Stimuli-responsive Biomaterials Research Articles

Unlocking the potential of stimuli-responsive biomaterials for bone regeneration

Bone defects caused by tumors, osteoarthritis, and osteoporosis attract great attention. Because of outstanding biocompatibility, osteogenesis promotion, and less secondary infection incidence ratio, stimuli-responsive biomaterials are increasingly used to manage this issue. These biomaterials respond to certain stimuli, changing their mechanical properties, shape, or drug release rate accordingly. Thereafter, the activated materials exert instructive or triggering effects on cells and tissues, match the properties of the original bone tissues, establish tight connection with ambient hard tissue, and provide suitable mechanical strength. In this review, basic definitions of different categories of stimuli-responsive biomaterials are presented. Moreover, possible mechanisms, advanced studies, and pros and cons of each classification are discussed and analyzed. This review aims to provide an outlook on the future developments in stimuli-responsive biomaterials.

Protease-Driven Phase Separation of Elastin-Like Polypeptides.

Elastin-like polypeptides (ELPs) are a promising material platform for engineering stimuli-responsive biomaterials, as ELPs undergo phase separation above a tunable transition temperature. ELPs with phase behavior that is isothermally regulated by biological stimuli remain attractive for applications in biological systems. Herein, we report protease-driven phase separation of ELPs. Protease-responsive "cleavable" ELPs comprise a hydrophobic ELP block connected to a hydrophilic ELP block by a protease cleavage site linker. The hydrophilic ELP block acts as a solubility tag for the hydrophobic ELP block, creating a temperature window in which the cleavable ELP reactant is soluble and the proteolytically generated hydrophobic ELP block is insoluble. Within this temperature window, isothermal, protease-driven phase separation occurs when a critical concentration of hydrophobic cleavage product accumulates. Furthermore, protease-driven phase separation is generalizable to four compatible protease-cleavable ELP pairings. This work presents exciting opportunities to regulate ELP phase behavior in biological systems using proteases.

Stimuli-responsive Biomaterials for Tissue Engineering Applications.

The use of ''smart materials,'' or ''stimulus responsive'' materials, has proven useful in a variety of fields, including tissue engineering and medication delivery. Many factors, including temperature, pH, redox state, light, and magnetic fields, are being studied for their potential to affect a material's properties, interactions, structure, and/or dimensions. New tissue engineering and drug delivery methods are made possible by the ability of living systems to respond to both external stimuli and their own internal signals) for example, materials composed of stimuliresponsive polymers that self assemble or undergo phase transitions or morphology transformation. The researcher examines the potential of smart materials as controlled drug release vehicles in tissue engineering, aiming to enable the localized regeneration of injured tissue by delivering precisely dosed drugs at precisely timed intervals.

Heat-activated growth of metastable and length-defined DNA fibers expands traditional polymer assembly

Biopolymers such as nucleic acids and proteins exhibit dynamic backbone folding, wherein site-specific intramolecular interactions determine overall structure. Proteins then hierarchically assemble into supramolecular polymers such as microtubules, that are robust yet dynamic, constantly growing or shortening to adjust to cellular needs. The combination of dynamic, energy-driven folding and growth with structural stiffness and length control is difficult to achieve in synthetic polymer self-assembly. Here we show that highly charged, monodisperse DNA-oligomers assemble via seeded growth into length-controlled supramolecular fibers during heating; when the temperature is lowered, these metastable fibers slowly disassemble. Furthermore, the specific molecular structures of oligomers that promote fiber formation contradict the typical theory of block copolymer self-assembly. Efficient curling and packing of the oligomers – or ‘curlamers’ – determine morphology, rather than hydrophobic to hydrophilic ratio. Addition of a small molecule stabilises the DNA fibers, enabling temporal control of polymer lifetime and underscoring their potential use in nucleic-acid delivery, stimuli-responsive biomaterials, and soft robotics.

Recent Advances in pH and Redox Responsive Polymer Nanocomposites for Cancer Therapy

Cancer therapy currently focuses on personalized targeted treatments. A promising approach uses stimuli-responsive biomaterials for site-specific drug release, such as pH- and redox-triggered polymer nanocomposites. These materials respond to the tumor microenvironment, enhance efficacy, and reduce off-target effects. Cancer cells with anomalous properties such as acidic cytosolic pH and elevated redox potential are targeted by these biomaterials. An imbalance in ions and biological thiols in the cytoplasm contributes to tumor growth. Functionalized polymer nanocomposites with large surface areas and specific targeting outperform conventional small-molecule materials. To overcome problems such as low bioavailability, uncontrolled drug release, and poor cell penetration, multifunctional nanomaterials make it easier for drugs to enter certain cellular or subcellular systems. High therapeutic efficacy is achieved through surface functionalization, site-specific targeting, and the use of stimuli-responsive components. In particular, pH and redox dual-stimuli-based polymeric nanocomposites for cancer therapeutics have scarcely been reported. This article provides recent progress in pH- and redox-responsive polymer nanocomposites for site-specific drug delivery in cancer therapy. It explores the design principles, fabrication methods, mechanisms of action, and prospects of these dual-stimuli-responsive biomaterials.

Active learning of the thermodynamics-dynamics trade-off in protein condensates.

Phase-separated biomolecular condensates exhibit a wide range of dynamic properties, which depend on the sequences of the constituent proteins and RNAs. However, it is unclear to what extent condensate dynamics can be tuned without also changing the thermodynamic properties that govern phase separation. Using coarse-grained simulations of intrinsically disordered proteins, we show that the dynamics and thermodynamics of homopolymer condensates are strongly correlated, with increased condensate stability being coincident with low mobilities and high viscosities. We then apply an "active learning" strategy to identify heteropolymer sequences that break this correlation. This data-driven approach and accompanying analysis reveal how heterogeneous amino acid compositions and nonuniform sequence patterning map to a range of independently tunable dynamic and thermodynamic properties of biomolecular condensates. Our results highlight key molecular determinants governing the physical properties of biomolecular condensates and establish design rules for the development of stimuli-responsive biomaterials.

Bio Evaluation of Lantibiotic Nisin Loaded Polyvinyl Alcohol – Sodium Alginate Crosslinked Hydrogel As Novel Dental Temporary Filling Material

The incidence of oro-dental disorders has emerged as a serious threat to the healthcare sector owing to the increasing complexity of the oral microbiome. Significant advances in biomaterial research have led to the advent of a plethora of drug delivery systems including nanocarriers, dendrimers, hydrogels and other kinds of stimuli-responsive polymeric biomaterials. Anti-microbial peptides (AMPs) have engendered considerable interest in the past decades as potential alternatives to traditional disinfecting agents and also emerged as potent antibiofilm agents. Among the most viable approaches in targeted drug delivery, hydrogels incorporated with AMPs are emerging as bio-functional platforms yielding increased stability and bioavailability. The antibacterial and antibiofilm activities of Nisin are studied using microbiological methods followed by the synthesis of Nisin loaded PVA-Alginate hydrogel for dental treatment. The physicochemical characteristics of Nisin loaded hydrogel were done by swelling behavior, release kinetics assay, FTIR spectroscopic methods and cytotoxicity studies. Nisin showed antibacterial activity towards clinical isolates of drug-resistant bacteria and the antibiofilm and anti-adhesion studies demonstrated that Nisin could control the bacterial count in the test sample. The polymerization of Nisin into hydrogels was done and the physico-chemical characterization of Nisin loaded hydrogel network could be envisaged as a potential drug delivery platform for oral infections. Nisin loaded PVA-Alginate biocompatible hydrogel exhibited apparent swellable, flexible, nonhaemolytic materials and active antimicrobial and nontoxic materials. Physicochemical properties of these Nisin loaded PVA-Alginate biocompatible hydrogels have great potential in biomaterial-based drug delivery systems in controlling the growth and proliferation of major oro-dental pathogens. This could be exploited for the temporary biocompatible dental filling materials to treat the caries. Exploring potential nisin loaded hydrogel delivery systems will provide a brighter future of more friendly, effective and personalized treatment to deal with dental caries.

Impact of Stimuli-Responsive Biomaterials in Gynecological Cancer Therapy

Impact of Stimuli-Responsive Biomaterials in Gynecological Cancer Therapy

Utilization of Stimuli-Responsive Biomaterials in the Formulation of Cancer Vaccines.

Immunology research has focused on developing cancer vaccines to increase the number of tumor-specific effector cells and their ability to fight cancer over the last few decades. There is a lack of professional success in vaccines compared to checkpoint blockade and adoptive T-cell treatment. The vaccine's inadequate delivery method and antigen selection are most likely to blame for the poor results. Antigen-specific vaccines have recently shown promising results in preclinical and early clinical investigations. To target particular cells and trigger the best immune response possible against malignancies, it is necessary to design a highly efficient and secure delivery method for cancer vaccines; however, enormous challenges must be overcome. Current research is focused on developing stimulus-responsive biomaterials, which are a subset of the range of levels of materials, to enhance therapeutic efficacy and safety and better regulate the transport and distribution of cancer immunotherapy in vivo. A concise analysis of current developments in the area of biomaterials that respond to stimuli has been provided in brief research. Current and anticipated future challenges and opportunities in the sector are also highlighted.

User-Controlled 4D Biomaterial Degradation with Substrate-Selective Sortase Transpeptidases for Single-Cell Biology.

Stimuli-responsive biomaterials show great promise for modeling disease dynamics ex vivo with spatiotemporal control over the cellular microenvironment. However, harvesting cells from such materials for downstream analysis without perturbing their state remains an outstanding challenge in 3/4-dimensional (3D/4D) culture and tissue engineering. In this manuscript, a fully enzymatic strategy for hydrogel degradation that affords spatiotemporal control over cell release while maintaining cytocompatibility is introduced. Exploiting engineered variants of the sortase transpeptidase evolved to recognize and selectively cleave distinct peptide sequences largely absent from the mammalian proteome, many limitations implicit to state-of-the-art methods to liberate cells from gels are sidestepped. It is demonstrated that evolved sortase exposure has minimal impact on the global transcriptome of primary mammalian cells and that proteolytic cleavage proceeds with high specificity; incorporation of substrate sequences within hydrogel crosslinkers permits rapid and selective cell recovery with high viability. In composite multimaterial hydrogels, it is shown that sequential degradation of hydrogel layers enables highly specific retrieval of single-cell suspensions for phenotypic analysis. It is expected that the high bioorthogonality and substrate selectivity of the evolved sortases will lead to their broad adoption as an enzymatic material dissociation cue and that their multiplexed use will enable newfound studies in 4D cell culture.

Alternative Chemistries for Free Radical-Initiated Targeting and Immobilization.

Stimuli-responsive biomaterials are an emerging strategy that leverage common pathophysiological triggers to target drug delivery to limit or avoid toxic side effects. Native free radicals, such as reactive oxygen species (ROS), are widely upregulated in many pathological states. We have previously demonstrated that native ROS are capable of crosslinking and immobilizing acrylated polyethylene glycol diacrylate (PEGDA) networks and coupled payloads in tissue mimics, providing evidence for a potential targeting mechanism. To build on these promising results, we evaluated PEG dialkenes and dithiols as alternative polymer chemistries for targeting. The reactivity, toxicity, crosslinking kinetics, and immobilization potential of PEG dialkenes and dithiols were characterized. Both the alkene and thiol chemistries crosslinked in the presence of ROS, generating high molecular weight polymer networks that immobilized fluorescent payloads in tissue mimics. Thiols were especially reactive and even reacted with acrylates in the absence of free radicals, and this motivated us to explore a two-phase targeting approach. Delivering thiolated payloads in a second phase, after the initial polymer net formation, allowed greater control over the payload dosing and timing. Two-phase delivery combined with a library of radical-sensitive chemistries can enhance the versatility and flexibility of this free radical-initiated platform delivery system.

Development and characterization of Factor Xa-responsive materials for applications in cell culture and biologics delivery.

Stimuli-responsive biomaterials may be used to better control the release of bioactive molecules or cells for applications involving drug delivery and controlled cell release. In this study, we developed a Factor Xa (FXa)-responsive biomaterial capable of controlled release of pharmaceutical agents and cells from in vitro culture. FXa-cleavable substrates were formed as hydrogels that degraded in response to FXa enzyme over several hours. Hydrogels were shown to release both heparin and a model protein in response to FXa. Additionally, RGD-functionalized FXa-degradable hydrogels were used to culture mesenchymal stromal cells (MSCs), enabling FXa-mediated cell dissociation from hydrogels in a manner that preserved multicellular structures. Harvesting MSCs using FXa-mediated dissociation did not influence their differentiation capacity or indoleamine 2,3-dioxygenase (IDO) activity (a measure of immunomodulatory capacity). In all, this FXa-degradable hydrogel is a novel responsive biomaterial system that may be used for on-demand drug delivery, as well as for improving processes for in vitro culture of therapeutic cells.

Applications and Future Aspects of 4D Printed Biopolymeric Scaffold Materials in Tissue Engineering: A Systematic Literature Review

The emergence of smart materials (stimulus-responsive materials) and cells enables 4D printing to enhance printed structures dynamically. By undergoing controlled morphological changes, engineered tissues may be made using these dynamic scaffolds. This article provides an overview of the use of stimuli-responsive biomaterials in tissue engineering and several 4D printing methodologies based on the functional change of printed objects. This review also goes through the existing and future prospects for using 4D printing in bone tissue engineering and the limitations in this field. Using a variety of stimuli-responsive biomaterials and 4D printing techniques, the form or function of these objects might evolve. These novel technologies have the potential to meet unmet medical needs, as shown by a recent review that summarised the use of 4D printing in bone tissue engineering. This current review is about the potential of this cutting-edge technology for tissue engineering in the biomedical area by delving further into the ongoing conversations regarding future issues and perspectives.

Divergent approach to nanoscale glycomicelles and photo-responsive supramolecular glycogels. Implications for drug delivery and photoswitching lectin affinity.

The field of stimuli-responsive supramolecular biomaterials has rapidly advanced in recent years, with potential applications in diverse areas such as cancer theranostics, tissue engineering, and catalysis. However, designing molecular materials that exhibit predetermined hierarchical self-assembly to control the size, morphology, surface chemistry, and responsiveness of the final nanostructures remains a significant challenge. In this study, we present a divergent synthetic approach for the fabrication of spherical micelles and functional 1D-glyconanotube-based photoresponsive gels from structurally related diazobenzene/diacetylene glycolipids. The resulting nanostructures were characterized using NMR, TEM, and SEM, confirming the formation of spherical and tubular nanostructures in both the gel and solution states. Upon UV irradiation, a reversible gel-sol transition was observed, resulting from the photoswitching of the azobenzene unit from the stretched trans form to the compact, metastable cis form. Our gels were shown to enable spatio-temporal control of the adhesion and release of the lectin Concanavalin A, demonstrating potential use as regenerable biomaterials to fight against infections with toxins and pathogens. Additionally, our micelles and gels were evaluated as nanocontainers for loading and controlled release of hydrophobic dyes and antitumoural agents, suggesting their possible use as smart theranostic drug delivery systems.

Reversible transformation of peptide assembly between densified-polysarcosine-driven kinetically and helix-orientation-driven thermodynamically stable morphologies.

Stimuli-responsive transformable biomaterials development can be manipulated practically by fine-tuning the built-in molecular design of their structural segments. Here, we demonstrate a peptide assembly by the bola-type amphiphilic polypeptide, glycolic acid-polysarcosine (PSar)13-b-(L-Leu-Aib)6-b-PSar13-glycolic acid (S13L12S13), which shows morphological transformations between hydrophilic chain-driven and hydrophobic unit-driven morphologies. The hydrophobic α-helical unit (L-Leu-Aib)6 precisely controls packing in the hydrophobic layer of the assembly and induces tubule formation. The densified, hydrophilic PSar chain on the assembly surface becomes slightly more hydrophobic as the temperature increases above 70 °C, starting to disturb the helix-helix interaction-driven formation of tubules. As a result, the S13L12S13 peptide assembly undergoes a reversible vesicle-nanotube transformation following a time course at room temperature and a heat treatment above 80 °C. Using membrane fluidity analysis with DPH and TMA-DPH and evaluating the environment surrounding the PSar side chain with NMR, we clarify that the vesicle was in a kinetically stable state driven by the dehydrated PSar chain, while the nanotube was in a thermodynamically stable state.

Recent advances in tailoring stimuli-responsive hybrid scaffolds for cardiac tissue engineering and allied applications.

To recapitulate bio-physical properties and functional behaviour of native heart tissues, recent tissue engineering-based approaches are focused on developing smart/stimuli-responsive materials for interfacing cardiac cells. Overcoming the drawbacks of the traditionally used biomaterials, these smart materials portray outstanding mechanical and conductive properties while promoting cell-cell interaction and cell-matrix transduction cues in such excitable tissues. To date, a large number of stimuli-responsive materials have been employed for interfacing cardiac tissues alone or in combination with natural/synthetic materials for cardiac tissue engineering. However, their comprehensive classification and a comparative analysis of the role played by these materials in regulating cardiac cell behaviour and in vivo metabolism are much less discussed. In an attempt to cover the recent advances in fabricating stimuli-responsive biomaterials for engineering cardiac tissues, this review details the role of these materials in modulating cardiomyocyte behaviour, functionality and surrounding matrix properties. Furthermore, concerns and challenges regarding the clinical translation of these materials and the possibility of using such materials for the fabrication of bio-actuators and bioelectronic devices are discussed.

Three-dimensional printing of smart constructs using stimuli-responsive biomaterials: A future direction of precision medicine.

Three-dimensional (3D) printing, which is a valuable technique for the fabrication of tissue-engineered constructs and biomedical devices with complex architectures, has brought about considerable progress in regenerative medicine, drug delivery, and diagnosis of diseases. However, because of the static and inanimate properties of conventional 3D-printed structures, it is difficult to use them in therapies for active and precise medicine, such as improved tissue regeneration, targeted or controlled drug delivery, and advanced pathophysiological monitoring. The integration of stimuli-responsive biomaterials into 3D printing provides a potential strategy for designing and building smart constructs that exhibit programmed functions and controllable changes in properties in response to exogenous and autogenous stimuli. These features make 3D-printed smart constructs the next generation of tissue-engineered products. In this review, we introduce the prevalent 3D printing techniques (with an emphasis on the differences between 3D printing and bioprinting, and biomaterials and bioink), the working principle of each technique, and the advantages of using 3D printing for the fabrication of smart constructs. Stimuli-responsive biomaterials that are widely used for 3D printing of smart constructs are categorized, followed by a summary of their applications in tissue regeneration, drug delivery, and biosensors. Finally, the challenges and future perspectives of 3D-printed smart constructs are discussed.

Smart Bacteria-Responsive Drug Delivery Systems in Medical Implants.

With the rapid development of implantable biomaterials, the rising risk of bacterial infections has drawn widespread concern. Due to the high recurrence rate of bacterial infections and the issue of antibiotic resistance, the common treatments of peri-implant infections cannot meet the demand. In this context, stimuli-responsive biomaterials have attracted attention because of their great potential to spontaneously modulate the drug releasing rate. Numerous smart bacteria-responsive drug delivery systems (DDSs) have, therefore, been designed to temporally and spatially release antibacterial agents from the implants in an autonomous manner at the infected sites. In this review, we summarized recent advances in bacteria-responsive DDSs used for combating bacterial infections, mainly according to the different trigger modes, including physical stimuli-responsive, virulence-factor-responsive, host-immune-response responsive and their combinations. It is believed that the smart bacteria-responsive DDSs will become the next generation of mainstream antibacterial therapies.

Inflammatory environment-adaptive patterned surface for spatiotemporal immunomodulation of macrophages

Designing biomaterials with precise immunomodulation can help to decipher the dynamic interactions between macrophages and biomaterials to match the tissue healing process. Although some advanced stimuli-responsive immunomodulatory biomaterials were reported for cell dynamic modulation, while most triggers need external stimuli by manual intervention, there would be the inevitable errors and uncertainties. Thus, developing immunomodulatory biomaterials with adaptive abilities, which can recognize the inflammation signals, change their properties spatiotemporally under the microenvironment triggers, and provide feedback to realize macrophages modulation in different healing stages, has become a promising strategy. In this work, we developed an inflammation-adaptive Arg-Gly-Asp (RGD) -patterned surface for spatiotemporal immunomodulation of macrophage. We fabricated a methacrylated hyaluronic acid (MA-HA) hydrogel with thiol-functionalized RGD-patterned surface by employing photolithography technology. Then, thiol-functionalized RGD contained ROS-cleavable linker was filled the remaining sites and consequently, a dynamic surface with temporary homogeneous RGD was obtained. Under the overproduction of ROS by the inflammation-activated macrophages, the linker was cleaved, and the homogeneous RGD surface was transformed to the RGD patterned surface, which triggered elongation of macrophages and consequently the upregulated expressions of arginase-1, IL-10 and TNF-β1, indicating the polarization toward to anti-inflammatory phenotype. Developing inflammatory environment-adaptive surface for spatiotemporal modulation of macrophages polarization provides a precise and smart strategy for the healing-matched immunomodulation to facilitate healing outcomes. Statement of significanceDesigning biomaterials with precise immunomodulation can help to decipher the dynamic interactions between macrophages and biomaterials to match tissue repair process. Some immunomodulatory biomaterials were reported for cell dynamic modulation, while most triggers need external manual intervention. Thus, we developed an immunomodulatory biomaterial with inflammation-adaptive patterned surface, which can recognize abnormal signals and change its properties spatiotemporally under the microenvironment triggers, and provide feedback to realize macrophages modulation in different stages. The dynamic surface can adapt to the changes of microenvironment and dynamically to match the cell behavior and tissue healing process on demand without external manual intervention. Additionally, the surface achieves the balance of macrophages with pro- and anti-inflammatory phenotypes in the tissue repair process.

Smart biomaterials: From 3D printing to 4D bioprinting.

This century is blessed with enhanced medical facilities on the grounds of the development of smart biomaterials. The rise of the four-dimensional (4D) bioprinting technology is a shining example. Using inert biomaterials as the bioinks for the three-dimensional (3D) printing process, static objects that might not be able to mimic the dynamic nature of tissues would be fabricated; by contrast, 4D bioprinting can be used for the fabrication of stimuli-responsive cell-laden structures that can evolve with time and enable engineered tissues to undergo morphological changes in a pre-planned way. For all the aptitude of 4D bioprinting technology in tissue engineering, it is imperative to select suitable stimuli-responsive biomaterials with cell-supporting functionalities and responsiveness; as a result, in this article, recent advances and challenges in smart biomaterials for 4D bioprinting are briefly discussed. An overview perspective concerning the latest developments in 4D-bioprinting is also provided.