Multiple Biomedical Applications Research Articles

Programmable Shape Morphing Metasponge

Smart materials respond to environmental signals by changing their microstructure and physical properties. Programming multiple behaviors and functions into a single material could increase its utility and adaptability to ever‐changing environmental conditions. A swellable and stretchable metamaterial hydrogel or “metasponge” engineered to morph into customized sizes and shapes that dynamically tune its physical properties and functions is reported. Multiple case studies that take advantage of the morphing properties of the metasponge, including robotic actuation, light guidance, optical and sonic invisibility (“cloaking”), adaptation of propulsion mode, sampling, and multiple biomedical applications, are illustrated. Developing multifunctional smart materials in which logic is programmed into the materials rather than electronic components could pave a new path to autonomy and dynamic responses in soft robots, sensors, and actuators.

Photothermal therapy of papillary thyroid cancer tumor xenografts with targeted thyroid stimulating hormone receptor antibody functionalized multiwalled carbon nanotubes

Multiwalled carbon nanotubes (MWCNTs) are being widely investigated in multiple biomedical applications including, and not limited to, drug delivery, gene therapy, imaging, biosensing, and tissue engineering. Their large surface area and aspect ratio in addition to their unique structural, optical properties, and thermal conductivity also make them potent candidates for novel hyperthermia therapy. Here we introduce thyroid hormone stimulating receptor (TSHR) antibody–conjugate–MWCNT formulation as an enhanced tumor targeting and light-absorbing device for the photoablation of xenografted BCPAP papillary thyroid cancer tumors. To ensure successful photothermal tumor ablation, we determined three key criteria that needed to be addressed: (1) predictive pre-operational modeling; (2) real-time monitoring of the tumor ablation process; and (3) post-operational follow-up to assess the efficacy and ensure complete response with minimal side effects. A COMSOL-based model of spatial temperature distributions of MWCNTs upon selected laser irradiation of the tumor was prepared to accurately predict the internal tumor temperature. This modeling ensured that 4.5W of total laser power delivered over 2 min, would cause an increase of tumor temperature above 45 ℃, and be needed to completely ablate the tumor while minimizing the damage to neighboring tissues. Experimentally, our temperature monitoring results were in line with our predictive modeling, with effective tumor photoablation leading to a significantly reduced post 5-week tumor recurrence using the TSHR-targeted MWCNTs. Ultimately, the results from this study support a utility for photosensitive biologically modified MWCNTs as a cancer therapeutic modality. Further studies will assist with the transition of photothermal therapy from preclinical studies to clinical evaluations.

A Soft Landing Approach for the Centrifugal Microgel Synthesis Process

Centrifugal microencapsulation has been shown to be a promising encapsulation technique, satisfying at the same time many requirements needed for biomedical applications (monodispersity, controlled size, spherical shape, sterile production environment) and allowing a high capsules production rate, using only conventional lab material. Another important advantage of this technology is the ability to process highly viscous biopolymer solutions. The usage of such solutions is desirable in multiple biomedical applications, because they yield capsules with improved mechanical properties (stiffness and yield strength) and with optimised porosity, which increases the immunoprotection in the case of biomaterial encapsulation applied to cell therapy and enhances a prolonged dissolution behaviour in the case of drug delivery applications. However, previous studies have shown that spherical capsules cannot be obtained using highly viscous solutions, and a capsule tail is always present when such solutions are used. This represents a significant limitation of this technology, since capsule shape regularity is an important requirement for various biomedical applications (e.g. cell therapy implants, drug delivery). In this article we propose and validate experimentally an adaptation of the centrifugal microencapsulation, based on the concept of “soft landing” [1]. This technique allows the production of ellipsoidal and spherical capsules using very viscous (typically up to several tens of Pa.s) biopolymer solutions.

Unveiling the Assembly of Neutral Marine Polysaccharides into Electrostatic-Driven Layer-by-Layer Bioassemblies by Chemical Functionalization

Marine-origin polysaccharides, in particular cationic and anionic ones, have been widely explored as building blocks in fully natural or hybrid electrostatic-driven Layer-by-Layer (LbL) assemblies for bioapplications. However, the low chemical versatility imparted by neutral polysaccharides has been limiting their assembly into LbL biodevices, despite their wide availability in sources such as the marine environment, easy functionality, and very appealing features for addressing multiple biomedical and biotechnological applications. In this work, we report the chemical functionalization of laminarin (LAM) and pullulan (PUL) marine polysaccharides with peptides bearing either six lysine (K6) or aspartic acid (D6) amino acids via Cu(I)-catalyzed azide-alkyne cycloaddition to synthesize positively and negatively charged polysaccharide-peptide conjugates. The successful conjugation of the peptides into the polysaccharide's backbone was confirmed by proton nuclear magnetic resonance and attenuated total reflectance Fourier-transform infrared spectroscopy, and the positive and negative charges of the LAM-K6/PUL-K6 and LAM-D6/PUL-D6 conjugates, respectively, were assessed by zeta-potential measurements. The electrostatic-driven LbL build-up of either the LAM-D6/LAM-K6 or PUL-D6/PUL-K6 multilayered thin film was monitored in situ by quartz crystal microbalance with dissipation monitoring, revealing the successful multilayered film growth and the enhanced stability of the PUL-based film. The construction of the PUL-peptide multilayered thin film was also assessed by scanning electron microscopy and its biocompatibility was demonstrated in vitro towards L929 mouse fibroblasts. The herein proposed approach could enable the inclusion of virtually any kind of small molecules in the multilayered assemblies, including bioactive moieties, and be translated into more convoluted structures of any size and geometry, thus extending the usefulness of neutral polysaccharides and opening new avenues in the biomedical field, including in controlled drug/therapeutics delivery, tissue engineering, and regenerative medicine strategies.

Tet-Regulated Expression and Optical Clearing for In Vivo Visualization of Genetically Encoded Chimeric dCas9/Fluorescent Protein Probes.

The catalytically inactive mutant of Cas9 (dCas9) endonuclease has multiple biomedical applications, with the most useful being the activation/repression of transcription. dCas9 family members are also emerging as potential experimental tools for gene mapping at the level of individual live cells and intact tissue. We performed initial testing on a set of tools for Cas9-mediated visualization of nuclear compartments. We investigated doxycycline (Dox)-inducible (Tet-On) intracellular distribution of constructs encoding dCas9 orthologs from St. thermophilus (St) and N. meningitides (Nm) fused with EGFP and mCherry fluorescent proteins (FP) in human A549 cells. We also studied time-dependent expression of these chimeric fluorescent constructs (dCas9-FP) after Tet-On induction in live cells and compared it with the time course of dCas9-FP expression in experimental dCas9-FP-expressing tumor xenografts using a combination of fluorescence imaging and in vivo contrast-assisted magnetic resonance imaging for assessing the extent of tumor perfusion. In vivo Dox-induction of mCherry-chimera expression occurred in tumor xenografts as early as 24 h post-induction and was visualized by using optical clearing (OC) of the skin. OC via topical application of gadobutrol enabled high-contrast imaging of FP expression in tumor xenografts due to a 1.1-1.2-fold increase in FI in both the red and green channels.

18F-fluorodeoxyglucose (18F-FDG) Functionalized Gold Nanoparticles (GNPs) for Plasmonic Photothermal Ablation of Cancer: A Review.

The meeting and merging between innovative nanotechnological systems, such as nanoparticles, and the persistent need to outperform diagnostic-therapeutic approaches to fighting cancer are revolutionizing the medical research scenario, leading us into the world of nanomedicine. Photothermal therapy (PTT) is a non-invasive thermo-ablative treatment in which cellular hyperthermia is generated through the interaction of near-infrared light with light-to-heat converter entities, such as gold nanoparticles (GNPs). GNPs have great potential to improve recovery time, cure complexity, and time spent on the treatment of specific types of cancer. The development of gold nanostructures for photothermal efficacy and target selectivity ensures effective and deep tissue-penetrating PTT with fewer worries about adverse effects from nonspecific distributions. Regardless of the thriving research recorded in the last decade regarding the multiple biomedical applications of nanoparticles and, in particular, their conjugation with drugs, few works have been completed regarding the possibility of combining GNPs with the cancer-targeted pharmaceutical fluorodeoxyglucose (FDG). This review aims to provide an actual scenario on the application of functionalized GNP-mediated PTT for cancer ablation purposes, regarding the opportunity given by the 18F-fluorodeoxyglucose (18F-FDG) functionalization.

Supramolecular presentation of bioinstructive peptides on soft multilayered nanobiomaterials stimulates neurite outgrowth.

Peptide amphiphiles (PAs) have emerged as effective molecular building blocks for creating self-assembling nanobiomaterials for multiple biomedical applications. Herein, we report a straightforward approach to assemble soft bioinstructive platforms to recreate the native neural extracellular matrix (ECM) aiming for neuronal regeneration based on the electrostatic-driven supramolecular presentation of laminin-derived IKVAV-containing self-assembling PA (IKVAV-PA) on biocompatible multilayered nanoassemblies. Spectroscopic and microscopic techniques show that the co-assembly of positively charged low-molecular-weight IKVAV-PA with oppositely charged high-molecular-weight hyaluronic acid (HA) triggers the formation of ordered β-sheet structures denoting a one-dimensional nanofibrous network. The successful functionalization of poly(L-lysine)/HA layer-by-layer nanofilms with an outer positively charged layer of self-assembling IKVAV-PA is demonstrated by the quartz crystal microbalance with dissipation monitoring and the nanofibrous morphological properties revealed by atomic force microscopy. The bioactive ECM-mimetic supramolecular nanofilms promote the enhancement of primary neuronal cells' adhesion, viability, and morphology when compared to the PA without the IKVAV sequence and PA-free biopolymeric multilayered nanofilms, and stimulate neurite outgrowth. The nanofilms hold great promise as bioinstructive platforms for enabling the assembly of customized and robust multicomponent supramolecular biomaterials for neural tissue regeneration.

In vitro and in vivo acute toxicity of a novel citrate-coated magnetite nanoparticle.

Magnetic nanoparticles (MNps) have become powerful tools for multiple biomedical applications such as hyperthermia drivers, magnetic resonance imaging (MRI) vectors, as well as drug-delivery systems. However, their toxic effects on human health have not yet been fully elucidated, especially in view of their great diversity of surface modifications and functionalizations. Citrate-coating of MNps often results in increased hydrophilicity, which may positively impact their performance as drug-delivery systems. Nonetheless, the consequences on the intrinsic toxicity of such MNps are unpredictable. Herein, novel magnetite (Fe3O4) nanoparticles covered with citrate were synthesized and their potential intrinsic acute toxic effects were investigated using in vitro and in vivo models. The proposed synthetic pathway turned out to be simple, quick, inexpensive, and reproducible. Concerning toxicity risk assessment, these citrate-coated iron oxide nanoparticles (IONps) did not affect the in vitro viability of different cell lines (HaCaT and HepG2). Moreover, the in vivo acute dose assay (OECD test guideline #425) showed no alterations in clinical parameters, relevant biochemical variables, or morphological aspects of vital organs (such as brain, liver, lung and kidney). Iron concentrations were slightly increased in the liver, as shown by Graphite Furnace Atomic Absorption Spectrometry and Perls Prussian Blue Staining assays, but this finding was considered non-adverse, given the absence of accompanying functional/clinical repercussions. In conclusion, this study reports on the development of a simple, fast and reproducible method to obtain citrate-coated IONps with promising safety features, which may be used as a drug nanodelivery system in the short run. (263 words).

A review on electrospun nanofibers for multiple biomedical applications

AbstractElectrospinning is a well‐known technique since 1544 to fabricate nanofibers using different materials like polymers, metals oxides, proteins, and many more. In recent years, electrospinning has become the most popular technique for manufacturing nanofibers due to its ease of use and economic viability. Nanofibers have remarkable properties like high surface‐to‐volume ratio, variable pore size distribution (10–100 nm), high porosity, low density, and are suitable for surface functionalization. Therefore, electrospun nanofibers have been utilized for numerous applications in the pharmaceutical and biomedical field like tissue engineering, scaffolds, grafts, drug delivery, and so on. In this review article, we will be focusing on the versatility, current scenario, and future endeavors of electrospun nanofibers for various biomedical applications. This review discusses the properties of nanofibers, the background of the electrospinning technique, and its emergence in chronological order. It also covers the various types of electrospinning methods and their mechanism, further elaborating the factors affecting the properties of nanofibers, and applications in tissue engineering, drug delivery, nanofibers as biosensor, skin cancer treatment, and magnetic nanofibers.

Apoptotic bodies for advanced drug delivery and therapy.

Extracellular vesicles (EVs) have emerged as promising candidates for multiple biomedical applications. Major types of EVs include exosomes, microvesicles, and apoptotic bodies (ABs). ABs are conferred most properties from parent cells in the final stages of apoptosis. A wide variety of sources and stable morphological features are endowed to ABs by the rigorous apoptotic program. ABs accommodate more functional biomolecules by relying on the larger volume and maintaining their naturalness in circulation. The predominant body surface ratio of ABs facilitates their recognition by recipient cells and is advantageous for interactions with microenvironments. ABs can modulate and alleviate symptoms of numerous diseases for their origins, circulation, and high biocompatibility. In addition, ABs have been emerging in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. Here, we aim to present a thorough discussion on current knowledge about ABs. Of particular interest, we will summarize the application of AB-based strategies for diagnosis and disease therapy. Perspectives for the development of ABs in biomedical applications are highlighted.

Catch bond-inspired hydrogels with repeatable and loading rate-sensitive specific adhesion.

Biological receptor-ligand adhesion governed by mammalian cells involves a series of mechanochemical processes that can realize reversible, loading rate-dependent specific interfacial bonding, and even exhibit a counterintuitive behavior called catch bonds that tend to have much longer lifetimes when larger pulling forces are applied. Inspired by these catch bonds, we designed a hydrogen bonding-meditated hydrogel made from acrylic acid-N-acryloyl glycinamide (AA-NAGA) copolymers and tannic acids (TA), which formed repeatable specific adhesion to polar surfaces in an ultra-fast and robust way, but hardly adhered to nonpolar materials. It demonstrated up to five-fold increase in shear adhesive strength and interfacial adhesive toughness with external loading rates varying from 5 to 500 mm min−1. With a mechanochemical coupling model based on Monte Carlo simulations, we quantitatively revealed the nonlinear dependence of rate-sensitive interfacial adhesion on external loading, which was in good agreement with the experimental data. Likewise, the developed hydrogels were biocompatible, possessed antioxidant and antibacterial properties and promoted wound healing. This work not only reports a stimuli-responsive hydrogel adhesive suitable for multiple biomedical applications, but also offers an innovative strategy for bionic designs of smart hydrogels with loading rate-sensitive specific adhesion for various emerging areas including flexible electronics and soft robotics.

Polydopamine nanocomposites and their biomedical applications: A review

AbstractPolydopamine (PDA) is the end product of the dopamine monomer's self‐oxidation polymerization process. PDA is gaining popularity in diagnostic and therapeutic purposes because of its unique properties like excellent biocompatibility, biodegradability, surface functionalization, adhesion, and photothermal, which can help in various biomedical applications. Many researchers have been working on polydopamine nanocomposites in recent years. PDA has been used to modify various structures, such as metal nanoparticles, in order to improve the nanosystem's stability and applicability. This review attempts to cover extremely recent works from 2018 to the present in light of recent developments in PDA nanocomposites. The development of novel PDA nanocomposites for therapeutic applications, such as PDA‐metal, PDA‐drug, PDA‐photosensitizers, and PDA‐biomolecules, has been covered in this review. The multiple biomedical applications highlighted in this review include the treatment of cancer, antimicrobial infections, and neurological disorders, as well as wound healing and biosensing. This review will not only help the new researcher to build their base but also for experts to extend their views in this field.

Biologically Synthesized Silver Nanoparticles and Their Diverse Applications.

Nanotechnology has become the most effective and rapidly developing field in the area of material science, and silver nanoparticles (AgNPs) are of leading interest because of their smaller size, larger surface area, and multiple applications. The use of plant sources as reducing agents in the fabrication of silver nanoparticles is most attractive due to the cheaper and less time-consuming process for synthesis. Furthermore, the tremendous attention of AgNPs in scientific fields is due to their multiple biomedical applications such as antibacterial, anticancer, and anti-inflammatory activities, and they could be used for clean environment applications. In this review, we briefly describe the types of nanoparticle syntheses and various applications of AgNPs, including antibacterial, anticancer, and larvicidal applications and photocatalytic dye degradation. It will be helpful to the extent of a better understanding of the studies of biological synthesis of AgNPs and their multiple uses.

Real-time fluorescence dynamics in one-step synthesis of gold nanoclusters coupling with peptide motifs

The molecule-like electronic structure endows gold nanoclusters (AuNCs) a most intriguing property, fluorescence, thereby AuNCs offer a great potential for biomedical applications. Recent efforts to improve the fluorescence of AuNCs mainly focus on tailoring size, structure and chemical environments. Herein, with the help of molecular dynamics simulation, we designed tyrosine-containing peptide motifs as the reducing agents, protecting ligands to synthesis P (peptide)-AuNCs in one-step reaction, which was developed to real-time monitor the fluorescence evolution of P-AuNCs. P-AuNCs with a quantum yield of ∼ 18 % were synthesized and further demonstrated for multiple biomedical applications, such as sensing of temperature (10–55 ℃) and metal ions (with a limit of detection of 5 nM for Hg2+), as well as cell labeling and imaging. With the excellent biocompatibility, wide spectral range and potential capacity for bio-recognition, this study provides a useful one-step synthesis strategy for screening out peptide motifs to real-time modulate the optical properties of peptide-containing hybrid nanomaterials.

Correlating Magnetic Hyperthermia and Magnetic Resonance Imaging Contrast Performance of Cubic Iron Oxide Nanoparticles with Crystal Structural Integrity.

Magnetic iron oxide nanoparticles have multiple biomedical applications in AC-field hyperthermia and magnetic resonance imaging (MRI) contrast enhancement. Here, two cubic particle suspensions are analyzed in detail, one suspension displayed strong magnetic heating and MRI contrast efficacies, while the other responded weakly. This is despite them having almost identical size, morphology, and colloidal dispersion. Aberration-corrected scanning transmission electron microscopy, electron energy loss spectroscopy, and high-resolution transmission electron microscopy analysis confirmed that the spinel phase Fe3O4 was present in both samples and identified prominent crystal lattice defects for the weakly responding one. These are interpreted as frustrating the orientation of the moment within the cubic crystals. The relationship between crystal integrity and the moment magnitude and dynamics is elucidated for the case of fully dispersed single nanocubes, and its connection with the emergent hyperthermia and MRI contrast responses is established.

Next-Generation Colloidal Materials for Ultrasound Imaging Applications.

Ultrasound has important applications, predominantly in the field of diagnostic imaging. Presently, colloidal systems such as microbubbles, phase-change emulsion droplets and particle systems with acoustic properties and multiresponsiveness are being developed to address typical issues faced when using commercial ultrasound contrast agents, and to extend the utility of such systems to targeted drug delivery and multimodal imaging. Current technologies and increasing research data on the chemistry, physics and materials science of new colloidal systems are also leading to the development of more complex, novel and application-specific colloidal assemblies with ultrasound contrast enhancement and other properties, which could be beneficial for multiple biomedical applications, especially imaging-guided treatments. In this article, we review recent developments in new colloids with applications that use ultrasound contrast enhancement. This work also highlights the emergence of colloidal materials fabricated from or modified with biologically derived and bio-inspired materials, particularly in the form of biopolymers and biomembranes. Challenges, limitations, potential developments and future directions of these next-generation colloidal systems are also presented and discussed.

Molecularly Precise, Bright, Photostable, and Biocompatible Cyanine Nanodots as Alternatives to Quantum Dots for Biomedical Applications

Fluorescent imaging with fluorophores has become a powerful way to explore complex biological systems and visualize nanoparticles for drug delivery. However, it is challenging to develop fluorophores with ideal physical and optical properties. We report a method to synthesize cyanine nanodots with a single-molecule structure, well-defined particle size, customizable fluorescent spectrum, and bright and stable fluorescence. These cyanine nanodots are acquired by the divergent synthesis of cyanine-dye-cored polylysine (PLL) dendrimers. We demonstrated the feasibility of the method by synthesizing cyanine 3 (Cy3), cyanine 5 (Cy5), or cyanine 7 (Cy7) cored single-molecule nanodots up to eight generations with a size of around 11 nm. We show that these cyanine nanodots are capable of multiple biomedical applications, including multicolor cellular tracing and cancer imaging. These cyanine nanodots possess many merits of organic dots and quantum dots that are promising for future application.

Molecularly Precise, Bright, Photostable, and Biocompatible Cyanine Nanodots as Alternatives to Quantum Dots for Biomedical Applications.

Fluorescent imaging with fluorophores has become a powerful way to explore complex biological systems and visualize nanoparticles for drug delivery. However, it is challenging to develop fluorophores with ideal physical and optical properties. We report a method to synthesize cyanine nanodots with a single-molecule structure, well-defined particle size, customizable fluorescent spectrum, and bright and stable fluorescence. These cyanine nanodots are acquired by the divergent synthesis of cyanine-dye-cored polylysine (PLL) dendrimers. We demonstrated the feasibility of the method by synthesizing cyanine 3 (Cy3), cyanine 5 (Cy5), or cyanine 7 (Cy7) cored single-molecule nanodots up to eight generations with a size of around 11 nm. We show that these cyanine nanodots are capable of multiple biomedical applications, including multicolor cellular tracing and cancer imaging. These cyanine nanodots possess many merits of organic dots and quantum dots that are promising for future application.

Mechanistic insight into differential interactions of iron oxide nanoparticles with native, glycated albumin and their effect on erythrocytes parameters

Nanoparticles and protein bioconjugates have been studied for multiple biomedical applications. We sought to investigate the interaction and structural modifications of bovine serum albumin (BSA) with iron oxide nanoparticles (IONPs). The IONPs were green synthesized using E. crassipes aqueous leaf extract following characterization using transmission electron microscopy, energy dispersive X-ray analysis and X-ray diffraction. Two different concentrations of native/glycated albumin (0.5 and 1.5 mg/ml) with IONPs were allowed to interact for 1 h at 37 °C. Glycation markers, protein modification markers, cellular antioxidant, and hemolysis studies showed structural modifications and conformational changes in albumin due to the presence of IONPs. UV–visible absorbance resulted in hyperchromic and bathochromic effects of IONPs-BSA conjugates. Fluorescence measurements of tyrosine, tryptophan, advanced glycated end products, and ANS binding assay were promising and quenching effects proved IONPs-BSA conjugate formation. In FTIR of BSA-IONPs, transmittance was increased in amide A and B bands while decreased in amide I and II bands. In summary, native PAGE, HPLC, and FTIR analysis displayed a differential behaviour of IONPs with native and glycated BSA. These results provided an understanding of the interaction and structural modifications of glycated and native BSA which may provide fundamental repercussions in future studies.

Liver Histopathological Changes Related to Intraperitoneal Administration of Salicylic Acid/Fe3O4 Nanoparticles to C57BL/6 Mice.

With a simple synthesis and easy engineering of physicochemical properties, iron oxide nanoparticles (IONPs) have become widely used in multiple biomedical applications. The study of IONPs toxicity has become an important issue, especially as the results reported so far are contradictory and range from lack of toxicity to cellular toxicity. The aim of this study was to evaluate the histopathological changes induced in mouse liver by long-term intraperitoneal injection of low doses of IONPs functionalized with salicylic acid (SaIONPs). The study was performed on C57BL/6 mice that received by intraperitoneal injection (IP), every two days, 0.6ml of SaIONPs aqueous suspension (35mg/kg body weight SaIONPs that contained 20mg/kg body weight of Fe3O4) for 28 days. The results of this study showed that the cumulative dose of 105mg/kg body weight SaIONPs (62mg/kg body weight of Fe3O4) induced histopathological changes in the subcapsular region of the mouse liver, possible by the release of salicylic acid into the peritoneal cavity. The cumulative dose of 244mg/kg body weight SaIONPs (145mg/kg body weight of Fe3O4) induced liver centrilobular necrosis, which requires the use of lower doses in biological applications. However, this may prove to be beneficial in the case of targeted accumulation of SaIONPs.