve regeneration, capture of stem cells, and regeneration of tissues of multiple structures and functions.

Photoacoustic imaging combines the merits of ultrasound imaging and optical imaging, and allows a fascinating imaging paradigm with deeper tissue penetration than optical imaging and higher spatial resolution than ultrasound imaging. Herein, we develop a supramolecular hybrid material composed of graphene oxide (GO) and a pillar[6]arene-based host–guest complex (CP6⊃PyN), which can be used as an ultrasound (US) and photoacoustic (PA) signal nanoamplifier. Triggered by the near-infrared (NIR) light mediated photothermal effect, CO2 nanobubbles are generated on the surface of GO@CP6⊃PyN due to the decomposition of the bicarbonate counterions, thus strongly amplifying its US and PA performances. Our study, for the first time, demonstrates enhanced US and PA activity in a supramolecular hybrid material on the basis of host–guest chemistry as a photoacoustic nanoplatform.

The gradient localization of biological cues is of paramount importance to guide directional migration of cells. In this study, poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate)-block- poly(2-hydroxyethyl methacrylate) (P(HEMA-co-GMA)-b-PHEMA) brushes with a uniform underneath P(HEMA-co-GMA) layer and a gradient thickness of PHEMA blocks were prepared by using surface-initiated atom-transfer radical polymerization and a dynamically controlled polymerization process. The polymer chains were subsequently functionalized with the cell-adhesive arginine-glycine-aspartic acid (RGD) peptides by reaction with the glycidyl groups, and their structures and properties were characterized by X-ray photoelectron spectrometry (XPS), quartz crystal microbalance with dissipation (QCM-D) and air contact angle. Adhesion and migration processes of smooth muscle cells (SMCs) were then studied. Compared with those on the sufficiently exposed RGD surface, the cell adhesion and mobility were well maintained when the RGD peptides were localized at 18.9 nm depth, whereas the adhesion, spreading and migration rate of SMCs were significantly impaired when the RGD peptides were localized at a depth of 38.4 nm. On the RGD depth gradient surface, the SMCs exhibited preferential orientation and enhanced directional migration toward the direction of reduced thickness of the second PHEMA brushes. Half of the cells were oriented within ± 30° to the x-axis direction, and 72% of the cells moved directionally at the optimal conditions. Cell adhesion strength, arrangement of cytoskeleton, and gene and protein expression levels of adhesion-related proteins were studied to corroborate the mechanisms, demonstrating that the cell mobility is regulated by the complex and synergetic intracellular signals resulted from the difference in surface properties. Statement of Significance Cell migration is of paramount importance for the processes of tissue repair and regeneration. So far, the gradient localization of biological cues perpendicular to the substrate, which is the usual case for the biological signaling molecules to locate in ECM in vivo, has been scarcely studied, and has not been used to guide the directional migration of cells. In this study, we prepare a depth gradient of RGD peptides along the polymer chains, which is used to guide the directional migration of SMCs after a second hydrophilic bock is prepared in a gradient manner. For the first time the directional migration of SMCs is achieved under the guidance of a depth gradient of RGD ligands. The mechanisms of different cell migration abilities are further discussed based on the results of cell adhesion, cell adhesion force, cytoskeleton alignment and expression of relative proteins and genes. This work paves a new strategy by fabricating a gradient polymer brushes with immobilized bioactive molecules to dominate the directional cell migration, and elucidates the mechanisms underlining the biased migration along RGD depth localization gradients, shedding a light for the design of novel biomaterials to control and guide cell migration and invasion.

The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) in terms of cellular spatial arrangement and directional migration as well as neurite orientation for bridging the proximal and distal stumps of the injured peripheral nervous system. In this study, stripe micropatterns having ridges/grooves of width 20/20 and 20/40 μm were fabricated on the surface of maleimide-functionalized biodegradable poly(ester carbonate) (P(LLA-MTMC)) films by the polydimethylsiloxane mold-pressing method, respectively. The laminin-derived CQAASIKVAV peptides end-capped with an SH group were then grafted by the thiol-ene click reaction under mild conditions to obtain micropatterned and peptide-grafted films. SCs cultured on these films, especially on the 20/40-μm film, displayed faster and aligned adhesion as well as a larger number of elongated cells with a higher length-to-width (L/W) ratio along the stripe direction than those on the flat-pep film. The migration rate of SCs was significantly enhanced in parallel to the stripe direction with a large net displacement. The micropatterned and peptide-grafted films, especially the 20/40-μm film, could promote SC proliferation and nerve growth factor (NGF) secretion in a manner similar to that of the peptide-grafted planar film. Moreover, the neurites of rat pheochromocytoma 12 (PC12) cells sprouted along the ridges with a longer average length on the micropatterned and peptide-grafted films. The synergistic effect of physical patterns and biological cues was evaluated by considering the results of cell adhesion force; immunofluorescence staining of vinculin; fluorescence staining of F-actin and the nucleus; as well as gene expression of neural cadherin (NCAD), neurocan (NCAN), and myelin protein zero (P0). Statement of Significance The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) and nerve cells, and thereby the regeneration of peripheral nerve system. In this study, the combined micropatterning and CQAASIKVAV grafting endowed the modified P(LLA-MTMC) films with both contact guidance and bioactive chemical cues to enhance cell proliferation, directional alignment and migration, longer net displacement and larger NGF secretion, and stronger neurite outgrowth of SCs and PC12 cells. Hence, the integration of physical micropatterns and bioactive molecules is an effective way to obtain featured biomaterials for the regeneration of nerves and other types of tissues.

The current technical dilemma for gold nanoparticles as photothermal (PT) transducers in cancer therapy is that strong absorption in the second near-infrared (NIR) window is accompanied by strong scattering of the NIR light, which then overrides the absorption, thus significantly weakening the light-to-heat conversion efficiency. Here we successfully prepared spiky gold nanoparticles (spiky Au NPs) with a controlled number of spikes, designed according to our simulations and experimentally verified. Their overall sizes and the numbers, lengths, and widths of the spikes were judiciously adjusted to locate their surface plasmon resonance peaks in the second NIR window and also to achieve a higher absorption-to-extinction ratio. As a result, the spiky Au NPs with optimal size and 6 spikes exhibited a record light-to-heat conversion efficiency (78.8%) under irradiation by 980 nm light. After surface PEGylation and conjugation with a lactoferrin (LF) ligand on the resulting spiky Au NPs, they in vivo displayed long circulation time (blood circulation half-life of ∼300 min) and high tumor accumulation due to their larger surface-to-volume ratio. Therefore, spiky Au NPs allowed complete ablation of tumors without recurrence merely after 3 min of light irradiation at 980 nm, opening up promising prospects of cancer photothermal therapy.

The stimuli-responsive nanomaterials are gaining more and more interest in the biological field, including cell imaging and biosensing etc. Nanomaterials in response to the bio-relevant stimuli (i.e., pH, enzymes and other bioactive molecules) can be utilized to enhance imaging (i.e., optical imaging, MRI, and multi-mode imaging) sensitivity via disease site-specific delivery and controlled release, which helps to diagnose cancer at an early stage or to monitor progression during treatment. In the triggered responsive process, smart nanomaterials undergo changes in physiochemical properties that can cause cytotoxicity or influence on cell functions due to the interactions between nanomaterials and cells. In order to promote the design and fabrication of effective platforms for therapeutics and diagnostics, special attention should be paid to these effects. By taking the advantages of intracellular stimuli, the controlled self-assembly in living cells can be achieved, which has been used for various in situ detections and insights into biological self-assembly. In this review, the recent advances in cell imaging, cytotoxicity and self-assembly of intracellular stimuli-responsive nanomaterials are summarized. Some principles for the further design and applications of intracellular stimuli-responsive nanomaterials and future perspectives are discussed.

The vascularization of an orbital implant is a key issue for reducing complications, such as exposure and infection. Here, we developed a facile layer-by-layer assembly approach to modify porous hydroxyapatite (pHA) orbital implants with five collagen (COL)/heparin (HEP) multilayers. SEM characterization showed that the average pore size of the pHA/(COL/HEP)5 scaffold was 316.8 ± 77.1 μm. After being coated with five COL/HEP multilayers, the mechanical strength was improved compared with that of the pHA scaffolds. The in vitro assay displayed that the pHA scaffolds covered with COL/HEP multilayers resulted in a larger number of human umbilical vein endothelial cells after being cultured for 14 days. The macroscopic evaluation and semi-quantitative vascular density analysis of the chicken chorioallantoic membrane assay showed that the pHA/(COL/HEP)5 scaffolds resulted in more intense angiogenesis than the pHA scaffolds. These studies demonstrate that the biomembrane-mimicking coating of COL/HEP multilayers is a simple and effective strategy to endow combined biological performances of pHA orbital implants and to potentially reduce implant-related complications.

The amphiphilic pyrene-containing random copolymers with light-responsive pyrene ester bonds were synthesized by copolymerizing 1-pyrenemethyl acrylate (PA) and N,N-dimethylacrylamide (DMA). The P(DMA-co-PA) copolymers formed spherical micelles in water, which were transformed into nanorods as a result of cleavage of the pyrene ester bonds under UV irradiation. In vitro culture with A549 cells and Raw cells showed that compared to the nonphotodegradable ones, the photodegradable P(DMA-co-PA) micelles caused significantly higher cytotoxicity under the same UV irradiation. The intracellular reactive oxygen species (ROS) level had a positive correlation with the cytotoxicity regardless of the cell types. The nonphotodegradable pyrene-containing micelles produced a lower level of ROS under UV irradiation. However, the photodecomposable P(DMA-co-PA) micelles produced a significant higher level of ROS under the same trigger of UV irradiation, which caused the shape transformation of micelles to nanorods and higher cytotoxicity simultaneously.

Selective enhancement of directional migration of Schwann cells (SCs) over fibroblasts (FIBs) plays a significant role in peripheral nerve regeneration, because this behavior facilitates neuron repair and avoids fibrosis. Herein a complementary density gradient of poly(3-dimethyl-methacryloyloxyethyl ammonium propane sulfonate) (PDMAPS, a zwitterionic polymer with antifouling property) and KHIFSDDSSE peptide (KHI, derived from neural cell adhesion molecule NCAM which mediates cell-cell adhesion) was fabricated. The gradient was visualized by fluorescent labeling, and further characterized by X-ray photoelectron spectrometry (XPS) and quartz crystal microbalance with dissipation (QCM-d). The SCs exhibited preferential orientation and enhanced directional migration on the gradient surface toward the region of lower PDMAPS density and higher KHI peptide density, while FIBs showed random migration. Moreover, the migration rate of the SCs was significantly enhanced to 2 folds, whereas that of the FIBs was reduced to 60% compared to their natural state on glass, leading to a faster migration rate of SCs than FIBs. The success of the complementary gradient relies on the appropriate interplay between the PDMAPS brushes and the cell-specific ligands, enabling the selective guidance of SCs migration.

Differentiation of mesenchymal stem cells (MSCs) is regulated by multivariate physical and chemical signals in a complicated microenvironment. In this study, polymerizable double bonds (GelMA) and osteo-inductive alendronate (Aln) (Aln-GelMA) were sequentially grafted onto gelatin molecules. The biocompatible hydrogels with defined stiffness in the range of 4-40 kPa were prepared by using polyethylene glycol diacrylate (PEGDA) as additional crosslinker. The Aln density was adjusted from 0 to 4 μM by controlling the ratio between the GelMA and Aln-GelMA. The combinational effects of stiffness and Aln density on osteogenic differentiation of MSCs were then studied in terms of ALP activity, collagen type I and osteocalcin expression, and calcium deposition. The results indicated that the stiffness and Aln density could synergistically improve the expression of all these osteogenesis markers. Their osteo-inductive effects are comparable to some extent, and high Aln density could be more effective than the stiffness.

The method of plasma-spray coating of hydroxyapatite (HA) onto pure titanium has been demonstrated to be effective to enhance the osteogenic differentiation and accelerate bone regeneration. Yet it is still a big challenge to figure out the interplay among implant surface properties, adsorbed proteins and cell-surface interactions. In this study, the plasma-sprayed HA-coated titanium (HA–Ti) surface was compared with the titanium substrate in terms of protein adsorption, cell adhesion and differentiation. The phase composition, wettability and topography were characterized. Compared to the Ti substrate, the HA–Ti had a smaller water contact angle, but larger micro-scale roughness, and showed a poorer ability to adsorb fibronectin (Fn), bovine serum albumin (BSA) and serum proteins. However, it could adsorb larger amount of recombinant human bone morphogenetic protein 2 (BMP-2). The osteoblasts and bone marrow mesenchymal stem cells (BMSCs) tended to adhere on the Ti substrate. By contrast, the BMSCs cultured on the HA–Ti showed a stronger tendency toward osteogenesis differentiation.

The current clinical treatments for complications caused by hepatobiliary surgery still have some inevitable weakness. The aim of the study was to fabricate a tissue-engineered bile duct that utilized a novel bilayered polymer scaffold combined with human bone marrow-derived mesenchymal stem cells (hMSCs) for new treatment of biliary disease. The biocompatibility of polycaprolactone (PCL) (PCL)/poly(lactide-co-glycolide) (PLGA) scaffold with hMSCs was first examined, and the hMSC-PCL/PLGA constructs (MPPCs) prepared. The MPPCs and blank scaffolds were then transplanted into 18 pigs for evaluation its efficacy on bile duct repairing, respectively. In vitro, the PCL/PLGA scaffold was verified to support the adhesion, proliferation and matrix deposition of hMSCs. There was no sign of bile duct narrowing and cholestasis in all experimental animals. At 6 months, the MPPCs had a superior repairing effect on the bile duct injury, compared with the blank PCL/PLGA scaffolds. Therefore, the implanted scaffolds could not only support the biliary tract and allow free bile flow but also had direct or indirect positive effects on repair of injured bile duct. Copyright © 2015 John Wiley & Sons, Ltd.

Eyelid reconstruction includes anterior lamella reconstruction and posterior lamella reconstruction. As an important skeletal component of the posterior lamella, tarsal plates repair is the key issue for eyelid reconstruction. Presently, neither traditional surgery nor autograft/allograft has achieved satisfactory repair effects. Poly(propylene fumarate)-co-2-hydroxyethyl methacrylate (PPF-HEMA) networks with mass ratios of 1 : 0.5, 1 : 1 and 1 : 2 were synthesized and used as the tarsal substitute in this study. Their chemical compositions, swelling ability, and mechanical properties were characterized. Porous scaffolds were fabricated by a gelatin particle leaching method. The in vitro studies of cytotoxicity on human dermal fibroblasts (HDFs) and degradation demonstrated that PPF-HEMA scaffolds did not have noticeable cell cytotoxicity and their degradation rates correlated with the ratio of PPF to HEMA. The PPF-HEMA networks, with mass ratios of 1 : 1 and 1 : 2, and an ADM control were implanted in rabbits with tarsal plate defects for in vivo biocompatibility and degradation behavior evaluation. PPF-HEMA scaffolds provided satisfactory repair results with mild tissue response and biocompatibility to fibroblast growth and fibrous capsulation compared to the ADM control. The tissue compatible and biodegradable PPF-HEMA networks with elastic mechanical properties were proven to be a suitable candidate for tarsal repair.

The chain length of ligands plays an important role in many biomedical applications. Yet the interaction of nanoparticles with surface-capped ligands of different length (especial the hydrophobic chains) and cells is neglected, and thereby the underlying mechanism influencing cellular uptake is unclear. Herein the role of alkyl length on AuNPs in mediating serum protein adsorption and the subsequent cellular uptake by A549 cells was studied. The AuNPs were modified with carboxylic alkyl thiols of different chain length (3MA, 11MA and 16MA), resulting in MA-AuNPs with a size of 5 nm in dry state and several tens of nm in media. The MA-AuNPs possessed a negatively charged surface, whose zeta potential was around −20 mV in serum-containing medium regardless of the length of ligands. Whereas the total amount of adsorbed serum proteins had no significant difference, the relative amounts of adhesion mediators especially vitronectin (Vn) depended on the alkyl length significantly. The 16MA-AuNPs adsorbed the largest amount of Vn, and were internalized by A549 cells with the largest quantity and good distribution in cytoplasm. Taking account all the results, the protein adsorption and its role in linking alkyl length on AuNPs to cellular uptake are figured out.

Tissue engineering has emerged as a powerful method to treat the loss of tissues and organs in the past several decades. Many commercial products based on tissue engineering have been applied in clinical practice. In addition to classical tissue engineering strategies, in situ tissue regeneration (in vivo tissue engineering) has become a more and more important therapy for damaged tissues and organs as it avoids in vitro cell manipulation and takes advantage of an in vivo microenvironment to regulate cell activities. Biomaterials are one of the key factors for in situ tissue regeneration and should possess unique features including physical properties, chemical composition, and biological functions to modulate cell behaviors such as adhesion, proliferation, migration, differentiation and neo-tissue formation. In this review, recent development of biomaterials used for in situ tissue regeneration has been summarized, classified by sources and the design of biomaterials including physical design, chemical composition, and biological functionalization was highlighted. In addition, the application of biomaterials for in situ tissue regeneration was also reviewed. Finally, a brief conclusion and some perspectives were given in terms of the future trend of biomaterials for in situ tissue regeneration.

Interaction with colloidal particles may change the structure and function of the cytoskeleton, and influence cell shape and signal pathways, and thereby modulate the differentiation of stem cells. In this study, bovine serum albumin-coated poly(lactic-co-glycolic acid) particles (PLGA–BSA) were prepared and incubated with rat mesenchymal stem cells (MSCs). It was found that they promote osteogenic ALP activity and the expression of collagen type I (COL) and osteocalcin (OCN) of MSCs, but inhibit the expression of adipogenic peroxisome proliferator-activated receptor-gamma (PPARγ) and lipoprotein lipase (LPL) at both mRNA and protein levels. The p38 pathway is altered in the presence of PLGA–BSA particles, which might be responsible for the particle-induced differentiation of MSCs.

Elastic polyurethane (PU) microcapsules were successfully fabricated via a simple and well controllable adsorption and crosslinking method on porous CaCO3 templates in organic solvent. The PU capsules possessed some amine groups, enabling well dispersion in water. These PU capsules with hydrophobic interiors could load hydrophobic substances such as drugs and dyes from organic solution spontaneously. And the loaded dyes can be well preserved. Their deformation and recovery behaviours were investigated after being forced to flow through a microchannel. Due to their good elasticity, more than 82% squeezed PU capsules could recover their original spherical shape even at a high deformation ratio of 32%. These elastic PU microcapsules with strong shape recovery ability may find diverse applications as microcontainer or microsensor which could survive through harsh conditions like forced deformation.

Killing of cancer cells by applying mechanical disruption has been an appealing emerging strategy for cancer treatment in recent years. In this study, photoresponsive submicron particles based on diazo-resin that are able to release N

Intervertebral disc (IVD) degeneration may cause many diseases and pain. Stem cell migration toward the site of IVD degeneration is a key factor for IVD regeneration. In the current study, we prepared albumin/heparin nanoparticles (BHNPs) as injectable carriers of stromal cell-derived factor-1α (SDF-1α, also known as C-X-C motif chemokine 12), a powerful chemoattractant for the homing of bone marrow resident mesenchymal stem cells (MSCs), for protection of the molecule against degradation for a sustained release. The NPs have relatively uniform small size, with a diameter of about 110 nm. The NPs possess a high loading capacity of SDF-1α with a sustained release profile. The bioactivity of the obtained BHNPs/SDF was then studied in vitro and in vivo. The BHNPs/SDF can induce migration of MSCs in a dose-dependent manner in vitro. After injected into the damaged disc, BHNPs/SDF induce much better regeneration of annulus fibrosus and nucleus pulposus, compared to SDF-1α and BHNPs alone, evidenced with better histological grade scores and higher expression of SOX9, Aggrecan, and Collagen type II at the level of both mRNA and protein. This study provides a simple nanoplatform to load SDF-1α and protect it against degradation, with potential application in inductive tissue regeneration in vivo. Statement of significance Stem cell migration toward the site of IVD degeneration is a key event to promote IVD regeneration. In the current study, we prepared albumin/heparin nanoparticles (BHNPs) as injectable carriers to protect SDF-1α against degradation and for the sustained release of the molecule. After injected into the damaged disc, BHNPs/SDF induced much better regeneration of IVD, compared to SDF-1α and BHNPs alone. This study provides a simple nanoplatform to load SDF-1α and protect it from degradation, with potential application in inductive tissue regeneration in vivo.

Despite the well-known anticancer activity of mono- and multi-nuclear platinum complexes, studies of the antitumor performances of platinum-based supramolecular coordination complexes are rare. Herein, we report on the synthesis of a four-armed amphiphilic copolymer Pt-PAZMB-b-POEGMA containing a theranostic metallacycle M, in which the tetraphenylethene derivative acts as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt) is an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions. The impact of the morphology and size of the assemblies on their endocytic pathways, uptake rates, internalization amounts and cytotoxicities were fully investigated. The self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. Controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of around 50 nm in size exhibited an excellent antitumor performance as well as a low systemic toxicity, due to an enhanced permeability and retention effect.

The widely used engineered nanoparticles have presented non-negligible immunotoxicity and specific patterns of inflammatory-activating behaviors, which remain to be revealed in a more systematic way. In this work, gold nanoparticles (GNPs) with 3 different diameters were prepared, and then were further modified with poly(ethylene glycol) (PEG) or chicken ovalbumin (OVA) to achieve different surface properties. Both types of GNPs had sizes of 12, 35, and 60nm and possessed negatively charged surface, showing good colloidal stability in cell culture medium, respectively. The conjugated amount of OVA was around 110ng/mm2 regardless of the particle size. All the particles showed neglectable influence on viability of RAW246.7 macrophages when cocultured in vitro. The GNPs of larger size or conjugated with OVA were internalized with significantly larger amount. While the OVA-coated GNPs induced higher secretion of tumor necrosis factor-α, interleukin-6, and interleukin-1β, the PEG coating did not induce significant inflammatory response especially when the size of NPs was larger than 35nm. Comparatively, smaller GNPs induced stronger inflammatory responses regardless of their surface-conjugated molecules.

A scaffold with an oriented porous architecture to facilitate cell infiltration and bioactive interflow between neo-host tissues is of great importance for in situ inductive osteochondral regeneration. In this study, a poly(lactide-co-glycolide) (PLGA) scaffold with oriented pores in its radial direction was fabricated via unidirectional cooling of the PLGA solution in the radial direction, following with lyophilization. Micro-computed tomography evaluation and scanning electron microscopy observation confirmed the radially oriented microtubular pores in the scaffold. The scaffold had porosity larger than 90% and a compressive modulus of 4 MPa in a dry state. Culture of bone marrow stem cells in vitro revealed faster migration and regular distribution of cells in the poly(lactide-co-glycolide) scaffold with oriented pores compared with the random PLGA scaffold. The cell-free oriented macroporous PLGA scaffold was implanted into rabbit articular osteochondral defect in vivo for 12 weeks to evaluate its inductive tissue regeneration function. Histological analysis confirmed obvious tide mark formation and abundant chondrocytes distributed regularly with obvious lacunae in the cartilage layer. Safranin O-fast green staining showed an obvious boundary between the two layers with distinct staining results, indicating the simultaneous regeneration of the cartilage and subchondral bone layers, which is not the case for the random poly(lactide-co-glycolide) scaffold after the same implantation in vivo. The oriented macroporous PLGA scaffold is a promising material for the in situ inductive osteochondral regeneration without the necessity of preseeding cells.