Smart‐Responsive Multifunctional Therapeutic System for Improved Regenerative Microenvironment and Accelerated Bone Regeneration via Mild Photothermal Therapy

Abstract

The treatment of bone defects remains a substantial clinical challenge due to the lack of spatiotemporal management of the immune microenvironment, revascularization, and osteogenic differentiation. Herein, deferoxamine (DFO)‐loaded black phosphorus nanosheets decorated by polydopamine layer are prepared (BPPD) and compounded into gelatin methacrylate/sodium alginate methacrylate (GA) hybrid hydrogel as a smart‐responsive therapeutic system (GA/BPPD) for accelerated bone regeneration. The BPPD nanocomposites served as bioactive components and near‐infrared (NIR) photothermal agents, which conferred the hydrogel with excellent NIR/pH dual‐responsive properties, realizing the stimuli‐responsive release of DFO and PO43 − during bone regeneration. Under the action of NIR‐triggered mild photothermal therapy, the GA/BPPD hydrogel exhibited a positive effect on promoting osteogenesis and angiogenesis, eliminating excessive reactive oxygen species, and inducing macrophage polarization to the M2 phenotype. More significantly, through macrophage M2 polarization‐induced osteoimmune microenvironment, this hydrogel platform could also drive functional cytokine secretion for enhanced angiogenesis and osteogenesis. In vivo experiments further demonstrated that the GA/BPPD system could facilitate bone healing by attenuating the local inflammatory response, increasing the secretion of pro‐healing factors, stimulating endogenous cell recruitment, and accelerating revascularization. Collectively, the proposed intelligent photothermal hydrogel platform provides a promising strategy to reshape the damaged tissue microenvironment for augmented bone regeneration.

Photothermal hydrogels for infection control and tissue regeneration

“…Recently, Wu et al successfully prepared GA BPPD hydrogels by encapsulating polydopamine-decorated deferoxamine (DFO)-loaded black phosphorus nanosheets (BPPD) in gelatin methacrylate/sodium alginate methacrylate (GA). Under mild NIR light irradiation conditions, the hydrogel induced macrophage polarization toward the M2 phenotype and promoted anti-inflammatory activity, angiogenesis, and release of osteoblast factors, thereby enhancing angiogenesis and attracting endogenous stem cells, which are key to the early stages of tissue healing ( Figure 6 ) ( Wu et al, 2024 ).…”

“… Schematic illustration for fabrication and application of smart-responsive multifunctional therapeutic system with mild photothermal activity for augmented bone regeneration through spatiotemporal manipulation of the immune microenvironment, stem cell recruitment and vascular development, and osteogenic differentiation throughout the whole healing process. Reproduced from ref ( Wu et al, 2024 ) with permission from Wiley, copyright 2024. …”

3D Printed Porous Zirconia Biomaterials based on Triply Periodic Minimal Surfaces Promote Osseointegration In Vitro by Regulating Osteoimmunomodulation and Osteo/Angiogenesis

“…Macrophages, as key effector cells in immune response, undergo polarization into the proinflammatory M1 type initially to participate in immune response and subsequently transform into the anti-inflammatory M2 type during the dynamic process of bone repair . Accumulating mounting evidence suggests that biomaterials with immunomodulatory properties can induce macrophage polarization toward an anti-inflammatory M2 phenotype, thereby creating a prohealing microenvironment that facilitates bone defect regeneration. − Meanwhile, porous biphasic calcium phosphate (BCP) ceramics can enhance the proportion of CD206 + M2 macrophages in vitro, upregulate the expression of markers associated with the M2 phenotype, increase ARG + M2 levels in vivo, and exhibit favorable osteoinductive potential …”

Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis

“…Besides, Qi et al found that NIR-derived mild thermal stimulation could protect cells from ROS-induced oxidative damage by inhibiting the activation of the nuclear transcription factor-κB (NF-κB) signaling pathway, thereby promoting tissue regeneration under chronic inflammatory conditions 21 . Motivated by these investigations, we previously designed a series of photothermal effect-reinforced multifunctional scaffolds for integrated immune regulation, vascular regeneration, bacterial elimination, and bone repair 22 , 23 . Nevertheless, the potential impact and mechanism of photothermal biomaterials on diabetic bone regeneration are still unclear, and we cannot completely address diabetic inflammatory microenvironment-induced complications, including high levels of ROS, inflammation, weak tissue regeneration ability, and susceptibility to bacterial infection.…”