Strontium-Containing Piezoelectric Biofilm Promotes Dentin Tissue Regeneration.

It remains an obstacle to induce the regeneration of hard dentin tissue in clinical settings. To overcome this, a P(VDF-TrFE) piezoelectric film with 2 wt% SrCl2 addition is designed. The biofilm shows a high flexibility, a harmonious biocompatibility, and a large piezoelectric d33 coefficient of 14 pC N-1, all contributing to building an electric microenvironment that favor the recruitment of dental pulp stem cells (DPSCs) and their differentiation into odontoblasts during normal chewing, speaking, etc. On the other hand, the strontium ions can be gradually released from the film, thus promoting DPSC odonto-differentiation. In vivo experiments also demonstrate that the film induces the release of dentin minerals and regeneration of dentin tissue. In the large animal dentin defect models, this piezoelectric film induces in situ dentin tissue formation effectively over a period of three months. This study illustrates a therapeutic potential of the piezoelectric film to improve dentin tissue repair in clinical settings.

Stabilization of Bio-Oss® particulates using photocurable hydrogel to enhance bone regeneration by regulating macrophage polarization.

Bone substitutes are widely used in maxillofacial and oral surgeries. However, in clinical practice, bone substitutes with various forms, including separated particulates, powders, and blocks, have exhibited poor handling properties and space maintenance characteristics, resulting in long surgery procedures and unstable volume of the newly formed bone. Movable separated particulates with high stiffness have induced local inflammatory responses that hinder bone regeneration. The present study aimed to develop a new method to enhance the stability and operability of bone substitutes commonly used in dentistry by premixing with photocurable hydrogel GelMA. The GelMA-encapsulated particulate had a strong capacity to aggregate separated particulates and firmly attach to the host bone defect after photocuring compared to particulates alone. Additionally, macrophages at the surface of the GelMA-stabilized particulates tended to present a more M2-like phenotype than those at the surface of Bio-Oss®, leading to more MMR+ multinucleated giant cell formation and the induction of blood vessel invasion and new bone formation. In conclusion, this hydrogel-coated bone substitute strategy facilitates bone regeneration with increased operability, a stable volume of osteogenic space, and a favorable osteogenic microenvironment, indicating its potential value in the field of maxillofacial and oral surgeries when bone substitutes are needed.

Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment.

Bone morphogenetic protein (BMP-2) has been approved by the FDA to promote bone regeneration, but uncertain osteogenic effect and dose-dependent side effects may occur. Osteoimmunomodulation plays an important role in growth factor-based osteogenesis. Here, we explored how proinflammatory signals affect the dose-dependent osteogenic potential of BMP-2. We observed that the expression level of local IL-1ß did not increase with the dose of BMP-2 in the mouse osteogenesis model. A low dose of BMP-2 could not promote new bone formation, but trigger the release of IL-1ß from M1 macrophages. As the dose of BMP-2 increased, the IL-1ß expression and M1 infiltration in local microenvironment were inhibited by IL-1Ra from MSCs under osteogenic differentiation induced by BMP-2, and new bone tissues formed, even excessively. Anti-inflammatory drugs (Dexamethasone, Dex) promoted osteogenesis via inhibiting M1 polarization and enhancing BMP-2-induced MSC osteo-differentiation. Thus, we suggest that the osteogenic effect of BMP-2 involves macrophage-MSC interaction that is dependent on BMP-2 dose and based on IL-1R1 ligands, including IL-1ß and IL-1Ra. The dose of BMP-2 could be reduced by introducing immunoregulatory strategies.

Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu.

Type II diabetes mellitus (TIIDM) remains a challenging clinical issue for both dentists and orthopedists. By virtue of persistent hyperglycemia and altered host metabolism, the pathologic diabetic micromilieu with chronic inflammation, advanced glycation end products accumulation, and attenuated biomineralization severely impairs bone regeneration efficiency. Aiming to "remodel" the pathologic diabetic micromilieu, we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles (Sr-MBGNs) and gelatin methacrylate (GelMA). Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr, Ca, and Si ions enhancing osteogenic, angiogenic, and immunomodulatory properties. In addition to angiogenic and anti-inflammatory outcomes, this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen, promoting cell focal adhesion, modulating osteoblast differentiation, and boosting the release of OCN, the noncollagenous proteins (intrafibrillar mineralization dependent), and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis. This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the "barren" diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.