Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia‐Mimetic Hydrogel

Abstract

Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)‐co‐poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia‐mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion‐chelating after injection, giving rise to the activation of HIF‐1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF‐1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial‐based iron ion‐chelating and ensuing hypoxia‐mimicking, representing a novel and promising concept for future application in bone regeneration.

Structurally Dynamic Hydrogels for Biomedical Applications: Pursuing a Fine Balance between Macroscopic Stability and Microscopic Dynamics

“…MSCs, derived primarily from the bone marrow, are capable of differentiating into different mesenchymal tissues including cartilage, bone, tendon, ligament, muscle, and adipose tissue. , Many studies on engineering MSC microenvironments have focused on controlling MSC differentiation into bone or cartilage for orthopedic tissue engineering applications. − Nevertheless, these tissue engineering applications commonly require the expansion of large numbers of MSCs prior to differentiation; , thus, designing an engineered niche for stem cell expansion may promote the transition of MSC-based therapies to the clinic. − MSCs are also known for their functions in immunomodulation. Many preclinical and clinical studies have shown that MSCs have anti-inflammatory and immune-privilege potential and suggested a key role of MSCs in regulating T cells and monocytes through either cytokine-dependent or cytokine-independent mechanisms. − These applications highlight once again the necessity of developing proper conditions for MSC expansion and behavior regulation.…”

Special Features of Polyester-Based Materials for Medical Applications

“…Poly(glycerol sebacate) (PGS) is a polyester synthesized from glycerin-3 and sebacic acid-2 that has received considerable attention in tissue-engineering applications [ 80 ]. PGS was modified by 3D-printing technology with nano-HA [ 32 ], PEG/TCP [ 81 ], PHB [ 82 ], PCL [ 83 , 84 ], poly(vinyl alcohol) (PVA) [ 85 ], and poly(acrylic acid) (PAA) [ 86 ] to obtain potential scaffolds for reconstruction of bone tissue, especially craniofacial bone. Among the characteristics of an ideal polyester for bone regeneration, there is increasing interest in the development of novel materials with antibacterial properties [ 87 ].…”

Mechanisms and applications of bioinspired underwater/wet adhesives

“…125,126 Therefore, there is an urgent demand for bone adhesives with low biological toxicity, high mechanical strength, strong water-resistant adhesion, high success rate for bone healing, and excellent fixation performance in wet biological environments. [127][128][129] The ideal bone adhesive can promote new bone regeneration and receive special attention as alternative treatments, offering the potential to make bone repair more personal. Using adhesives to replace traditional invasive materials for bone fracture fixation and repair may revolutionize orthopedic surgery.…”