Magnetic Nanoparticle-Mediated Orientation of Collagen Hydrogels for Engineering of Tendon-Mimetic Constructs

Abstract

Despite the high incidence of tendon injuries worldwide, an optimal treatment strategy has yet to be defined. A key challenge for tendon repair is the alignment of the repaired matrix into orientations which provide maximal mechanical strength. Using oriented implants for tissue growth combined with either exogenous or endogenous stem cells may provide a solution. Previous research has shown how oriented fiber-like structures within 3D scaffolds can provide a framework for organized extracellular matrix deposition. In this article, we present our data on the remote magnetic alignment of collagen hydrogels which facilitates long-term collagen orientation. Magnetic nanoparticles (MNPs) at varying concentrations can be contained within collagen hydrogels. Our data show how, in response to the magnetic field lines, MNPs align and form string-like structures orientating at 90 degrees from the applied magnetic field from our device. This can be visualized by light and fluorescence microscopy, and it persists for 21 days post-application of the magnetic field. Confocal microscopy demonstrates the anisotropic macroscale structure of MNP-laden collagen gels subjected to a magnetic field, compared to gels without MNP dosing. Matrix fibrillation was compared between non- and biofunctionalized MNP hydrogels, and different gels dosed with varying MNP concentrations. Human adipose stem cells (hASCs) seeded within the magnetically aligned gels were observed to align in parallel to MNP and collagen orientation 7 days post-application of the magnetic field. hASCs seeded in isotropic gels were randomly organized. Tenocyte-likeness of the cells 7 days post-seeding in collagen I scaffolds was confirmed by the positive expression of tenomodulin and scleraxis proteins. To summarize, we have developed a convenient, non-invasive protocol to control the collagen I hydrogel architecture. Through the presence or absence of MNP dosing and a magnetic field, collagen can be remotely aligned or randomly organized, respectively, in situ. Tendon-like cells were observed to organize in parallel to unidirectionally aligned collagen fibers and polydirectionally in non-aligned collagen constructs. In this way, we were able to engineer the constructs emulating a physiologically and pathologically relevant tendon niche. This can be considered as an innovative approach particularly useful in tissue engineering or organ-on-a-chip applications for remotely controlling collagen matrix organization to recapitulate the native tendon.

Remote Activation of M2 Macrophage Polarization via Magneto-Mechanical Stimulation To Promote Osteointegration

“…A few studies had proposed the roles for magnetic-responsive biomaterial in promoting tissue regeneration. Aligned collagen fibers mediated by IOPs mimicked the structure of native tendon and could be used in tendon repair . In addition, a hydroxyapatite scaffold increased vascularization and bone regeneration via releasing vascular endothelial growth factor (VEGF) in a magnetic-controlled manner .…”

“…Aligned collagen fibers mediated by IOPs mimicked the structure of native tendon and could be used in tendon repair. 24 In addition, a hydroxyapatite scaffold increased vascularization and bone regeneration via releasing vascular endothelial growth factor (VEGF) in a magnetic-controlled manner. 25 In this study, the magnetic-responsive coating coordinately interacting with magnetic field, as a combination of biochemical and physical properties, was expected to modulate macrophage polarization and enhance osteointegration.…”

Strategies for Anisotropic Fibrillar Hydrogels: Design, Cell Alignment, and Applications in Tissue Engineering

“… , However, magnets with such a high magnetic field induction are quite difficult to find and may often be prohibited for use in many laboratories. Therefore, magnetic nanoparticles are often used to produce anisotropic hydrogels, which move toward the magnet and through their motion align the fibrils, which then bind. − This kind of experiment requires a magnetic field with much lower induction.…”

Magnetically anisotropic hydrogels for tissue engineering

“…These results highlight the feasibility of using magnetically anisotropic hydrogels for developing tendon-mimicking connective tissues. Furthermore, Wright et al 113 prepared collagen I hydrogels with anisotropic structures by adding anti-collagen I-labeled MNPs to a fluorescent collagen solution and immersing them in a 50–52 mT magnetostatic field for 30 min. It was observed that the F-actin filaments of hASCs seeded within the magnetically anisotropic hydrogel were unidirectional, parallel to the orientation of MNPs and fibrous collagen (Fig.…”