Developing materials with remote controllability of macroscale ligand presentation can mimic extracellular matrix (ECM) remodeling to regulate cellular adhesion in vivo. Herein, we designed charged mobile nanoligands with superparamagnetic nanomaterials amine-functionalized and conjugated with polyethylene glycol linker and negatively charged RGD ligand. We coupled negatively a charged nanoligand to a positively charged substrate by optimizing electrostatic interactions to allow reversible planar movement. We demonstrate the imaging of both macroscale and in situ nanoscale nanoligand movement by magnetically attracting charged nanoligand to manipulate macroscale ligand density. We show that in situ magnetic control of attracting charged nanoligand facilitates stem cell adhesion, both in vitro and in vivo, with reversible control. Furthermore, we unravel that in situ magnetic attraction of charged nanoligand stimulates mechanosensing-mediated differentiation of stem cells. This remote controllability of ECM-mimicking reversible ligand variations is promising for regulating diverse reparative cellular processes in vivo.
Cells dynamically interact with native nanostructured extracellular matrix at a molecular level in vivo. Developing remotely and actively controllable nanoengineered biomaterials can manipulate and unravel complex cell-material interactions that dynamically occur in the nanoscale in vivo. In this review, we discuss emerging advances in a myriad of recent nanoengineering technologies to design remotely manipulable materials that enable dynamic nanobiomedical engineering at the molecular level. In particular, we focus on remote active stimuli, such as magnetic fields, light, in situ self-assembly, and ultrasound, to manipulate dynamic cell-material interactions in both in vitro and in vivo settings. Remote active control can be particularly appealing with targeting capability for particular locations at any prescribed time points with a degree of reversibility. The unique remote controllability enables the regulation of cellular signaling, adhesion, differentiation, and polarization; cell, drug, and gene delivery; and in situ self-assembly. These materials allow the remote control in regenerative medicine, immunotherapy, cancer therapy, and biocatalysis as well as mechanistic studies on dynamic nanoscale cell-material interactions. We also highlight current challenges in the remote active control, such as reproducibility, tissue-penetrative capability, noninvasive surgery, spatial localization, and temporal variation. Albeit remotely and actively controllable nanoengineered biomaterials are in the nascent stage of development, they can evolve into multiresponsive, reversible, and cost-effective three-dimensional systems with safe and convenient long-term control at the cell, tissue, and organ level toward clinical patient-tailorable on-demand therapy. K E Y W O R D S dynamic nanobiomedical engineering, magnetic control, nanoengineered biomaterial, photonic control, remote active control, self-assembly-based control This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Natural extracellular matrix (ECM) can regulate the interactions between cells and ligands by exhibiting heterogeneous nano-sequences periodically displaying adhesive ligands, such as RGD ligand in vivo. [1,2] Cell-adhesive ECM proteins, such as fibronectin, vitronectin, and collagen, were shown to form periodically sequenced RGD ligand-bearing nanostructures (67-100 nm). [1] Periodic structure in reflectance was also observed from native tissues. [2] The ligation of integrin with adhesive ligand mediates the assembly of cytoskeletal actin filaments and focal adhesion (FA) complexes to activate mechanosensing signaling pathways that can regulate cellular differentiation. [3,4] Strategically developing materials with heterogeneously sequenced ligand nanostructures can emulate ECM [5] microenvironment to help elucidate the interactions between cells and nano-ligands with tunable frequency and sequences. This can effectively regulate diverse cellular adhesion and functionality in vivo, such as FA, mechanosensing, and differentiation of stem cells. [6] The native extracellular matrix (ECM) can exhibit heterogeneous nanosequences periodically displaying ligands to regulate complex cell-material interactions in vivo. Herein, an ECM-emulating heterogeneous barcoding system, including ligand-bearing Au and ligand-free Fe nano-segments, is developed to independently present tunable frequency and sequences in nano-segments of cell-adhesive RGD ligand. Specifically, similar exposed surface areas of total Fe and Au nano-segments are designed. Fe segments are used for substrate coupling of nanobarcodes and as ligand-free nanosegments and Au segments for ligand coating while maintaining both nanoscale (local) and macroscale (total) ligand density constant in all groups. Low nano-ligand frequency in the same sequences and terminally sequenced nano-ligands at the same frequency independently facilitate focal adhesion and mechanosensing of stem cells, which are collectively effective both in vitro and in vivo, thereby inducing stem cell differentiation. The Fe/RGD-Au nanobarcode implants exhibit high stability and no local and systemic toxicity in various tissues and organs in vivo. This work sheds novel insight into designing biomaterials with heterogeneous nano-ligand sequences at terminal sides and/or low frequency to facilitate cellular adhesion. Tuning the electrodeposition conditions can allow synthesis of unlimited combinations of ligand nano-sequences and frequencies, magnetic elements, and bioactive ligands to remotely regulate numerous host cells in vivo.
The receptor−ligand interactions in cells are dynamically regulated by modulation of the ligand accessibility. In this study, we utilize size-tunable magnetic nanoparticle aggregates ordered at both nanometer and atomic scales. We flexibly anchor magnetic nanoparticle aggregates of tunable sizes over the cell-adhesive RGD ligand (Arg-Gly-Asp)-active material surface while maintaining the density of dispersed ligands accessible to macrophages at constant. Lowering the accessible ligand dispersity by increasing the aggregate size at constant accessible ligand density facilitates the binding of integrin receptors to the accessible ligands, which promotes the adhesion of macrophages. In high ligand dispersity, distant magnetic manipulation to lift the aggregates (which increases ligand accessibility) stimulates the binding of integrin receptors to the accessible ligands available under the aggregates to augment macrophage adhesion-mediated pro-healing polarization both in vitro and in vivo. In low ligand dispersity, distant control to drop the aggregates (which decreases ligand accessibility) repels integrin receptors away from the aggregates, thereby suppressing integrin receptor− ligand binding and macrophage adhesion, which promotes inflammatory polarization. Here, we present "accessible ligand dispersity" as a novel fundamental parameter that regulates receptor−ligand binding, which can be reversibly manipulated by increasing and decreasing the ligand accessibility. Limitless tuning of nanoparticle aggregate dimensions and morphology can offer further insight into the regulation of receptor−ligand binding in host cells.
Native extracellular matrix (ECM) can exhibit cyclic nanoscale stretching and shrinking of ligands to regulate complex cell–material interactions. Designing materials that allow cyclic control of changes in intrinsic ligand‐presenting nanostructures in situ can emulate ECM dynamicity to regulate cellular adhesion. Unprecedented remote control of rapid, cyclic, and mechanical stretching (“ON”) and shrinking (“OFF”) of cell‐adhesive RGD ligand‐presenting magnetic nanocoils on a material surface in five repeated cycles are reported, thereby independently increasing and decreasing ligand pitch in nanocoils, respectively, without modulating ligand‐presenting surface area per nanocoil. It is demonstrated that cyclic switching “ON” (ligand nanostretching) facilitates time‐regulated integrin ligation, focal adhesion, spreading, YAP/TAZ mechanosensing, and differentiation of viable stem cells, both in vitro and in vivo. Fluorescence resonance energy transfer (FRET) imaging reveals magnetic switching “ON” (stretching) and “OFF” (shrinking) of the nanocoils inside animals. Versatile tuning of physical dimensions and elements of nanocoils by regulating electrodeposition conditions is also demonstrated. The study sheds novel insight into designing materials with connected ligand nanostructures that exhibit nanocoil‐specific nano‐spaced declustering, which is ineffective in nanowires, to facilitate cell adhesion. This unprecedented, independent, remote, and cytocompatible control of ligand nanopitch is promising for regulating the mechanosensing‐mediated differentiation of stem cells in vivo.
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