Hydrogels composed of natural biopolymers are attractive for tissue regeneration applications owing to their advantages such as biocompatibility and ease of administration, etc.. Yet, the low oxygen level and the crosslinked network inside bulk hydrogels, as well as the hypoxic status in defect areas, hamper cell viability, function, and eventual tissue repair. Herein, based on Ca2+-crosslinked alginate hydrogel, oxygen-generating calcium peroxide (CaO2) was introduced, which could provide a dynamic crosslinking alongside the CaO2 decomposition. Compared to the CaCl2-crosslinked alginate hydrogel, bone marrow mesenchymal stromal cells cultured with CaO2-contained system displayed remarkably improved biological behaviors. Furthermore, in vivo evaluations were carried out on a subcutaneous implantation in rats, and the results demonstrated the importance of the local oxygen availability in a series of crucial events for tissue regeneration, such as activating cell viability, migration, angiogenesis, and osteogenesis. In summary, the obtained Ca2+-crosslinked alginate hydrogel achieved a better microenvironment for cell ingrowth and potential tissue regeneration as the CaCl2 crosslinker being replaced by oxygen-generating CaO2 nanoparticles, due to its contribution in remedying the local hypoxic condition, promisingly, the release of Ca2+ makes the hydrogel to be a possible candidate scaffold for bone tissue engineering. 

Self-reinforcement hydrogel with sustainable oxygen-supply for enhanced cell ingrowth and potential tissue regeneration.

The skeletal system is essential for preserving body structure and facilitating mobility; however, bone diseases frequently result in significant disabilities, necessitating the investigation into biomaterials for bone restoration. Nevertheless, these biomaterials may elicit immune reactions that obstruct the healing process. Macrophages assume a pivotal role in modulating inflammation and sustaining immune homeostasis essential for bone regeneration. A comprehensive understanding of the molecular interactions between biomaterials and macrophages is imperative for the development of sophisticated biomaterials designed to regulate the bone immune environment and promote bone remodeling. This review delves into the generation, polarization, and interaction of macrophages with principal cell types implicated in osteogenesis, detailing the molecular mechanisms by which macrophages influence bone repair and their response to biomaterials. Additionally, it discusses strategies for the precise modulation of macrophage functionality via intelligent mechanisms, and outlines the challenges and constraints in designing biomaterials that integrate bone immune functions. By elucidating these mechanisms and challenges, the review lays the groundwork for the creation of advanced biomaterials endowed with smart bone immunomodulatory capabilities, heralding novel approaches for the treatment of bone defects and the advancement of bone regeneration therapies. 

Macrophage-mediated immunomodulation in biomaterial-assisted bone repair: Molecular insights and therapeutic prospects

The utilization of 3D printing has become increasingly common in the construction of composite scaffolds. In this study, magnetic mesoporous bioactive glass (MMBG) was incorporated into polyhydroxybutyrate (PHB) to construct extrusion-based 3D printed scaffold. After fabrication of the PHB/MMBG composite scaffolds, they were coated with chitosan (Cs) and chitosan/multi-walled carbon nanotubes (Cs/MWCNTs) solutions utilizing deep coating method. FTIR was conducted to confirm the presence of Cs and MWCNTs on the scaffolds' surface. The findings of mechanical analysis illustrated that presence of Cs/MWCNTs on the composite scaffolds increases compressive young modulus significantly, from 16.5 to 42.2 MPa. According to hydrophilicity evaluation, not only MMBG led to decrease the contact angle of pure PHB but also scaffolds surface modification utilization of Cs and MWCNTs, the contact angle decreased significantly from 82.34° to 54.15°. Furthermore, investigation of cell viability, cell metabolism and inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) proved that the scaffolds not only do not stimulate the immune system, but also polarize macrophage cells from M1 phase to M2 phase. The present study highlights the suitability of 3D printed scaffold PHB/MMBG with Cs/MWCNTs coating for bone tissue engineering. 

Chitosan/MWCNTs nanocomposite coating on 3D printed scaffold of poly 3-hydroxybutyrate/magnetic mesoporous bioactive glass: A new approach for bone regeneration.

The distribution, phenotype, and requirement of macrophages for fracture-associated inflammation and/or early anabolic progression during endochondral callus formation were investigated. A murine femoral fracture model [internally fixed using a flexible plate (MouseFix)] was used to facilitate reproducible fracture reduction. IHC demonstrated that inflammatory macrophages (F4/80+Mac-2+) were localized with initiating chondrification centers and persisted within granulation tissue at the expanding soft callus front. They were also associated with key events during soft-to-hard callus transition. Resident macrophages (F4/80+Mac-2neg), including osteal macrophages, predominated in the maturing hard callus. Macrophage Fas-induced apoptosis transgenic mice were used to induce macrophage depletion in vivo in the femoral fracture model. Callus formation was completely abolished when macrophage depletion was initiated at the time of surgery and was significantly reduced when depletion was delayed to coincide with initiation of early anabolic phase. Treatment initiating 5 days after fracture with the pro-macrophage cytokine colony stimulating factor-1 significantly enhanced soft callus formation. The data support that inflammatory macrophages were required for initiation of fracture repair, whereas both inflammatory and resident macrophages promoted anabolic mechanisms during endochondral callus formation. Overall, macrophages make substantive and prolonged contributions to fracture healing and can be targeted as a therapeutic approach for enhancing repair mechanisms. Thus, macrophages represent a viable target for the development of pro-anabolic fracture treatments with a potentially broad therapeutic window...

Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification

An overview of nanobioceramics-reinforced chitosan combined with cells and growth factors for bone tissue engineering applications. 

Nanoceramics-reinforced Chitosan Scaffolds for Bone Tissue Engineering

Alginate/chitosan modified immunomodulatory titanium implants for promoting osteogenesis in vitro and in vivo

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Alginate/chitosan modified immunomodulatory titanium implants for promoting osteogenesis in vitro and in vivo