Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration

Abstract

Sensory nerves promote osteogenesis through the release of neuropeptides. However, the potential application and mechanism in which sensory nerves promote healing of bone defects in the presence of biomaterials remain elusive. The present study identified that new bone formation was more abundantly produced after implantation of silicified collagen scaffolds into defects created in the distal femur of rats. The wound sites were accompanied by extensive nerve innervation and angiogenesis. Sensory nerve dysfunction by capsaicin injection resulted in significant inhibition of silicon-induced osteogenesis in the aforementioned rodent model. Application of extracellular silicon in vitro induced axon outgrowth and increased expression of semaphorin 3 A (Sema3A) and semaphorin 4D (Sema4D) in the dorsal root ganglion (DRG), as detected by the upregulation of signaling molecules. Culture medium derived from silicon-stimulated DRG cells promoted proliferation and differentiation of bone marrow mesenchymal stem cells and endothelial progenitor cells. These effects were inhibited by the use of Sema3A neutralizing antibodies but not by Sema4D neutralizing antibodies. Knockdown of Sema3A in DRG blocked silicon-induced osteogenesis and angiogenesis almost completely in a femoral defect rat model, whereas overexpression of Sema3A promoted the silicon-induced phenomena. Activation of “mechanistic target of rapamycin” (mTOR) pathway and increase of Sema3A production were identified in the DRG of rats that were implanted with silicified collagen scaffolds. These findings support the role of silicon in inducing Sema3A production by sensory nerves, which, in turn, stimulates osteogenesis and angiogenesis. Taken together, silicon has therapeutic potential in orthopedic rehabilitation.

A multi-functional SiO32−-releasing hydrogel with bioinspired mechanical properties and biodegradability for vascularized skeletal muscle regeneration

“…52 In addition, silicate ions could promote in situ bone regeneration by activating the mammalian target of the rapamycin (mTOR) signaling pathway in the nervous system. 19 The activation of the mTOR signaling pathway promoted myogenic differentiation through upregulating key myogenic determinant genes. 53 Therefore, the myogenic effect of SRH extracts might be related to the stimulation of IGF-1 secretion and the activation of mTOR signaling.…”

“…Owing to their known angiogenic activity, 17,18 silicate ions have been used to enhance vascularization in various tissues such as bone, adipose tissue, and skin. [18][19][20] However, the therapeutic effect of silicate ions for promoting vascularized skeletal muscle regeneration remains unclear. Herein, we propose a new biomaterial-based strategy for skeletal muscle repair by the local delivery of silicate ions from a hydrogel scaffold and test its efficacy in promoting vascularized muscle regeneration.…”

Nervous System-Driven Osseointegration

“…There was significant nerve innervation and angiogenesis at the wound sites. Silicon appears to have therapeutic promise in orthopedic rehabilitation, according to this study ( Figure 4 A–C) [ 205 ]. The researchers employed multi-electrode stimulation of the sympathetic nervous system in the infraorbital nerve after implanting cylindrical titanium implants inside the tooth sockets of beagles for one week.…”

“… Surface alteration influences osseointegration and innervation. ( A – C ): Through sensory nerve innervation, SCS stimulates bone repair [ 205 ]. ( A ) The SCS group had substantially greater BV/TV, Tb, Th, and BMD values than the other three groups; ( B ) Von Kossa staining; and ( C ) in vivo calcein labeling.…”

Multifunctional silicon calcium phosphate composite scaffolds promote stem cell recruitment and bone regeneration

“…Recent studies have shown that silicon can play an important role in the proliferation and differentiation of rat bone marrow mesenchymal stem cells, and in particular, can promote collagen synthesis in osteoblasts. 20 In addition, bone homeostasis requires adequate intake of silicon. Silicon calcium phosphate (SiCP) porous scaffolds have been successfully prepared before to optimize the advantage of silicon and calcium phosphate.…”