Dynamic Biointerfaces Research Articles

Triple‐network‐based conductive polymer hydrogel for soft and elastic bioelectronic interfaces

AbstractConductive polymer hydrogels have greatly improved the compatibility of electronic devices with biological tissues for human–machine interfacing. Hydrogels that possess low Young's modulus, low interfacial impedance, and high tensile properties facilitate high‐quality signal transmission across dynamic biointerfaces. Direct incorporation of elastomers with conductive polymers may result in undesirable mechanical and/or electrical performance. Here, a covalent cross‐linking network and an entanglement‐driven network with conductive poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) have been combined. The triple‐network conductive hydrogel shows high stretchability (with fracture strain up to 900%), low impedance (down to 91.2 Ω cm2), and reversible adhesion. Importantly, ultra‐low modulus (down to 6.3 kPa) and strain‐insensitive electrical/electrochemical performance were achieved, which provides a guarantee for low current stimulation. The material design will contribute to the progression of soft and conformal bioelectronic devices, and pave the way to future implantable electronics.

Self-assembling materials functionalizing bio-interfaces of phospholipid membranes and extracellular matrices.

This Feature Article focuses on recent studies on the development of self-assembling materials that mimic and control dynamic bio-interfaces. Extracellular matrix (ECM) is a fundamental tissue at the cellular interface constructed by networks of fibrous proteins, which regulates a variety of cellular activities. Reconstruction of ECM has been demonstrated by self-assembling peptides. By combining the dynamic properties of the self-assembling peptides conjugated with full-length proteins, peptide-based supramolecular materials enable neuronal migration and regeneration of injured neural tissue. The phospholipid bilayer is the main component of the cell membrane. The morphology and deformation of the phospholipid bilayer relate directly to dynamic interfacial functions. Stabilization of the phospholipid nanosheet structure has been demonstrated by self-assembling peptides, and the stabilized bicelle is functional for extended blood circulation. By using a photo-responsive synthetic surfactant showing a mechanical opening/closing motion, endocytosis-like outside-in membrane deformation is triggered. The outside-in deformation allows for efficient encapsulation of micrometer-size substances such as phage viruses into the liposomes, and the encapsulated viruses can be delivered to multiple organs in a living body via blood administration. These supramolecular approaches to mimicking and controlling bio-interfaces present powerful ways to develop unprecedented regenerative medicines and drug delivery systems.

DNA-Based Daisy Chain Rotaxane Nanocomposite Hydrogels as Dual-Programmable Dynamic Scaffolds for Stem Cell Adhesion.

Interlocked DNA nanostructures perform programmable movements in nanoscales such as sliding, contraction, and expansion. However, utilizing nanoscaled interlocked movements to regulate the functions of larger length scaled matrix and developing their applications has not yet been reported. Herein we describe the assembly of DNA-based daisy chain rotaxane nanostructure (DNA-DCR) composed of two hollow DNA nanostructures as macrocycles, two interlocked axles and two triangular prism-shaped DNA structures as stoppers, in which three mechanical states─fixed extended state (FES), sliding state (SS), and fixed contracted state (FCS)─are characterized by using toehold-mediated strand displacement reaction (SDR). The DNA-DCRs are further used as nanocomposites and introduced into hydrogel matrix to produce interlocked hydrogels, which shows modulable stiffness by elongating the interlocked axles to regulate the hydrogel swelling with hybridization chain reaction (HCR) treatment. Then the DCR-hydrogels are employed as dynamic biointerfaces for human mesenchymal stem cells (hMSCs) adhesion studies. First, hMSCs showed lower cell density on bare DCR-hydrogel treated with HCR-initiated swelling for stiffness decreasing. Second, the cell adhesion ligand (RGD) modified DNA-DCRs are constructed for hydrogel functionalization. DCR(RGD) hydrogel endows the mobility of RGDs by switching the mechanical states of DNA-DCR. HMSCs showed increased cell density on DCRSS(RGD) hydrogel than on DCRFCS(RGD) hydrogel. Therefore, our DNA-DCR nanocomposite hydrogel exhibit dual-programmable performances including swelling adjustment and offering sliding for incorporated ligands, which can be both utilized as dynamic scaffolds for regulating the stem cell adhesion. The dual-programmable cross-scale regulation from interlocked DNA nanostructures to hydrogel matrix was achieved, demonstrating a new pathway of DNA-based materials.

Recapitulating dynamic ECM ligand presentation at biomaterial interfaces: Molecular strategies and biomedical prospects.

The extracellular matrix (ECM) provides not only physical support for the tissue structural integrity, but also dynamic biochemical cues capable of regulating diverse cell behaviors and functions. Biomaterial surfaces with dynamic ligand presentation are capable of mimicking the dynamic biochemical cues of ECM, showing ECM-like functions to modulate cell behaviors. This review paper described an overview of present dynamic biomaterial interfaces by focusing on currently developed molecular strategies for dynamic ligand presentation. The paradigmatic examples for each strategy were separately discussed. In addition, the regulation of some typical cell behaviors on these dynamic biointerfaces including cell adhesion, macrophage polarization, and stem cell differentiation, and their potential applications in pathogenic cell isolation, single cell analysis, and tissue engineering are highlighted. We hope it would not only clarify a clear background of this field, but also inspire to exploit novel molecular strategies and more applications to match the increasing demand of manipulating complex cellular processes in biomedicine.

Multi-scale adaptions of dynamic bio-interfaces

Biodevices including wearable sensors, medical implants or protheses (e.g., tissue engineering scaffolds and neural electrodes), have attracted extensive attentions over the past several decades due to their great potentials in multiple areas of healthcare, diagnostics, and rehabilitation. The performances and efficiency of biodevice-tissue integration and adaption are significantly affected by their bio-interfaces, which should be therefore carefully considered and optimized. This perspective briefly summarizes the emerging biodevices with bio-inspired dynamic bio-interfaces for accommodating the dynamic natures of cell functions or human body tissues on molecular-, nano-/micro-, and macro-scales, which hold promises to bring in breakthroughs to some future technologies such as personalized medicine, artificial organs, and human-machine interaction and integration.

Engineering the drug carrier biointerface to overcome biological barriers to drug delivery.

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery. In this review, we examine how key material design parameters lead to dynamic biointerfaces and improved drug delivery across biological barriers. We provide a brief overview of approaches used to engineer key physicochemical properties of drug carriers, such as morphology, surface chemistry, and topography, as well as the development of dynamic responsive materials for barrier navigation. We then discuss essential biological barriers and how biointerface engineering can enable drug carriers to better navigate and overcome these barriers to drug delivery.

Biomimetic fabrication of dynamic biointerfaces with optional and diversified bioactivities through reversible covalent and bioorthogonal chemistry

As extracellular matrix (ECM) mimics, dynamic biointerfaces with reversible ligand presentation have shown great significance in the field of biology and medicine. However, current systems are trapped in the monotony of bioactivity, which makes it hard to mimic the multipotential of natural ECM. In this work, we reported a dynamic biomaterial interface with optional and diversified bioactivities by the combination of reversible catechol-boronate and bioorthogonal click chemistry. Due to the specificity and thoroughness of bioorthogonal reaction, different types of biomolecules including small molecular saccharide, macromolecular peptides and DNA aptamers could be on-demand and reversible binding on biomaterial interfaces through sugar-sensitive catechol-boronate interactions. In this design, the obtained dynamic biointerface showed biocompatible sugar-responsiveness and enabled reversible presentation of diversified bioactivities, exhibiting the multipotential to manipulate a variety of cell-biomaterial interactions. Cell capture/release experiments confirmed our dynamic biointerface could reversibly and selectively bind different cancer cells and even the bacterial microorganism. In short, apart from the original significance in ECM mimicking, the optional and diversified bioactivities on our developed dynamic biointerface will also show promising prospects in biomedical science, in particular, the cell isolation area for diagnostics and therapeutics.

Mobility Tuning of Polyrotaxane Surfaces to Stimulate Myocyte Differentiation

Polyrotaxanes, consisting of poly(ethylene glycol) and α-cyclodextrins, are mechanically interlocked supermolecules. The structure allows α-cyclodextrins to move along the polymer, referred to as molecular mobility. Here, polyrotaxane-based triblock copolymers, composed of polyrotaxanes with different degrees of methylation and poly(benzyl methacrylate) at both terminals, are coated on culture surfaces to fabricate dynamic biointerfaces for myocyte differentiation. The molecular mobility increases with the degree of methylation and the contact angle hysteresis of water droplets and air bubbles. When the mouse myoblast cell line C2C12 is cultured on methylated polyrotaxane surfaces, the expression levels of myogenesis-related genes, myogenin (Myog) and myosin heavy chain (Myhc) are altered by the degree of methylation. Polyrotaxane surfaces with intermediate degrees of methylation promote the highest expression levels among all the surfaces. The polyrotaxane surface provides an appropriate environment for myocyte differentiation by accurately adjusting the degrees of methylation.

A Magnetic Dynamic Microbiointerface with Biofeedback Mechanism for Cancer Cell Capture and Release.

Dynamic biointerfaces with reversible surface bioactivities enable dynamic modulation of cell-material interactions, thus attracting great attention in biomedical science. Herein, we demonstrated a paradigm shift of dynamic biointerfaces from macroscopical substrates to micron-sized particles by reversible engineering of a phenylboronic acid (PBA)-functionalized magnetic microbead with mussel-inspired cancer cell-targeting peptide. Due to reversible catechol-boronate interactions between the peptides and microbeads, the micron-sized dynamic biointerface exhibited sugar-responsive cancer-targeting activity, showing the potential as a microplatform for magnetic and noninvasive isolation of cancer cells through natural biofeedback mechanism (e.g., human glycemic volatility). Our results demonstrated that the dynamic magnetic platform was capable of selective cancer cell capture (∼85%) and sugar-triggered release of them (>93%) in cell culture medium with high efficiency. More importantly, by using this platform, a decent number of target cells (∼23 on average) could be magnetically isolated and identified from artificial CTC blood samples (1 mL) spiked with 100 cancer cells. In view of the biomimetic nature, high capture efficiency, excellent selectivity, and superiority in cell separation and purification processes, the dynamic magnetic microplatform reported here would be a promising and general tool for rare cell detection and separation and cell-based disease diagnosis.

Dynamic Synthetic Biointerfaces: From Reversible Chemical Interactions to Tunable Biological Effects.

Dynamic synthetic biointerface is a new concept of biomaterials with smart surface properties capable of controlled display of bioactive ligands, dynamic modulation of cell-biomaterial interactions, and subsequently clever manipulation of fundamental cell behaviors like adhesion, migration, proliferation, differentiation, apoptosis, and so on. As mimics of the extracellular matrix (ECM), such molecularly dynamic biointerfaces have attracted increasing attention because of their tunable biological effects with great significance in in situ cell biology, tissue engineering, drug targeting, and cell isolation for cancer theranostics. Approaches to control bioligand presentation on materials mainly rely on surface functionalization with dynamic or reversible chemical linkers to which the ligands are tethered. Photoelectric-transformable or photocleavable chemistry, host-guest supramolecular chemistry, and multiple noncovalent interactions were initially employed for fabrication of dynamic synthetic biointerfaces. However, the external stimuli required in these systems, including electrochemical potential, electrochemical reaction, and near-infrared or UV light, are mostly invasive to living cells; and few of them are able to respond to the stimuli occurring in natural biological processes. In addition, most of current systems focused only on the control of cell adhesion, other cell behaviors like migration, differentiation and apoptosis have rarely been explored. Therefore, the development of novel synthetic biointerfaces that permit access to noninvasive control of diverse cell behaviors still represents a key challenge in biomaterials science. Our group pioneers the use of reversible covalent bonds, metal coordinative interactions, and the molecular affinity of molecularly imprinted synthetic receptors as the dynamic driving forces for the fabrication of smart biointerfaces. Several typical biological stimuli, such as glycemic volatility, body temperature fluctuations, regional disparity of pH values, and specific biomolecules, were tactfully involved in our systems. In this Account, we highlight the strategies we have used on the exploitation of dynamic synthetic biointerfaces based on the above three types of reversible chemical interactions. While our attention has been focused on biologically stimuli-responsive or other noninvasive ligand presentation, the versatility of dynamic synthetic biointerfaces in control of cell adhesion, directing cell differentiation, and targeting cell apoptosis has also been successfully demonstrated. In addition, a paradigm shift of dynamic synthetic biointerfaces from macroscopic to microscopic scale (e.g., nanobiointerfaces) was conceptually demonstrated in our research. The potential applications of these developed dynamic systems, including fundamental cell biology, surface engineering of biomaterials, scaffold-free tissue engineering, cell-based cancer diagnosis, and drug targeting cancer therapy, were also introduced, respectively. Although the development of dynamic synthetic biointerfaces is still in its infancy, we strongly believe that further efforts in this field will play a continuously and increasingly significant role in bridging the gap between chemistry and biology.

An Epitope-Imprinted Biointerface with Dynamic Bioactivity for Modulating Cell-Biomaterial Interactions.

In this study, an epitope‐imprinting strategy was employed for the dynamic display of bioactive ligands on a material interface. An imprinted surface was initially designed to exhibit specific affinity towards a short peptide (i.e., the epitope). This surface was subsequently used to anchor an epitope‐tagged cell‐adhesive peptide ligand (RGD: Arg‐Gly‐Asp). Owing to reversible epitope‐binding affinity, ligand presentation and thereby cell adhesion could be controlled. As compared to current strategies for the fabrication of dynamic biointerfaces, for example, through reversible covalent or host–guest interactions, such a molecularly tunable dynamic system based on a surface‐imprinting process may unlock new applications in in situ cell biology, diagnostics, and regenerative medicine.

An Epitope‐Imprinted Biointerface with Dynamic Bioactivity for Modulating Cell–Biomaterial Interactions

AbstractIn this study, an epitope‐imprinting strategy was employed for the dynamic display of bioactive ligands on a material interface. An imprinted surface was initially designed to exhibit specific affinity towards a short peptide (i.e., the epitope). This surface was subsequently used to anchor an epitope‐tagged cell‐adhesive peptide ligand (RGD: Arg‐Gly‐Asp). Owing to reversible epitope‐binding affinity, ligand presentation and thereby cell adhesion could be controlled. As compared to current strategies for the fabrication of dynamic biointerfaces, for example, through reversible covalent or host–guest interactions, such a molecularly tunable dynamic system based on a surface‐imprinting process may unlock new applications in in situ cell biology, diagnostics, and regenerative medicine.

Cell Adhesion on Dynamic Supramolecular Surfaces Probed by Fluid Force Microscopy-Based Single-Cell Force Spectroscopy.

Biomimetic and stimuli-responsive cell-material interfaces are actively being developed to study and control various cell-dynamics phenomena. Since cells naturally reside in the highly dynamic and complex environment of the extracellular matrix, attempts are being made to replicate these conditions in synthetic biomaterials. Supramolecular chemistry, dealing with noncovalent interactions, has recently provided possibilities to incorporate such dynamicity and responsiveness in various types of architectures. Using a cucurbit[8]uril-based host–guest system, we have successfully established a dynamic and electrochemically responsive interface for the display of the integrin-specific ligand, Arg-Gly-Asp (RGD), to promote cell adhesion. Due to the weak nature of the noncovalent forces by which the components at the interface are held together, we expected that cell adhesion would also be weaker in comparison to traditional interfaces where ligands are usually immobilized by covalent linkages. To assess the stability and limitations of our noncovalent interfaces, we performed single-cell force spectroscopy studies using fluid force microscopy. This technique enabled us to measure rupture forces of multiple cells that were allowed to adhere for several hours on individual substrates. We found that the rupture forces of cells adhered to both the noncovalent and covalent interfaces were nearly identical for up to several hours. We have analyzed and elucidated the reasons behind this result as a combination of factors including the weak rupture force between linear Arg-Gly-Asp and integrin, high surface density of the ligand, and increase in effective concentration of the supramolecular components under spread cells. These characteristics enable the construction of highly dynamic biointerfaces without compromising cell-adhesive properties.

Dynamic biointerfaces: from recognition to function.

The transformation of recognition signals into regulating macroscopic behaviors of biological entities (e.g., biomolecules and cells) is an extraordinarily challenging task in engineering interfacial properties of artificial materials. Recently, there has been extensive research for dynamic biointerfaces driven by biomimetic techniques. Weak interactions and chirality are two crucial routes that nature uses to achieve its functions, including protein folding, the DNA double helix, phospholipid membranes, photosystems, and shell and tooth growths. Learning from nature inspires us to design dynamic biointerfaces, which usually take advantage of highly selective weak interactions (e.g., synergetic chiral H-bonding interactions) to tailor their molecular assemblies on external stimuli. Biomolecules can induce the conformational transitions of dynamic biointerfaces, then drive a switching of surface characteristics (topographic structure, wettability, etc.), and eventually achieve macroscopic functions. The emerging progresses of dynamic biointerfaces are reviewed and its role from molecular recognitions to biological functions highlighted. Finally, a discussion is presented of the integration of dynamic biointerfaces with the basic biochemical processes, possibly solving the big challenges in life science.

Formation of supported bacterial lipid membrane mimics

In recent years, a large effort has been spent on advancing the understanding of how surface-supported membranes are formed through vesicle fusion. The aim is to find simple model systems for investigating biophysical and biochemical interactions between constituents of cell membranes and, for example, drugs and toxins altering membrane function. Designing and controlling the self-assembly of model membranes onto sensor substrates thus constitutes an important field of research, enabling applications in, e.g., drug screening, dynamic biointerfaces, artificial noses, and research on membrane-active antibiotics. The authors have developed and investigated the formation of strongly negatively charged supported lipid membranes which systematically mimic bacterial membrane composition on three important biosensor materials: SiO(2), TiO(2), and indium tin oxide. By tuning the electrostatic interaction through balancing the lipid vesicle charge with the ionic strength of Ca(2+) as a fusion promoter, the authors have optimized the self-assembly and obtained new insights into the details of lipid vesicle-surface interaction. The results will be useful for future development and application of specialized lipid membrane surface coatings prepared from complex lipid compositions. The adsorption processes were characterized by a quartz crystal microbalance with dissipation monitoring, optical waveguide lightmode spectroscopy, and fluorescence recovery after photobleaching, which allowed the determination of formation also of nonplanar supported lipid membranes.