High Biocompatibility Research Articles

Fluorinated PAMAM-Arginine Carrier Prodrugs for pH-Sensitive Sustained Ibuprofen Delivery

ObjectiveThe development of an efficient, multifunctional drug delivery system overcoming different obstacles generally associated with drug formulations, including the poor accumulation of the active principle in the target site and its sustained release for prolonged time.MethodsOur study proposes the development of a fluorinated poly(amidoamine) (PAMAM) carrier prodrug combining drug release boosted in alkaline environments with a possible implementation in 19F MRI applications. In particular, we functionalized the terminal primary amines of PAMAM G2 and G4 through an ad hoc designed fluorinated ibuprofen-arginine Michael acceptor to obtain multifunctional ibuprofen-PAMAM-Arg conjugates.ResultsThese carriers demonstrated pH-dependent and sustained ibuprofen release for more than 5 days. This advantage was observed in both weak alkaline and physiological buffer solutions, allowing to overcome the limits associated to the burst release from similar fluorinated Arg-PAMAM dendrimers with ibuprofen physically encapsulated.ConclusionThese findings, coupled to the high biocompatibility of the system, suggest a potential synergistic biomedical application of our conjugates, serving as vehicles for drug delivery and as 19F magnetic resonance imaging contrast agents.

Zwitterionic nanoparticles from indocyanine green dimerization for imaging-guided cancer phototherapy

Indocyanine green (ICG), the only near-infrared (NIR) dye approved for clinical use, has received increasing attention as a theranostic agent wherein diagnosis (fluorescence) is combined with therapy (phototherapy), but suffers rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here we report that dimerized ICG can self-assemble to form zwitterionic nanoparticles (ZN-dICG), which generate fluorescence self-quenching but exhibit superior photothermal and photodynamic properties over ICG. The zwitterionic moieties confer ZN-dICG an ultralow critical micelle concentration and high colloidal stability with low non-specific binding in vivo. In addition, ZN-dICG can respond to the over-generated reactive oxygen species (ROSs) and dissociate to restore NIR fluorescence of ICG, amplifying the sensitivity via albumin binding for low-background imaging of tumors. Following systemic administration, ZN-dICG accumulated in tumors of xenograft-bearing mice for imaging primary and metastatic tumors, and induced tumor ablation under laser irradiation. The discovery of ZN-dICG would contribute to the design of translational phototheranostic platform with high biocompatibility. Statement of significanceIndocyanine green (ICG) has been extensively studied as a phototheranostic agent that combines imaging with phototherapies, but it suffers from rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here, we report a strategy to construct ICG dimers (ICG-tk-ICG) by conjugating two ICG molecules via a thioketal bond, which can self-assemble into zwitterionic nanoparticles (ZN-dICG) at ultralow critical micelle concentrations, exhibiting superior photothermal and photodynamic properties over ICG. ZN-dICG responds to the over-generated ROS in tumors and dissociates to restore the NIR fluorescence of ICG, enhancing the sensitivity via albumin binding for low-background imaging of tumors. This study offers a supramolecular strategy that may potentiate the clinical translation of ICG in imaging-guided cancer phototherapy.

Structure of ZnxFe3−xO4 nanoparticles studied by neutron diffraction and its relation with their response in magnetic hyperthermia experiments

The mixed zinc-ferrite spinel magnetic nanoparticles (MNPs) with the general formula ZnxFe3−xO4 are among the most extensively studied families of Fe oxides due to their interesting and diverse chemical, electronic, and magnetic properties. These systems offer the possibility of surface functionalization and possess high biocompatibility, making them highly attractive for applications in biomedicine, such as magnetic fluid hyperthermia (MFH). The efficiency of the MFH process relies on the magnetic, structural and morphological properties of the MNPs. The substitution with the Zn ion and the cationic distribution, as well as the synthesis process employed, have a direct impact on the final properties of these oxides. Therefore, it is essential to have tools that enable a comprehensive characterization of the system to assess its performance in MFH. In this study, we have synthesized four ZnxFe3−xO4 MNP systems using three different methods: two by thermal decomposition at high temperatures, one by co-precipitation, and another by co-precipitation followed by ball milling. We analyze the effect of these various synthesis processes on the magnetic and crystallographic properties, aiming to correlate them with the response of each system in MFH. Neutron diffraction data are employed to determine the cation site occupation and to investigate the correlation with the synthesis method. MFH measurements were conducted in media of diverse viscosities, revealing different values of specific loss power, thus demonstrating a clear dependence on the synthesis process and Zn content.

Facile fabrication of fluorescent composite sensor based on carbon dots/ mesoporous silica nanospheres for sensitive detection of Hg(II) in cells

Mercury ion (Hg(II)) is one of the most toxic heavy metals in the environment and has seriously damaged human health. Based on this, we designed a novel fluorescence-enhanced carbon dots/mesoporous silica fluorescent composite (CDs/MSNs) fluorescent composite sensor for rapid and sensitive detection of Hg(II) in environmental and biological systems. Carbon dots (CDs) are one of the most promising carbon-based nanomaterials of the new generation, and we chose them as template molecules, and CDs were embedded in mesoporous silica nanospheres (MSNs) by hydrothermal method to form CDs/MSNs fluorescent composite with aggregation-induced emission enhancement (AIEE). Notably, the CDs/MSNs fluorescent composite has a yellow luminescence with a photoluminescence intensity several times higher than the original one, and have high stability, excellent selectivity, and good biocompatibility, which can realize the selective and sensitive detection of Hg(II) in the environment, with a limit of detection as low as 0.89 μM. The material can also be used as an effective luminescent biological probe for the detection of Hg(II) in cells. and these properties provide long-term practical applications of CDs/MSNs fluorescent composite in the fields of biological detection.

In Situ Gelation Strategy for Efficient Drug Delivery in a Gastrointestinal System.

Developing a microenvironment-responsive drug delivery system (DDS) for the gastrointestinal system is of great interest to enhance drug efficiency and minimize side effects. Unfortunately, the rapid-flowing digestive juice in the gastrointestinal tract and the continuous contraction and peristalsis of the gastrointestinal tract muscle accelerate the elimination of drug carriers. In this study, a boric hydroxyl-modified mesoporous Mg(OH)2 drug carrier is prepared to prolong the drug retention time. Results show that the newly designed DDS presents high biocompatibility and can immediately turn the free polyhydric alcohol molecules into a gelation form. The in situ-formed gelation network presents high viscosity and can prevent the drug carriers from being washed away by the digestive juice in the gastrointestinal tract.

Development of a composite using calcined bone powder and silane cross-linked alginate as bone substitute material.

Calcined bone is an attractive natural material for use as a bone substitute because of its cost-effectiveness and high biocompatibility, which are comparable to that of synthetic hydroxyapatite. However, the calcination process has significantly weakened the mechanical properties. In this study, a composite of calcined bovine bone powder reinforced with silane cross-linked alginate was prepared to assess its biocompatibility, osteoconductivity, and mechanical compatibility as a bone substitute material. Culture studies with osteoblast-like cells (MC3T3-E1) showed no cytotoxicity toward the composite and exhibited general cell proliferative properties in its presence. In contrast, the composite reduced the alkaline phosphatase activity of osteoblasts but led to significant noncellular apatite deposition on the surface. In addition, quasi-static compression tests of the composite revealed mechanical properties comparable to those of human cancellous bone. The mechanical properties remained stable under wet conditions and did not deteriorate significantly even after 2 weeks of immersion in simulated body fluid at 37°C. The results show that this composite, composed of calcined bone powder and silane cross-linked alginate, is a promising bone substitute material with biocompatibility, osteoconductivity, and mechanical compatibility.

The Horizons of Medical Mineralogy: Structure-Bioactivity Relationship and Biomedical Applications of Halloysite Nanoclay.

Medical mineralogy explores the interactions between natural minerals and living organisms such as cells, tissues, and organs and develops therapeutic and diagnostic applications in drug delivery, medical devices, and healthcare materials. Many minerals (especially clays) have been recognized for pharmacological activities and therapeutic potential. Halloysite clay (Chinese medicine name: Chishizhi), manifested as one-dimensional aluminum silicate nanotubes (halloysite nanotubes, HNTs), has gained applications in hemostasis, wound repair, gastrointestinal diseases, tissue engineering, detection and sensing, cosmetics, and daily chemicals formulations. Various biomedical applications of HNTs are derived from hollow tubular structures, high mechanical strength, good biocompatibility, bioactivity, and unique surface characteristics. This natural nanomaterial is safe, abundantly available, and may be processed with environmentally safe green chemistry methods. This review describes the structure and physicochemical properties of HNTs relative to bioactivity. We discuss surface area, porosity and surface defects, hydrophilicity, heterogeneity and charge of external and internal surfaces, as well as biosafety. The paper provides comprehensive guidance for the development of this tubule nanoclay and its advanced biomedical applications for clinical diagnosis and therapy.

In situ shaping of intricated 3D bacterial cellulose constructs using sacrificial agarose and diverted oxygen inflow

Bacterial cellulose (BC) is gathering increased attention due to its remarkable physico-chemical features. The high biocompatibility, hydrophilicity, and mechanical and thermal stability endorse BC as a suitable candidate for biomedical applications. Nonetheless, exploiting BC for tissue regeneration demands three-dimensional, intricately shaped implants, a highly ambitious endeavor. This challenge is addressed here by growing BC within a sacrificial viscoelastic medium consisting of an agarose gel cast inside polydimethylsiloxane (PDMS) molds imprinted with the features of the desired implant. BC produced with and without agarose has been compared through SEM, TGA, FTIR, and XRD, probing the mild impact of the agarose on the BC properties. As a first proof of concept, a PDMS mold shaped as a doll's ear was used to produce a BC perfect replica, even for the smallest features. The second trial comprised a doll face imprinted on a PDMS mold. In that case, the BC production included consecutive deactivation and activation of the aerial oxygen stream. The resulting BC face clone fitted perfectly and conformally with the template doll face, while its rheological properties were comparable to those of collagen. This streamlining concept conveys to the biosynthesized nanocelluloses broader opportunities for more advanced prosthetics and soft tissue engineering uses.

Highly Biocompatible Graphite Electrodes by Using Interface‐Stable Coating and the Application to Hemodialysis

AbstractIn the treatment of kidney diseases such as chronic kidney disease (CKD) and acute tubular necrosis (ATN), prolonged contact between conductivity sensors and patients' bodily fluids is required, necessitating high biocompatibility for the electrodes. However, the widely used graphite electrodes exhibit limited biocompatibility, showing a cell survival rate of only 88% under indirect contact conditions, and <56% under direct contact conditions. Here, the surface detachment of graphite electrodes in liquid environments leading to cell death upon contact is observed and a solution is proposed to enhance biocompatibility and ensure conductivity, by forming a layer of interface‐stable coating (ISC) as a conductive isolation membrane on their surface. For applications with contact requirements, graphite‐like carbon (GLC) coated graphite electrodes are investigated and developed, resulting in an exceptional cell survival rate exceeding 96% under indirect contact conditions, and a relatively high survival rate exceeding 91% under direct contact conditions, both accompanied by significant proliferation. GLC‐coated graphite electrodes are successfully to monitor the dialysate conductivity in a hemodialysis machine and achieve stable monitoring with temperature compensation. The results demonstrate ISC graphite electrodes' potential in biomedical fluid monitoring, with the developed process applicable to other fields.

Core-Shell Gel Nanofiber Scaffolds Constructed by Microfluidic Spinning toward Wound Repair and Tissue Regeneration.

Growing demand for wound care resulting from the increasing chronic diseases and trauma brings intense pressure to global medical health service system. Artificial skin provides mechanical and microenvironmental support for wound, which is crucial in wound healing and tissue regeneration. However, challenges still remain in the clinical application of artificial skin since the lack of the synergy effect of necessary performance. In this study, a multi-functional artificial skin is fabricated through microfluidic spinning technology by using core-shell gel nanofiber scaffolds (NFSs). This strategy can precisely manipulate the microstructure of artificial skin under microscale. The as-prepared artificial skin demonstrates superior characteristics including surface wettability, breathability, high mechanical strength, strain sensitivity, biocompatibility and biodegradability. Notably, this artificial skin has the capability to deliver medications in a controlled and sustained manner, thereby accelerating the wound healing process. This innovative approach paves the way for the development of a new generation of artificial skin and introduces a novel concept for the structural design of the unique core-shell gel NFSs.

A highly sensitive and specific fluorescent probe for detecting ONOO– in liver-injured cells and tissues

The liver is a vital organ in the human body that performs important physiological functions. During the damage process, the liver produces a large amount of ONOO–, which is difficult to directly capture and detect in the physiological environment. Therefore, this work introduced the design and synthesis of HN-ONOO, a novel naphthylimide-based fluorescent probe, aiming to dynamically monitor the changes of ONOO– during liver damage. HN-ONOO demonstrated a stable response to ONOO–, achieving quantitative detection. Since the high biocompatibility of HN-ONOO, we observed different degrees of up-regulation of ONOO– in the liver inflammation damage, alcohol damage, drug damage, fat accumulation model, and mice drug-damaged livers. These results suggest that HN-ONOO can recognize and detect the liver injury marker ONOO–. In addition, HN-ONOO, as a powerful tool for early detection of liver damage and detoxification research, provides a new approach for related research.

Regulated anthocyanin release through novel pH-responsive peptide hydrogels in simulated digestive environment

The instability of anthocyanins significantly reduces their bioavailability as food nutrients. This proof-of-concept study aimed to develop efficient carriers for anthocyanins to overcome this challenge. Characterization of the hydrogels via SEM (scanning electron microscope) and rheological analysis revealed the formation of typical gel structures. MTT (methyl thiazolyl tetrazolium) and hemolysis assays confirmed that their high biocompatibility. Encapsulation efficiency analysis and fluorescence microscopy images demonstrated successful and efficient encapsulation of anthocyanins by pH-responsive hydrogels. Stability studies further validated the effect of peptide hydrogels in helping anthocyanin molecules withstand factors such as gastric acid, high temperatures, and heavy metals. Subsequently, responsive studies in simulated gastric (intestinal) fluid demonstrated that the pH-responsive peptide hydrogels could protect anthocyanin molecules from gastric acid while achieving rapid and complete release in intestinal fluid environments. These results indicate that these peptide hydrogels could stabilize anthocyanins and facilitate their controlled release, potentially leading to personalized delivery systems.

Delivery of mRNA Using Biomimetic Vectors: Progress and Challenges.

Messenger RNA (mRNA) is an emerging class of therapeutic agents for treating a wide range of diseases. However, due to the instability and low cell transfection rate of naked mRNA, the expression of delivered mRNA in target cells or tissues in vivo requires delivery strategies. Biomimetic vectors hold advantages such as high biocompatibility, tissue specific targeting ability and efficient delivery mechanisms, potentially overcoming challenges faced by other delivery vectors. In this review, biomimetic vector-based mRNA delivery systems are summarized and discuss the possible challenges and prospects of such delivery systems, which may contribute to the progress and application of mRNA-based therapy in the biomedical field.

Variations of chemical, physical, mechanical properties, and biological and antimicrobial effectiveness of Ti alloys by coating with CaP doped with different amounts of Zn via micro-arc oxidation (MAO) technique

Titanium alloys are preferred metals as implant materials due to their advantageous combination of low density and high biocompatibility. However, the augmentation of implant surfaces with calcium-based coatings becomes essential to regulate corrosion rates and enhance the osteoconductive properties of the implant material. In this study, titanium alloys, specifically Ti6Al4V, underwent a transformative process wherein they were coated with calcium phosphate (CaP) ceramics doped with zinc (Zn) via micro-arc oxidation (MAO) technique, using varying concentrations of Zn compound in the electrolyte solutions. The chemical and physical properties of the freshly prepared samples were analyzed, both initially and after culturing them with Saos-2 cells. Furthermore, the antimicrobial efficacy against E. coli was examined. The findings unveiled the remarkable efficiency of the MAO technique in forming an uniformly distributed coat on Ti6Al4V, thereby enhancing its mechanical resilience and biocompatibility, depending upon the preparation parameters employed. It was shown that Zn doped calcium coating is very efficient to regulate various parameters such as corrosion rate and mechanical strength, and an increase in Zn content exhibited a favorable impact on cell attachment and antimicrobial efficacy. Surface modification of metallic implants via MAO technique can be applied in the production of advanced implant materials.

Bacterial-Infection-Triggered Release of Antibacterial Aldehyde from Triblock Copolyether Hydrogels.

Bacterial infections pose a significant threat to public health worldwide. Hydrogel-based biomaterials have proven to be particularly useful in addressing persistent bacterial infections due to their stimuli-responsive degradability, high biocompatibility, ability to release antibacterial agents on demand, and long-lasting antibacterial activity. Herein, we fabricated ABA-type triblock copolyether hydrogels, wherein, hexanal, a bioactive aldehyde with antibacterial activity, was affixed to the hydrophobic micellar core via acetal linkage. The hydrogel exhibited degradation under acidic environment via the hydrolysis of acetal linkages, leading to the concomitant release of hexanal to exhibit highly potent bactericidal activity against both Escherichia coli and Staphylococcus aureus. Furthermore, a dual-mode release of the model therapeutic agent Nile Red from the hydrophobic micellar core of the hydrogel in conjunction with hexanal was demonstrated using this system. We anticipate that this study will provide a new platform for the development of hydrogels with tailorable release profiles for biologically active compounds that are activated by the acidification triggered by bacterial infection.

A Review on Soft Ionic Touch Point Sensors

A touch sensor is an essential component in meeting the growing demand for human‐machine interfaces. These sensors have been developed in wearable, attachable, and even implantable forms to acquire a wide range of information from humans. To be applied to the human body, sensors are required to be biocompatible and not restrict the natural movement of the body. Ionic materials are a promising candidate for soft touch sensors due to their outstanding properties, which include high stretchability, transparency, ionic conductivity, and biocompatibility. Here, this review discusses the unique features of soft ionic touch point sensors, focusing on the ionic material and its key role in the sensor. The touch sensing mechanisms include piezocapacitive, piezoresistive, surface capacitive, piezoelectric, and triboelectric and triboresistive sensing. This review analyzes the implementation hurdles and future research directions of the soft ionic touch sensors for their transformative potential.

A low fouling and high biocompatibility electrochemical sensor based on the electrospun gelatin‐PLGA‐CNTs nanofibers for dopamine detection in blood

AbstractThe ability to fabricate resisting nonspecific protein adsorption electrochemical sensor capable of high biocompatibility in vivo will undoubtedly underpin key future developments in life sciences. Herein, a gelatin‐poly(lactide‐co‐glycolide)‐carbon nanotubes nanofibers‐membrane in three‐dimensional porous structure without any chemical crosslinking is constructed on the carbon fiber microelectrode (e‐Gelatin‐PLGA‐CNTs/CFME) using a one‐step electrospinning technology. The nanofibers‐membrane still presents good three‐dimensional porous structure and excellent hydrophily after implantation in BSA solution. In addition, the dopamine hydrochloride (DA) sensitivity at e‐Gelatin‐PLGA‐CNTs/CFME after implantation in human blood samples exhibits almost the same as preimplantation (91% ± 9%, n = 3). Importantly, the nanofibers‐membrane possesses fast cell proliferation and a low hemolysis rate (2.27% ± 0.76%), satisfying the required biocompatibility as a constructed material for the detection in vivo. The constructed micro‐electrochemical sensor realizes the detection of DA in human blood samples. Consequently, this strategy offers a new and facile platform for the development of implanted electrochemical sensor.

Fabrication of Nanocatalytic Medicine from Self-Assembling Peptides Containing an ATCUN-Like Copper-Binding Motif for Anticancer Therapy.

Development of nanomaterials with multiple enzymatic activities via a facile approach receives growing interests in recent years. Although peptide self-assembling provides an effective approach for the construction of biomimetic materials in recent years, fabrication of artificial enzymes from self-assembling peptides with multiple catalytic activities for anticancer therapy is still a challenge. Here, we report a simple method to prepare nanocatalysts with multienzyme-like activities from self-assembling peptides containing ATCUN copper-binding motifs. With the aid of the coordination interactions between the ATCUN motif and Cu(II) ions, these peptides could perform supramolecular self-assembly to form nanomaterials with biomimetic peroxidase, ascorbate oxidase and glutathione peroxidase activities. Moreover, these trienzyme-like effects can elevate oxidative stress levels and suppress the antioxidative capability of cancer cells, which synergistically induce the apoptosis of cancer cells. Because of the high biocompatibility, catalytic activities and drug encapsulation properties, this self-assembled peptide provides a biomimetic platform for the development of new nanocatalytic medicines for multimodal synergistic cancer therapies.

Isolation and Characterization of Milk Exosomes for Use in Advanced Therapies.

Exosomes are cell-derived extracellular vesicles (EVs) with diameters between 30 and 120 nm. In recent years, several studies have evaluated the therapeutic potential of exosomes derived from different fluids due to their low immunogenicity and high biocompatibility. However, producing exosomes on a large scale is still challenging. One of the fluids from which they could be isolated in large quantities is milk. Moreover, regeneration is a well-known property of milk. The present work seeks to optimize a method for isolating exosomes from bovine and human milk, comparing different storage conditions and different extraction protocols. We found differences in the yield extraction associated with pre-storage milk conditions and observed some differences according to the processing agent. When we removed milk fat globules and added rennet before freezing, we obtained a cleaner final fraction. In summary, we attempted to optimize a rennet-based new milk-exosome isolation method and concluded that pre-treatment, followed by freezing of samples, yielded the best exosome population.

Biofabrication of TiO2 nanoparticles via Aspergillus niger DS22 supernatant: bioreactor optimization and multi-activity profiling

AbstractThe study presents a safe and eco-friendly green synthesis of titanium dioxide nanoparticles (TiO2 NPs) using Aspergillus niger DS22 (ON076463.1) cell-free filtrate, focusing on optimizing factors affecting nitrate reductase enzyme production within the framework TiO2 NP biosynthesis. Maximum enzyme activity was accomplished by growing A. niger DS22 in a modified MYGP medium at pH 6, 0.5% peptone, 0.15% yeast extract, 0.25% KNO3, 2% glucose, and 200 rpm for 4 days at 30 °C. Statistical optimization takes place, where a central composite design was employed for testing the reaction variables. The individual and interactive effects of process variables lead to optimal biosynthesis conditions with 10−4 M (K2TiF6) concentration, for 96 h, 28 °C, pH 9, and Ti+4 salt solution:filtrate ratio (10%, v/v). Kinetic conversion rates in 1-L shake flask and 10-L stirred tank bioreactor were calculated and compared. Current findings revealed that the yield coefficient of biomass dry weight (Yx/s) and the yield coefficient of TiO2 NP dry weight (Y pn/s) in the bioreactor exceed those of the shake flask (0.85 g/L and 0.51 g/L; 0.04 g/L and 0.11 g/L, respectively). TiO2 NPs showed anticancer activities with high biocompatibility (at 1000 µg/mL) against MCF-7 and HepG-2 cell lines, with 97.35% and 97.71% cytotoxicity, respectively. TiO2 NPs had a moderate antioxidant activity of 57.8% recorded by DPPH assay. Moreover, TiO2 NPs had anticoagulant activities and decolorization efficiency for methyl orange dye. The current study paves the way for maximizing TiO2 NP production, which can be used in industrial and medical sectors. Graphical Abstract