Immunomodulation of Telmisartan-Loaded PCL/PVP Scaffolds on Macrophages Promotes Endogenous Bone Regeneration

Abstract

Biomaterial–immune system interactions play an important role in postimplantation osseointegration to retain the functionality of healthy and intact bones. Therefore, appropriate osteoimmunomodulation of implants has been considered and validated as an efficient strategy to alleviate inflammation and enhance new bone formation. Here, we fabricated a nanostructured PCL/PVP (polycaprolactone/polyvinylpyrrolidone) electrospinning scaffold for cell adhesion, tissue ingrowth, and bone defect padding. In addition, telmisartan, an angiotensin 2 receptor blocker with distinct immune bioactivity, was doped into PCL-/PVP-electrospun scaffolds at different proportions [1% (TPP-1), 5% (TPP-5), and 10% (TPP-10)] to investigate its immunomodulatory effects and osteoinductivity/conductivity. Telmisartan-loaded scaffolds displayed in vitro anti-inflammatory bioactivity on lipopolysaccharide-induced M1 macrophages by polarizing them to an M2-like phenotype and exhibited pro-osteogenic properties on bone marrow-derived mesenchymal stem cells (BMSCs). Histological analysis and micro-CT results of a rat skull defect model also showed that the telmisartan-loaded scaffolds induced a higher M2/M1 ratio, less inflammatory infiltration, and better bone regenerative patterns. Furthermore, activation of the BMP2 (bone morphogenetic protein-2)-Smad signaling pathway was found to be dominant in telmisartan-loaded scaffold-mediated macrophage–BMSC interactions. These findings indicate that telmisartan incorporation with PCL/PVP nanofibrous scaffolds is a potential therapeutic strategy for promoting bone healing by modulating M1 macrophages to a more M2 phenotype at early stages of postimplantation.

The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

“…Particular focus has been placed on the role of phenotype switching, which remains controversial [ 253 ]. For instance, a recent study has revealed the utilization of a nanostructured polycaprolactone (PCL)/polyvinylpyrrolidone electrospun biomaterial in bone tissue regeneration via polarization of macrophages toward the M2 phenotype [ 254 ]. Generally, immunomodulation through biomaterials can be achieved via various strategies, including: 1) mediation of their physicochemical properties, 2) delivery of immunoregulatory activators, and 3) alteration of their mechanical properties [ 255 ].…”

Electrospun fiber‐based immune engineering in regenerative medicine

“…Based on experimental results, using fibers loaded with telmisartan enhances this interaction, exhibiting pro-osteogenic properties on bone marrowderived mesenchymal stem cells (BMSCs). 121 Additionally, Ye et al designed a core-shell-structured suture for acute tendon rupture surgery. In their construction, the polyamide (PA)-6 (PA-6) with excellent mechanical strength was designed as the core, and while heparinloaded PLLA as the shell, the bilayer fiber structure was twisted into a rope for in vivo tissue suturing 122 ; compared with non-heparin-loaded suture group and commercial suture group, the high heparin concentration leads to milder inflammation and faster healing when applicated in vivo, indicating promising tissue repairing capability of this electrospun suture (Figure 7B).…”

“…Reproduced with permission. 121 Copyright 2022, American Chemical Society. (B) illustration the structure of electrospun sutures laden with heparin.…”

“…In addition, the bone morphogenetic protein‐2 (BMP2)‐Smad signaling pathway plays a crucial role in the interaction between mesenchymal stem cells (MSCs) and macrophages. Based on experimental results, using fibers loaded with telmisartan enhances this interaction, exhibiting pro‐osteogenic properties on bone marrow‐derived mesenchymal stem cells (BMSCs) 121 . Additionally, Ye et al.…”

Engineered 3D-Printed Polyvinyl Alcohol Scaffolds Incorporating β-Tricalcium Phosphate and Icariin Induce Bone Regeneration in Rat Skull Defect Model

“…Biomaterials can be created and produced into scaffolds for skull deformities using the generated digital data [ 13 , 15 ]. Calcium phosphate bone cements [ 16 ], polymers [ 17 , 18 ], titanium alloy [ 19 ], CuS-PEG-PCL scaffold [ 20 ] and other materials are currently widely used in skull and bone deformities [ 21 , 22 , 23 , 24 ]. The defect position can be covered and protected by the skull defect repair scaffold.…”