Smart Biomaterials Research Articles

Design of Stimuli‐Responsive Peptides and Proteins

AbstractStimuli‐responsive peptides and proteins are an exciting class of smart biomaterials for various applications and have received significant attention over the past decades. A wide variety of stimuli such as temperature, pH, ions, enzymes, magnetic field, redox, etc., are explored. This article provides a review of five intensively studied types of stimuli‐responsive peptides and proteins, their design principles and applications, including temperature‐, pH‐, light‐, metal ion‐, and enzyme‐responsive with an emphasis on the key design concepts and switch function. Moreover, typical examples of their applications are discussed to provide a better understanding of the design concept and underlying methodology. This review will facilitate and inspire future innovation toward new peptide‐ and protein‐based materials and their diverse applications.

Lipoplex-Functionalized Thin-Film Surface Coating Based on Extracellular Matrix Components as Local Gene Delivery System to Control Osteogenic Stem Cell Differentiation.

A gene-activated surface coating is presented as a strategy to design smart biomaterials for bone tissue engineering. The thin-film coating is based on polyelectrolyte multilayerscomposed of collagen I and chondroitin sulfate, two main biopolymers of the bone extracellular matrix, which are fabricated by layer-by-layer assembly. For further functionalization, DNA/lipid-nanoparticles (lipoplexes) are incorporated into the multilayers. The polyelectrolyte multilayer fabrication and lipoplex deposition are analyzed by surface sensitive analytical methods that demonstrate successful thin-film formation, fibrillar structuring of collagen, and homogenous embedding of lipoplexes. Culture of mesenchymal stem cells on the lipoplex functionalized multilayer results in excellent attachment and growth of them, and also, their ability to take up cargo like fluorescence-labelled DNA from lipoplexes. The functionalization of the multilayer with lipoplexes encapsulating DNA encoding for transient expression of bone morphogenetic protein 2 induces osteogenic differentiation of mesenchymal stem cells, which is shown by mRNA quantification for osteogenic genes and histochemical staining. In summary, the novel gene-functionalized and extracellular matrix mimicking multilayer composed of collagen I, chondroitin sulfate, and lipoplexes, represents a smart surface functionalization that holds great promise for tissue engineering constructs and implant coatings to promote regeneration of bone and other tissues.

Green Hydrogel Synthesis: Emphasis on Proteomics and Polymer Particle-Protein Interaction.

The field of drug discovery has seen significant progress in recent years. These advances drive the development of new technologies for testing compound's effectiveness, as well as their adverse effects on organs and tissues. As an auxiliary tool for drug discovery, smart biomaterials and biopolymers produced from biodegradable monomers allow the manufacture of multifunctional polymeric devices capable of acting as biosensors, of incorporating bioactives and biomolecules, or even mimicking organs and tissues through self-association and organization between cells and biopolymers. This review discusses in detail the use of natural monomers for the synthesis of hydrogels via green routes. The physical, chemical and morphological characteristics of these polymers are described, in addition to emphasizing polymer-particle-protein interactions and their application in proteomics studies. To highlight the diversity of green synthesis methodologies and the properties of the final hydrogels, applications in the areas of drug delivery, antibody interactions, cancer therapy, imaging and biomarker analysis are also discussed, as well as the use of hydrogels for the discovery of antimicrobial and antiviral peptides with therapeutic potential.

Physics of droplet impact on flexible materials: A review

Droplet impact on a flexible substrate is a prevalent phenomenon in nature and various advanced technologies such as soft bio-printing, tissue engineering, smart biomaterials and flexible electronics. Recent rapid advancement in new functional surfaces, ultra-high-speed imaging, nanotechnology, deep learning, advanced computational strength and the relation between fluid dynamics and interfacial science have intensified the physical understanding of droplet impact on soft materials. Once a droplets impacts on a solid surface, it deposits, spreads, rebounds or splashes. Given the importance of the droplet impact onto soft substrates in biotechnology, medicine and advanced flexible electronics, a deep physical understanding of such complex phenomenon is vital. This review initially presents the liquid-solid interaction physics and relevant interfacial science. Next, this review discusses the physics of droplet impact on soft materials with different physical and interfacial characteristics. Moreover, this review presents advancements in droplet impact on elastic materials relevant to new technologies such as soft electronics, elastic smart biomaterials, tissue engineering and the fight against COVID-19 pandemic. Finally, this review lays out future research directions related to current problems in such complex physical phenomenon.

Dual Dynamic Covalently Crosslinked Alginate Hydrogels with Tunable Properties and Multiple Stimuli-Responsiveness.

Alginate is a biopolymer that can be crosslinked with calcium ions to fabricate cytocompatible hydrogels. However, using calcium ions to crosslink alginate provides limited properties and functions to alginate hydrogels, restricting their biomedical applications. Here, phenylboronic acid-functionalized polyethyleneimine (PBA-PEI) was developed to introduce two orthogonal dynamic covalent crosslinks in the alginate hydrogels, where PBA-PEI was used to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds. The grafting degree of PBA in the PEI structure was applied to fine-tune the properties of PBA-PEI/ADA hydrogels, including the rheological property, mechanical strength, swelling behavior, and antibacterial activity. In particular, the highly sensitive boronate ester bonds in the network enabled PBA-PEI/ADA hydrogels to be responsive to several stimuli, such as glucose, fructose, and hydrogen peroxide. Taken together, PBA-PEI/ADA hydrogels with tunable properties and multiple stimuli-responsiveness have been demonstrated as smart biomaterials for advanced biomedical applications.

Entropy-Driven Thermo-gelling Vitrimer.

Thermo-gelling polymers have been envisioned as promising smart biomaterials but limited by their weak mechanical and thermodynamic stabilities. Here, we propose a new thermo-gelling vitrimer, which remains at a liquid state because of the addition of protector molecules preventing the crosslinking, and with increasing temperature, an entropy-driven crosslinking occurs to induce the sol–gel transition. Moreover, we find that the activation barrier in the metathesis reaction of vitrimers plays an important role, and experimentally, one can use catalysts to tune the activation barrier to drive the vitrimer to form an equilibrium gel at high temperature, which is not subject to any thermodynamic instability. We formulate a mean-field theory to describe the entropy-driven crosslinking of the vitrimer, which agrees quantitatively with computer simulations and paves the way for the design and fabrication of novel vitrimers for biomedical applications.

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.

NIR‐triggered hydrogel with dynamic stiffness via ion chelation to modulate macrophage phenotypes

AbstractThe immune system plays a central role in tissue repair and regeneration. Macrophages have emerged as a primary target because of their critical roles in regulating multiple phases of tissue repair through their unique plasticity and ability to rapidly shift phenotypes. Smart biomaterials, which able to harness macrophage phenotypes on demand during the healing process, have become a promising strategy. Here, a novel integrated hydrogel with near‐infrared (NIR) responsive dynamic stiffness was conducted, and found sequentially polarizing bone marrow‐derived macrophages from pro‐inflammatory to anti‐inflammatory phenotype in situ. Under NIR irradiation, ethylene diamine tetraacetic acid released from the IR780‐mixed phase change material into the hydrogel, resulting in the decrease of hydrogel stiffness in situ by chelating the calcium ion (Ca2+) in the calcium alginate hydrogel. The up‐regulation of arginase‐1 and interleukin‐10 were quantified by immunostaining and enzyme‐linked immune sorbent assay, respectively. The result indicated the transformation of macrophage from the pro‐inflammatory to anti‐inflammatory phenotype by dynamic stiffness drop. The modulation of macrophage phenotypes by stiffness‐degradation without the stimuli of cytokines offers an effective and noninvasive strategy to manipulate inflammatory or tissue‐regenerative immune responses to achieve optimized healing or therapeutical outcomes.

Advances and challenges in developing smart, multifunctional microneedles for biomedical applications.

Microneedles (MNs) have been developed as minimally invasive tools for diagnostic and therapeutic applications. However, in recent years, there has been an increasing interest in developing smart multifunctional MN devices to provide automated and closed-loop systems for body fluid extraction, biosensing, and drug delivery in a stimuli-responsive manner. Although this technology is still in its infancy and far from being translated into the clinic, preclinical trials have shown some promise for the broad applications of multifunctional MN devices. The main challenge facing the fabrication of smart MN patches is the integration of multiple modules, such as drug carriers, highly sensitive biosensors, and data analyzers in one miniaturized MN device. Researchers have shown the feasibility of creating smart MNs by integrating stimuli-responsive biomaterials and advanced microscale technologies, such as microsensors and microfluidic systems, to precisely control the transportation of biofluids and drugs throughout the system. These multifunctional MN devices can be envisioned in two distinct strategies. The first type includes individual drug delivery and biosensing MN units with a microfluidic system and a digital analyzer responsible for fluid transportation and communication between these two modules. The second type relies on smart biomaterials that can function as drug deliverers and biosensors by releasing drugs in a stimuli-responsive manner. These smart biomaterials can undergo structural changes when exposed to external stimuli, such as pH and ionic changes, mimicking the biological systems. Studies have demonstrated a high potential of hydrogel-based MN devices for a wide variety of biomedical applications, such as drug and cell delivery, as well as interstitial fluid extraction. Biodegradable hydrogels have also been advantageous for fabricating multifunctional MNs due to their high loading capacity and biocompatibility with the drug of choice. Here, we first review a set of MN devices that can be employed either for biosensing or delivery of multiple target molecules and compare them to the conventional and more simple systems, which are mainly designed for single-molecule sensing or delivery. Subsequently, we expand our insight into advanced MN systems with multiple competencies, such as body fluid extraction, biosensing, and drug delivery at the point of care. The improvement of biomaterials knowledge and biofabrication techniques will allow us to efficiently tune the next generation of smart MNs and provide a realistic platform for more effective personalized therapeutics.

Molecular Mapping of Antifungal Mechanisms Accessing Biomaterials and New Agents to Target Oral Candidiasis.

Oral candidiasis has a high rate of development, especially in immunocompromised patients. Immunosuppressive and cytotoxic therapies in hospitalized HIV and cancer patients are known to induce the poor management of adverse reactions, where local and systemic candidiasis become highly resistant to conventional antifungal therapy. The development of oral candidiasis is triggered by several mechanisms that determine oral epithelium imbalances, resulting in poor local defense and a delayed immune system response. As a result, pathogenic fungi colonies disseminate and form resistant biofilms, promoting serious challenges in initiating a proper therapeutic protocol. Hence, this study of the literature aimed to discuss possibilities and new trends through antifungal therapy for buccal drug administration. A large number of studies explored the antifungal activity of new agents or synergic components that may enhance the effect of classic drugs. It was of significant interest to find connections between smart biomaterials and their activity, to find molecular responses and mechanisms that can conquer the multidrug resistance of fungi strains, and to transpose them into a molecular map. Overall, attention is focused on the nanocolloids domain, nanoparticles, nanocomposite synthesis, and the design of polymeric platforms to satisfy sustained antifungal activity and high biocompatibility with the oral mucosa.

Tuning Protein Hydrogel Mechanics through Modulation of Nanoscale Unfolding and Entanglement in Postgelation Relaxation.

Globular folded proteins are versatile nanoscale building blocks to create biomaterials with mechanical robustness and inherent biological functionality due to their specific and well-defined folded structures. Modulating the nanoscale unfolding of protein building blocks during network formation (in situ protein unfolding) provides potent opportunities to control the protein network structure and mechanics. Here, we control protein unfolding during the formation of hydrogels constructed from chemically cross-linked maltose binding protein using ligand binding and the addition of cosolutes to modulate protein kinetic and thermodynamic stability. Bulk shear rheology characterizes the storage moduli of the bound and unbound protein hydrogels and reveals a correlation between network rigidity, characterized as an increase in the storage modulus, and protein thermodynamic stability. Furthermore, analysis of the network relaxation behavior identifies a crossover from an unfolding dominated regime to an entanglement dominated regime. Control of in situ protein unfolding and entanglement provides an important route to finely tune the architecture, mechanics, and dynamic relaxation of protein hydrogels. Such predictive control will be advantageous for future smart biomaterials for applications which require responsive and dynamic modulation of mechanical properties and biological function.

Cyanostilbene-functionalized dithienylethenes with aggregation -induced emission for photoswitching behavior in multi-media

Photochromic materials that undergo reversibility and nondestructive readout are of imperious demands in optoelectronics and functional biomaterials. The development of these materials showing high performance of photochromism and fluorescent switching in larger polar solvents or solid state still remains huge challenge. In this contribution, we rationally designed and prepared two novel cyanostilbene-functionalized dithienylethenes with aggregation-induced emission, whose chemical structures were well confirmed by 1H NMR, 13C NMR, HRMS (ESI), and XRD. Preliminary evaluation of their photoswitching behavior revealed good photochromism and fluorescent switching behaviors in different solvents, aggregated and solid states. Moreover, the water-soluble nanoparticles were fabricated by using an amphiphilic Pluronic F127 as the encapsulating matrix. Remarkably, excellent photoswitching behavior was also observed in the water-soluble nanosystem. It was interesting that they could be applied in recording and erasing information storage. Accordingly, they may be applied in the field of smart optoelectronics and functional biomaterials as novel multi-media photochromic materials.

Titanium Nanosurface with a Biomimetic Physical Microenvironment to Induce Endogenous Regeneration of the Periodontium.

The periodontium supports the teeth by dentoalveolar fibrous joints that serve unique oral functions. Endogenous regeneration of the periodontium around artificial teeth (dental implants) provides a cost-effective solution for the extension of healthy life expectancy but remains a challenge in regenerative medicine. Biomimetics can create smart biomaterials that tune endogenous cells at a tissue-material interface. Here, we created a smart titanium nanosurface mimicking the surface nanotopography and micromechanical properties of the tooth root cementum (TRC), which is essential for the induction of dentoalveolar fibrous joints to regenerate the periodontium. After transplantation into the rat renal capsule, only the titanium artificial tooth with the TRC-mimetic nanosurface formed a complex dentoalveolar fibrous joint structure, with bone tissue, periodontal ligament (PDL), and TRC, in the decellularized jawbone matrix. TRC-mimetic titanium implants induce the formation of functional periodontium, even in a jawbone implantation model, which generally causes osseointegration (ankyloses). In human PDL cells, TRC analogousness in the surface mechanical microenvironment regulates matrix mineralization through bone sialoprotein expression and phosphorus metabolism, which are critical for cementogenesis. Therefore, the titanium nanosurfaces with nanotopographical and mechanical microenvironments mimicking the TRC surface induce dentoalveolar fibrous joints for periodontal regeneration by interfacial tuning of endogenous cells.

Microorganism-derived biological macromolecules for tissue engineering.

According to literature, certain microorganism productions mediate biological effects. However, their beneficial characteristics remain unclear. Nowadays, scientists concentrate on obtaining natural materials from live creatures as new sources to produce innovative smart biomaterials for increasing tissue reconstruction in tissue engineering and regenerative medicine. The present review aims to introduce microorganism-derived biological macromolecules, such as pullulan, alginate, dextran, curdlan, and hyaluronic acid, and their available sources for tissue engineering. Growing evidence indicates that these materials can be used as biological material in scaffolds to enhance regeneration in damaged tissues and contribute to cosmetic and dermatological applications. These natural-based materials are attractive in pharmaceutical, regenerative medicine, and biomedical applications. This study provides a detailed overview of natural-based biomaterials, their chemical and physical properties, and new directions for future research and therapeutic applications.

Polymeric micelle/nano hydrogel composite matrix as a novel multi-drug carrier

According to the World Health Organization (WHO), fatality of cancer is 9.6 million in 2018. Of these, 1.8 million deaths are due to colorectal cancer. However, it doesn't seem that proper medications are unavailable. Instead, the medications should reach the site of action without causing any further side effects. With the advent of smart biomaterials this target is on its verge to be achieved. Previous reports prove that the side effects induced by Cisplatin (CIS) could be greatly decreased by curcumin (CUR). Hence, if these two drugs are used in unison, greater efficacy with lesser toxicity could be achieved. However, to incorporate two drugs and to release them simultaneously without any premature leakage can be achieved by polymeric micelles. To increase the core and hydrophobicity, monomers with large alkyl chains like triethylene tetraamine (TETA) and oleic acid (OA) were grafted to the backbone of heparin (HEP) skeleton. To target these drugs, folic acid was entrapped within hydroxyl appetite (HAP) based hydrogel and was dispersed onto polymeric micelle (PM). This coating could further act as a potential barrier to sustain the drug release as evident from similar previous studies. All the reaction steps were monitored using FTIR, XRD, H1 NMR, DLS and SEM studies. The in vitro swelling and release studies proved promising with folic acid showing burst release followed by the sustained release of chemotherapeutic drugs. The efficacy was further ascertained by MTT assay on normal and HCT 116 colon cancer cell lines. This was further proved by fluorescence studies. Thus, the present material could act as a promising candidate for the treatment of colorectal cancer with high efficacy and minimal toxicity.

Nonlinear Steady State and Dynamic Response Analysis of Focused Ultrasound Actuated Smart Biomaterials

The nonlinear steady state and dynamic response analysis of focused ultrasound smart biomaterials is presented in this paper. The increasing demand in scientific research to develop robust governing nonlinear model with adequate boundary conditions for proper understanding of the dynamics of smart biomaterials by applying focused ultrasound excitations is of great concern particularly in remote biomedical applications. Hence, in this study, a model which describes the nonlinear steady state and dynamic response of the materials for focused ultrasound actuator which is a nonlinear partial differential equation has been developed. The Galerkin Decomposition and the Differential Transform Methods are applied to obtain the solution of the governing equations. The solutions were validated with the numerical Runge-Kutta method of fourth order and verified with results obtained in recent studies and good agreement is established among them. The effects attenuating coefficient, modal number, and damping term on the steady state response of the smart biomaterials are investigated. From the results, it is observed that the steady state deflection of the system as indicated by the attenuating coefficient is lowest for clamped-clamped boundary condition and highest for clamped-free or cantilever condition. In addition, an increase in modal number and magnitude of the damping term results in an increase in the number of nodes and anti-nodes and a decrease in the amplitude of vibration over time respectively. Hence, this study establishes the practical applications of attenuating coefficient and boundary conditions as controlling factors in the design of smart biomaterials.

Osteogenesis of Iron Oxide Nanoparticles-Labeled Human Precartilaginous Stem Cells in Interpenetrating Network Printable Hydrogel.

Smart biomaterials combined with stem cell-based therapeutic strategies have brought innovation in the field of bone tissue regeneration. However, little is known about precartilaginous stem cells (PCSCs), which can be used as seed cells and incorporated with bioactive scaffolds for reconstructive tissue therapy of bone defects. Herein, iron oxide nanoparticles (IONPs) were employed to modulate the fate of PCSCs, resulting in the enhanced osteogenic differentiation potential both in vitro and in vivo. PCSCs were isolated from the ring of La-Croix extracted from polydactylism patient and identified through immunohistochemically staining using anti-FGFR-3 antibodies. Potential toxicity of IONPs toward PCSCs was assessed through cell viability, proliferation, and attachment assay, and the results demonstrated that IONPs exhibited excellent biocompatibility. After that, the effects of IONPs on osteogenic differentiation of PCSCs were evaluated and enhanced ALP activity, formation of mineralized nodule, and osteogenic-related genes expressions could be observed upon IONPs treatment. Moreover, in vivo bone regeneration assessment was performed using rabbit femur defects as a model. A novel methacrylated alginate and 4-arm poly (ethylene glycol)-acrylate (4A-PEGAcr)-based interpenetrating polymeric printable network (IPN) hydrogel was prepared for incorporation of IONPs-labeled PCSCs, where 4A-PEGAcr was the common component for three-dimensional (3D) printing. The implantation of IONPs-labeled PCSCs significantly accelerated the bone formation process, indicating that IONPs-labeled PCSCs could endow current scaffolds with excellent osteogenic ability. Together with the fact that the IONPs-labeled PCSCs-incorporated IPN hydrogel (PCSCs-hydrogels) was biosafety and printable, we believed that PCSCs-hydrogels with enhanced osteogenic bioactivity could enrich the stem cell-based therapeutic strategies for bone tissue regeneration.

Recent Advances and Perspective of Nanotechnology-Based Implants for Orthopedic Applications.

Bioimplant engineering strives to provide biological replacements for regenerating, retaining, or modifying injured tissues and/or organ function. Modern advanced material technology breakthroughs have aided in diversifying ingredients used in orthopaedic implant applications. As such, nanoparticles may mimic the surface features of real tissues, particularly in terms of wettability, topography, chemistry, and energy. Additionally, the new features of nanoparticles support their usage in enhancing the development of various tissues. The current study establishes the groundwork for nanotechnology-driven biomaterials by elucidating key design issues that affect the success or failure of an orthopaedic implant, its antibacterial/antimicrobial activity, response to cell attachment propagation, and differentiation. The possible use of nanoparticles (in the form of nanosized surface or a usable nanocoating applied to the implant’s surface) can solve a number of problems (i.e., bacterial adhesion and corrosion resilience) associated with conventional metallic or non-metallic implants, particularly when implant techniques are optimised. Orthopaedic biomaterials’ prospects (i.e., pores architectures, 3D implants, and smart biomaterials) are intriguing in achieving desired implant characteristics and structure exhibiting stimuli-responsive attitude. The primary barriers to commercialization of nanotechnology-based composites are ultimately discussed, therefore assisting in overcoming the constraints in relation to certain pre-existing orthopaedic biomaterials, critical factors such as quality, implant life, treatment cost, and pain alleviation.

3D printing of polyurethane/nanocellulose shape memory composites with tunable glass transition temperature

Shape memory polyurethane (SMPU) has been widely recognized as promising potential smart materials. While, porous SMPU presented imperfect shape memory and mechanical properties. In this work, nanocellulose was incorporated in SMPU to improve the comprehensive properties of the porous SMPU by 3D printing prototyping. The shape fixation ratio (Rf) and the shape recovery rate (Rr) were improved to above 99.0%, with adding appropriate proportion of cellulose nanocrystals (CNCs) and ball milled nanocellulose (BMC). And the highest tensile strength of the 3D printed SMP composite was 12.05 MPa, which was 71% higher than pure PU (7.02 MPa), more importantly, these composites have tunable glass transition temperature (Tg), that is to say, when under the appropriate preparation, the composites with Tg close to human body temperature can be obtained, which enables the potential applications in smart biomaterials.

Wnt3a loaded deformable hydrogel acts as a 3D culture platform for in situ recruitment of stem cells to efficiently repair bone defects via the asymmetric division

Biomaterial-based tissue engineering has emerged as a hotspot in the field of osteanagenesis. Due to invasive operation in the transplantation process always bring irreparable damage to patients, approaches that enable innate repair mechanisms hold considerable promise for bone repair. To this end, a rational design based on in situ recruitment of stem cells is proposed to circumvent the troublesome problem. In this study, an interpenetration network hydrogel is developed utilizing chitosan (CS), in which the enriched bone marrow mesenchymal stem cells (BMSCs) can undergo a tridimensional and freely proliferation. Moreover, the encapsulation of biological growth factor Wnt3a promotes the differentiation of osteoprogenitor cells with an asymmetric cell divisions (ACD) manner, thereby accelerating bone formation. With this “smart biomaterials”, a robust instant stem cell ingrowth within the deformable hydrogel and a high efficiency of bone regeneration on a murine skull are observed, both of which are vital for clinical applications. Such an osteoinductive system represents the advanced design concept to repair bone defects effectively, and offers a promising strategy for the development of future bone tissue engineering.