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Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition.

ABSTRACT: Biofunctionalization with siRNA targeting the key negative modulators of bone turnover involved in the molecular mechanism of osteoporosis, such as casein kinase-2 interacting protein-1 (Ckip-1), may lead to enhanced Ti osseointegration in the osteoporotic condition. In this study, even siRNA loading was accomplished by the thermal alkali (TA) treatment to make the Ti ultrahydrophilic and negatively charged to facilitate the physical adsorption of the positively charged CS/siR complex, designated as TA-CS/siR. The intracellular uptake of the CS/siR complex and the gene knockdown efficiency were assessed with bone marrow mesenchymal stem cells (MSCs) as well as the green fluorescent protein (GFP) expressing H1299 cells. In vitro osteogenic activity of TA-CS/siCkip-1 targeting Ckip-1 was assessed with MSCs. In vivo osseointegration of TA-CS/siCkip-1 was assessed in the osteoporotic rat model. TA-CS/siR showed excellent siRNA delivery efficiency and gene silencing effect. TA-CS/siCkip-1 significantly improved the in vitro osteogenic differentiation of MSCs in terms of the enhanced alkaline phosphatase and collagen product and extracellular matrix mineralization, and led to dramatically enhanced in vivo osseointegration in the osteoporostic rat model, showing promising clinical potential for the osteoporotic condition application. TA-CS/siR may constitute a general approach for developing the advanced Ti implants targeting specific molecular mechanism.

SUBMITTER: Zhang L

PROVIDER: S-EPMC4455222 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition.

Zhang Li L Wu Kaimin K Song Wen W Xu Haiyan H An Ran R Zhao Lingzhou L Liu Bin B Zhang Yumei Y

Scientific reports 20150604

Biofunctionalization with siRNA targeting the key negative modulators of bone turnover involved in the molecular mechanism of osteoporosis, such as casein kinase-2 interacting protein-1 (Ckip-1), may lead to enhanced Ti osseointegration in the osteoporotic condition. In this study, even siRNA loading was accomplished by the thermal alkali (TA) treatment to make the Ti ultrahydrophilic and negatively charged to facilitate the physical adsorption of the positively charged CS/siR complex, designate ...[more]

PMID: 26040545

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Project description:ObjectivesThis study determined whether implant surfaces that promote osseointegration in normal rats can promote osseointegration in osteoporotic rats without pharmacologic intervention.Materials and methodsVirgin female 8-month-old CD Sprague Dawley rats (N = 25) were ovariectomized. At 6 weeks, microstructured/non-nanostructured/hydrophobic, microstructured/nanostructured/hydrophobic, or microstructured/nanostructured/hydrophilic Ti implants (Ø2.5 × 3.5 mm; Institut Straumann AG, Basel, Switzerland) were placed in the distal metaphysis of each femur. At 28 days, bone quality and implant osseointegration were assessed using microCT, histomorphometrics, and removal torque values (RTVs). Calvarial osteoblasts were isolated and cultured for 7 days on Ø15 mm Ti disks processed to exhibit similar surface characteristics as the implants used for the in vivo studies. The phenotype was assessed by measuring the production of osteocalcin, osteoprotegerin, osteopontin, BMP2, VEGF, and RANKL.ResultsMicrostructured/nanostructured/hydrophilic implants promoted increased bone-to-implant contact and RTVs in vivo and increased osteoblastic marker production in vitro compared to microstructured/non-nanostructured/hydrophobic and microstructured/nanostructured/hydrophobic implants, suggesting that osseointegration occurs in osteoporotic animals, and implant surface properties improve its rate.ConclusionsAlthough all modified implants were able to osseointegrate in rats with OVX-induced osteoporosis without pharmacologic intervention, the degree of osseointegration was greater around microstructured/nanostructured/hydrophilic implant surfaces. These results suggest that when appropriate microstructure is present, hydrophilicity has a greater influence on Ti implant osseointegration compared to nanostructures. Moreover, modified implant surfaces can exert their control over the altered bone turnover observed in osteoporotic patients to stimulate functional osseointegration. These results provide critical insight for developing implants with improved osseointegration in patients with metabolic disorders of bone remodeling.

Project description:Innovative nanomaterials are required for the coatings of titanium (Ti) implants to ensure the activation of Ti surfaces for improved osseointegration, enhanced bone fracture healing and bone regeneration. This paper presents a systematic investigation of biomimetic composite (BC) coatings on Ti implant surfaces in a rat model of a diaphyseal femoral fracture. Methodological approaches of surface modification of the Ti implants via the usual joining methods (e.g., grit blasting and acid etching) and advanced physicochemical coating via a self-assembled dip-coating method were used. The biomimetic procedure used multi-substituted hydroxyapatite (ms-HAP) HAP-1.5 wt% Mg-0.2 wt% Zn-0.2 wt% Si nanoparticles (NPs), which were functionalized using collagen type 1 molecules (COL), resulting in ms-HAP/COL (core/shell) NPs that were embedded into a polylactic acid (PLA) matrix and finally covered with COL layers, obtaining the ms-HAP/COL@PLA/COL composite. To assess the osseointegration issue, first, the thickness, surface morphology and roughness of the BC coating on the Ti implants were determined using AFM and SEM. The BC-coated Ti implants and uncoated Ti implants were then used in Wistar albino rats with a diaphyseal femoral fracture, both in the absence and the presence of high-frequency pulsed electromagnetic shortwave (HF-PESW) stimulation. This study was performed using a bone marker serum concentration and histological and computer tomography (micro-CT) analysis at 2 and 8 weeks after surgical implantation. The implant osseointegration was evaluated through the bone-implant contact (BIC). The bone-implant interface was investigated using FE-SEM images and EDX spectra of the retrieved surgical implants at 8 weeks in the four animal groups. The obtained results showed significantly higher bone-implants contact and bone volume per tissue volume, as well as a greater amount of newly formed bone, in the BC-coated Ti implants than in the uncoated Ti implants. Direct bone-implant contact was also confirmed via histological examination. The results of this study confirmed that these biomimetic composite coatings on Ti implants were essential for a significant enhancement of osseointegration of BC-coated Ti implants and bone regeneration. This research provides a novel strategy for the treatment of bone fractures with possible orthopedic applications.

Project description:Metabolic bone is highly innervated by both sensory and sympathetic nerves. In addition to skeletal development, neural regulation participates in local bone remodeling, which is important for successful osseointegration of titanium implants. Neurectomy is a model used to investigate the lack of neural function on bone homeostasis, but the relative impacts of direct denervation to bone or denervation-induced muscle paralysis are less well defined. To investigate this difference, we used two nerve intervention models, sciatic and femoral neurectomy (SFN) v. botox-induced muscle paralysis (BTX) and assessed the resulting femoral bone phenotype and Ti implant osseointegration. Male Sprague Dawley rats (19) were randomly divided into three groups: implant control (n = 5), SFN (n = 7), and BTX (n = 7). Ti implants (microrough/hydrophilic [modSLA], Institut Straumann AG) were placed in the distal metaphysis of each femur on day 24 post-SFN or BTX. Bone and muscle were examined on day 28 after implant insertion. Both nerve intervention models impaired osseointegration. MicroCT and histology indicated that both models had reduced trabecular bone formation. Only BTX reduced cortical bone formation and increased cortical bone porosity. BTX resulted in more bone loss characterized by the least trabecular and cortical bone, as well as osseointegration. Osteoblasts isolated from the tibia exhibited a model-specific phenotype when they were grown on Ti substrates in vitro. Neurectomy caused more severe muscle atrophy than botox injection. These results indicate that neural regulation directly modulates bone formation and osseointegration. Muscle paralysis modulated the effects of loss of neural inputs into bone, supporting the hypothesis that mechanical loading of bone is a factor in achieving successful osseointegration. The different effects of botox and neurectomy on bone phenotype indicated that the sensory and sympathetic nerves had a role in the osseointegration process.

Project description:Titanium (Ti) biomaterials have been applied to a wide range of implantable medical devices. When placed in bone marrow, Ti-biomaterials integrate to the surrounding bone tissue by mechanisms that are not fully understood. We have previously identified an unexpected upregulation of circadian clock molecule neuronal PAS domain 2 (Npas2) in successfully integrated implant with a rough surface. This study aimed to elucidate the molecular mechanism of osseointegration through determining the role of Npas2. Human bone marrow stromal cells (BMSC) that were cultured on a Ti disc with SLA surface exhibited increased NPAS2 expression compared to BMSC cultured on a machined surface. A mouse model was developed in which miniature Ti implants were surgically placed into femur bone marrow. The implant push-out test and bone-to-implant contact measurements demonstrated the establishment of osseointegration in 3 weeks. By contrast, in Npas2 functional knockout (KO) mice, the implant push-out value measured for SLA surface Ti implant was significantly decreased. Npas2 KO mice demonstrated normal femur bone structure surrounding the Ti implant; however, the recovered implants revealed abnormal remnant mineralized tissue, which lacked dense collagen architecture typically found on recovered implants from wild type mice. To explore the mechanisms leading to the induced Npas2 expression, an unbiased chemical genetics analysis was conducted using mouse BMSC carrying an Npas2-reporter gene for high throughput screening of Library of Pharmacologically Active Compounds. Npas2 modulating compounds were found clustered in regulatory networks of the ?2-adrenergic receptor and its downstream cAMP/CREB signaling pathway. Mouse primary BMSC exposed to SLA Ti disc significantly increased the expression of ?2-adrenergic receptors, but the expression of ?2-adrenergic receptor was unaffected. Our data provides the first evidence that peripheral clock gene component Npas2 plays a role in facilitating the enhanced osseointegration through neuroskeletal regulatory pathways induced by BMSC in contact with rough surface Ti implant.

Dataset Information

Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition.

Publications

Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition.

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