<p>Bone-Targeting Liposome-Encapsulated Salvianic Acid A Improves Nonunion Healing Through the Regulation of HDAC3-Mediated Endochondral Ossification</p>

Abstract

Nonunion is a major complication in fracture repair and remains a challenge in orthopaedics and trauma surgery. In this study, we aimed to evaluate the effectiveness of treatment of nonunion with a large radial defect using a bone-targeting liposomeencapsulated salvianic acid A (SAA-BTL)-incorporated collagen sponge and further elucidate whether the effects were closely related to histone deacetylase 3 (HDAC 3)-mediated endochondral ossification in nonunion healing process. Methods: Fifteen New Zealand female rabbits were randomly divided into three groups. Segmental radius critical size defects (15 mm) were created via surgery on both the forelimbs of the rabbits. The SAA-BTL/SAA/saline-incorporated collagen sponges were implanted into the defects in the three groups, respectively, for four weeks of treatment. X-ray imaging, micro-computed tomography (CT) analysis, histology, and immunofluorescence analysis (HDAC3, collagen II, VEGFA, and osteocalcin) were performed to determine the effects of the treatments. In addition, a short interfering RNA was applied to induce HDAC3 knockdown in the chondrogenic cell line ATDC5 to investigate the roles of HDAC3 and SAA intervention in endochondral ossification in nonunion healing. Results: X-ray imaging and micro-CT results revealed that SAA-BTL-incorporated collagen sponges significantly stimulated bone formation in the nonunion defect rabbit model. Furthermore, immunofluorescence double staining and histology analysis confirmed that SAA-BTL significantly increased the expression of P-HDAC3, collagen II, RUNX2, VEGFA, and osteocalcin in vivo; accelerated endochondral ossification turnover from cartilage to bone; and promoted long bone healing of nonunion defects. ATDC5 cells knocked down for HDAC3 showed significantly decreased expression of HDAC3, which resulted in reduced expression of chondrogenesis, osteogenesis, and angiogenesis biomarker genes (Sox9, Col10a1, VEGFA, RUNX2, and Col1a1), and increased expression of extracellular matrix degradation marker (MMP13). SAA treatment reversed these effects in the HDAC3 knockdown cell model. Conclusion: SAA-BTL can improve nonunion healing through the regulation of HDAC3mediated endochondral ossification.

Bioactive Scaffolds Integrated with Liposomal or Extracellular Vesicles for Bone Regeneration

“…The local delivery of salvianic acid A, a bone anabolic agent, along with the bone-targeting liposomes targeting bone fracture site, significantly enhanced the interaction with the bone, the retention of the liposomes in the bone, and the fracture healing in vivo. In recent study, Zhou et al reported the collagen sponge incorporated with bone-targeting liposomes formed by phosphorylated cholesterols loaded salvianic acid A for endochondral ossification [24]. The criticalsized segmental defect rabbit model was assessed to determine the effect of bone regeneration via regulation of histone deacetylase 3 (HDAC3), which is related to the formation and development of the bone extracellular matrix (ECM).…”

“…Several liposomal systems for hydrophilic small molecule drug delivery have been investigated regarding controlled/sustained delivery against rapid diffusional clearance. Liposomal formulations containing salvianic acid A, as a potent inducer of osteogenesis and angiogenesis, combined with collagen scaffolds successfully stimulated bone fracture healing in mice and rabbit model [23,24].…”

Preparation of a novel antibacterial magnesium carbonate coating on a titanium surface and its in vitro biocompatibility

“…Cell viability were assessed after 1 and 4 days of culture using a dual staining kit for live and dead cells (Abbkine, China). 45 Stained cells were observed using an inverted fluorescence microscope (Leica, Germany). Additionally, on days 1, 4, and 7, cell proliferation was quantified using the CCK-8 assay kit (Vazyme) by measuring absorbance at 450 nm with a microplate reader (Thermo Fisher Scientific, Waltham, USA).…”

Traditional Chinese Medicine Compound-Loaded Materials in Bone Regeneration

“…Micro-CT showed significantly increased union callus formation with elevated BV and TV values in the 4th week postsurgery. Histological images showed increased bone areas in the callus, and immunofluorescence images showed increased expression of collagen II, P-HDAC3, VEGFA, osteocalcin, and RUNX2 in the callus (Zhou et al, 2020).…”