Intelligent Biomaterials Research Articles

Smart Nucleic Acid Hydrogels with High Stimuli-Responsiveness in Biomedical Fields.

Due to their hydrophilic, biocompatible and adjustability properties, hydrogels have received a lot of attention. The introduction of nucleic acids has made hydrogels highly stimuli-responsiveness and they have become a new generation of intelligent biomaterials. In this review, the development and utilization of smart nucleic acid hydrogels (NAHs) with a high stimulation responsiveness were elaborated systematically. We discussed NAHs with a high stimuli-responsiveness, including pure NAHs and hybrid NAHs. In particular, four stimulation factors of NAHs were described in details, including pH, ions, small molecular substances, and temperature. The research progress of nucleic acid hydrogels in biomedical applications in recent years is comprehensively discussed. Finally, the opportunities and challenges facing the future development of nucleic acid hydrogels are also discussed.

Enzyme-responsive strategy as a prospective cue to construct intelligent biomaterials for disease diagnosis and therapy

Stimulus-responsive materials have been widely studied and applied in biomedical fields. Under the stimulation of enzymes, enzyme-responsive materials (ERMs) can be triggered to change their structures, properties and functions. Herein, natural enzymes act as the endogenous trigger. Owing to the specificity of natural enzymes, ERMs can exert functions in the specific tissues containing these enzymes, while remaining inert in other tissues. This is beneficial for modulating the therapy efficacy and alleviating systemic or local toxicities in vivo when ERMs are used to deliver therapeutic molecules. This article focuses on introducing enzyme-responsive strategies, ERMs and their applications in cancer and cardiovascular disease diagnosis, therapy and theranostics. Enzyme-responsive strategies provide a promising research cue to construct intelligent biomaterials for disease treatment and diagnosis.

Polymorphic transient glycolipid assemblies with tunable lifespan and cargo release

HypothesisIn living systems, dynamic processes like dissipative assembly, polymorph formation, and destabilization of hydrophobic domains play an indispensable role in the biochemical processes. Adaptation of biological self-assembly processes to an amphiphilic molecule leads to the fabrication of intelligent biomaterials with life-like behavior. ExperimentsAn amphiphilic glycolipid molecule was engineered into various dissipative assemblies (vesicles and supramolecular nanotube-composed hydrogels) by using two activation steps, including heating-cooling and shear force in method-1 or boric acid/glycolipid complexation and shear force in method-2. The influence of number of activation steps on vesicle to nanotube phase transitions and activation method on the properties of hydrogels were investigated, where the morphological transformations and destabilization of hydrophobic domains resulted from a bilayer to a higher-order crystal structure. FindingsHydrophobic and hydrophilic cargos encapsulated in the dissipative assemblies (vesicles and injectable hydrogels) can be released in a controlled manner via changing the activation method. The reported adaptive materials engineered by dual activation steps are promising self-assembled systems for programmed release of loaded cargos at a tunable rate.

Controlled Drug Delivery Systems: Current Status and Future Directions.

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.

Micropatterning of Mammalian Cells on Plasma Polymerized Polypyrrole Thin Films

Microscaled patterns have been used to construct exquisite intelligent biomaterials and can be applied in tissue engineering to create different biological signals and modulate cell behavior. This study proposed to create micropatterns for cell attachment and proliferation by combining 3-D printed mask with the plasma polymerized pyrrole (ppPy) on an antifouling polymer-modified substrate. The antifouling moieties selected in this study are the zwitterionic molecules of sulfobetaine methacrylate (SBMA) copolymerized with acrylic acid (AAc). The cell-pattern interactions were facilitated by cultivating L-929 mouse fibroblasts on the substrates with the well-defined chemical features providing by the multilayers composed of plasma polymers and zwitterionic copolymers. The results showed that both the attachment and proliferation of L-929 fibroblast cells were excellently confined within the ppPy functionalized patterns. Moreover, the cell density per unit area increased as a function of the ppPy deposition time, indicating cell proliferation was modulated by amine functionality. This study provides an alternative method to pattern biomolecules using plasma deposition which could be further applied in fields of biomaterials and biosensing.

Structure-Based Programming of Supramolecular Assemblies in Living Cells for Selective Cancer Cell Inhibition.

Here we report on the design, synthesis, and assembly of an enzymatic programmable peptide system inspired by endocytic processes to induce molecular assemblies formation spatiotemporally in living cancer cells, resulting in glioblastoma cell death mainly in necroptosis. Our results indicate the stability and glycosylation of molecules play an essential role in determining the final bioactivity. Detailed mechanistic studies by CLSM, Flow cytometry, western blot, and Bio-EM suggest the site-specific formation of assemblies, which could induce the LMP and activate the downstream cell death pathway. Moreover, we also demonstrate that our strategy can boost the activity of commercial chemotherapy drug by escaping lysosome sequestration. We expected this work would be expanded towards artificial intelligent biomaterials for cancer therapy and imaging precisely.

Structure‐Based Programming of Supramolecular Assemblies in Living Cells for Selective Cancer Cell Inhibition

AbstractHere we report on the design, synthesis, and assembly of an enzymatic programmable peptide system inspired by endocytic processes to induce molecular assemblies formation spatiotemporally in living cancer cells, resulting in glioblastoma cell death mainly in necroptosis. Our results indicate the stability and glycosylation of molecules play an essential role in determining the final bioactivity. Detailed mechanistic studies by CLSM, Flow cytometry, western blot, and Bio‐EM suggest the site‐specific formation of assemblies, which could induce the LMP and activate the downstream cell death pathway. Moreover, we also demonstrate that our strategy can boost the activity of commercial chemotherapy drug by escaping lysosome sequestration. We expected this work would be expanded towards artificial intelligent biomaterials for cancer therapy and imaging precisely.

A State-of-the-Art of Functional Scaffolds for 3D Nervous Tissue Regeneration.

Exploring and developing multifunctional intelligent biomaterials is crucial to improve next-generation therapies in tissue engineering and regenerative medicine. Recent findings show how distinct characteristics of in situ microenvironment can be mimicked by using different biomaterials. In vivo tissue architecture is characterized by the interconnection between cells and specific components of the extracellular matrix (ECM). Last evidence shows the importance of the structure and composition of the ECM in the development of cellular and molecular techniques, to achieve the best biodegradable and bioactive biomaterial compatible to human physiology. Such biomaterials provide specialized bioactive signals to regulate the surrounding biological habitat, through the progression of wound healing and biomaterial integration. The connection between stem cells and biomaterials stimulate the occurrence of specific modifications in terms of cell properties and fate, influencing then processes such as self-renewal, cell adhesion and differentiation. Recent studies in the field of tissue engineering and regenerative medicine have shown to deal with a broad area of applications, offering the most efficient and suitable strategies to neural repair and regeneration, drawing attention towards the potential use of biomaterials as 3D tools for in vitro neurodevelopment of tissue models, both in physiological and pathological conditions. In this direction, there are several tools supporting cell regeneration, which associate cytokines and other soluble factors delivery through the scaffold, and different approaches considering the features of the biomaterials, for an increased functionalization of the scaffold and for a better promotion of neural proliferation and cells-ECM interplay. In fact, 3D scaffolds need to ensure a progressive and regular delivery of cytokines, growth factors, or biomolecules, and moreover they should serve as a guide and support for injured tissues. It is also possible to create scaffolds with different layers, each one possessing different physical and biochemical aspects, able to provide at the same time organization, support and maintenance of the specific cell phenotype and diversified ECM morphogenesis. Our review summarizes the most recent advancements in functional materials, which are crucial to achieve the best performance and at the same time, to overcome the current limitations in tissue engineering and nervous tissue regeneration.

TEMPO-oxidized cellulose nanofibers/polyacrylamide hybrid hydrogel with intrinsic self-recovery and shape memory properties

Shape memory hydrogels attract increasing attention due to their promising applications as intelligent biomaterials for actuators, biomedicine and sensory applications. Nonetheless, the integration of synergistic characteristics providing good mechanical properties and ideal self-recovery rate still remains a challenge. To tackle this, we develop a novel nanocomposite hydrogel by radical polymerization. TEMPO-oxidized cellulose nanofibers (TOCNs) with high strength and ultra-high aspect ratio were introduced to improve the energy dissipation mechanism and enhance the fatigue resistance of polyacrylamide (PAAM) hydrogel. Interestingly, the nanocomposite hydrogel displays unprecedented shape memory properties through coordination with Fe3+. The resulting TOCN/PAAM hydrogel achieves excellent energy dissipation capability (9.68 MJ m−3 at 60% strain), satisfactory viscoelasticity (51.1 kPa) and good self-recovery rate (about 93.2% after 30 min recovery). In particular, the 3% TOCN/PAAM-Fe3+ hydrogel exhibits better tensile performance. This nanocomposite hydrogel with good shape memory properties and excellent mechanical strength has broad application prospects in soft actuators and sensory research.

Interaction of microbial functional amyloids with solid surfaces

HypothesisSelf-assembling protein subunits hold great potential as biomaterials with improved functions. Among the self-assembled protein structures functional amyloids are promising unique properties such as resistance to harsh physical and chemical conditions their mechanical strength, and ease of functionalization. Curli proteins, which are functional amyloids of bacterial biofilms can be programmed as intelligent biomaterials. ExperimentsIn order to obtain controllable curli based biomaterials for biomedical applications, and to understand role of each of the curli forming monomeric proteins (namely CsgA and CsgB from Escherichia coli) we characterized their binding kinetics to gold, hydroxyapatite, and silica surfaces. FindingsWe demonstrated that CsgA, CsgB, and their equimolar mixture have different binding strengths for different surfaces. On hydroxyapatite and silica surfaces, CsgB is the crucial element that determines the final adhesiveness of the CsgA-CsgB mixture. On the gold surface, on the other hand, CsgA controls the behavior of the mixture. Those findings uncover the binding behavior of curli proteins CsgA and CsgB on different biomedically valuable surfaces to obtain a more precise control on their adhesion to a targeted surface.

Electroactive Composite of FeCl3 -Doped P3HT/PLGA with Adjustable Electrical Conductivity for Potential Application in Neural Tissue Engineering.

Conducting polymers (CPs) is one of intelligent biomaterials with the specific properties of reversible redox states, which have a significant effects on the cell behaviors and nerve tissue regeneration. However, the effects of CPs with different electrical conductivity on the behaviors of nerve cells are rarely reported. Therefore, a kind of Poly(3-hexylthiophene) (P3HT) with certain molecular weight is synthesized by Kumada catalyst transfer polymerization (KCTP) method and employed to prepare bioabsorbable and electroactive intelligent composites of Poly(3-hexylthiophene)/Poly(glycolide-lactide) (P3HT/PLGA). FeCl3 doping electroactive membranes with different electrical conductivities are prepared to investigate the cell behaviors. On the substrate with higher electrical conductivity, the proliferation of rat adrenal pheochromocytoma cells (PC12 cells) is significantly promoted and neurite length is increased obviously. In particular, the most significant improvements are the neuron gene expression of Synapsin 1 and microtubule-associated protein 2 (MAP2) by the composites with high conductivity. These results suggest that P3HT/PLGA with suitable electrical conductivity have a positive role in promoting neural growth and differentiation, which is promising for advancing potential application of nerve repair and regeneration.

Advanced Drug Delivery Nanosystems for Shikonin: A Calorimetric and Electron Paramagnetic Resonance Study

Drug delivery is considered a mature scientific and technological platform for producing innovative medicines with nanosystems composed of intelligent bio-materials that carry active pharmaceutical ingredients forming advanced drug delivery nanosystems (aDDnSs). Shikonin and its enantiomer alkannin are natural products that have been extensively studied in vitro and in vivo for, among others, their antitumor activity, and various efforts have been made to prepare shikonin-loaded drug delivery systems. This study is focused on chimeric aDDnSs and specifically on liposomal formulations combining three lipids (egg-phosphatidylcholine; dipalmitoyl phosphatidylcholine; and distearoyl phosphatidylcholine) and a hyperbranched polymer (PFH-64-OH). Furthermore, PEGylated liposomal formulations of all samples were also prepared. Calorimetric techniques and electron paramagnetic resonance were used to explore and evaluate the interactions and stability of the liposomal formulations, showing that the presence of hyperbranched polymers promote the overall stability of the chimeric aDDnSs based on the drug release profile enhancement. Furthermore, results showed that polyethylene glycol enhances drug stabilization inside the liposomes, forming a stable and promising carrier for shikonin with improved characteristics.

Force and time-dependent self-assembly, disruption and recovery of supramolecular peptide amphiphile nanofibers

Biological feedback mechanisms exert precise control over the initiation and termination of molecular self-assembly in response to environmental stimuli, while minimizing the formation and propagation of defects through self-repair processes. Peptide amphiphile (PA) molecules can self-assemble at physiological conditions to form supramolecular nanostructures that structurally and functionally resemble the nanofibrous proteins of the extracellular matrix, and their ability to reconfigure themselves in response to external stimuli is crucial for the design of intelligent biomaterials systems. Here, we investigated real-time self-assembly, deformation, and recovery of PA nanofibers in aqueous solution by using a force-stabilizing double-pass scanning atomic force microscopy imaging method to disrupt the self-assembled peptide nanofibers in a force-dependent manner. We demonstrate that nanofiber damage occurs at tip-sample interaction forces exceeding 1 nN, and the damaged fibers subsequently recover when the tip pressure is reduced. Nanofiber ends occasionally fail to reconnect following breakage and continue to grow as two individual nanofibers. Energy minimization calculations of nanofibers with increasing cross-sectional ellipticity (corresponding to varying levels of tip-induced fiber deformation) support our observations, with high-ellipticity nanofibers exhibiting lower stability compared to their non-deformed counterparts. Consequently, tip-mediated mechanical forces can provide an effective means of altering nanofiber integrity and visualizing the self-recovery of PA assemblies.

A Strategy to Enhance Secretion of Extracellular Matrix Components by Stem Cells: Relevance to Tissue Engineering.

The ability of cells to secrete extracellular matrix proteins is an important property in the repair, replacement, and regeneration of living tissue. Cells that populate tissue-engineered constructs need to be able to emulate these functions. The motifs, KTTKS or palmitoyl-KTTKS (peptide amphiphile), have been shown to stimulate production of collagen and fibronectin in differentiated cells. Molecular modeling was used to design different forms of active peptide motifs to enhance the efficacy of peptides to increase collagen and fibronectin production using terminals KTTKS/SKTTK/SKTTKS connected by various hydrophobic linkers, V4A3/V4A2/A4G3. Molecular dynamic simulations showed SKTTKS-V4A3-SKTTKS (P3), with palindromic (SKTTKS) motifs and SKTTK-V4A2-KTTKS (P5), maintained structural integrity and favorable surface electrostatic distributions that are required for functionality. In vitro studies showed that peptides, P3 and P5, showed low toxicity to human adipose-derived stem cells (hADSCs) and significantly increased the production of collagen and fibronectin in a concentration-dependent manner compared with the original active peptide motif. The 4-day treatment showed that stem cell markers of hADSCs remained stable with P3. The molecular design of novel peptides is a promising strategy for the development of intelligent biomaterials to guide stem cell function for tissue engineering applications.

Vision for Functionally Decorated and Molecularly Imprinted Polymers in Regenerative Engineering.

The emerging field of regenerative engineering offers a great challenge and an even greater opportunity for materials scientists and engineers. How can we develop materials that are highly porous to permit cellular infiltration, yet possess sufficient mechanical integrity to mimic native tissues? How can we retain and deliver bioactive molecules to drive cell organization, proliferation, and differentiation in a predictable manner? In the following perspective, we highlight recent studies that have demonstrated the vital importance of each of these questions, as well as many others pertaining to scaffold development. We posit hybrid materials synthesized by molecular decoration and molecular imprinting as intelligent biomaterials for regenerative engineering applications. These materials have potential to present cell adhesion molecules and soluble growth factors with fine-tuned spatial and temporal control, in response to both cell-driven and external triggers. Future studies in this area will address a pertinent clinical need, expand the existing repertoire of medical materials, and improve the field's understanding of how cells and materials respond to one another.

Multifunctional nanogels with dual temperature and pH responsiveness

Over the last 10 years, the development of intelligent biomaterials for medical and pharmaceutical applications has attracted growing interest by combining interdisciplinary efforts. Between them nanogels represent one of the most attractive carriers for innovative drug delivery systems. In the present investigation new variants of multi-responsive nanogels have been synthesized by crosslinking poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane) copolymer (having different molar ratios between comonomers) with 1,12-dodecandiol. The new structures were obtained by using modification of itaconic anhydride moieties in the copolymer. This is a convenient method for the preparation of a network with increased functionality, which further may ensure new strategies for coupling various bioactive compounds, especially owing to the behavior of the used copolymers, which present dual pH and temperature sensitive characteristics. The chemical structure of the new compounds was confirmed by FTIR and 1H RMN spectra. Also, the evaluation of thermal stability by thermogravimetric analysis sustains the covalent bonds occurring between the copolymer and diol. The dual responsiveness of the nanogel structures to temperature and pH was put into evidence by DLS studies. This feature can be used for the development of drug delivery systems, which can mimic biological response behavior to a certain extent. The new synthesized nanogels were tested as drug delivery systems by using diclofenac as a model drug. The results obtained from in vitro and in vivo investigation confirm the bioactivity of the nanogel networks.

The challenge to improve the response of biomaterials to the physiological environment.

New applications of biomaterials often require advanced structures containing synthetic and natural components that are tuned to provide properties unique to a specific application. We discuss how structural characteristics of biomaterials, especially hydrophilic ones, can be used in conjunction with non-ideal thermodynamics to develop advanced medical systems. We show a number of examples of biocompatible, intelligent biomaterials that can be used for organ replacement, biosensors, precise drug delivery over days or weeks, and regenerative medicine.

Study of Bone Tissue Stress and Strain State Aimed at Development of Intelligent Biomaterials for Osteoimplantation

This article studies the stress and strain state of simulated microvolumes of compact bone tissue under uniaxial compression, having different orientation of collagen-mineral fibers, different porosity and mineral content. The purpose of the study is to work out recommendations on development of artificial mechanically compatible biomaterials for osteoimplants. It has been found out that it is necessary to take into account the effective mechanical parameters defining the distribution of the bone tissue stress and strain when making individual implants.

Hierarchically macroporous silver monoliths using Pluronic F127: Facile synthesis, characterization and its application as an efficient biomaterial for pathogens

Herein we report the facile synthesis of three dimensional macroporous (MP) silver monoliths serving as intelligent biomaterials against Gram negative (Escherichia coli, Salmonella typhimurium) and Gram positive (Bacillus subtilis) bacteria with more efficacy against Gram negative bacteria. The macroporous silver monoliths were examined by Fourier transform infra red (FTIR) spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD) study, field emission scanning electron microscopy (FESEM), energy dispersion X-ray spectroscopy analysis (EDX) and Brunauer–Emmet–Teller (BET) adsorption technique. From the antibacterial activity results, it was concluded that macroporous silver monoliths can serve as efficient disinfection agents. The enhanced antibacterial properties of macroporous silver monoliths was possibly due to high surface free energy of the surface Ag+ atoms leading to cell membrane damage followed by cell death.

Three-dimensional bioprinting in tissue engineering and regenerative medicine.

With the advances of stem cell research, development of intelligent biomaterials and three-dimensional biofabrication strategies, highly mimicked tissue or organs can be engineered. Among all the biofabrication approaches, bioprinting based on inkjet printing technology has the promises to deliver and create biomimicked tissue with high throughput, digital control, and the capacity of single cell manipulation. Therefore, this enabling technology has great potential in regenerative medicine and translational applications. The most current advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review, including vasculature, muscle, cartilage, and bone. In addition, the benign side effect of bioprinting to the printed mammalian cells can be utilized for gene or drug delivery, which can be achieved conveniently during precise cell placement for tissue construction. With layer-by-layer assembly, three-dimensional tissues with complex structures can be printed using converted medical images. Therefore, bioprinting based on thermal inkjet is so far the most optimal solution to engineer vascular system to the thick and complex tissues. Collectively, bioprinting has great potential and broad applications in tissue engineering and regenerative medicine. The future advances of bioprinting include the integration of different printing mechanisms to engineer biphasic or triphasic tissues with optimized scaffolds and further understanding of stem cell biology.