Search

Osteoarthritis (OA) is a common chronic inflammatory disease in the joints. It is one of the leading causes of disability with increasing morbidity, which has become one of the serious clinical issues. Current treatments would only provide temporary relief due to the lack of early diagnosis and effective therapy, and thus the replacement of joints may be needed when the OA deteriorates. Although the intra-articular injection and oral administration of drugs are helpful for OA treatment, they are suffering from systemic toxicity, short retention time in joint, and insufficient bioavailability. Nanomedicine is potential to improve the drug delivery efficiency and targeting ability. In this focused progress review, the particle-based drug loading systems that can achieve targeted and triggered release are summarized. Stimuli-responsive nanocarriers that are sensitive to endogenous microenvironmental signals such as reactive oxygen species, enzymes, pH, and temperature, as well as external stimuli such as light for OA therapy are introduced in this review. Furthermore, the nanocarriers associated with targeted therapy and imaging for OA treatment are summarized. The potential applications of nanotherapies for OA treatment are finally discussed.

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 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.

Protein adsorption on biomaterials strongly mediates the subsequent cell responses. Here adsorption of fibronectin (Fn) on salt-treated PEI(PSS/PDDA)7 multilayers was characterized. The amounts of adsorbed Fn increased linearly along with the increase of thickness of multilayers pretreated with 1 M and 5 M NaCl solutions (Multilayer-1M and 5M), but was independent on the thickness of Multilayer-3M. The normalized relative RGD activity of Fn were significantly higher on the Multilayer-3M than on others. By comparison of cellular behaviors of VSMCs being cultured in the normal and Fn-depleted serum-containing medium, the significant role of Fn on modulating the behaviors of VSMCs was verified. The Fn adsorption model and its role on linking the biomaterials surface to the VSMCs behaviors are proposed.

The amphiphilic pyrene-containing random copolymers with pH-sensitive hydrazone bonds are synthesized by copolymerizing hydrophobic pyrene-containing methacrylhydrazone with hydrophilic N,N-dimethylacrylamide. The hydrolysable copolymers form spherical micelles at pH 6, which are further transformed into pure 1-pyrenecarboxaldehyde nanorods due to cleavage of the hydrazone bonds. Likewise, the shape transformation is observed under pH 5.5 phosphate buffered saline. Moreover, the hydrolysable micelles being co-cultured with A549 cells cause higher cytotoxicity than the non-hydrolysable ones without shape transformation, which are synthesized by reducing the hydrazone bonds with NaHB4 .

The dual-labeled microcapsules via nanoparticle/polymer assembly based on polyamine-salt aggregates can be fabricated for the ratiometric intracellular pH sensing. After deposition of SiO2 nanoparticles on the poly(allylamine hydrochloride)/multivalent anionic salt aggregates followed by silicic acid treatment, the generated microcapsules are stable in a wide pH range (3.0 ∼ 8.0). pH sensitive dye and pH insensitive dye are simultaneously labeled on the capsules, which enable the ratiometric pH sensing. Due to the rough and positively charged surface, the microcapsules can be internalized by several kinds of cells naturally. Real-time measurement of intracellular pH in several living cells shows that the capsules are all located in acidic organelles after being taken up. Furthermore, the negatively charged DNA and dyes can be easily encapsulated into the capsules via charge interaction. The microcapsules with combination of localized pH sensing and drug loading abilities have many advantages, such as following the real-time transportation and processing of the carriers in cells.

Maleimide-functionalized poly(ester carbonate)s are synthesized by ring-opening copolymerization of furan-maleimide functionalized trimethylene carbonate (FMTMC) with L-lactide and a subsequent retro Diels-Alder reaction. The maleimide groups on poly(ester carbonate)s are amenable to Michael addition with thiol-containing molecules such as 3-mercapto-1-propanol, 2-aminoethanethiol hydrochloride, and mercaptoacetic acid under mild conditions, enabling the formation of biodegradable materials with various functional groups (e.g., hydroxyl, amine, and carboxyl). In particular, the maleimide-functionalized poly(ester carbonate) is clicked with a laminin-derived peptide CQAASIKVAV. In vitro culture of PC12 cells shows that the maleimide-functionalized polymers, especially the CQAASIKVAV-grafted one, could support cell proliferation and neurite outgrowth. The maleimide-functionalized poly(ester carbonate)s provide a versatile platform for diverse functionalization and have comprehensive potential in biomedical engineering.

Selective adhesion and directional migration of endothelial cells (ECs) on biomaterials is critical to realize the rapid endothelialization. In this study, a Cys-Ala-Gly (CAG) peptide density gradient is generated on homogeneous cell-resisting poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) brushes by immersing the brushes in a complementary gradient solution of CAG and competitive mercapto-terminated methoxyl poly(ethylene glycol). The adhesion and spreading of smooth muscle cells (SMCs) is impaired effectively on the gradient surface. About six folds of adherent ECs over SMCs are achieved at the position (10 mm) of highest CAG density on the gradient surface in a co-culture condition. Due to the gradient cues, ECs migrate fastest with the best directionality of 86.7% at the middle of the gradient, leading to the maximum net displacement as well.

It is of paramount importance to study the cellular uptake processes of particles with defined surface property, especially the uptake pathways and intracellular transportation. In this study, aptamer AS1411 molecules, which are known to specifically bind the over-expressed nucleolin on cancer cell membrane, were conjugated onto bovine serum albumin-decorated poly(D,L-lactide-co-glycolide; PLGA, Φ400 nm) particles with a density of 1-1.7 molecule/10 nm(2). The aptamer-modified PLGA particles were preferably ingested by liver cancer cells with higher amount and faster rate. The clathrin-mediated endocytosis and macropinocytosis pathways played a more important role in uptake of the aptamer modified particles.

A bioactive scaffold with desired microstructure is of great importance to induce infiltration of somatic and stem cells, and thereby to achieve the in situ inductive tissue regeneration. In this study, a scaffold with oriented pores in the radial direction is prepared by using methacrylated hyaluronic acid (HA-MA) via controlled directional cooling of a HA-MA solution, and followed with photo-crosslinking to stabilize the structure. Poly(lactide-co-glycolide) (PLGA) is further infiltrated to enhance the mechanical strength, resulting in a compressive modulus of 120 kPa. In vitro culture of bone marrow stem cells (BMSCs) reveals spontaneous cell aggregation inside this type of scaffold with a spherical morphology. In vivo transplantation of the cell-free scaffold in rabbit knees for 12 w regenerates simultaneously both cartilage and subchondral bone with a Wakitani score of 2.8. Moreover, the expression of inflammatory factor interleukin-1β (IL-1β) is down regulated, although tumor necrosis factor-α (TNF-α) is remarkably up regulated. With the anti-inflammatory, bioactive properties and good restoration of full thickness cartilage defect in vivo, the oriented macroporous HA-MA/PLGA hybrid scaffold has a great potential for the practical application in the in situ cartilage regeneration.

The mechanism of the cellular uptake of polyelectrolyte microcapsules and its influences on the functions and toxicity of human SMCs are explored. The covalently assembled poly(allylamine hydrochloride)/glutaraldehyde microcapsules are easily ingested by SMCs mainly through macropinosis and caveolae-mediated endocytosis pathways. The capsules mainly disperse in cytoplasm without colocalization in early endosomes and cell nucleus. The results of gene chips reveal substantial and profound alternation of cell phenotypes and functions. Uptake of the microcapsules cause a slight decrease of cell viability, but leads to significant changes in cytoskeleton organization, cell cycle, as well as cell adhesion and migration ability.

Annealing of PDADMAC/PSS multilayer microcapsules assembled on PSS-doped CaCO(3) particles at 80 °C for 30 min reduces their size dramatically from 6.9 ± 0.3 to 3.1 ± 0.5 µm. Methylene blue molecules are encapsulated by spontaneous deposition and post-annealing with a concentration of 22 mg · mL(-1), which is 1000 times higher than the feeding value. The unreleased MB molecules are retained stably for a long time, which are then protected by the capsules against reductive enzymes and keep their photodynamic activity. The viability of HeLa cells incubated with the MB-loaded capsules decreases sharply from ≈ 75 (dark cytotoxicity) to ≈ 20% after irradiation with a laser at 671 nm and 60 J · cm(-2) for 75 s.

PLLA microspheres were aminolyzed in hexanediamine/propanol solution to introduce free amino groups on their surface, which were further transferred into aldehyde groups by a treatment of glutaraldehyde. Chitosan-graft-lactose was then covalently coupled via Schiff base formation. Morphological variation and chitosan-graft-lactose immobilization were characterized. In vitro culture of rabbit auricular chondrocytes demonstrated that the PLLA microcarriers could effectively support the cell attachment and particularly induce cell aggregation on their surface. The formed cell aggregates/microcarriers composite showed higher viability and extracellular matrix production. Thus, the PLLA microcarriers can be potentially used as an injectable delivery system for cartilage repair.

N,N,N-Trimethylchitosan chloride with different degrees of quaternization has been synthesized and characterized by (1)H NMR spectroscopy. The particle size ranges from 150 to 600 nm, which is dependent on the N/P ratio and is less influenced by the degree of quaternization. The majority of the particles have a spherical morphology. The zeta potential of the particles increases with the N/P ratio and the quaternization degree of TMC. Short-term contact experiments show good biocompatibility of TMC, but long-term contact experiments reveal its high toxicity. This study suggests that TMC is a promising gene carrier, but further modification is still required to improve its cytocompatibility.

A drug delivery system based on spontaneous deposition of soluble, low-molecular-weight therapeutic agents has been developed for the purpose of sustaining drug release. Layer-by-layer assembly of oppositely charged polyelectrolytes onto melamine formaldehyde (MF) colloidal particles, followed by removal of the cores at low pH has yielded intact hollow microcapsules having the ability to induce deposition of various water-soluble substances. Dynamic observation by confocal laser scanning microscopy provided direct evidence of such deposition. Dependence of loading rate on molecular weight was investigated. Efficient loading of an anti-cancer drug, daunorubicin (DNR), was confirmed by transmission electron microscopy (TEM). Its release was quantified by fluorometry. The results indicated that loading, and subsequent release, could be tuned by factors such as feeding concentrations, temperature, and salt concentrations. The intrinsic mechanism of loading and release was discussed taking into account the interaction between the drugs and the poly(styrene sulfonate)/MF complex existing in the hollow capsules. With culture of the HL-60 cell line, a kind of human leukemia cell, the presence of DNR-loaded capsules was seen to steadily decrease the cyto-viability. Fluorescence intensity averaged from inside the circles as a function of incubation time.

Various biomacromolecules including proteins and polysaccharides are printed on a substrate capped with a bovine serum albumin (BSA) precursor layer to create clear co-patterns of these molecules. Characterizations by confocal laser scanning microscopy (CLSM) and atomic force microscopy (AFM) demonstrate the successful production and clear boundaries of the co-patterns. Rinsing the BSA-adsorbed substrate and the biomacromolecules-inked stamp before microcontact printing (microCP) is crucial for the creation of clear and stable co-patterns. The patterns are mainly stabilized by electrostatic interactions and van der Waals forces. Characterizations by ellipsometry, UV-Vis and fluorescence spectroscopy reveal that printing by a flat PDMS stamp yields a denser layered structure of proteins with a higher amount than that of adsorbed proteins. By printing, however, a lower enzymatic catalytic activity for horseradish peroxidase (HRP) or binding capability for avidin (both normalized to amount) is determined. A conformational transition from alpha-helix to beta-sheet of HRP is observed by ATR-IR. By contrast, a BSA precursor layer can effectively improve the functionality of the printed HRP or avidin and preserve the original conformation of the proteins, although the absolute transferred amount of these proteins is decreased.

Protein adsorption on biomaterials strongly mediates the subsequent cell responses. Here adsorption of fibronectin (Fn) on salt-treated PEI(PSS/PDDA)7 multilayers was characterized. The amounts of adsorbed Fn increased linearly along with the increase of thickness of multilayers pretreated with 1 M and 5 M NaCl solutions (Multilayer-1M and 5M), but was independent on the thickness of Multilayer-3M. The normalized relative RGD activity of Fn were significantly higher on the Multilayer-3M than on others. By comparison of cellular behaviors of VSMCs being cultured in the normal and Fn-depleted serum-containing medium, the significant role of Fn on modulating the behaviors of VSMCs was verified. The Fn adsorption model and its role on linking the biomaterials surface to the VSMCs behaviors are proposed.

The dual-labeled microcapsules via nanoparticle/polymer assembly based on polyamine-salt aggregates can be fabricated for the ratiometric intracellular pH sensing. After deposition of SiO2 nanoparticles on the poly(allylamine hydrochloride)/multivalent anionic salt aggregates followed by silicic acid treatment, the generated microcapsules are stable in a wide pH range (3.0 ∼ 8.0). pH sensitive dye and pH insensitive dye are simultaneously labeled on the capsules, which enable the ratiometric pH sensing. Due to the rough and positively charged surface, the microcapsules can be internalized by several kinds of cells naturally. Real-time measurement of intracellular pH in several living cells shows that the capsules are all located in acidic organelles after being taken up. Furthermore, the negatively charged DNA and dyes can be easily encapsulated into the capsules via charge interaction. The microcapsules with combination of localized pH sensing and drug loading abilities have many advantages, such as following the real-time transportation and processing of the carriers in cells.

Maleimide-functionalized poly(ester carbonate)s are synthesized by ring-opening copolymerization of furan-maleimide functionalized trimethylene carbonate (FMTMC) with L-lactide and a subsequent retro Diels-Alder reaction. The maleimide groups on poly(ester carbonate)s are amenable to Michael addition with thiol-containing molecules such as 3-mercapto-1-propanol, 2-aminoethanethiol hydrochloride, and mercaptoacetic acid under mild conditions, enabling the formation of biodegradable materials with various functional groups (e.g., hydroxyl, amine, and carboxyl). In particular, the maleimide-functionalized poly(ester carbonate) is clicked with a laminin-derived peptide CQAASIKVAV. In vitro culture of PC12 cells shows that the maleimide-functionalized polymers, especially the CQAASIKVAV-grafted one, could support cell proliferation and neurite outgrowth. The maleimide-functionalized poly(ester carbonate)s provide a versatile platform for diverse functionalization and have comprehensive potential in biomedical engineering.

It is of paramount importance to study the cellular uptake processes of particles with defined surface property, especially the uptake pathways and intracellular transportation. In this study, aptamer AS1411 molecules, which are known to specifically bind the over-expressed nucleolin on cancer cell membrane, were conjugated onto bovine serum albumin-decorated poly(D,L-lactide-co-glycolide; PLGA, Φ400 nm) particles with a density of 1-1.7 molecule/10 nm(2). The aptamer-modified PLGA particles were preferably ingested by liver cancer cells with higher amount and faster rate. The clathrin-mediated endocytosis and macropinocytosis pathways played a more important role in uptake of the aptamer modified particles.

Annealing of PDADMAC/PSS multilayer microcapsules assembled on PSS-doped CaCO(3) particles at 80 °C for 30 min reduces their size dramatically from 6.9 ± 0.3 to 3.1 ± 0.5 µm. Methylene blue molecules are encapsulated by spontaneous deposition and post-annealing with a concentration of 22 mg · mL(-1), which is 1000 times higher than the feeding value. The unreleased MB molecules are retained stably for a long time, which are then protected by the capsules against reductive enzymes and keep their photodynamic activity. The viability of HeLa cells incubated with the MB-loaded capsules decreases sharply from ≈ 75 (dark cytotoxicity) to ≈ 20% after irradiation with a laser at 671 nm and 60 J · cm(-2) for 75 s.

Gelatin is a nature-derived protein having good cytocompatibility, and widely used in tissue engineering particularly in a form of a hydrogel. To obtain the hydrogel with good enough mechanical properties, however, measures are still need to be taken. In this work, the gelatin molecule was modified with methacrylic acid (MA) to obtain crosslinkable gelatin (GM), which formed a chemically crosslinked hydrogel by photoinitiating polymerization. The gelation time could be easily tuned and showed an inverse relationship with the GM concentration. After photo-irradiation for 20 min there was no detectable double carbon bond in the hydrogen spectrum of high resolution magic angle spinning nuclear magnetic resonance spectroscopy ((1)H HR-MAS NMR). With the increase of the GM concentration, storage modulus and loss modulus of the hydrogels increased, but their swelling ratio and mesh size decreased. Weight loss of the hydrogels was also affected by the polymer concentration. Transform growth factor-beta1 (TGF-beta1) was incorporated into the GM hydrogel to improve its bioactivity. In vitro chondrocyte culture showed that the GM hydrogel had indeed good performance to support chondrocyte growth and maintain chondrocytic phenotype. Incorporation of TGF-beta1 could further improve the biological activity in terms of cell proliferation and extracellular matrix secretion.

Poly[(D,L-lactide)-co-glycolide] nanoparticles coated with polyethyleneimine on their surface were prepared by an emulsification-solvent evaporation method and subsequently surface modified by LBL assembly. The assembly of poly(acrylic acid) and polyethyleneimine on a planar substrate and on the PLGA nanoparticles was monitored by QCM-D, zeta-potential, flow cytometry and TEM. Carboxylic and amino groups in the multilayers were crosslinked by carbodiimide condensation, which was also later used to graft poly(ethylene glycol) (PEG). Rhodamine 6G, 5(6)-carboxyfluorescein and fluorescein were incorporated into the nanoparticles and their release profiles were recorded at 60 degrees C and at 37 degrees C for rhodamine 6G, for nanoparticles with a multilayer coating, and those that were crosslinked and grafted with PEG.