Osseointegration of Titanium Implants in a Botox-Induced Muscle Paralysis Rat Model Is Sensitive to Surface Topography and Semaphorin 3A Treatment

Abstract

Reduced skeletal loading associated with many conditions, such as neuromuscular injuries, can lead to bone fragility and may threaten the success of implant therapy. Our group has developed a botulinum toxin A (botox) injection model to imitate disease-reduced skeletal loading and reported that botox dramatically impaired the bone formation and osseointegration of titanium implants. Semaphorin 3A (sema3A) is an osteoprotective factor that increases bone formation and inhibits bone resorption, indicating its potential therapeutic role in improving osseointegration in vivo. We first evaluated the sema3A effect on whole bone morphology following botox injections by delivering sema3A via injection. We then evaluated the sema3A effect on the osseointegration of titanium implants with two different surface topographies by delivering sema3A to cortical bone defect sites prepared for implant insertion and above the implants after insertion using a copper-free click hydrogel that polymerizes rapidly in situ. Implants had hydrophobic smooth surfaces (PT) or multiscale biomimetic micro/nano topography (SLAnano). Sema3A rescued the botox-impaired bone formation. Furthermore, biomimetic Ti implants improved the bone-to-implant contact (BIC) and mechanical properties of the integrated bone in the botox-treated rats, which sema3A enhanced. This study demonstrated the value of biomimetic approaches combining multiscale topography and biologics in improving the clinical outcomes of implant therapy.

Strategies for Improving Impaired Osseointegration in Compromised Animal Models

“…For example, in a sciatic neurectomy model, a decrease in the expression of the axon guidance signaling molecule semaphorin 3A (sema3A) in tibial bone (Ma et al 2016) was observed, aligning with reported decreases in serum levels of sema3A in postmenopausal women with osteoporosis (OP; Liu et al 2014). Studies in our lab show an increase in the local production of sema3A by BMSCs cultured on microtextured Ti surfaces (Deng, Cohen, Sabalewski et al 2023), suggesting that it might possess therapeutic potential as an osteogenic agent. In addition, factors such as BMP2, BMP4, platelet-derived growth factor, insulin-like growth factor (IGF1), FGF1, VEGF165, TGFβ1, and parathyroid hormone have been investigated for accelerating bone regeneration around dental implants (Berger, Bosh, Jacobs et al 2021).…”

“…4). Further, we have shown that impaired osseointegration of multiscale microrough titanium implants can be rescued by local seme3A treatment delivered by a click hydrogel carrier (Deng, Cohen, Berger et al 2023) (Fig. 5).…”

“…Studies by our group show that microtextured surfaces with increased wettability support the production of an osteoinductive microenvironment by BMSCs, characterized by the release of BMP2 and upregulation of BMP receptors in vivo. These implant surfaces also exhibit favorable BIC in certain compromised models, as demonstrated by better BIC and mechanical properties of the newly formed peri-implant bone at the interface (Deng, Cohen, Berger 2023). However, not all nanomodifications yield comparable results (Lotz et al 2020).…”

“…ZDF lean homozygous wild-type rats were selectively inbred for almost 30 generations with a substrain of Charles River Sprague Dawley rats (SD; Wang et al 2022). The quantity of trabecular bone in ZDSD diabetic rat femurs is considerably lower than in SD rats, and lower yield force, load-to-failure, and stiffness values indicate that the cortical strength of long bones is decreased (Deng, Cohen, Sabalewksi et al 2023). Cumulatively, the alterations in skeletal health observed in ZDSD rats indicate a reduced potential for osseointegration.…”

“…Microtextured implants outperform smooth ones in both healthy and compromised animals (Deng, Cohen, Berger 2023). Numerous methods for roughening smooth implants exist, including sandblasting and acid etching, electrophoretic deposition, anodization, and hydrothermal treatments.…”