Integrated bioactive scaffold with aptamer‐targeted stem cell recruitment and growth factor‐induced pro‐differentiation effects for anisotropic meniscal regeneration

Abstract

Reconstruction of the knee meniscus remains a significant clinical challenge owing to its complex anisotropic tissue organization, complex functions, and limited healing capacity in the inner region. The development of in situ tissue-engineered meniscal scaffolds, which provide biochemical signaling to direct endogenous stem/progenitor cell (ESPC) behavior, has the potential to revolutionize meniscal tissue engineering. In this study, a fiber-reinforced porous scaffold was developed based on aptamer Apt19S-mediated mesenchymal stem cell (MSC)-specific recruitment and dual growth factor (GF)-enhanced meniscal differentiation. The aptamer, which can specifically recognize and recruit MSCs, was first chemically conjugated to the decellularized meniscus extracellular matrix (MECM) and then mixed with gelatin methacrylate (GelMA) to form a photocrosslinkable hydrogel. Second, connective tissue growth factor (CTGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and transforming growth factor-β3 (TGF-β3)-loaded PLGA microparticles (MPs) were mixed with aptamer-conjugated MECM to simulate anisotropic meniscal regeneration. These three bioactive molecules were delivered sequentially. Apt19S, which exhibited high binding affinity to synovium-derived MSCs (SMSCs), was quickly released to facilitate the mobilization of ESPCs. CTGF incorporated within PLGA NPs was released rapidly, inducing profibrogenic differentiation, while sustained release of TGF-β3 in PLGA MPs remodeled the fibrous matrix into fibrocartilaginous matrix.The in vitro results showed that the sequential release of Apt19S/GFs promoted cell Li Hao, Zhao Tianyuan, and Cao Fuyang contributed equally to this study.

Applications and prospects of different functional hydrogels in meniscus repair

“…Multiple studies reported that stem cells are useful in replacing the injured meniscus and restoring its native function when combined with tissue engineering ( Jacob et al, 2021 ; Bian et al, 2022 ). Basing in vitro and in vivo experiments, Li et al proved that Apt/GF-scaffolds increased neomeniscal formation in rabbit critical-sized meniscectomies through mesenchymal stem cell (MSC)-specific recruitment ( Li H. et al, 2022 ). Sasaki et al isolated stem cells from adipose, and demonstrated that adipose-derived stem cells (ASCs)-seeded hydrogels preloaded with TGF-β3 enhanced healing of radial meniscal tears in an in vitro meniscal repair model ( Sasaki et al, 2018 ).…”

Biodegradable Dual-Cross-Linked Hydrogels with Stem Cell Differentiation Regulatory Properties Promote Growth Plate Injury Repair via Controllable Three-Dimensional Mechanics and a Cartilage-like Extracellular Matrix

“…11 Notwithstanding that growth factors, such as transforming growth factor-β (TGF-β), can promote chondrogenic differentiation of MSCs, they yield significant off-target effects on the cartilage matrix and lead to hypertrophy of MSCs. 12 Moreover, the guidance of MSC differentiation through cell signaling by these growth factors occurs in a dose-and timedependent manner, with unstable and uncertain outcomes. Therefore, alternative strategies to promote chondrogenic differentiation and the survival rate of MSCs are urgently needed to refine cell transplantation therapy.…”

“…The conventional view is that chondrogenic differentiation of MSCs usually requires the induction of growth factors . Notwithstanding that growth factors, such as transforming growth factor-β (TGF-β), can promote chondrogenic differentiation of MSCs, they yield significant off-target effects on the cartilage matrix and lead to hypertrophy of MSCs . Moreover, the guidance of MSC differentiation through cell signaling by these growth factors occurs in a dose- and time-dependent manner, with unstable and uncertain outcomes .…”

Preparation of a composite hydrogel of polyvinyl alcohol/chitosan fiber with anisotropic properties for sustained drug release

“…[8][9][10]31 The diameter of fiber filler can be at the scale of nanometer, 18,19,25,32,33 or micron, 15,16,20 or even bigger. [12][13][14]17 The alignment of fiber filler can be completed by pre-stretching as mentioned above, and can also be realized during hydrogel formation. For example, Fu et al 34 have extruded a mixture containing precursor of 2-hydroxyethyl methacrylate and carbon fiber through the nozzle of a 3D printing system, in which the carbon fiber was aligned by the applied shear force; the monomer in the printed slurry was quickly polymerized to fix the aligned carbon fiber, so that a mechanically enhanced hydrogel with anisotropic microstructure and properties was prepared.…”

“…In addition to creating anisotropic microchannels, anisotropically aligning components of hydrogel can also lead to formation of anisotropic hydrogel. So, well ordered materials such as aligned wood cellulose skeleton 12,13 biodegradable fiber and fabric [14][15][16] and bacteria cellulose membrane 17 have been directly embedded in hydrogel as support for anisotropic hydrogel preparation. Liquid crystal of cholesteric phase can serve as strong filler to result in anisotropic structure and properties of the obtained hydrogel.…”