Nanomaterial Nitric Oxide Delivery in Traumatic Orthopedic Regenerative Medicine

Abstract

Achieving bone fracture union after trauma represents a major challenge for the orthopedic surgeon. Fracture non-healing has a multifactorial etiology and there are many risk factors for non-fusion. Environmental factors such as wound contamination, infection, and open fractures can contribute to non-healing, as can patient specific factors such as poor vascular status and improper immunologic response to fracture. Nitric oxide (NO) is a small, neutral, hydrophobic, highly reactive free radical that can diffuse across local cell membranes and exert paracrine functions in the vascular wall. This molecule plays a role in many biologic pathways, and participates in wound healing through decontamination, mediating inflammation, angiogenesis, and tissue remodeling. Additionally, NO is thought to play a role in fighting wound infection by mitigating growth of both Gram negative and Gram positive pathogens. Herein, we discuss recent developments in NO delivery mechanisms and potential implications for patients with bone fractures. NO donors are functional groups that store and release NO, independent of the enzymatic actions of NOS. Donor molecules include organic nitrates/nitrites, metal-NO complexes, and low molecular weight NO donors such as NONOates. Numerous advancements have also been made in developing mechanisms for localized nanomaterial delivery of nitric oxide to bone. NO-releasing aerogels, sol- gel derived nanomaterials, dendrimers, NO-releasing micelles, and core cross linked star (CCS) polymers are all discussed as potential avenues of NO delivery to bone. As a further target for improved fracture healing, 3d bone scaffolds have been developed to include potential for nanoparticulated NO release. These advancements are discussed in detail, and their potential therapeutic advantages are explored. This review aims to provide valuable insight for translational researchers who wish to improve the armamentarium of the feature trauma surgeon through use of NO mediated augmentation of bone healing.

Control of Orthodontic Tooth Movement by Nitric Oxide Releasing Nanoparticles in Sprague-Dawley Rats

“…These NO manipulation during tooth movement studies appear to indicate that stimulation of NO production is bone catabolic, enhancing osteoclast activity and orthodontic tooth movement. Yet, it is well known that the efficacy of manipulating NO through these methods (delivery of L-arginine and/or L-NAME) is likely inadequate for optimal changes in NO efficacy ( Anastasio et al, 2020 ). For this reason, here we utilized an NO producing biomaterial to establish NO effects on tooth movement.…”

“…Other studies also showed that NO is an essential mediator of the bone anabolic effects of both estrogen and mechanical loading in mice ( Armour et al, 2001 ; Rangaswami et al, 2009 ; Rangaswami et al, 2010 ; Marathe et al, 2012 ). NO releasing biomaterials were more recently proposed for better treatment of bone fractures and osteoporosis ( Anastasio et al, 2020 ). In addition, of particular relevance to the current study, intraperitoneal injections of an NO producing biomaterial into female ovariectomized mice was shown to increase cGMP levels and downstream signaling, increase osteoprogenitor proliferation, increase osteoblast gene expression, reduce osteocyte apoptosis, reduce osteoclast numbers and reduce bone resorption.…”

The Role of Nitric Oxide in Stem Cell Biology

“…In addition, it has been reported that VEGF release is modulated by NO over angiogenesis taking place in bone remodeling [111]. Thus, the use of NO for the traumatic orthopedic regenerative medicine has been currently proposed [112]. It is also known that NO derived from eNOS plays a key role in bone formation observed through eNOS knockout mice models [113].…”

“…Concerning the role of NO in SCs biology, previously, the effect of NO scaffolds on osteogenic differentiation of human mesenchymal bone marrow cells has been presented [115]. The proper concentration of NO in situ is essential during a prolonged period to obtain the benefits on osteoblast function [30,112]. In this line, 3D bone scaffold designed for nanoparticulated NO release has shown benefit as an antimicrobial device and tissue regeneration, improving fracture healing through enhancing angiogenesis and osteogenic differentiation [116].…”

Metal-based nano-delivery platform for treating bone disease and regeneration

“…There are a wide variety of nanobiomaterials, including carbon-based, metal-based, virus-based, lipid-based, polymer-based, liposomes, cubes, micelles, exosomes, and cell membrane coatings ( Sharma et al, 2021 ). Nanobiomaterials exhibit numerous excellent properties: nanoscale, large specific surface area, adjustable volume, favorable biocompatibility, and abundant modifiable surfaces ( Eivazzadeh-Keihan et al, 2020b ; Anastasio et al, 2021 ). Therefore, they have various applications such as nano-delivery systems ( Vangijzegem et al, 2019 ; Hu S. et al, 2021 ), biomaterial modification ( Liu et al, 2020d ; Zhong et al, 2020 ; Xue Y. et al, 2021 ), biosensors ( Fiorani et al, 2019 ; Singh et al, 2022 ), in vivo tracking, and imaging agents ( Liu Y. et al, 2021 ; Kalva et al, 2022 ), gas storage ( Wang X. et al, 2021 ; Zhu et al, 2022 ), and chemical catalysis ( Fang et al, 2021 ; Khalil et al, 2021 ).…”