Supramolecular Gels Incorporating Cordyline terminalis Leaf Extract as a Polyphenol Release Scaffold for Biomedical Applications.

Cordyline terminalis leaf extract (aqCT) possesses abundant polyphenols and other bioactive compounds, which are encapsulated in gelatin-polyethylene glycol-tyramine (GPT)/alpha-cyclodextrin (α-CD) gels to form the additional functional materials for biomedical applications. In this study, the gel compositions are optimized, and the GPT/α-CD ratios equal to or less than one half for solidification are found. The gelation time varies from 40.7 min to 5.0 h depending on the increase in GPT/α-CD ratios and aqCT amount. The aqCT extract disturbs the hydrogen bonding and host-guest inclusion of GPT/α-CD gel networks, postponing the gelation. Scanning electron microscope observation shows that all gels with or without aqCT possess a microarchitecture and porosity. GPT/α-CD/aqCT gels could release polyphenols from 110 to 350 nmol/mL at the first hour and sustainably from 5.5 to 20.2 nmol/mL for the following hours, which is controlled by feeding the aqCT amount and gel properties. GPT/α-CD/aqCT gels achieved significant antioxidant activity through a 100% scavenging DPPH radical. In addition, all gels are non-cytotoxic with a cell viability more than 85%. Especially, the GPT3.75α-CD10.5aqCT gels with aqCT amount of 3.1-12.5 mg/mL immensely enhanced the cell proliferation of GPT3.75α-CD10.5 gel without extract. These results suggest that the inherent bioactivities of aqCT endowed the resulting GPT/α-CD/aqCT gels with effective antioxidant and high biocompatibility, and natural polyphenols sustainably release a unique platform for a drug delivery system or other biomedical applications.

Decellularized Porcine Epiphyseal Plate-Derived Extracellular Matrix Powder: Synthesis and Characterization.

The aim of this study was to develop a porcine epiphyseal plate-derived extracellular matrix powder (PEPEP) for epiphyseal plate regeneration. PEPEP was characterized by chemical assay to determine the contents of DNA and epiphyseal plate complex chemical components (glycosaminoglycan and hydroxyproline). The effects of PEPEP on the viability, proliferation, and differentiation of human bone marrow mesenchymal stem cells (hBMSCs) were also evaluated. hBMSCs cultured in PEPEP exhibited a good distribution with excellent viability after 72 h, demonstrating the ability of PEPEP to support hBMSC proliferation. At week 4 and 6 in vitro, the PEPEP + hBMSCs structure showed chondrogenic ability and an increase in expression of collagen type I, type II, and type X. PEPEP showed a promising ability to enhance cartilage formation and promote chondrocyte differentiation, maturation, and hypertrophy. The results provide insights into the feasibility of PEPEP as a potential material for tissue engineering applications.

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect.

Oxaliplatin (OXA) was coupled to PEGylated polyamidoamine dendrimers of fourth generation (G4-PEG@OXA) in the comparison to PEGylated ones of odd generation (G3.5-PEG@OXA). Proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy were used to confirm the successful incorporation of OXA as well as the synthesis of carrier systems. Both two types of carrier systems exhibited in sphere nanoparticle shape with size of less than 100 nm that was in the range being able to cause toxicity on cancer cells. The average drug loading efficiency (DLE) of G4-PEG@OXA was obtained at 84.63% that was higher than DLE of G3.5-PEG of 75.69%. The release kinetic of G4-PEG@OXA and G3.5-PEG@OXA did not show any burst release phenomenon while free OXA was released over 40% at the first hour. The sustainable release of OXA was achieved when it was encapsulated in these carriers, but the G4 generation liberated OXA (3.4%-6.4%) slower than G3.5 one (11.9%-22.8%). The in vitro cytotoxicities of G4-PEG@OXA were evaluated in HeLa cell lines using resazurin assay and live/dead staining test. Although the free OXA showed a rather moderate killing ability, the G4-PEG@OXA still displayed the low viability of HeLa that was better to the result of G3.5-PEG@OXA due to released OXA amount. The benefit of this system was to overcome the burst release phenomenon to minimize OXA toxicity without compromising its efficiency.

Soy Lecithin-Derived Liposomal Delivery Systems: Surface Modification and Current Applications.

The development of natural phospholipids for nanostructured drug delivery systems has attracted much attention in the past decades. Lecithin that was derived from naturally occurring in soybeans (SL) has introduced some auspicious accomplishments to the drug carrying aspect, like effectual encapsulation, controlled release, and successful delivery of the curative factors to intracellular regions in which they procure these properties from their flexible physicochemical and biophysical properties, such as large aqueous center and biocompatible lipid, self-assembly, tunable properties, and high loading capacity. Despite the almost perfect properties as a drug carrier, liposome is known to be quite quickly eliminated from the body systems. The surface modification of liposomes has been investigated in many studies to overcome this drawback. In this review, we intensively discussed the surface-modified liposomes that enhancing the targeting, cellular uptake, and therapeutic response. Moreover, the recent applications of soy lecithin-derived liposome, focusing on cancer treatment, brain targeting, and vaccinology, are also summarized.

Modified Carboxyl-Terminated PAMAM Dendrimers as Great Cytocompatible Nano-Based Drug Delivery System.

Polyamidoamine (PAMAM) dendrimers are extensively researched as potential drug delivery system thanks to their desirable features such as controlled and stable structures, and ease of functionalization onto their surface active groups. However, there have been concerns about the toxicity of full generation dendrimers and risks of premature clearance from circulation, along with other physical drawbacks presented in previous formulations, including large particle sizes and low drug loading efficiency. In our study, carboxyl-terminated PAMAM dendrimer G3.5 was grafted with poly (ethylene glycol) methyl ether (mPEG) to be employed as a nano-based drug delivery system with great cytocompatibility for the delivery of carboplatin (CPT), a widely prescribed anticancer drug with strong side effects so that the drug will be effectively entrapped and not exhibit uncontrolled outflow from the open structure of unmodified PAMAM G3.5. The particles formed were spherical in shape and had the optimal size range (around 36 nm) that accommodates high drug entrapment efficiency. Surface charge was also determined to be almost neutral and the system was cytocompatible. In vitro release patterns over 24 h showed a prolonged CPT release compared to free drug, which correlated to the cytotoxicity assay on malignant cell lines showing the lack of anticancer effect of CPT/mPEG-G3.5 compared with CPT.

Enhanced tissue adhesiveness of injectable gelatin hydrogels through dual catalytic activity of horseradish peroxidase.

Development of bioadhesives with tunable mechanical strength, high adhesiveness, biocompatibility, and injectability is greatly desirable in all surgeries to replace or complement the sutures and staples. Herein, the dual catalytic activity of horseradish peroxidase is exploited to in situ form the hydroxyphenyl propionic acid-gelatin/thiolated gelatin (GH/GS) adhesive hydrogels including two alternative crosslinks (phenol-phenol and disulfide bonds) with fast gelation (few seconds - several minutes) and improved physicochemical properties. Their elastic moduli increase from 6.7 to 10.3 kPa by adding GS polymer that leads to the better stability of GH/GS hydrogels than GH ones. GH/GS adhesive strength is respectively 6.5-fold and 15.8-fold higher than GH-only and fibrin glue that is due to additional disulfide linkages between hydrogels and tissues. Moreover, in vitro cell study with human dermal fibroblast showed the cell-compatibility of GH/GS hydrogels. Taken together, GH/GS hydrogels can be considered as promising potential adhesive materials for various biomedical applications.

Correction: Nguyen et al. Green Silver Nanoparticles Formed by Phyllanthus urinaria, Pouzolzia zeylanica, and Scoparia dulcis Leaf Extracts and the Antifungal Activity. Nanomaterials 2020, 10, 542.

In the original publication [...].

Large-scale smart bioreactor with fully integrated wireless multivariate sensors and electronics for long-term in situ monitoring of stem cell culture.

Achieving large-scale, cost-effective, and reproducible manufacturing of stem cells with the existing devices is challenging. Traditional single-use cell-bag bioreactors, limited by their rigid and single-point sensors, struggle with accuracy and scalability for high-quality cell manufacturing. Here, we introduce a smart bioreactor system that enables multi-spatial sensing for real-time, wireless culture monitoring. This scalable system includes a low-profile, label-free thin-film sensor array and electronics integrated with a flexible cell bag, allowing for simultaneous assessment of culture properties such as pH, dissolved oxygen, glucose, and temperature, to receive real-time feedback for up to 30 days. The experimental results show the accurate monitoring of time-dynamic and spatial variations of stem cells and myoblast cells with adjustable carriers from a plastic dish to a 2-liter cell bag. These advances open up the broad applicability of the smart sensing system for large-scale, lower-cost, reproducible, and high-quality engineered cell manufacturing for broad clinical use.

Injectable reactive oxygen and nitrogen species-controlling hydrogels for tissue regeneration: current status and future perspectives.

The dual role of reactive oxygen and nitrogen species (RONS) in physiological and pathological processes in biological systems has been widely reported. It has been recently suggested that the regulation of RONS levels under physiological and pathological conditions is a potential therapy to promote health and treat diseases, respectively. Injectable hydrogels have been emerging as promising biomaterials for RONS-related biomedical applications owing to their excellent biocompatibility, three-dimensional and extracellular matrix-mimicking structures, tunable properties and easy functionalization. These hydrogels have been developed as advanced injectable platforms for locally generating or scavenging RONS, depending on the specific conditions of the target disease. In this review article, the design principles and mechanism by which RONS are generated/scavenged from hydrogels are outlined alongside a discussion of their in vitro and in vivo evaluations. Additionally, we highlight the advantages and recent developments of these injectable RONS-controlling hydrogels for regenerative medicines and tissue engineering applications.

Multifunctional surfaces through synergistic effects of heparin and nitric oxide release for a highly efficient treatment of blood-contacting devices.

Thrombosis and inflammation after implantation remain unsolved problems associated with various medical devices with blood-contacting applications. In this study, we develop a multifunctional biomaterial with enhanced hemocompatibility and anti-inflammatory effects by combining the anticoagulant activity of heparin with the vasodilatory and anti-inflammatory properties of nitric oxide (NO). The co-immobilization of these two key molecules with distinct therapeutic effects is achieved by simultaneous conjugation of heparin (HT) and copper nanoparticles (Cu NPs), an NO-generating catalyst, via a simple tyrosinase (Tyr)-mediated reaction. The resulting immobilized surface showed long-term, stable and adjustable NO release for 14 days. Importantly, the makeup of the material endows the surface with the ability to promote endothelialization and to inhibit coagulation, platelet activation and smooth muscle cell proliferation. In addition, the HT/Cu NP co-immobilized surface enhanced macrophage polarization towards the M2 phenotype in vitro, which can reduce the inflammatory response and improve the adaptation of implants in vivo. This study demonstrated a simple but efficient method of developing a multifunctional surface for blood-contacting devices.

Calcium peroxide-mediated in situ formation of multifunctional hydrogels with enhanced mesenchymal stem cell behaviors and antibacterial properties.

Injectable hydrogels can serve as therapeutic vehicles and implants for the treatment of various diseases as well as for tissue repair/regeneration. In particular, the horseradish peroxidase (HRP) and hydrogen peroxide (H2O2)-catalyzed hydrogelation system has attracted much attention, due to its ease of handling and controllable gel properties. In this study, we introduce calcium peroxide (CaO2) as a H2O2-generating reagent to gradually supply a radical source for the HRP-catalyzed crosslinking reaction. This novel therapy can create stiff hydrogels without compromising the cytocompatibility of the hydrogels due to the use of initially high concentrations of H2O2. The physico-chemical properties of the hydrogels can be controlled by varying the concentrations of HRP and CaO2. In addition, the controlled and sustained release of bioactive molecules, including H2O2, O2, and Ca2+ ions, from the hydrogels could stimulate the cellular behaviors (attachment, migration, and differentiation) of human mesenchymal stem cells. Moreover, the hydrogels exhibited killing efficacy against both Gram-negative and Gram-positive bacteria, dependent on the H2O2 and Ca2+ release amounts. These positive results suggest that hydrogels formed by HRP/CaO2 can be used as potential matrices for a wide range of biomedical applications, such as bone regeneration and infection treatment.

Self-Assemblable Polymer Smart-Blocks for Temperature-Induced Injectable Hydrogel in Biomedical Applications.

Self-assembled temperature-induced injectable hydrogels fabricated via self-assembly of polymer smart-blocks have been widely investigated as drug delivery systems and platforms for tissue regeneration. Polymer smart-blocks that can be self-assembly play an important role in fabrication of hydrogels because they can self-assemble to induce the gelation of their copolymer in aqueous solution. The self-assembly occurs in response to an external stimulus change, such as temperature, pH, glucose, ionic strength, light, magnetic field, electric field, or their combination, which results in property transformations like hydrophobicity, ionization, and conformational change. The self-assembly smart-block based copolymers exist as a solution in aqueous media at certain conditions that are suitable for mixing with bioactive molecules and/or cells. However, this solution turns into a hydrogel due to the self-assembly of the smart-blocks under exposure to an external stimulus change in vitro or injection into the living body for a controllable release of loaded bioactive molecules or serving as a biomaterial scaffold for tissue regeneration. This work reports current scenery in the development of these self-assembly smart-blocks for fabrication of temperature-induced injectable physically cross-linked hydrogels and their potential application as drug delivery systems and platforms for tissue engineering.

The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation.

Poly(ethylene glycol) (PEG) is widely used as a gold standard in bioconjugation and nanomedicine to prolong blood circulation time and improve drug efficacy. The conjugation of PEG to proteins, peptides, oligonucleotides (DNA, small interfering RNA (siRNA), microRNA (miRNA)) and nanoparticles is a well-established technique known as PEGylation, with PEGylated products have been using in clinics for the last few decades. However, it is increasingly recognized that treating patients with PEGylated drugs can lead to the formation of antibodies that specifically recognize and bind to PEG (i.e., anti-PEG antibodies). Anti-PEG antibodies are also found in patients who have never been treated with PEGylated drugs but have consumed products containing PEG. Consequently, treating patients who have acquired anti-PEG antibodies with PEGylated drugs results in accelerated blood clearance, low drug efficacy, hypersensitivity, and, in some cases, life-threatening side effects. In this succinct review, we collate recent literature to draw the attention of polymer chemists to the issue of PEG immunogenicity in drug delivery and bioconjugation, thereby highlighting the importance of developing alternative polymers to replace PEG. Several promising yet imperfect alternatives to PEG are also discussed. To achieve asatisfactory alternative, further joint efforts of polymer chemists and scientists in related fields are urgently needed to design, synthesize and evaluate new alternatives to PEG.

Comparison of biogenic silver nanoparticles formed by Momordica charantia and Psidium guajava leaf extract and antifungal evaluation.

Exploiting plant extracts to form metallic nanoparticles has been becoming the promising alternative routes of chemical and physical methods owing to environmentally friendly and abundantly renewable resources. In this study, Momordica charantia and Psidium guajava leaf extract (MC.broth and PG.broth) are exploited to fabricate two kinds of biogenic silver nanoparticles (MC.AgNPs and PG.AgNPs). Phytoconstituent screening is performed to identify the categories of natural compounds in MC.broth and PG.broth. Both extracts contain wealthy polyphenols which play a role of reducing agent to turn silver (I) ions into silver nuclei. Trace alkaloids, rich saponins and other oxygen-containing compounds creating the organic corona surrounding nanoparticles act as stabilizing agents. MC.AgNPs and PG.AgNPs are characterized by UV-vis and FTIR spectrophotometry, EDS and TEM techniques. FTIR spectra indicate the presence of O-H, C = O, C-O-C and C = C groups on the surface of silver nanoparticles which is corresponded with three elements of C, O and Ag found in EDS analysis. TEM micrographs show the spherical morphology of MC.AgNPs and PG.AgNPs. MC.AgNPs were 17.0 nm distributed in narrow range of 5-29 nm, while the average size of PG.AgNPs were 25.7 nm in the range of 5-53 nm. Further, MC.AgNPs and PG.AgNPs exhibit their effectively inhibitory ability against A. niger, A. flavus and F. oxysporum as dose-dependence. Altogether, MC.AgNPs and PG.AgNPs will have much potential in scaled up production and become the promising fungicides for agricultural applications.

Green Silver Nanoparticles Formed by Phyllanthus urinaria, Pouzolzia zeylanica, and Scoparia dulcis Leaf Extracts and the Antifungal Activity.

Phytoconstituents presenting in herbal plant broths are the biocompatible, regenerative, and cost-effective sources that can be utilized for green synthesis of silver nanoparticles. Different plant extracts can form nanoparticles with specific sizes, shapes, and properties. In the study, we prepared silver nanoparticles (P.uri.AgNPs, P.zey.AgNPs, and S.dul.AgNPs) based on three kinds of leaf extracts (Phyllanthus urinaria, Pouzolzia zeylanica, and Scoparia dulcis, respectively) and demonstrated the antifungal capacity. The silver nanoparticles were simply formed by adding silver nitrate to leaf extracts without using any reducing agents or stabilizers. Formation and physicochemical properties of these silver nanoparticles were characterized by UV-vis, Fourier transforms infrared spectroscopy, scanning electron microscope, transmission electron microscope, and energy dispersive X-ray spectroscopy. P.uri.AgNPs were 28.3 nm and spherical. P.zey.AgNPs were 26.7 nm with hexagon or triangle morphologies. Spherical S.dul.AgNPs were formed and they were relatively smaller than others. P.uri.AgNPs, P.zey.AgNPs and S.dul.AgNPs exhibited the antifungal ability effective against Aspergillus niger, Aspergillus flavus, and Fusarium oxysporum, demonstrating their potentials as fungicides in the biomedical and agricultural applications.

Graphene oxide immobilized surfaces facilitate the sustained release of doxycycline for the prevention of implant related infection.

Preventing implant-associated infection, which can lead to implant failure and increased medical costs, is one of the biggest challenges in the orthopaedic surgeons. Therefore, the development of stable and highly effective surface modifications to increase the antimicrobial properties of implants is required. In this study, graphene oxide (GO-)-immobilized titanium dioxide (TiO2) was developed to efficiently carry and release antimicrobial drugs. Firstly, tyramine-conjugated GO (GOTA) was synthesized and immobilized onto the surfaces of TiO2 through tyrosinase (Tyr)-catalyzed oxidative reaction (GOTA/TiO2). Doxycycline hyclate (Dox) was then loaded onto GOTA/TiO2 via non-covalent interactions between GO and Dox (Dox/GOTA/TiO2), including electrostatic interaction, π-π stacking, hydrophobic interaction, and hydrogen bonds. The amount of loaded drug was able to be controlled, reaching a maximum of 36 µg/cm2. in vitro experiments revealed that the sustained release of Dox from the TiO2 surfaces continued for over 30 days. Compared with bare TiO2 and GOTA/TiO2, Dox/GOTA/TiO2 exhibited superior antibacterial activity against both gram-negative Escherichia coli and gram-positive Staphylococcus aureus bacteria, without affecting the viability of human dermal fibroblasts. The obtained results indicated that GO-immobilized TiO2 is an effective carrier for antimicrobial drug delivery to reduce implant-associated infection through the synergistic antimicrobial effect of GO and the prescribed drugs.

Functionalized mesoporous silica nanoparticles and biomedical applications.

Since the first report in early 1990s, mesoporous silica nanoparticles (MSNs) have progressively attracted the attention of scientists due to their potential applications in physic, energy storage, imaging, and especially in biomedical engineering. Owning the unique physiochemical properties, such as highly porosity, large surface area and pore volume, functionalizable, tunable pore and particle sizes and biocompatibility, and high loading cavity, MSNs offer efficient encapsulation and then controlled release, and in some cases, intracellular delivery of bioactive molecules for biomedical applications. During the last decade, functionalized MSNs that show respond upon the surrounding stimulus changes, such as temperature, pH, redox, light, ultrasound, magnetic or electric fields, enzyme, redox, ROS, glucose, and ATP, or their combinations, have continuously revolutionized their potential applications in biomedical engineering. Therefore, this review focuses on discussion the recent fabrication of functionalized MSNs and their potential applications in drug delivery, therapeutic treatments, diagnostic imaging, and biocatalyst. In addition, some potential clinical applications and challenges will also be discussed.

Origanum majorana L. Essential Oil-Associated Polymeric Nano Dendrimer for Antifungal Activity against Phytophthora infestans.

In this study, the introduction of Origanum majorana L. essential oil into a polyamidoamine (PAMAM) G4.0 dendrimer was performed for creation of a potential nanocide against Phytophthora infestans. The characteristics of marjoram oil and PAMAM G4.0 was analyzed using transmission electron spectroscopy (TEM), nuclear magnetic resonance spectroscopy (1H-NMR) and gas chromatography mass spectrometry (GC-MS). The success of combining marjoram oil with PAMAM G4.0 was evaluated by FT-IR, TGA analysis, and the antifungal activity of this system was also investigated. The results showed that the antifungal activity of oil/PAMAM G4.0 was high and significantly higher than only PAMAM G4.0 or marjoram essential oil. These results indicated that the nanocide oil/PAMAM G4.0 helped strengthen and prolong the antifungal properties of the oil.

Recent Progress and Advances of Multi-Stimuli-Responsive Dendrimers in Drug Delivery for Cancer Treatment.

Despite the fact that nanocarriers as drug delivery systems overcome the limitation of chemotherapy, the leakage of encapsulated drugs during the delivery process to the target site can still cause toxic effects to healthy cells in other tissues and organs in the body. Controlling drug release at the target site, responding to stimuli that originated from internal changes within the body, as well as stimuli manipulated by external sources has recently received significant attention. Owning to the spherical shape and porous structure, dendrimer is utilized as a material for drug delivery. Moreover, the surface region of dendrimer has various moieties facilitating the surface functionalization to develop the desired material. Therefore, multi-stimuli-responsive dendrimers or 'smart' dendrimers that respond to more than two stimuli will be an inspired attempt to achieve the site-specific release and reduce as much as possible the side effects of the drug. The aim of this review was to delve much deeper into the recent progress of multi-stimuli-responsive dendrimers in the delivery of anticancer drugs in addition to the major potential challenges.