Liver‐Inspired Polyetherketoneketone Scaffolds Simulate Regenerative Signals and Mobilize Anti‐Inflammatory Reserves to Reprogram Macrophage Metabolism for Boosted Osteoporotic Osseointegration

Abstract

Tissue regeneration is regulated by morphological clues of implants in bone defect repair. Engineered morphology can boost regenerative biocascades that conquer challenges such as material bioinertness and pathological microenvironments. Herein, a correlation between the liver extracellular skeleton morphology and the regenerative signaling, namely hepatocyte growth factor receptor (MET), is found to explain the mystery of rapid liver regeneration. Inspired by this unique structure, a biomimetic morphology is prepared on polyetherketoneketone (PEKK) via femtosecond laser etching and sulfonation. The morphology reproduces MET signaling in macrophages, causing positive immunoregulation and optimized osteogenesis. Moreover, the morphological clue activates an anti‐inflammatory reserve (arginase‐2) to translocate retrogradely from mitochondria to the cytoplasm due to the difference in spatial binding of heat shock protein 70. This translocation enhances oxidative respiration and complex II activity, reprogramming the metabolism of energy and arginine. The importance of MET signaling and arginase‐2 in the anti‐inflammatory repair of biomimetic scaffolds is also verified via chemical inhibition and gene knockout. Altogether, this study not only provides a novel biomimetic scaffold for osteoporotic bone defect repair that can simulate regenerative signals, but also reveals the significance and feasibility of strategies to mobilize anti‐inflammatory reserves in bone regeneration.

Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications

“…d, e IF staining and biomarker (CCR7 and CD206) expression by flow cytometry of RAW 264.7 cells cultured on various scaffolds. f A heatmap describing the fold-change in expressed polarization genes after treatment with different groups [ 190 ]. Copyright 2023, Wiley–VCH GmbH.…”

“…Arg-2, another enzyme involved in L-arginine metabolism, modulates mitochondrial dynamics to upregulate OXPHOS, polarizing M1 macrophages to M2 phenotype [ 278 , 279 ]. Jiang et al [ 190 ] engineered a liver-inspired polyetherketoneketone (PEKK) scaffold with a thickness of 30 μm by femtosecond laser etching technology and sulfonation reaction. They reemerged hepatocyte growth factor receptor (MET) signaling in LPS-induced CVX-BMDMs/RAW 264.7 cells, followed by activating downstream Ras pathway, which promoted the retrograde transfer of Arg-2 from mitochondria into the cytoplasm and remodeled energy/arginine metabolism by enhancing OXPHOS to mobilize M2 phenotype for improving rat osteoporotic bone defect (demonstrated by flow cytometry, IF, ELISA, and RT-qPCR) (Fig.…”

SIRT3 regulates cardiolipin biosynthesis in pressure overload-induced cardiac remodeling by PPARγ-mediated mechanism

“…Mitochondrial ATP was calculated by subtracting glycolytic ATP from total ATP. Luminenscence was measured using a microplate reader Varioscan Lux (Thermo Fisher Scientific) [ 19 ].…”

Hierarchically structured biomaterials for tissue regeneration

“…Biomaterial structures can also regulate metabolic function due to relevant signaling pathways activated by influencing cell behavior. For instance, in order to meet the unique metabolic direction and the vast demand for nutrient delivery of flat bone regeneration, researchers have designed different configurations of flow channels in hydroxyapatite porous scaffolds [136] . Curved channels exhibited higher permeability, enhancing material transport and cell sedimentation by forming eddies.…”

“…To address the limitations of current hierarchically structured biomaterials, several aspects should be considered. Firstly, the design of biomimetic hierarchical structures Osteochondral tissue [76,[151][152] ; tendon-bone [155] Freeze-drying Improve mechanical properties; control cell arrangement and differentiation Periodontium [111] 3D printing Provide structure and function similar to native tissues Trachea [161][162][163] ; cornea [171] Multi-layered scaffolds Cast molding Guide cell arrangement; improve cell metabolism and matrix anabolism Annulus fibrosus [138] Electrospinning Mimic the structure of native tissue; improve mechanical and bioactivity Temporomandibular joint disc [45] 3D printing Mimic the structure of native tissue; regulate cellcell interactions Bone [144][145]147,150] ; flat bone [136] Electrospinning and 3D printing Mimic the structure of native tissue; guide cell alignment and differentiation Myocardium [49] ; skeletal muscle tissue [122] ; adipo tissue [123] Scaffolds with integrated units Freeze-drying and cast molding Improve perfusion properties and neurogenesis; direct the growth of neotissues Peripheral nerve [57,128] Electrospinning Mimic the structure of native tissue; improve mechanical strength; enhance cell bioactivity Bone [48,132] ; skin [159] 3D printing Mimic the structure of native tissue; enhance cell bioactivity Osteochondral regeneration [59] ; bone [119,127,130] Electrospinning and 3D printing Mimic the structure of native tissue; guide cell arrangement Myocardium [168] Freezing drying Improve mechanical performance and angiogenesis Soft gingival tissue [58] Scaffolds with varying length scales…”