Physical and Soluble Cues Enhance Tendon Progenitor Cell Invasion into Injectable Synthetic Hydrogels

Abstract

Synthetic hydrogels represent an exciting avenue in the field of regenerative biomaterials given their injectability, orthogonally tunable mechanical properties, and potential for modular inclusion of cellular cues. Separately, recent advances in soluble factor release technology have facilitated control over the soluble milieu in cell microenvironments via tunable microparticles. A composite hydrogel incorporating both of these components can robustly mediate tendon healing following a single injection. Here, a synthetic hydrogel system with encapsulated electrospun fiber segments and a novel microgel‐based soluble factor delivery system achieves precise control over topographical and soluble features of an engineered microenvironment, respectively. It is demonstrated that three‐dimensional migration of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle‐delivered soluble cues in both a tendon progenitor cell spheroid model and an ex vivo murine Achilles tendon model. These results indicate that fiber reinforced hydrogels can drive the recruitment of endogenous progenitor cells relevant to the regeneration of tendon and, likely, a broad range of connective tissues.

Applications of functionally-adapted hydrogels in tendon repair

“…Mouse Achilles tendon explants were encapsulated in the hydrogel system to testify the effect of TPC recruitment. The hydrogel system significantly enhanced TPCs recruitment and induced tenogenic differentiation of TPCs ( Kent et al, 2022 ).…”

A precision microgel platform to direct vascular morphogenesisin vitro

“…In sum, our starPEG-sGAG μGUIDe platform for precision morphogen delivery presents significant advancements over previous approaches 4–7,12 to locally probe and engineer tissue development. A key advantage of this platform is the far-going tunability of the μGUIDe morphogen affinity achieved through the customizable charge properties (sulfation patterns and concentrations of the incorporated sGAG components), which offers unprecedented options in tailoring morphogen gradient formation with cellular resolution.…”

“… The dynamic organization of tissue development is reciprocally controlled by localized gradients of morphogens emanating from distinct clusters of cells that act as signaling centers 1 . While microgels 2,3 have shown promise to recapitulate this process in engineered tissue constructs, their capacity to tailor morphogen distribution in space and time remained limited 4–7 . Here, we introduce a library of sulfated glycosaminoglycan (sGAG)-based microgels that offer unprecedented control over morphogen affinity (μGUIDe, μGel Units to Instruct Development), thus enabling precise formation of concentration gradients.…”

“…Morphogen administration from reservoirs 8 and perfusable microchannels 9,10 provides control over dosage, but suffers from limited resolution, reliance on fluid flow, and possible spatial constraints to the developing tissues. An emerging alternative involves supplying morphogens via cell- or cell aggregate-sized microgels within tissue constructs 4–7,11,12 . However, current microgel materials are limited in the control and tunability of morphogen supply and thus concentration gradient formation.…”

Injectable Biomimetic Hydrogel Guided Functional Bone Regeneration by Adapting Material Degradation to Tissue Healing

“…Recently, injectable hydrogels have attracted increasing attention in tissue engineering and translational medicine because of their tunable physicochemical properties in response to the surrounding environment. [19,20] Wu et al reported a mild photothermal GelMA/PMMA/PDA hydrogel platform with beneficial osteogenic ability for bone defect regeneration. [21] Zhou et al constructed a hydrogel platform with tunable stiffness based on magnetic nanoparticles cross-linked GelMA for cartilage regeneration.…”